TW201035095A - Pyrazolo[1,5-a]pyridine derivatives - Google Patents

Abstract

Pyrazolo[1,5-a]pyridine derivatives of formula I, wherein the meaning for R1, R2 and R3 is as disclosed in the description. These compounds are useful as JAK3 kinase inhibitors.

Description

201035095 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a novel series of [1,5-a]pyridin derivatives, methods for preparing the same, and pharmaceutical compositions containing the same And their medical use. [Prior Art] Janus kinase (JAK) is a cytoplasmic protein tyrosine kinase that plays an important role in regulating the cellular functions of the lymphoid-hematopoietic system, and these cellular functions are decisive for cell proliferation and cell survival. JAK involves a signaling event initiated by a cytokine that activates a signal transduction protein and a transcriptional activator (ST AT ) protein via tyrosine phosphorylation. JAK/ST AT communication has been involved in many abnormal immune responses (such as graft rejection and autoimmune diseases) as well as solid and hematological malignancies (such as leukemia and lymphoma) and myeloproliferative diseases, and has therefore become a drug invention. Interesting target. Four members of the JAK family have been identified to date: JAK1, JAK2, JAK3 and Tyk2. Unlike JAK1, JAK2, and Tyk2, which are ubiquitous, JAK3 is mainly found in hematopoietic cells. JAK3 binds to the yc-subunits of the receptors of IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 in a non-covalent manner. These cytokines play an important role in the proliferation and differentiation of T lymphocytes. Mouse T cells lacking JAK3 did not respond to IL-2. This cytokine IL-2 is necessary for the regulation of T lymphocytes. In this regard, antibodies against the 1 L -2 receptor are known to prevent graft rejection. In patients with X-severe combined immunity 5 * 201035095 Defective Disease (Χ-SCID), the degree of AK3 expression and the YC subunit gene defect of the receptor have been identified, and the extremely low JAK3 expression level is expressed. Immunosuppressive effects are the result of changes in the JAK3 signaling pathway. Animal studies have suggested that JAK3 not only plays a key role in the maturation of T and B lymphocytes, but also requires JAK3 to maintain lymphocyte function. The novel immunomodulatory immunological activity can be used to treat T cell proliferative diseases such as graft rejection and autoimmune diseases. It has also been shown that JAK3 plays an important role in mast cells because degranulation caused by antigen and release of transmitter are substantially reduced in mast cells of mice lacking JAK3. JAK3 deficiency does not affect hypertrophic cell proliferation and does not affect the extent of IgE receptor expression. On the other hand, JAK3-/- and JAK3+/+ mast cells contain the same intracellular transmitter. Therefore, JAK3 is considered to be necessary for the delivery of IgE-induced transmitters in mast cells, and accordingly, inhibition of JAK3 will be effective in treating allergic reactions. In summary, JAK3 kinase inhibitors have been identified as a novel class of potent immunosuppressive agents for the prevention of graft rejection and the treatment of immune, autoimmune, inflammatory and proliferative diseases such as psoriasis, psoriasis Arthritis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus, type I diabetes and diabetes mellitus, allergic reactions and leukemia (see literature such as O'Shea JJ) Et a丨, Nat. Re v . Drug. Discov. 2004, 3(7): 5 5 5 - 6 4 ; C e tko vic - C vr 1 je M . et al, C urr. P h arm. Des. 2004, 1 0(1 5): 1767-84; Cetkovic-Cvrlje M. et al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2): 69-82). -6- 201035095 Thus, it is desirable to provide novel compounds which inhibit the JAK/STAT signaling pathway, and in particular, such compounds are capable of inhibiting JAK3 activity and are good candidates for the drug. The compound should exhibit good activity in both in vitro and in vivo pharmacological assays, a good oral absorption upon administration by the oral route, a metabolically stable and well-developed pharmacokinetic corridor. Furthermore, the compound should not exhibit maternality and should exhibit a few side effects. 〇 SUMMARY OF THE INVENTION One aspect of the invention pertains to a compound of formula I

Or the salt of the other,

Ri represents hydrogen, Ci-4 alkyl, ®Ci-4 alkyl, vial Cl.4, alkyl, halogen, -CN, a CONR4R4 '-COR5, -C〇2R5 '-OR4 '-SO2R5 ' -SO2NR4R4 '-NR4R4 '-NR6COR4 '-NR6CONR4R4, -NR6C〇2R5, -NR6s〇2R5 or Cyi ' where Cy is optionally substituted by one or more R8; R2 represents hydrogen, Ci.4 alkyl, halogen Cl-4 alkyl, vial CI.4, R7-CL4 alkyl or Cy2, wherein Cy2 is optionally substituted by one or more R8 201035095 R3 represents C,-4 alkyl, halogen Ci-4 alkane a group, a hydroxy Cq alkyl group, a Rn_Cl4 alkyl group, -CONR9R9, -CORio, _CO2R10, -s〇2r10, -SOiNRgR9 or Cys' wherein the Cys system is optionally substituted with ~ or more R ports or R2 and R3 are compatible with nitrogen The atomic bonds together form Cy4s, wherein €>4 is optionally substituted by one or more R1 2; each R4 represents hydrogen or Rs; each R·5 represents C1-4, halogen Ci_4, 〇14 oxy Ci-4 thiol, thiol C! _4, cyano Ci-4, Cy^Ci 4 fluorenyl or cyi, wherein cyi is optionally one or more R8 is substituted; R6 represents hydrogen or Cu alkyl; R7 represents -CN, -CONR4R4, -COR5, -C〇2R 5, _〇r4, —SΟ2R5 -SO2NR4R4, -NR4R4, -NR6COR4, -NR6CONR4R4 -NR6C02R5, -NR6S02R5 or Cy, wherein cyi is optionally substituted by one or more R 8; each Rs is represented by ^_4 alkyl, halo-alkyl, c, a 1. "decyloxy C!-4 alkyl, hydroxy C, -4 alkyl, cyanoCl. 4 alkyl, halogen or __ each R 9 Each represents hydrogen or R i 〇; each Rio represents 匕^alkyl, halo-Ci-4 alkyl, yl, Rh-C,-4-alkyl or Cy5, wherein Cy5 is optionally substituted by r13; 1 represents halogen, -CN -ORi4 ' -〇CONR14r]4

-CONR14Ri4 ' -cor15 —S02R15 ' —S02NR14RJ

Co

2R 201035095 -NR14R14, -NR6COR14 ' -nr6conr14r14, -nr6co2r15, -NR6S02Ri5 or Cy5, wherein Cy5 is optionally substituted by one or more R13; each R12 represents 匚^alkyl, halo-Ch-alkyl, hydroxy Cm alkyl, Rm-Cm alkyl, or R12 represents any of the meanings described for Rm; each Rl3 represents a Ci-4, a halogen Ci_4, a Ci-4 alkoxy (^-4 alkyl, Hydroxy C^.4 alkyl, cyano Ci-4 alkyl, halogen, -CN, -CONRj6Ri6 '~COR)7 '-CO2R17 '-OR16 '-OCONRieRi6 '-SO2R17 ' ~S〇2NRi6Ri6 ' —NR16R16 ' — NReCOR]6 '-NR6CONRi6R16, -NR6C〇2Ri7 or -NR6S02R17; each RI4 represents hydrogen or R15; each Ris represents a <^-4 alkyl 'halo Cm alkyl, Cu alkoxy octan a hydroxyCualkyl group, a cyano Cualkyl group, a Cys-C^alkyl group or a Cy5 group, wherein the Cy5 group is optionally substituted by one or more R13; each R16 represents hydrogen or Rl7; Q each R , 7 each represents Cm alkyl, sec-Ci-4 alkyl, C, -4 alkoxy

Ci-4 alkyl, hydroxyCh4 alkyl or cyano C^4 alkyl;

Cydt is a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic carbocyclic ring optionally containing from 1 to 3 heteroatoms independently selected from N, S or oxime, wherein the ring system is available via any The C or N atom used is bonded to the remainder of the molecule, and wherein one or more of the C or S ring atoms are optionally oxidized to form a CO, SO or 302 group;

Cy2 represents a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic carbocyclic ring optionally containing from 1 to 3 heteroatoms selected from N, S or hydrazine 201035095, wherein the ring system is via any a c atom for use is bonded to the remainder of the molecule ' and wherein one or more C or S ring atomic systems are optionally oxidized to form a CO, SO or 302 group;

Cy3 represents a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic or 8 to 12 membered bicyclic carbocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from N, argon or fluorene, wherein The ring is bonded to the remainder of the molecule via any available c atom, and wherein one or more of the C or S ring atoms are optionally oxidized to form a CO, SO or so2 group;

Cy4 represents a saturated or partially unsaturated 3 to 7 membered monocyclic heterocyclic ring optionally fused to a saturated, partially unsaturated or aromatic 5 or 6 membered carbocyclic or heterocyclic ring, wherein Cy4 is optionally Containing a total of from 1 to 4 heteroatoms independently selected from N, LV or 0; and wherein one or more C or S atomic groups of Cy4 are optionally oxidized to form a CO, SO or so2 group;

Cy5 represents a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic or 8 to 12 membered bicyclic carbocyclic ring optionally having from 1 to 4 heteroatoms independently selected from n, ly or 0, wherein The ring is bonded via any of the available (: or 1^ atoms to the remainder of the molecule, and wherein one or more of the C or S ring atoms are optionally oxidized to form a C0, SO or so2 group. The invention also relates to salts and solvates of the compounds of formula I. Certain compounds of formula I may contain chiral centers which are capable of producing a variety of different stereoisomers. The present invention relates to each of these stereoisomers and to them. The compound of formula I is a JAK (especially AK 3 ) kinase inhibitor and is therefore useful for treating or preventing any disease mediated by the enzyme. -10· 201035095 Therefore, another aspect of the invention relates to Treatment of compound 1

Or a salt thereof, the center of which represents hydrogen, c, -4 alkyl, halo C, -4 alkyl, hydroxy C, -4 alkyl, fen, halogen, _CN, -CONR4R4 '-COR5, -C〇 2Rs '-OR4 ' -SO2R5 ' -SO2NR4R4 ' -NR4R4 ' -NR6COR4 ' -nr6conr4r4, -nr6co2r5, -NR6S02R5 or cyi, where cy| is optionally substituted by one or more r8; r2 represents hydrogen, c, _4 An alkyl group, a halogen Cu alkyl group, a hydroxy Cu alkyl group, a R7_Ci.4 hospital group or Cy2, wherein the Cy2 group is optionally substituted by one or more R.8. R3 represents a Cm alkyl group, a halogen Ci-4 alkyl group, a hydroxyl group. (^-4 alkyl, Rn_Cl4 alkyl'-CONR9R9, -COR10, -CO2Ri0, -SO2R10, -s〇2NR9R9 or Cy3, wherein Cy3 is optionally substituted by one or more R!2; or R2 and R3 The Cy4 group may be bonded together with a nitrogen atom, wherein Cy4 is optionally substituted by one or more R 12 ; each R 4 represents hydrogen or R 5 ; each R 5 represents (^4 alkyl, halogen C) !_4 alkyl, Cl.4 alkoxy Cu alkyl, hydroxy ci-4 alkyl, cyano Cu alkyl 'Cert-C^ alkyl or -11 - 201035095

Cyi' wherein Cyi is optionally substituted by one or more feet 8; R6 represents hydrogen or Cb4 alkyl; R7 represents -CN, -C〇NR4R4, -COR5, -C02R5, -OR4, -SO2R5 '-S02NR4R4 ' -NR4R4 '-nr6cor4, -nr6conr4r4, -NR6C02R5, -NR6S02R5 or Cy, wherein Cy! is optionally substituted by - or multiple R8; each Rs represents (^.4 alkyl, halogen C^. Alkyl, Cm alkoxy C^-4 alkyl, hydroxy (^.4 alkyl, cyano C!-4 alkyl, halogen or hydroxy; each R 9 each represents hydrogen or R i 〇; each R1() each represents an alkyl group, a halogen Cm alkyl group, a hydroxy C^4 alkyl group, an Rn-Ci-4 alkyl group or a Cy5 group, wherein the Cy5 group is optionally substituted with one or more R!3;

Rii stands for halogen, -CN, -CONR14Ri4, -CORis, -CO2R15 ' -OR14 ' -OCONR14R14 ' -SO2R15 ' -SO2NR14R14 ' -nr14r14, -nr6cor14, -nr6conrI4r14, -nr6co2r15, -NR6S02R15 or Cy5, of which Cy5 is optional Substituted by one or more Ri3; each R12 represents C, .4 alkyl, halo Cm alkyl, hydroxy Cu alkyl, Rh-C^-4 alkyl or R12 represents any of the meanings described for Rh; Each Ri3 represents Cm alkyl, halogen C,-4 alkyl, Ci-4 alkoxy C, .4 alkyl, hydroxy Cm alkyl, cyano C, .4 alkyl, halogen, -CN, -CONR16Ri6 ' -COR17 ' -CO2R17 ' -ORie ' -OCONR,6Ri6 ' -SO2R17 ' -SO2NR16R16 ' ~NR]6Rl6 ' —NR6COR16 ' -NR 6 C ONR 1 6 R 1 6 ' -N R6 C O2 R 17 ^ -NR 6 SO 2 R 17 > -12- 201035095 Each R 1 4 represents hydrogen or R 1 5 ; each R 15 represents each <^-4 alkyl, halo Cm alkyl, Ch alkoxy Cm alkyl, hydroxy Cm alkyl, cyano Cu alkyl, Cys-Cw alkyl or Cy5, wherein Cy5 is optionally substituted by one or more R13; each R 16 represents hydrogen or R 1 7 Each R17 represents a Ci-4 alkyl group, a halogen Cm alkyl group, a Ch alkoxy 〇 1-4 院 base group, a base group ^^1 _4 thiol or gas radical [1.4 fen, 0 CyiR saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic carbocyclic ring, optionally containing 1 to 3 independently selected from N, S or hydrazine a hetero atom, wherein the ring is bonded to the remainder of the molecule via any C or N atom available, and wherein one or more of the c or S ring atoms are optionally oxidized to form CO, so or so2 base;

Cy2R is a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic carbocyclic ring optionally containing from 1 to 3 heteroatoms independently selected from N, S or fluorene, wherein the ring system is available via any The C atom is bonded to the remainder of the molecule Q, and one or more of the c or s ring atoms are optionally oxidized to form a CO, so or so2 group;

Cy3 represents a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic or 8 to 12 membered bicyclic carbocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from N, S or 0, wherein The ring system is bonded to the remainder of the molecule via any C atom available, and wherein one or more of the C or S ring atomic systems are optionally oxidized to form a C0, SO or S〇2 group;

Cy4 represents a saturated or partially unsaturated 3 to 7 membered monocyclic heterocyclic ring 'optionally fused to a saturated, partially unsaturated or aromatic 5 or 6 membered carbocyclic or heterocyclic-13 - 201035095, wherein Cy4 is Optionally comprising a total of from 1 to 4 heteroatoms independently selected from N, S or hydrazine; and wherein one or more C*S atomic systems of Cy4 are optionally oxidized to form a CO, SO or so2 group;

Cy5 represents a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic or 8 to 12 membered bicyclic carbocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from N, S or hydrazine, wherein The ring system is bonded to the remainder of the molecule via any C or N atom available for use, and one or more of the <: or 3 ring atomic systems are optionally oxidized to form a CO, so or so2 group. Another aspect of the invention pertains to a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Another aspect of the invention pertains to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a disease mediated by JAK (particularly JAK3). Preferably, the disease by JAK (particularly JAK3) is at least one disease selected from the group consisting of graft rejection, immunity, autoimmune or inflammatory diseases, neurodegenerative diseases or proliferative diseases. In a preferred system, the disease caused by JAK (especially JAK3) is selected from the group consisting of transplant rejection or immunization, autoimmune or inflammatory diseases. Another aspect of the invention pertains to the manufacture of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture or prevention of at least one agent selected from the group consisting of a graft rejection, an immune, an autoimmune or inflammatory disease, a neurodegenerative disease or a proliferative disease. The drug's use of the disease. In a preferred system, the condition is selected from the group consisting of transplant rejection or immune 'autoimmune or inflammatory disease. Another aspect of the invention pertains to a compound of formula I or a pharmaceutically acceptable salt of from 14 to 201035095, which is manufactured for treatment or prevention selected from the group consisting of graft rejection, rheumatoid arthritis, psoriatic arthritis, silver Psoriasis, type 1 diabetes, diabetes caused by diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, hypersensitivity to mast cell media, leukemia, lymphoma or associated with leukemia and lymphoma The medicinal use of thromboembolic and allergic diseases. Another aspect of the invention pertains to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAK (particularly JAK3). Preferably, the disease by the JAK (particularly JAK3) is at least one disease selected from the group consisting of graft rejection, immunity, autoimmune or inflammatory diseases, neurodegenerative diseases or proliferative diseases. In a better system, the disease by JAK (especially IAK3) is selected from graft rejection or immune, autoimmune or inflammatory diseases. Another aspect of the invention relates to a compound of formula I for use in the treatment or prevention of at least one disease selected from the group consisting of a graft rejection, an immune, an autoimmune or inflammatory disease, a neurodegenerative disease, or a proliferative disease, or a pharmaceutically acceptable compound thereof Salt. In a preferred system, the disease is selected from the group consisting of graft rejection or immune, autoimmune or inflammatory diseases. Another aspect of the invention relates to the treatment or prevention of a sputum caused by graft rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, diabetes, multiple Compounds of the formula I, such as sclerosis, systemic lupus erythematosus, atopic dermatitis, allergic reactions to mast cell media, leukemia, lymphoma or thromboembolic and allergic complications associated with leukemia and lymphoma Pharmaceutically acceptable salts -15 - 201035095 Another aspect of the invention pertains to the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease mediated by JAK (particularly JAK3). Preferably, the disease caused by JAK (especially JAK3) is at least one disease selected from the group consisting of graft rejection, immunity, autoimmune or inflammatory diseases, neurodegenerative diseases or proliferative diseases. In a better system, the disease by JAK (especially JAK3) is selected from graft rejection or immune, autoimmune or inflammatory diseases. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of at least one disease selected from the group consisting of a graft rejection, an immune, an autoimmune or inflammatory disease, a neurodegenerative disease or a proliferative disease use. In a preferred system, the condition is selected from the group consisting of graft rejection or immune, autoimmune or inflammatory diseases. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention selected from the group consisting of graft rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes , diabetes caused by diabetes, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, allergic reactions to mast cell media, leukemia, lymphoma or thromboembolic and allergic associated with leukemia and lymphoma The use of a disease of sedation. Another aspect of the invention relates to a method of treating or preventing a disease in a vector (especially JAK3) by a subject in need thereof, in particular a human comprising administering to the individual a compound of formula I or a pharmaceutically acceptable compound thereof Salt. Preferably, the disease caused by J A K (particularly J A K 3 ) is at least -16-201035095 A disease selected from the group consisting of graft rejection, immunity, autoimmune or inflammatory disease, neurodegenerative disease or proliferative disease. In a better system, the disease caused by JAK (especially JAK3) is selected from graft rejection or immune, autoimmune or inflammatory diseases. Another aspect of the invention relates to a method of treating or preventing at least one disease selected from the group consisting of a graft rejection, an immune, an autoimmune or an inflammatory disease, a neurodegenerative disease or a proliferative disease in an individual in need thereof, in particular a human. And comprising administering to the individual a compound of formula I or a pharmaceutically acceptable salt thereof. In a preferred system, the disease is selected from the group consisting of graft rejection or immune, autoimmune or inflammatory diseases. Another aspect of the invention relates to a treatment or prevention of an individual in need thereof, in particular a human, selected from the group consisting of graft rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, diabetes Caused by complications, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, allergic reactions to mast cell media, leukemia, lymphoma or thromboembolic and allergic sputum associated with leukemia and sputum lymphoma A method of treating a disease comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the individual. Another aspect of the invention relates to a method of preparing a compound of formula I above, which comprises: (a) a formula Reaction of a compound of formula VIII with a compound of formula IX

VIII IX -17- 201035095 wherein R 1 , R 2 and R 3 are as defined in claim 1 and X represents halogen; or (b) in one or more steps, a compound of formula XII is converted to a compound of formula I

Wherein R! is as defined in claim 1; or (c) in one or more steps, converting a compound of formula I to another compound of formula I. In the above definition, a CL4 alkyl group as a part of a group or a group means a straight or branched alkyl chain having 1 to 4 carbon atoms, which includes a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl, isobutyl, secondary butyl and tertiary butyl. The d -4 alkoxy group as a part of a group or a group represents a group of the formula -OCi-4 alkyl group wherein the Ch alkyl moiety has the same meaning as described above. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, di-butoxy and tert-butoxy. Halogen or a halogen referred to herein means fluorine, chlorine, bromine or iodine. C, -4 oxime C^4;!: The complete group represents a group formed by replacing one or more hydrogen atoms of a Ci4 alkyl group with one or more of the above-defined Ch4 alkoxy groups, wherein (^- The oxy groups may be the same or different. Examples include, in particular, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxy Base, -butoxymethyl, tert-butoxymethyl, -18- 201035095 dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethyl, 1 , 2 -diethoxyethyl, 丨-butoxyethyl, 2_secondary ethyl, 3-methoxypropyl, 2-butoxypropyl, 丨-methoxy-2-propyl, 3-tert-butoxypropyl and 4-methoxybutyl. Halogen c, _4 alkyl represents a plurality of halogen atoms (ie, fluorine, chlorine, bromine or iodine) from one or more hydrogen atoms of the C4 alkyl group. The halogen atoms may be the same or different in the formation of the substitution. Examples include, in particular, triterpenes, fluoromethyl: fluorenyl-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoro-2-bromoethyl Base, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl'yl, 3-chloropropyl, 2,2,3,3-tetrafluoropropene Base, 2,2,3,3,3-pentafluoroheptafluoropropyl, 4-fluorobutyl and nonafluorobutyl. Hydroxy C! -4 alkyl represents one or more hydrogens of c! _4 alkyl The original or multiple hydroxyl groups are substituted for the resulting group. Examples include, in particular, hydroxy hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxy, 2-hydroxypropyl, 1-hydroxypropyl. Base, 2,3-dihydroxypropyl ' 4-0, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl. Cyano C!.4 alkyl represents C,.4 alkyl One or more hydrogenogens or a plurality of cyano groups are substituted for the resulting group. Examples include, in particular, cyanodicyanomethyl ' 1-cyanoethyl, 2-cyanoethyl, 3·cyano 2, 3-Dicyanopropyl and 4-cyanobutyl.

Cy^Cw alkyl represents a group formed by substitution of a hydrogen atom of a C, -4 alkyl group with a - group. Examples include, inter alia, (morpholinyl) 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 4-(yl)butyl, (piperidin-1 -yl) Methyl, (4-methylpiped-1 -yl-ethoxybutoxy)ethoxy group is mono- or aryl, its fluoromethylethyl, 3-fluoropropylpropyl, sub-methyl , propyl hydroxy butyl is monomethyl, propyl, -Cyi methyl, gustoline-4-)methyl-19- 201035095 (4· methyl gene n幷, 〗 '綦) 芮 (4-B Kepi D, u a 4_ butyl piperidone and neutralized methylmethyl, 2 - (1,1-di-oxo, 2-(4-methylpipen-1-yl)ethyl, 3-yl, 4-(4-methylpipen-1-yl)butyl, benzyl, (4-propylpiperidin-1-yl)methyl, (, (1,1-di-oxo) Thio-sulphate _4_yl) thiomorpholin-4-yl)ethyl, 3-( 1,1-di- oxythioxo-4-yl)propyl and 4 _ 1, 1-tertiary oxythioxomorph-4-yl)butyl.

The Cys-CM alkyl group represents a group formed by substituting a hydrogen atom of a Cl-4 alkyl group with a Cy5 group. Examples include, in particular, (glymphin-4-yl)methyl, 2-(morpholin-4-yl)ethyl, 3-(miso-4-yl)propyl, 4-(picolin-4-yl) Butyl, (porphyrin-1 -yl)methyl, 2-(porphyrin-1-yl)ethyl, 3-(porphyrin-1-yl)propyl, 4_(porphyrin-丨·yl)butyl, (pyridin-1-yl)methyl, (4-methylpyridin-1-yl)methyl, 2-(4-methylpyran-1-yl)ethyl, 3- (4-methylindole quinone-1-yl)propyl, 4-(4-methylpyridin-1-yl)butyl, (4-ethylpyridin-1-yl)methyl, (4- Propylpyridin-1-yl)methyl, (4. butylpyridinium-indenyl)methyl, (1, aceto-oxythioxo-4-yl)methyl, 2 - (1 1-tertiary oxythioxomorph-4-yl)ethyl ' 3-(1,1-dioxaoxythioxo-4-yl)propyl and 4 - (1,1-di-side) Oxythiozoline-4-yl)butyl. Ruler 7-. The .4 alkyl group represents a group formed by substituting a hydrogen atom of a Cl 4 alkyl group with a moie group.

Rn-Ci_4 hospital base table is not caused by c _4 hospital base - a hydrogen atom is replaced by a base.

Cy is a 3- to 7-membered monocyclic carbocyclic or heterocyclic ring. When it is a heterocyclic ring, the heterocyclic ring contains 1 to 3 hetero atoms independently selected from N, s or fluorene. Cyi is saturated -20- 201035095 (. , partially unsaturated or aromatic and bonded to the rest of the molecule via any C or N atom available. When C y! is saturated or partially unsaturated, One or more C or S atomic groups of the ring are optionally oxidized to form a CO ' SO or 302 base '. As defined above for the compound of Formula I, 〇71 is optionally substituted, and the substituents may be The same or different and may be located at any available position of the ring system. Examples of C y! groups include, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydroanthracene. Base, 吖0 decyl, oxiranyl, propylene oxide, imidazolidinyl, isotetrahydrothiazolyl, isoxazolidinyl, oxazolidinyl, pyrazolyl, pyrrolidinyl, tetrahydrogen Thiazolyl, dioxoalkyl, morpholinyl, thioporphyrinyl, 1,1-dioxaoxythiomasinyl' piperidinyl, piperidinyl, piperidinyl, piperidyl, tetra Hydroperylpyridyl, piperidinyl, oxalinyl, oxazolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolyl, isothiazole Lolinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-oxo-piperidinyl, 2-sided oxy-piperidinyl, 2-sided oxy-1 ,2-dihydropyridyl, 2_sideoxy Q-group-1,2-dihydropyrazine, 2-sided oxy-1,2-dihydropyrimidinyl, 3-sided oxy-2,3- Dihydroindole, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3 - Triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl 1,2,4-thiadiazolyl, pyridyl, pyridinyl, pyrimidinyl and hydrazine.

The Cy2 group refers to a 3- to 7-membered monocyclic carbocyclic or heterocyclic ring. When it is a heterocyclic ring, the heterocyclic ring contains 1 to 3 hetero atoms independently selected from N, S or fluorene. Cy2 is saturated, partially unsaturated or aromatic and is bonded to the rest of the molecule via any available C atom -21 - 201035095. When Cy2 is saturated or partially unsaturated, one or more of the C or S atomic systems of the ring are optionally oxidized to form a CO, S or S2 group. Cy2 is optionally substituted as defined above for the compound of formula I. The substituents may be the same or different and may be located at any available position in the ring system. Examples of the Cya group include, in particular, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a tetrahydroindenyl group, a fluorenyl group, an oxiranyl group, an oxypropylene group, an imidazolidinyl group. , isotetrahydrothiazolyl, isoxazolidinyl, oxazolidinyl, pyrazolyl, pyrrolidinyl, tetrahydrothiazolyl, dioxoalkyl, morpholinyl, thiochilinyl, 1,1 - two-sided oxythioporphyrinyl, piperino, piperidinyl, piperidinyl, piperidyl, tetrahydropyranyl, piperidinyl, oxalinyl, oxazolinyl, pyrroline , thiazolinyl, pyrazolinyl, pyridinoline, isoxazolinyl, isothiazolinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-side Oxy-piperidinyl, 2 _ pendant oxy-anthracene, 2 - pendant oxy-1,2-chloropyrene than steep, 2-tertiary oxy 1,2 - dihydropyrrole , 2-o-oxy-1,2-dihydropyrimidinyl, 3-oxo-2,3-dihydroindenyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, Isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl Tetrazolyl, 1,3,4-oxadiazolyl, 1,3,4·thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl , pyridyl D, pyrimidinyl and hydrazine.

The Cy3 group refers to a carbocyclic or heterocyclic ring of a 3 to 7 membered monocyclic ring or an 8 to 12 membered bicyclic ring. When it is a heterocyclic ring, the heterocyclic ring contains 1 to 4 hetero atoms independently selected from N, S or oxime. Two rings can be formed by two adjacent C or N atoms fused or two rings via two non-adjacent C or N atoms forming a bridged ring or by two -22-201035095

The V rings are bonded via a single common c atom forming a spiro ring to form a bicyclic ring saturated, partially unsaturated or aromatic and via any of the available c atoms to the remainder of the molecule. One or more C or S atomic systems in the 'saturated or partially saturated ring' in Cy3 are optionally oxidized to form a SO, SO or S〇2 group. As defined above for the compounds of formula I, Cy3 may be optionally substituted; if substituted, the substituents may be the same or different and may be used in any position of the ring system. An example of a C y3 group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetradecyl, fluorenyl, oxiranyl, propylene oxide, imidazolium. Tetrahydrothiazolyl 'isoxazolidinyl, oxazolidinyl, pyrazolidinyl, pyridyl, tetrahydrothiazolyl, dioxoalkyl, morpholinyl, thiochilinyl' Tertiary porphyrin, piperage, piperazine, piperidinyl, benzyl, tetrahydropyranyl 'piperidinyl, oxalinyl, oxazolinyl, pyridyl, oxazolinyl, pyrazole Polinyl, imidazolinyl, isoxazolinyl, oxazolinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 4-Q-yl-piperidinyl, 2-sided oxygen Base-pipelined base, 2-sided oxy-1,2-dihydropyridyl, 2-sided oxy-1,2-dihydropyrrole, 2-sided oxy-I,2-dihydropyrimidine 3 - pendant oxy-2,3-dihydroanthracene, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, yl, pyrazolyl ' 1,2,3 -triazolyl, 1, 2,4-triazolyl, tetrazole 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4 -oxadiazolyl, 1 thiadiazolyl, Pyridyl, pyridyl, pyrimidinyl, indenyl, benzoyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, indolyl, benzothienyl, benzo Thiazolyl, quinolyl, isoquinoline 0 cy3 is not classified as CO. It is located in the form of hydrazine, isobromidine ι, ι-piperidoline isothiazolidine, cumyl imidazolyl, 2 , 4-imidazolyl, linyl-23- 201035095, hydrazine, quinazolinyl, quinoxalinyl, porphyrinyl, naphthyridyl, fluorenyl, imidazopyridyl, pyridopyridinyl , thienopyridinyl, imidazopyrimidinyl, imidazopyrylene, imidazolium D-mercapto, pyrazolopyranyl, pyrazolopyridyl, pyrazolopyrimidinyl, benzo[1,3] Dioxanyl, quinone imino, 1-sided oxy-1,3-dihydroisobenzofuranyl, 1,3-dioxy-1,3-dihydroisobenzofuranyl, 2-sided oxy-2,3-dihydro-1H-indenyl, 1-tertiaryoxy-2,3-dihydro-1 Η-isoindenyl, perhydroquinolinyl, 1-side oxygen Base-perhydroisoquinolyl, 1-sided oxy-1,2-dihydroisoquinolinyl, 4-sided oxy-3,4-dihydro Quinazolinyl, 2-aza-bicyclo[2.2.1]heptyl, 5-azabicyclo[2.1.1]hexyl, 2Η-spiro[benzofuran-3,4'-piperidinyl], 311-Spirulina [isobenzofuran-1,4'-piperidinyl]' 1-sided oxy- 2,8-diazaspiro[4.5]decyl and 1-sided oxy-2,7-di Azaspiro[4.5]fluorenyl.

The Cy4 group refers to a saturated or partially unsaturated 3 to 7 membered monocyclic heterocyclic ring. Cy4 is optionally fused to a saturated, partially unsaturated or aromatic 5 or 6 membered carbocyclic or heterocyclic ring. Cy4 contains a total of from 1 to 4 heteroatoms independently selected from N, S or hydrazine. One or more of the C or S atomic systems in the 'saturated or partially unsaturated ring in Cy4 are optionally oxidized to form a C Ο, S Ο or S Ο 2 group. Cy4 is optionally substituted as defined above for the compound of formula I; if substituted, the substituents may be the same or different and may be located at any available position in the ring system. Examples of the Cy4 group include, in particular, a fluorenyl group, a fluorenyl group, a tetrahydroindenyl '1,4-diazinyl group, a pyrrolidinyl group, an imidazolidinyl group, an isoxazolidinyl group, an oxazolidinyl group, and a pyridyl group. Zyridinyl, tetrahydrothiazolyl, isotetrahydrothiazolyl, imidazolinyl, pyrrolinyl, pyrazolinyl, piperidinyl, piperidinyl, misoyl, thiochilinyl '1,1 - two-side oxythioporphyrinyl, pipetj-mercapto, liter-24-201035095 piperidinyl, 2-sided oxy-azinyl, 2-sided oxy-tetrahydroindenyl' 2 - pendant oxy-1,4-diazinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 2-oxo-piperidinyl, 3·sideoxy- Piperidinyl, 4-oxo-piperidinyl, 2-formoxy-imidazolidinyl, 2-oxo-oxazolidinyl, 2·oxy-1,2-dihydropyridyl, 2-tertiaryoxy-1,2-dihydropyrrole, 2-tertiaryoxy-1,2-dihydropyrimidinyl, 3-oxo-2,3-dihydroindoleyl, 1,2 , 3,6-tetrahydropyridyl, perhydroisoquinolyl, 1-sided oxy-1,2-dihydroisoquinolinyl, 4-0 oxo-3,4-dihydroquinazoline , 5-aza-bicyclo[2.1.1]hexyl, 2-aza-bicyclo[2.2.1] Heptyl, 6-aza-bicyclo[3.2.1]octyl, octahydropyrrolo[1,2-3]pyrrino, 211-spiro[benzofuran-3,4'-piperidinyl], 311-Snail [isobenzofuran-1,4'-piperidinyl], 2,8-diazaspiro[4.5]indol-1-one, 2,7-diazaspiro[4.5]癸- 1-keto, 2-aza-bicyclo[2.2.1]hept-6-one and 6-aza-bicyclo[3.2.1]oct-7-one.

The Cy5 group refers to a carbocyclic or heterocyclic ring of a 3 to 7 membered monocyclic ring or an 8 to 12 membered bicyclic ring. When it is a heterocyclic ring, the heterocyclic ring contains 1 to 4 heterologous oximes independently selected from N, S or oxime. A double ring may be formed by two rings fused via two adjacent C or N atoms or two rings may form a double ring via two non-adjacent C or N atoms forming a bridged ring, or by forming a single ring via two rings A common C atom bond can form a double ring. Cy5 is saturated, partially unsaturated or aromatic and is bonded to the remainder of the molecule via any C or N atom available. In Cy5, one or more C or S atomic systems of a saturated or partially unsaturated ring are optionally oxidized to form a CO, SO or S〇2 group. As defined above for the compounds of formula I, hydrazine 75 is optionally substituted; if substituted, the substituents may be the same or different and may be present at any available position in the ring system. Examples of the Cy5 group include -25-201035095, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydroindenyl, fluorenyl, oxiranyl, propylene oxide , imidazolidinyl, isotetrahydrothiazolyl, isoxazolidinyl, oxazolidinyl, pyrazolyl, pyrrolidinyl, tetrahydrothiazolyl, dioxoalkyl, morpholinyl, thiochilinyl 1,1-di-oxythiosulphonyl, piperazine, piperidinyl, piperidinyl, piperidyl, tetrahydropyranyl, piperidinyl, oxalin, oxazole Orolinyl, pyrrolinyl, thiazolinyl, pyrazolinyl, imidazolinyl, isoxazolyl, isothiazolinyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl , 4-oxo-piperidinyl, 2-oxo-piperidinyl, 2 · oxo-1,2-dihydropyridyl, 2-tertiaryoxy-1,2-dihydropyridyl Plough, 2-terxyloxy-1,2-dihydropyrimidinyl, 3-oxo-2,3-dihydroindolyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, thiazole Base, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1, 2,3-triazolyl, 1 2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,2,4 -thiadiazolyl, pyridyl, pyridinyl, pyrimidinyl, hydrazine, benzimidazolyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, fluorenyl, isodecyl , benzothienyl, benzothiazolyl, sialolinyl, isoquinolinyl, indenyl, quinazolinyl, quinoxalinyl, porphyrinyl, alpha naphthyridyl, oxazolyl, imidazo Pyridyl, pyrrolopyridyl, thienopyridyl, imidazopyrimidinyl, imidazopyrylene, imidazolinium, pyrazolopyrrino, pyrazolopyridyl, pyrazolopyrimidinyl, benzene And [1,3]dioxin, quinone imine, 1-latoxy-1,3-dihydroisobenzofuranyl, 1,3-di-oxy-1,3-dihydro Isobenzofuranyl, 2_sideoxy-2,3-dihydro-1Η-fluorenyl, 1-oxo-2,3-dihydro-1 Η-isoindenyl, perhydroquinoline 1, 1-side oxygen-26- 201035095 keto-perhydroisoquinolyl, 1-sided oxy-1,2-dihydroisoquinolinyl, cis-3,4-dihydroquinazolinyl, 2 -aza-bicyclic [2. 2.1] heptyl,: bicyclo [2.1.1] hexyl, 2H-spiro [benzofuran-3,4'-piperidinyl], isobenzofuran-1,4'-piperidinyl], 1-side Oxy-2,8-diazaspiro and 1-sided oxy-2,7-diazaspiro[4.5]decyl. In the definitions of Cy 3 and Cy 5 above, all of the possible configurations of the individual atoms are included when the illustrated examples are bicyclic. Thus, the term 0 pyrazolopyridyl can include, for example, 1 H-pyrazolo[3,4-b]pyridin 1H-pyrazolo[l,5-a]pyridinyl, 1H-pyrazolo[3, The term "4-c]pyridinium pyrazolo[4,3-c]pyridinyl and 1H-pyrazolo[4,3-b]pyridinyl and the like may include, for example, 1H-imidazo[4 , 5-b] pyridinyl [l, 2_a] pyridinyl and imidazo[l,5_a] pyridyl, and the like, and the term pyridyl may include, for example, 1H-pyrazolo[3,4-d Pyrimidinyl, ΙΗ-Ε 4 , 3 - d ] pyrimidinyl, pyrazolo[ 1 , 5 - a ] pyrimidinyl and pyrazolo[ 1 , 5 -yl and the like. As exemplified in the definition of a ring group as used throughout the specification, a generic ring group (eg, pyridyl 'thienyl or fluorenyl) includes all available bonding positions unless corresponding to the ring group. The restriction is indicated, for example, in Cy2 and Cy3, which stipulates that the ring system is bound via a bond. Thus, for example, in the definition that the bonding position does not include any restriction 5 C y 5 , the term piperidinyl includes 1-piperidinyl, 2-piperidinyl and 4-piperidinyl; and pyrrolidinyl The term includes 1-pyrrolidinylpyridinyl and 3-pyrrolidinyl. "Alternatively substituted by one or more" means that a group may be via a 4-sided oxygen 5-aza_31 spiro [[4.5] 癸 refers to, for example, pyridine, E '1H- group, imidazole, imidazole In the case of the oxazolopyrazole c] methane formula, the C atom in the package definition: cyi and, 3-piperider, 2-pyridyl or multiple -27- 201035095 (f, 1, 2, 3 or 4) More preferably 1, 2 or 3 and very preferably 丨 or 2) substituents are substituted for the position where the radical has sufficient substitution. The substituents such as μ may be the same or different and may be located at any Where a non-aromatic ring is used as a substituent for a non-aromatic ring, the non-aromatic ring may be substituted for one hydrogen atom or may replace two hydrogen atoms on the same C atom to form a spiro ring. Wherein, when a non-aromatic ring is present as a substituent for an alkyl group, the non-aromatic ring may replace one hydrogen atom or may replace two hydrogen atoms and share a C atom with the alkyl group, thereby forming a group such as:

Although two or more substituents having the same number in the definition of the substituent (e.g., a CONR4R4'_NRmRi4, -NR6c〇NRi6Ri6, etc.) are present, it is not intended that the radicals must be identical. Each such base is independently selected from the their possible meanings, and thus the bases may be the same or different. For the sake of clarity, in the definition of a radical (or group) or a particular preferred system, the presence or absence of the term "independently selected, or ''representative') shall not be recognized. To impose any restrictions on this definition. Within the definition provided, 'all terms/words should be given the broadest possible meaning', which means that unless otherwise clearly stated otherwise, in any definition of any term/word, the two bases shall not The contraction limit is interpreted as the same. Throughout the specification, the term "treatment" means to remove, alleviate or ameliorate the cause or effect of a disease. For the purposes of the present invention, treatment includes but -28 - 201035095 is not limited to the alleviation, amelioration or removal of one or more symptoms of the disease, the reduction of the extent of the disease, the stable (ie non-deteriorating) state of the disease, the delay in the progression of the disease, or Slow, improved or alleviated disease states and reduced (even partial or total) disease. As used herein, "prevention" refers to preventing the occurrence of a disease in an individual who is prone to disease or has a risk factor but does not exhibit a disease sign. Prevention also includes preventing the recurrence of the disease in an individual who has previously suffered from the disease. Accordingly, the present invention is directed to a compound of formula I above. In another preferred embodiment, the invention relates to compounds of formula I, wherein R, represents hydrogen, <^_4 alkyl, halo Cm alkyl, hydroxy Ci.4 alkyl, RrCM alkyl, halogen, -CN, - CONR4R4, -C02R5, -OR4 or -nr6cor4 In another preferred embodiment, the invention relates to a compound of formula I, wherein R, represents hydrogen, Cl-4 alkyl, halo-Ci-4 alkyl, hydroxy C, .4 Alkyl, RkCm alkyl fluorenyl, halogen or -CN. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents hydrogen or -CN. In another preferred embodiment, the invention relates to compounds of formula I, wherein h represents hydrogen. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents -CN. In another preferred embodiment, the invention relates to compounds of formula I, wherein R? represents R-CN, -CONR4R4, -C02R5, -OR4 or -NR6COR4. -29- 201035095 In another preferred embodiment, the invention relates to a compound of formula I, wherein R 2 represents hydrogen, Cm moie, halo-Ch-alkyl, hydroxy C|_4 alkyl, RrC, .4 alkyl or Cyz' Cyz is optionally substituted by one or more R8: and the ruler 3 represents a Cl-4, a halogenated Cl-4, a base C|-4, a Rh-Ci-4 alkyl, a -CONR9R9, -CORi. , -CO2R10, -SC^R,. , -SO2NR9R9 or

Cy3, wherein Cy3 is optionally substituted with one or more r12. In another preferred embodiment, the invention relates to compounds of formula I, wherein R2 represents hydrogen, C,-4 alkyl, halo Cm alkyl, hydroxyCl-4 alkyl or r7_Ci.4 alkyl. In another preferred embodiment, the invention is directed to a compound of formula I, wherein r2 represents hydrogen, a Ci-4, a halogen C1-4, or a thio-Ci-4. In another preferred embodiment, the invention relates to compounds of formula I, wherein r2 represents hydrogen or Cl-4 alkyl' preferably hydrogen, methyl or ethyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein r3 represents a trans-Ci-4, a R11-C1-4, or a Cy3, wherein the Cy3 is optionally via one or more R 1 2 Replace. In another preferred embodiment, the invention is directed to a compound of formula I, wherein r3 represents Cy3, wherein Cy3 is optionally substituted with one or more R12. In another preferred embodiment, the invention relates to a compound of formula I, wherein Cy3 represents a 3 to 7 membered saturated monocyclic carbocycle' which optionally contains 1 or 2 heteroatoms independently selected from N, S or oxime, Wherein the ring is bonded to the remainder of the molecule via any C atom available, wherein one or more C or S ring atoms are optionally oxidized to form c〇, SO or S02 groups' and wherein Cy3 -30- 201035095 is optionally substituted with one or more r12. In another preferred embodiment, the invention relates to a compound of formula I, wherein Cy3 represents a 5 or 6 membered saturated monocyclic carbocyclic ring, optionally containing 1 or 2 heteroatoms independently selected from N, S or 0, Wherein the ring is bonded to the remainder of the molecule via any C atom available, wherein one or more C or S ring atoms are optionally oxidized to form a CO, SO or S02 group, and wherein the Cy3 is Optionally substituted with one or more R, 2. In another preferred embodiment, the invention relates to a compound of formula I, wherein Cy3 represents cyclohexyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl, wherein Cy3 is optionally one or more Replaced by R 1 2 . In another preferred embodiment, the invention relates to compounds of formula I, wherein Cy3 represents cyclohexyl, 3-piperidinyl or 4-piperidinyl, wherein the Cys is optionally substituted with one or more R,2. In another preferred embodiment, the invention relates to compounds of formula I, wherein Cy3 represents cyclohexyl or 3-hydrazone, wherein Cy3 is optionally substituted with one or more OR12. In another preferred embodiment, the invention relates to compounds of formula I, wherein Cy3 represents cyclohexyl, which is optionally substituted by - or a plurality of R 1 2 . In another preferred embodiment, the invention is directed to a compound of formula I, wherein Cy3 represents a 3-indole D group, which is optionally substituted with one or more R 1 2 . In another preferred embodiment, the invention relates to a compound of formula I, wherein Cy3 represents 4-piperidinyl, which is optionally substituted by one or more R 1 2 . In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents cys; and -31 - 201035095

Cy3 represents the basis of the formula cy3as Cy3b:

Wherein Rl2a represents -C〇R15; and wherein additionally 〇733 and Cy3b are each optionally substituted with one or more R12 in another preferred system, the invention being directed to a compound of formula I, wherein R3 represents Cy3;

Cy3 represents the base of the formula Cy3a or Cy3b:

Wherein Rl2a represents -COR15; and wherein additionally 〇7^ and Cy3b are independently and optionally substituted by one or more R12's Κ12 series independently selected from the group consisting of Ci-4, and C|-4 , based on the base of Ci-4 or Rii-Cm. In another preferred embodiment, the invention relates to a compound of formula I, wherein R 3 represents C y 3 ;

Cy3 represents the base of Cy3a* Cy3b: -32- 201035095

Cy3a Cy3b

Wherein Rl2a represents -COR"; and wherein additionally and Cyn are independently and optionally substituted by one or more R12; the Ri2 are independently selected from the group consisting of Cm alkyl, haloCl.4 alkyl, hydroxyCl_4 alkane

Base or Ri1_Ci_4 yard base;

Rl4 represents hydrogen;

Ri5 represents Ci-4 alkyl or cyano C,-4 alkyl, preferably cyanomethyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents Cy3; and Cy3 represents a group of formula Cy3a*Cy3b:

Wherein Rl2a represents -COR15. In another preferred embodiment, the invention is directed to a compound of formula I wherein r 3 represents c y 3 ;

Cy3 represents the base of the formula Cy3a or Cy3b · -33- 201035095

Cy3a

Cy3b wherein R12a represents -COR15; R 14 represents hydrogen;

Ri5 represents a Ci.4 alkyl or cyano Ci-4 alkyl group, preferably a cyanomethyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents Cy3;

Cy3 represents the basis of the formula Cy3a:

Cy3a; wherein R 1 2 a represents -C O R 1 5 ; and wherein additionally C y 3 a is optionally substituted with one or more r, 2 . In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents Cy3;

Cy3 represents the basis of the formula Cy3b:

OR14

And s.

Cy3 represents the basis of the formula Cy3a:

Rl2a wherein R12a represents -c〇R15.另一 ο In another preferred system, the invention relates to a compound of formula I, wherein R3 represents Cy3;

Cy3 stands for the base of Cy3b: , or14

Cy3b. In another preferred embodiment, the invention relates to a compound of formula I, wherein R3 represents Cy3;

Cy3 represents the basis of the formula Cy3a:

R 12a wherein R 12a represents -COR 15 ; and R 15 represents a Cb 4 alkyl group or a cyano Cb 4 alkyl group, preferably a cyanomethyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein 1 represents hydrogen or -CN; and -35-201035095 R2 represents hydrogen, Ci-4 alkyl, halo-alkyl, hydroxy-C4 alkyl or R7-C, .4 alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents -CN; and R2 represents hydrogen, Ci-4 alkyl, halo CL4 alkyl, hydroxy C^4 alkyl or R 7 - C 1 . base. In another preferred embodiment, the invention relates to compounds of formula I, wherein 1^ represents hydrogen or -CN; and R2 represents hydrogen, C!-4 alkyl, halo-alkyl or hydroxy-Cm-alkyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents -CN; and ft 2 represents hydrogen, C!-4 alkyl, halo Cw alkyl or hydroxy Cm alkyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein 1^ represents hydrogen or -CN; and R2 represents hydrogen or C^4 alkyl, preferably hydrogen, methyl or ethyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; and R2 represents hydrogen or a C-alkyl group, preferably hydrogen, methyl or ethyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein 1 represents hydrogen or -CN;

Rs represents Cy3, wherein 0丫3 is optionally substituted by one or more R12 in another preferred system, the invention is directed to a compound of formula I, wherein Ri represents -CN; and -36-201035095 R3 represents Cy3, Wherein Cy3 is optionally substituted by one or more R12 in another preferred system, and the invention relates to compounds of formula I, wherein Ri represents hydrogen or -CN; R2 represents hydrogen, Cm alkyl, halo Cm alkyl, Hydroxy Cm alkyl or R7~Ci_4, and R3 represents Cy3, wherein Cy3 is optionally substituted by one or more RI2. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; R2 represents hydrogen, Cm alkyl, halo Cm alkyl, hydroxy Cu alkyl or Ry-Cu alkyl; and R3 represents Cy3 Wherein Cy3 is optionally substituted by one or more R12 in another preferred system, the invention being directed to a compound of formula I wherein 〇RM represents hydrogen or -CN; R2 represents hydrogen or alkyl, preferably hydrogen And methyl or ethyl; and R3 represents Cy3, wherein Cy3 is optionally substituted by one or more R12 in another preferred system, and the invention relates to a compound of formula I, wherein R! represents -CN; R2 represents Hydrogen or alkyl, preferably hydrogen, methyl or ethyl; and R3 represents Cy3, wherein Cy3 is optionally substituted by one or more R12 -37-201035095 in another preferred system I compound 'where 1 represents hydrogen or -CN; R2 represents hydrogen, Cr4 alkyl, halo-Cu alkyl, hydroxy Cu alkyl or R 7 - c 1 - 4; R3 stands for Cy3, and

Cy3 represents a 5 or 6 membered saturated monocyclic carbocyclic ring optionally containing 1 or 2 heteroatoms independently selected from N, S or fluorene, wherein the ring system is via any C atom available for use with the molecule The remainder is bonded wherein one or more C or S ring atomic systems are optionally oxidized to form a CO, SO or S〇2 group ' and wherein the Cy3 is optionally substituted with one or more R12. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents -CN; R2 represents hydrogen, Cu alkyl, _Cl_4 alkyl, hydroxy Cb4 alkyl or R7-CU alkyl; «3 represents Cy3; And

Cy3 represents a 5 or 6 membered saturated monocyclic carbocyclic ring optionally containing 1 or 2 heteroatoms independently selected from N, S or 0, wherein the ring is via any C atom available for use with the molecule The remainder is bonded wherein one or more C or S ring atomic systems are optionally oxidized to form a c〇, SO or 302 group, and wherein the Cy3 is optionally substituted with one or more R12. In another preferred embodiment, the invention relates to compounds of formula I, wherein R| represents hydrogen or -CN; R2 represents hydrogen or 4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3; and -38 - 201035095

Cy3 represents a 5 or 6 membered saturated monocyclic carbocyclic ring optionally containing 1 or 2 heteroatoms independently selected from N, S or fluorene, wherein the ring system is via any C atom available for use with the molecule The remainder is bonded wherein one or more of the c or S ring atomic systems are optionally oxidized to form a CO, SO or S〇2 group ' and wherein the Cy3 is optionally substituted with one or more R12. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; R2 represents hydrogen or Cu alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents a 5 or 6 membered saturated monocyclic carbocyclic ring optionally containing 1 or 2 heteroatoms independently selected from N, S or 0, wherein the ring is via any C atom available for use with the molecule The remainder is bonded wherein one or more of the 0 or S ring atomic systems are optionally oxidized to form a C0, SO or S02 group ' and wherein the Cy3 is optionally substituted with one or more R12. In another preferred embodiment, the invention relates to a compound of formula I, wherein 1 represents hydrogen or -CN; rule 2 represents hydrogen, Ci-4, a halogen Ci-4, a base C|-4, or R 7 - C 1 - 4 yard base; R3 stands for Cy3;

Cy3 represents cyclohexyl, 3-piperidinyl or 4-piperidinyl, wherein Cy3 is optionally substituted by one or more R!2. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; R2 represents hydrogen, C,-4 alkyl, halo C, _4 alkyl, hydroxy Cm alkyl or -39- 201035095 R 7 - C 1 - 4 yard base, R3 stands for Cy3; and

Cy3 represents a cyclohexyl group, a 3-piperidinyl group or a 4-piperidinyl group wherein the Cy3 group is optionally substituted with one or more R1 2 . In another preferred embodiment, the invention is directed to a compound of formula I wherein 1 represents hydrogen or -CN; Κ·2 represents chloro or Ci.4 pharmaceutically acceptable 'hydrogen, methyl or ethyl; R3 represents Cy3; And

Cy3 represents cyclohexyl, 3-piperidinyl or 4-piperidinyl, wherein Cy3 is optionally substituted by one or more R12. In another preferred embodiment, the invention relates to a compound of formula I, wherein R 1 represents -CN; Κ·2 represents hydrogen or ^-4, preferably hydrogen, methyl or ethyl; and rule 3 represents Cy3; And

Cy3 represents a cyclohexyl group, a 3-pipe steep group or a 4-pipe steep group, wherein the Cy3 group is optionally substituted with one or more RI2. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents hydrogen or -CN; R2 represents hydrogen, C,-4 alkyl, haloalkylalkyl, hydroxy Cmalkyl or R7-C1. 4 yard base; R3 stands for Cy3; and

Cys represents a cyclohexyl group which is optionally substituted by one or more r12. In another preferred embodiment, the invention relates to a compound of formula I, wherein R 1 represents -CN; -40- 201035095 Κ·2 represents hydrogen 1, Ci_4, a halogen Ci_4, a base, a Ci_4, or a R 7 - C 1 _ 4 yard base; R3 stands for Cy3; and

Cy3 represents a cyclohexyl group which is optionally substituted by one or more R12. In another preferred embodiment, the invention relates to compounds of formula I, wherein 1^ represents hydrogen or -CN; R2 represents hydrogen or Cb4 alkyl, preferably hydrogen, methyl or ethyl; QR3 represents Cy3; And

Cy3 represents a cyclohexyl group which is optionally substituted by one or more R, 2 groups. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; R2 represents hydrogen or C!^alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents a cyclohexyl group wherein the Cy3 group is optionally substituted with one or more R12. Q In another preferred system, the invention relates to a compound of formula I, wherein 1^ represents hydrogen or -CN; Κ·2 represents nitrogen, Ci.4, _Ci-4, and thio-Ci-4 Or R 7 - C 1 . 4 yard base; R3 stands for Cy3 ;

Cy3 represents 3-piperidinyl or 4-piperidinyl, wherein the Cy3 is optionally substituted with one or more R i 2 . In another preferred embodiment, the invention relates to a compound of formula I, wherein R! represents -CN; -41 - 201035095 represents hydrogen, Cu alkyl, sec Cu alkyl, hydroxy Cu alkyl or R7-C 1.4 hospital R3 represents Cy3; and cy3 represents 3-piperidinyl or 4-piperidinyl, wherein Cy3 is optionally substituted with - or a plurality of R12. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents hydrogen or -CN; represents hydrogen or alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents 3-piperidinyl or 4-piperidinyl, wherein the Cy3 is optionally substituted with one or more R, 2 groups. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents -CN; R2 represents hydrogen or CL4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3; and cy3 Represents 3-piperidinyl or 4-piperidinyl, wherein the Cy3 is optionally substituted with - or a plurality of R12. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents hydrogen or -CN; ft 2 represents hydrogen, c^4 alkyl, halo-Cu-based, via-based Ci-4, or h-CH Alkyl; R3 represents Cy3; and Cy3 represents 3-piperidinyl, which is optionally substituted by one or more R12-42-201035095 in another preferred system, the invention being concerned with a compound of formula I, Wherein Ri represents -CN; Κ·2 represents gas, Ci-4, thio-Ci-4 fluorenyl, thio-Ci-4 or R7-CL4 alkyl; R3 represents Cy3;

Cy3 represents 3-piperidinyl which is optionally substituted by one or more R12 in another preferred system, and the invention relates to compounds of formula I wherein 1 represents hydrogen or -CN; R2 represents hydrogen or C ^4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents 3-piperidinyl which is optionally substituted by one or more R12 in another preferred system. The invention relates to compounds of formula I, wherein R! represents -CN; 〇R2 represents hydrogen or cumane a base, preferably hydrogen, methyl or ethyl; represents Cy3;

Cy3 represents 3-piperidinyl which is optionally substituted by one or more R12 in another preferred system, and the invention relates to compounds of formula I wherein iMt represents hydrogen or -CN, preferably -CN; 112 represents hydrogen or a Cb4 alkyl group, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents the base of Cy3a* Cy3b: -43- 201035095

Wherein Rl2a represents a CONR14R14, -cc>Rl5, -c〇2R|5, _s〇2Ri5, -S02NRI4R" or Cy5' wherein Cy5 is optionally substituted by one or more ri3; and wherein additionally €733 and €丫 313 is independently and optionally substituted by one or more r12 in another preferred system. The invention relates to a compound of formula I, wherein Ri represents hydrogen or —CN, preferably —CN; R 2 represents hydrogen or Cb 4 alkyl. Preferably, hydrogen 'methyl or ethyl; R3 represents Cy3; and Cy3 represents a group of formula Cy3a or Cy3b:

Rl2a

Cy3a Cy3b

Wherein R 1 2a represents -COR 15 ; and wherein additionally C y 3 a and C y 3 b are independently and optionally substituted by one or more R, 2 in another preferred system, the invention being directed to a compound of formula I, wherein 1 represents hydrogen or -CN, preferably -CN; R2 represents hydrogen or <^_4 alkyl' preferably hydrogen, methyl or ethyl; -44- 201035095 R3 represents Cy3;

Cy3 represents the base of the formula Cy3a*Cy3b:

Where R12a represents -COR15;

Wherein additionally, 〇733 and Cy3b are independently and optionally substituted by one or more R12's. The %Rl2 system is selected from the group consisting of Ci_4, Cu1-4, or Ci-4, or Rll- Ci.4 hospital base. In another preferred embodiment, the invention relates to compounds of formula I, wherein 1 represents hydrogen or -CN, preferably -CN; R2 represents hydrogen or Ci-4 alkyl, preferably hydrogen, methyl or ethyl; R3 stands for Cy3;

Cy3 represents the basis of the formula Cy3a_ Cy3b:

Wherein R 12a represents -COR15; wherein additionally Cy3i^a Cy3b is independently and optionally substituted by one or more R12, which are independently selected from the group consisting of Cu alkyl, halo Cm alkyl, hydroxy C, .4 alkyl or Rll-Cl.4 hospital base; R 1 4 represents hydrogen; and -45- 201035095 R15 represents a CU4 alkyl group or a cyano C^-4 alkyl group, preferably a cyanomethyl group. In another preferred embodiment, the invention relates to a compound of formula I, wherein hydrogen or -CN; R2 represents hydrogen or a Cu alkyl group, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 stands for the base of 〇733 or Cy3b:

Wherein R12a represents -COR15. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; ft 2 represents hydrogen or Cb4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents the base of formula 0丫33 or Cy3b:

Wherein R12a represents -COR15. In another preferred embodiment, the invention relates to compounds of formula I, wherein 1 represents hydrogen or -CN; R2 represents hydrogen or alkyl, preferably hydrogen, methyl or ethyl; -46-201035095 R3 represents Cy3;

Cy3 represents the base of the formula Cy3a*Cy3b:

Wherein Rl2a represents -COR!5; 〇 Rm represents hydrogen;

Rm represents a -4 alkyl group or a cyano c!-4 alkyl group, preferably a cyanomethyl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; R2 represents hydrogen or Ci-4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 stands for the base of 〇733 or 〇丫315:

Wherein Rl2a represents -COR15; R14 represents hydrogen;

Rl5 represents a Ci-4 or a cyano Ci-4, preferably cyanomethyl. In another preferred embodiment, the invention relates to compounds of formula I, wherein R 1 represents hydrogen or -CN, preferably · c N ; R 2 represents hydrogen, c..4 alkyl, halo C, .4 alkyl, Hydroxy C|-4 alkyl or -47- 201035095 R7-CM alkyl; R3 represents Cy3;

Cy3 represents the basis of the formula Cy3a:

Wherein R12a represents a C〇NR14R"'-CORis, a CO2R15, -S02NR14RI4S Cy5, wherein the Cy5 is optionally monosubstituted; and wherein the additional Cy3a is optionally substituted with one or more R12. In another preferred embodiment, the invention relates to the compound of formula 1 wherein Ri represents hydrogen or -CN; R2 represents hydrogen or <^.4 alkyl, preferably hydrogen, methyl or B represents R3;

Cy3 represents the basis of the formula Cy3a:

Cy3a; wherein Ri2a represents -CONRl4Ri4, -COR15, -CO2R15, -S02NRMR14 or Cy5, wherein Cy5 is optionally monosubstituted; and wherein additionally Cy3jS is optionally substituted with one or more R12 for another preferred In the system, the invention relates to a compound of the formula I -48-, -S 〇2R15 or a plurality of R13 wherein; -S 0 2 R 1 5 or a plurality of Rl 3 ), wherein 201035095

Ri represents -CN; R2 represents hydrogen or Cl-4, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents the basis of the formula Cy3a:

-C Ο 2 R 15 ' - S Ο 2 R -50^11141114 or 〇75, wherein Cy5 is optionally substituted by one or more R]; and wherein additionally C y 3 a is optionally passed through - or Multiple R12 substitutions. In another preferred embodiment, 'the invention relates to a compound of formula I, wherein Ri represents hydrogen or -CN' preferably -CN ·' R2 represents hydrogen, Cl-4, chiral Cl. 4, trans-base Cl · 4 alkyl or R7-C1-4 yard base; rule 3 represents Cy3;

Cy3 stands for the base of cyw:

Wherein R12a represents a C〇NRi4Rl4, —COR15, —C02R15, —SO2R15,-3 0^11141114 or Cy5, wherein Cy5 is optionally substituted by one or more R13 -49- 201035095; and wherein C y3 a is additionally Alternatively, it may be substituted by a plurality of R 1 2 groups independently selected from the group consisting of c, .4 alkyl, halo Cm alkyl, hydroxy Ci.4 alkyl or Rh-Ci-4 alkyl. In another preferred embodiment, the invention relates to a compound of formula I wherein Ri represents hydrogen or -CN; R. 2 represents hydrogen or hydrazine, preferably hydrogen, methyl or ethyl; and rule 3 represents Cy3;

Cy3 represents the basis of the formula Cy3a:

And -S〇2NR" Rl4 or cy5, wherein cy5 is optionally substituted with one or more Ri3; and wherein additionally C y3 a is optionally substituted by - or a plurality of R ! 2 'the R , 2 It is independently selected from Cm alkyl, haloCl 4 alkyl, hydroxy Cm alkyl or Rn-Cw alkyl. In another preferred embodiment, the invention relates to the compound of formula I wherein R | represents -CN; R2 represents hydrogen or C, _4 alkyl, preferably hydrogen, methyl or ethyl; R 3 represents C y 3 ; Cy3 stands for the base of Cy3a: -50- 201035095

Rl2a

-CO2R - S〇2R丨5 or more R!3 Ο Ο wherein Rl2a represents _C〇NR14Rm, -CORi5, a S〇2NRi4Rl4 or Cy5, wherein Cy5 is optionally twisted; and additionally CySa Optionally, or - a plurality of 2 substituents, each independently selected from the group consisting of Ci-4 alkyl, halo-alkylalkyl, hydroxy<^-4 alkane- or alkoxy. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents hydrogen or -CN, preferably -CN: R2 represents hydrogen, Cw alkyl, halo-Ch-alkyl, hydroxy c, 1 '4 R 7 - C 1 . 4 yard base; R 3 represents C y 3 ; Cy3 represents the base of formula Cy3a: medium

Rl2a wherein Ri2a represents -COR, 5; and wherein additionally Cy3aS is optionally substituted with one or more Ri2. In another preferred embodiment, the invention relates to a compound of formula I, Ri represents hydrogen or -CN, preferably -CN; wherein -51 - 201035095 R·2 represents hydrogen, Cl. 4:l: fluorenyl, haloCl -4 alkyl, hydroxy Cm alkyl or Rt-Cu alkyl; R3 represents Cy3;

Cy3 stands for the base of Cysa:

Where R

Wherein the additional C y3 a is optionally substituted by one or more R, 2, and the R ι is independently selected from the group consisting of Ci-4, and the halogen C 垸 4 ' Or ruler 1 匸丨 匸丨 alkyl. In another preferred embodiment, the invention is directed to a compound of formula I wherein the heart represents hydrogen or -CN; R2 represents hydrogen or Cu alkyl ', preferably hydrogen 'methyl or ethyl; h represents Cy3;

Cy3 represents the basis of the formula Cy3a:

Where Ri2a stands for -COR

Rl2a wherein additionally Cy3JS is optionally substituted with one or more R!2. In another preferred embodiment, the invention relates to compounds of formula I, wherein -52-201035095 R 1 represents -c N ; R 2 represents hydrogen or a C-alkyl group, preferably hydrogen, methyl or ethyl; R 3 represents C y 3 ;

Cy3 represents the basis of the formula Cy3a:

Rl2a wherein additionally Cy3a is optionally substituted with one or more R, 2 groups. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents hydrogen or -CN; R2 represents hydrogen or C i -4 alkyl 'preferably hydrogen, methyl or ethyl; R 3 represents C y 3 ;

Cy3 represents the basis of the formula Cy3a:

Cy3a; wherein Rl2a represents -COR15; and wherein additionally Cy(R) is optionally substituted by one or more Ru, which are independently selected from Cm alkyl, halo C, -4 alkyl, hydroxy Cm alkyl or Rii_c alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents -CN; -53- 201035095 R2 represents hydrogen or c, _4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents the base of the formula Cy3a: where Rl2a stands for -COR"

Wherein additional CySa is optionally substituted with one or more Rlz, which are independently selected from the group consisting of Ci-4, halogen C1-4, base Ci_4, or Rii_c alkyl. In another preferred embodiment, the invention relates to a compound of formula I, wherein Ri represents hydrogen or -CN, preferably -CN; R2 represents hydrogen, Cm alkyl, halo Cm alkyl, hydroxyCl4 or R7- CI - 4 hospital base; R3 stands for Cy3;

Cy3 represents the basis of the formula Cy3a:

Wherein additionally 〇733 is optionally substituted by one or more R12; and R!5 represents 6-4 alkyl or cyano (^-4 alkyl, preferably cyanomethyl. In another preferred system The present invention relates to a compound of formula I, wherein -54- 201035095

Ri represents hydrogen or -CN, preferably -CN; R. 2 represents hydrogen, C1-4, based on C1-4, residue R7-CW alkyl; and ruthenium R 3 represents C y 3 ;

Cy3 represents the basis of the formula Cy3a:

Wherein R12a represents -CORj substituted 'the R1:4 alkyl or Rn.Ci^ wherein additionally C y 3 a is optionally independently selected from the group consisting of Cu alkyl, halogen Ci-4 via one or more R groups An alkyl group, a hydroxy c alkyl group;

Rl5 represents a hospital group or a chloro group Ci_4 "complete base" preferably a gas methyl group in another preferred system, O Ri represents hydrogen or -CN; R2 represents hydrogen or Cb4 alkyl R3 represents Cy3; a compound wherein, preferably, hydrogen, methyl or ethyl;

Cy3 represents the basis of the formula Cy3a:

-55- 201035095 wherein the additional 〇733 is optionally substituted by one or more R, 2;

Ru represents an alkyl group or a cyano group <^_4 alkyl group, preferably a cyanomethyl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein R 1 represents -CN; R 2 represents hydrogen or <^-4, preferably hydrogen, methyl or ethyl; R 3 represents C y 3 ;

Cy3 represents the basis of the formula Cy3a:

Wherein additionally, 33 is optionally substituted by one or more R!2; and R15 represents a G.4 alkyl or cyano Cw alkyl 'preferably cyanomethyl. In another preferred embodiment, the invention relates to a compound of formula 1, wherein 1 represents hydrogen or -CN; R2 represents hydrogen or <^-4 alkyl' preferably hydrogen, methyl or ethyl; and rule 3 represents Cy3 ;

Cy3 represents the basis of the formula Cy3a:

Rl2a where R 12a represents -COR 1 5

Wherein additionally cy 3 a is optionally substituted by one or more R 12 'the R - 56 - 201035095 are independently selected from the group consisting of a Ch alkyl group, a halogen Ct-4 alkyl group, a hydroxy Ch 4 alkyl group or a Ru-Cl alkane. And R15 represents a C!·4 hospital base or a cyano Cl.4 hospital base, preferably a cyanomethyl group. In another preferred embodiment, the invention relates to compounds of formula I, wherein Ri represents -CN; R2 represents hydrogen or alkyl, preferably hydrogen, methyl or ethyl; R 3 represents C y 3 ; 0 Cy3 represents Base of Cy3a:

Wherein R 1 2 a represents _ C ◦ R 1 5 ; wherein additionally 〇 733 is optionally substituted by one or more Ri 2 'the R! are independently selected from C,-4 alkyl, halo-Ci-4 A hydroxy-Ci-4 alkyl group or a Ru-Cu Q alkyl group; and RI5 represents a q.4 alkyl group or a cyano h.4 alkyl group, preferably a cyanomethyl group. In another preferred embodiment, the invention relates to the compound of formula 1 wherein Ri represents hydrogen or -CN; R2 represents hydrogen or Ci-4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3; and Cy3 represents Cy3a base: -57- 201035095

Cy3a; wherein R12a represents -COR15. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; R2 represents hydrogen or Cm alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3; and Cy3 represents formula Cy3a Base:

Cy3a; wherein R) 2a represents -COR15. In another preferred embodiment, the invention relates to compounds of formula I, wherein 1 represents hydrogen or -CN; R2 represents hydrogen or C; .4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents Cy3;

Cy3 represents the basis of the formula Cy3a:

-58- 201035095 where Rl2a stands for -C〇R15;

Rl5 represents a Ci-4 or a cyano-Ci-4, preferably cyanomethyl. In another preferred system, the invention relates to a compound of formula I, wherein

Ri represents -CN; R2 represents hydrogen or Ci-4, preferably hydrogen, methyl or ethyl; h represents Cy3;

Cy3 represents the base of the formula Cy3a·

R 12a wherein R 1 2a represents -COR! R 15 represents Ci-4 alkyl or cyano Ci-4 alkyl, preferably cyanomethyl, in another preferred system, the invention is directed to a compound of formula I, wherein R 1 represents hydrogen Or -CN; Ruler 2 represents nitrogen or Ci-4, 'preferably nitrogen, methyl or ethyl, R3 represents Cy3; and represents the base of formula Cy3b:

〇R*l4

Cy3b ° In another preferred system, the invention relates to compounds of formula i, wherein R1 represents -CN; I represents hydrogen or C, _4 alkyl, preferably hydrogen, methyl or ethyl; -59- 201035095 R3 represents Cy3; and

Cy3 represents the basis of the formula Cy3b:

Cy3b ° In another preferred system, the invention relates to compounds of formula i, wherein 1^ represents hydrogen or -cn; R2 represents hydrogen or c^4 alkyl, preferably hydrogen, methyl or ethyl; R3 represents cy3 ;

Cy3 represents the basis of the formula Cy3b:

Cy3b; and R 1 4 represents hydrogen. In another preferred embodiment, the invention relates to compounds of formula I, wherein R! represents -CN; R2 represents hydrogen or Cm alkyl, preferably hydrogen 'methyl or ethyl; and rule 3 represents Cy3;

Cy3 represents the basis of the formula Cy3b:

Cy3b; and 201035095 R 1 4 represents ammonia. The present invention encompasses all possible combinations of the specific or preferred systems described above. In another preferred embodiment, the invention relates to a compound of the formula I or a salt thereof, which is selected from the compounds exemplified in the examples 1 to 10, in another preferred system, the invention a compound selected from the group consisting of: trans-5-cyano-3-[6-(4-hydroxycyclohexylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine, trans -5-Cyano-3-[6-(4-hydroxycyclohexyl-N-methylamino)pyridin-2-yl]卩ϋD sits and [1,5 - a ] 5- 5-cyano-3-[6-(N-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2-yl]pyrazolo[1,5-a]pyridine, 5- Cyano-3-[6-(piperidin-4-ylamino)pyridin-2-yl]pyrazoloindole[l,5-a]pyridine, 5-cyano-3 -[ 6 -(methyl (piperidin-4-yl)amino)pyridin-2-yl]pyrazolo[1,5-a]pyridine, 5-cyano-3-[6-(1-(2-cyanoethyl) Piperidin-3-ylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine, (R)-5-cyano-3-[6-(1-(2-cyano) Ethyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine and (1〇-5-cyano-3-[6-(1^1- Methyl-1-(2-cyanoethyl) piperidin-3-yl Pyridin-2-yl]pyrazolo[1 ,5 - a ]pyridine '-61 - 201035095 or a salt thereof. In another preferred system, the invention relates to a compound of formula I selected from: Trans-5-cyano-3-[6-(4-hydroxycyclohexylmethylamino)pyridin-2-yl]pyrazolo[1,5 _ a ]pyridine, trans-5-cyano- 3-[6-(N-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2-yl]pyrazolo[l,5-a]pyridine, 5-cyano-3-[6 - (1-(2.Cyanoethyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine, (R)-5-cyano-3 -[6-(1-(2-cyanoethenyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine and (R)-5-cyanide 3-[6-(N-methyl-1-(2-cyanoethyl)piperidinyl-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine Or a salt thereof. In another preferred embodiment, the invention is directed to a compound of formula I which provides greater than 5 % JAK3 inhibitory activity at 10 μM in a J AK3 assay such as described in Example 17. Preferably, more than 50% of the JAK3 inhibitory activity at 1 μΜ and more preferably more than 5〇% of JAK3 inhibitory activity at 0.1 μΜ. In another preferred embodiment, the present invention is directed to a compound of formula I which provides more than 50 °/ at 1 〇 μΜ in a J ΑΚ 2 assay such as described in Example 18. The JAK2 inhibitory activity, preferably more than 50% of the JAK2 inhibitory activity at 1 μΜ and more preferably more than 50% of the JAK2 inhibitory activity at 0.5 μΜ. The compounds of the present invention contain one or more basic nitrogens and thus form salts with organic or inorganic acids. Examples of such salts include inorganic acid salts (the inorganic-62-201035095 acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid) and organic acid salts (especially the organic acid Such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trans-maleic acid 'oxalic acid, acetic acid, maleic acid, ascorbic acid, citric acid, lactic acid, Tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid). Some of the compounds of the present invention may contain one or more acidic protons and thus may also form a salt with a base. Examples of such salts include salts formed with inorganic cations such as sodium, potassium, calcium, magnesium 0, lithium, aluminum, zinc, and the like, and pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkanes. The salt formed by the base amine, lysine, arginine, N-methylglucamine, procaine and the like has no limitation on the type of salt that can be used, but only the salt thereof It is pharmaceutically acceptable when used for therapeutic purposes. The term "pharmaceutically acceptable salts" means that the salts are suitable for contact with tissues of humans and other mammals in accordance with medical judgment without causing excessive toxicity, irritation, allergic reactions and the like. Pharmaceutically acceptable salts are well known in the art. A salt of a compound of formula I can be obtained during the final isolation and purification of a compound of the invention, or a salt of a compound of formula 1 can be prepared by reacting a compound of formula I with a sufficient amount of the desired acid or base to form a salt. . The salt of the compound of formula I can be converted to the other salt of the compound of formula I by ion exchange using an ion exchange resin. The compounds of formula I and their salts may differ in certain physical properties, but for the purposes of the present invention, the compounds of formula I are equivalent to the salts thereof. The scope of the invention includes all salts of the compounds of formula I. -63- 201035095 The compounds of the present invention can be reacted with a solvent to form a complex or can be precipitated or crystallized from a solvent to form a complex. These complexes are referred to as solvates. As used herein, the term "solvate" refers to a complex formed from a solute (a compound of formula I or a salt thereof) and a solvent in a stoichiometric manner. Examples of the solvent include pharmaceutically acceptable solvents such as water, ethanol and the like. The complex formed with water is called a hydrate. The scope of the invention includes solvates of the compounds of the invention (or salts thereof), including hydrates. The compounds of formula I can exist in different physical forms (i.e., amorphous and crystalline forms). Furthermore, the compounds of the present invention can be crystallized into more than one type, a property known as a polymorph. Polymorphs can be distinguished by a variety of different physical properties known in the art, such as X-ray diffraction pattern, melting point or solubility. The scope of the invention includes all physical forms of the compounds of formula I, including all polymorphic forms (polymorphs) of the compounds of formula I. Certain compounds of the invention may be in the form of several non-image isomers and/or several optical isomers. The non-image isomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to produce optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or product of formula I. Optically pure isomers can also be obtained separately by mirror-specific synthesis. The present invention encompasses all individual isomers and mixtures thereof (e.g., mixtures of racemic or non-image isomers), whether or not the mixture is obtained via synthesis or by physically mixing the individual isomers. The compound of formula I can be obtained by following the methods described below. It is readily apparent to those skilled in the art that, depending on the chemical structure of a given compound, the precise method used to prepare the given compound can be varied. Further, in some of the methods described below, it may be necessary or appropriate to utilize a conventional protecting group to protect the reaction group or the unstable group. The nature of such protecting groups and the methods of introducing and removing such protecting groups are well known in the art (see, for example, Greene TW and Wuts PGM, "Protecting Groups in Organic Synthesis", John Wiley & Sons, No. 3 Edition, 1999) Q. A tertiary butoxycarbonyl (B OC ) group can be used as an example of an amine functional protecting group. When a protecting group is present, a subsequent deprotection step is required, which can be carried out under standard conditions of organic synthesis, such as those described in the above references. Unless otherwise stated, the meaning of the different substituents in the methods described below is the meaning described in the above formula 1 compound. Generally, a compound of formula 1 can be obtained by the method described in the reaction scheme of Figure 1.

-65- 201035095

Reaction Scheme 1 wherein R, R2 and R3 are as defined in the above formula I; χ represents halogen; and A represents iodine, 2,4-dinitrophenolate, p-toluenesulfonate or 2, 4,6-trimethylbenzenesulfonate. In the presence of an aqueous solution of HI and a base such as K2C03, NaOH or KOH, and in a solvent such as dichloromethane, tetrahydrofuran, water, ethanol, methanol, isopropanol or acetonitrile, preferably heated under reflux Step a can be carried out by reacting a compound of formula II with an aminosulfonic acid to give a hydrazine compound. Alternatively, it is heated in the presence of a solvent such as dichloromethane and preferably at a temperature to room temperature by using a hydrazine compound and 2,4-dinitrophenylhydroxylamine, o- (p-toluenesulfonyl)hydroxylamine or o-(mercaptosulfonyl)hydroxylamine (which is in the presence of a 7% aqueous solution of HC104 and in a solvent such as dioxane, and preferably at - The reaction is carried out by cooling, -66-201035095 from methyl N-nonylsulfonyloxyethyl imidate in 5 ° C, and step a can be carried out to obtain a compound of formula III. In step b, in the presence of a base (such as K2C03 'NaOH or KOH) and in a solvent (such as N,N-dimethylformamide, dimethyl hydrazine, dichloromethane) at room temperature and oxygen atmosphere. The reaction of the compound of formula 111 with ethyl propiolate is carried out in toluene to give the compound of formula IV. It can be carried out by reacting a compound of the formula IV with water in a ratio of 1:1 and an acid such as H2S 〇40, polyphosphoric acid, HCl, HBr or HI, preferably at a temperature of from 120 to 150 °C. Step c ' is used to obtain a compound of formula V. The compound of formula V and N-brobroamyl can be used in the presence of benzoquinone or azobisisobutyronitrile (AIBN) in a solvent such as methylene chloride or carbon tetrachloride at room temperature. The quinone imine (NBS) reaction is carried out to carry out step d, whereby a compound of formula VI is obtained. The reaction of the compound of formula VI with the compound of formula V 11 can be carried out in step e using the conditions of the Suzuki coupling reaction described in the literature. Example Q, for example, in the presence of a Pd catalyst (such as Pd(PPh3)4) and a base (such as K2C03) in a mixture of a solvent (such as dimethoxyethane) and water, and preferably at 8 5 The reaction is carried out under heating to give a compound of the formula v 111. When X represents fluorine, it may be in a solvent such as N-methylpyrrolidone, ν,ν-dimethylformamide in the presence of a base such as diisopropylethylamine, triethylamine or K2C03. , in dimethyl amide, dimethyl decylamine or pyridine) and preferably in 190. (: heating, by reacting a compound of the formula V111 with an amine of the formula 1 to carry out the step f, thereby obtaining a compound of the formula 1. When X represents chlorine, bromine or iodine, the use of the document described in the literature (-67-201035095)

The conditions of the Buchwald coupling reaction can be carried out by reacting a compound of the formula VlII with an amine of the formula IX. For example, in Pd catalysts

In the presence of Pd2(dba)3), scales (such as 2-dicyclohexylphosphino-2', 4,6, _tripropene biphenyl (X-Phos®)) and a base (such as K2C03), In solution 1 (such as tertiary butanol) and preferably at 1 Torr. (: Heating, the reaction can be carried out to give a compound of formula I. Alternatively, the compound of formula VIII can be administered by the method described in Figure 2 below using the reaction:

Wherein R! is as defined in the above formula I; X represents halogen; and A represents iodine, 2,4-dinitrophenolate, p-toluenesulfonate or 2,4,6-trimethyl Benzene sulfonate. In step a of Reaction Scheme 2, the reaction of a compound of formula X with trimethylmethane alkyl acetylene can be carried out using the conditions of the Sonogashira coupling reaction described in the literature. For example, the reaction can be carried out at room temperature and in the presence of a Pd catalyst such as Pd(PPh3)4, Cul and a base such as isopropylamine, and the deprotection reaction of the germyl group described in the literature. The compound of formula XI can be obtained after the deprotection reaction of the trimethylmethanealkyl group. In step b, a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene, K2C03, diisopropylethylamine, triethylamine, KOH, Cs2C03-68- In the presence of 201035095 or tertiary potassium butoxide, in a solvent such as acetonitrile, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, ethanol or dimethyl hydrazine The reaction of a compound of formula XI with a compound of formula III can be carried out by heating or preferably at a temperature of from 40 to 80 ° C to give a compound of formula V1II. Alternatively, a compound of formula I can be obtained by using the method described in Scheme 3 below:

Reaction Figure 3

Ri

R3 wherein Ri, and R3 are as defined in the above formula I; and X represents halogen. In the third step of Reaction Scheme 3, the reaction of the compound of formula V111 with diphenylmethylimine can be carried out using the conditions of the Buchwald coupling reaction described in the literature. For example, it can be a Pd catalyst (such as Pd2(dba)3), a phosphine (such as 2,2'-bis(diphenylphosphino)-oxime, Ι1-binaphthalene (BINAP)) and a base (such as a tertiary butyl) The reaction is carried out in a solvent such as toluene and preferably under reflux in the presence of sodium oxide, and after an acidic hydrolysis step in the presence of an acid such as HCl, an amine of formula XII is obtained. Finally, in step b, the amine of the formula is converted to the compound of formula I by one or several steps using standard amine conversion reactions in organic chemistry and under standard laboratory conditions. For compounds of formula I wherein R2 is not hydrogen, step b should be carried out twice. Such transformation reactions include, for example, by reacting with an alkylating agent under standard conditions or by reductive amination -69 - 201035095, ie, a reducing agent such as sodium cyanoborohydride or triethoxyhydrogen Reaction with an aldehyde or a ketone in the presence of sodium borate), a substitution reaction of a primary or secondary amine; optionally in the presence of a catalytic amount of a base such as 4-dimethylaminopyridine, in a suitable solvent (such as dioxane, chloroform 'dichloromethane or D Π )) and optionally in the presence of a base (such as triethylamine or hydrazine), with a sulfonium halide (such as sulfonium chloride) Reaction to convert the amine to sulfonamide: The amine is converted to the guanamine, carbamate or urea under standard conditions. Further, some of the compounds of the present invention may be obtained from other compounds of formula I by one or more steps, using standard reactions in organic chemistry, by one or more steps, by appropriate conversion of the functional groups. Such transformation reactions can be carried out on Ri, R2 or R3 groups, including, for example, by reaction with hydrogen, hydrazine or formic acid in the presence of a suitable catalyst such as Pd/C, or in the presence of NiCl2 or SnCl22 By reacting with sodium borohydride, reducing the nitro group to an amine group; by reacting with an alkylating agent under standard conditions or by a reductive amination reaction, ie, a reducing agent (such as sodium cyanoborohydride or three) Reaction with an aldehyde or a ketone in the presence of sodium acetoxyborohydride to carry out a substitution reaction of a primary or secondary amine; optionally in the presence of a catalytic amount of a base such as 4-dimethylaminopyridine By using a suitable solvent such as dioxane, chloroform, dichloromethane or pyridine, and optionally in the presence of a base such as triethylamine or pyridine, with a sulfonium halide such as sulfonium chloride Reaction, conversion of an amine to a sulfase-70-201035095 amine; conversion of an amine to a guanamine, carbamate or urea under standard conditions; reaction of an amidino group with an alkylating agent under basic conditions Conversion of an alcohol to an ether, ester or urethane under standard conditions; Oxidizing the alcohol partially or completely to form a ketone, aldehyde or carboxylic acid; reducing the aldehyde or ketone to a ketone by reaction with a reducing agent such as sodium borohydride; by reacting with a reducing agent such as diisobutyl The aluminum hydride or Li A1H4) reaction reduces the carboxylic acid or carboxylic acid derivative to an alcohol; the alcohol is converted to a halogen by reaction with SOC12, PBr3 or tetrabutylammonium bromide in the presence of P205 or Pl3; The dentate atom is converted to an amine by reaction with an amine in the presence of a suitable solvent and preferably under heating; the primary guanamine is converted to a _CN group under standard conditions or vice versa. Similarly, any aromatic ring of the compound of the present invention can be subjected to an electrophilic aromatic substitution reaction or a nucleophilic aromatic substitution reaction which is broadly described in the literature. Some of these interconversion reactions are described in more detail in the examples. It will be apparent to those skilled in the art that such interconversion reactions can be carried out on the compounds of formula I and any suitable synthetic intermediates therefor. Compounds of the formula π and X are commercially available or can be prepared by conventional methods described in the literature and starting from commercially available compounds and by interconversion reaction of a compound such as the formula -71 - 201035095 I described above. And the compounds of formula II and X can be protected with a suitable protecting group. As described above, the action of the compounds of the present invention is by inhibiting the JAK/STAT signaling pathway, particularly by inhibiting JAK3 activity. Thus, the compounds of the invention are expected to be useful in the treatment or prevention of diseases in mammals, including humans, wherein JAK (especially JAK3) plays a role. Such diseases include, but are not limited to, graft rejection, immunity, autoimmune and inflammatory diseases, neurodegenerative diseases, and proliferative diseases (see, for example, O'Shea JJ et al, Nat. Rev. Drug. Discov. 2004, 3 ( 7): 5 5 5 -6 4 ; C etkovic - C vr 1 je M . et al, C urr. Pharm. D es . 2004, 1 0( 1 5 ): 1 767-84; Cetkovic-Cvrlje M. et Al, Arch. Immunol. Ther. Exp. (Warsz), 2004, 52(2): 6 9-82) o Acute or chronic graft rejection that can be treated or prevented by the use of a compound of the invention includes any type of cell , tissues or organs (such as heart, lung, liver, kidney, pancreas, uterus, joints, islets, bone marrow, limbs, cornea, skin, liver cells, pancreatic beta cells, pluripotent cells, neuronal cells, and cardiomyocytes) Graft or allograft rejection and graft versus host response (see, for example, Rousvoal G. et al, Transpl. Int. 2006, 1 9(1 2): 1 01 4-2 1; Borie DC. et al5 Transplantation 2005, 7 9(7): 79 1 -80 1; Paniagua R. et a 1, Transplantation 2005, 8 0(9): 1 283-92; Hi guchi T. et al, J. Heart Lung Transplant. 2005, 24(1 0): 1 557-64; S aem ann MD. et al, Transpl Int. 2004, 1 7(9): 48 1 -89; Silva Jr HT. et al, Drugs 2006? 66(1 3 ): 1665-1684 ) o -72- 201035095 Immunity, autoimmune and inflammatory diseases, including rheumatic diseases, which can be treated or prevented by the use of the compounds of the invention (eg rheumatoid arthritis and psoriatic arthritis), autoimmune blood diseases (eg hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia and neutropenia), autologous Immune gastritis and inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), scleroderma, type I diabetes and diabetes caused by sputum, hepatitis B, hepatitis C, primary biliary Q cirrhosis, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus, psoriasis, atopic dermatitis, contact dermatitis, eczema, sunburn, inhibition of HI V replication, autoimmunity Infertility of origin, autoimmune thyroid disease (Grave's disease), interstitial Cystatitis, and allergic reactions to mast cell media such as asthma, cutaneous vasculitis, allergies, bronchitis, rhinitis, and (nasal) sinusitis (see, for example, Sorbero LA. et a 1, Drugs of the Future 2007, 32 (8): 674-680; O'Shea J, J. et al, Nat. Rev. Drug. Discov. 2004, 3(7): 5 5 5 -64; ❹ Cetkovic-Cvrlje M. et al, C ur R. P harm . Des. 2004, 10(15): 1 767-84; Muller-Ladner U. et al5 J. Immunol. 2000, 16 4(7); 3894-3901 ; Walker J G. et a 1, Ann. Rheum. Dis. 2006,65 (2): 1 49- 5 6; Milici AJ. et al, Arthritis Rheum. 2006,54 (9,Suppl): abstr 78 9; Kremer JM. et al, Arthritis Rheum. 2006,54,4116,presentation no. L 4 0; Cetko vic-Cvrlje M. et al, Arch Immunol. Ther. Exp. (Warsz), 2004, 52(2): 6 9-82; Malaviya R. et al J. Pharmacol. Exp. Ther. 2000, 295(3): 9 1 2-26; Malaviya R. et al, J. Biol. Chem. -73- 201035095 1 999, 2 7 4(3 8): 27028 -38; Wilkinson B et al, Ann. Rheum. D is . 2007, 6 6 (S upp 1 2): Abst. THU0099; Matsumoto M. et al, J. Immunol. 1 999, 1 6 2(2): 1 056-63 ). Neurodegenerative diseases which can be treated or prevented by the use of the compounds of the invention include, in particular, amyotrophic lateral sclerosis and Alzheimer's disease (see, for example, Trieu VN. et al, Biochem. Biophys. Res. Commun. 2000, 267 (1) : 2 2-5 ) ° Proliferative diseases which can be treated or prevented by the use of the compounds of the invention include, inter alia, leukemia, lymphoma, glioblastoma multiforme, colon cancer, and thromboembolism associated with such diseases Sexual and allergic complications (see, for example, Sudbeck EA. et al, Clin. Cancer Res. 1999, 5(6): 1 5 69-8 2; Narla RK. et al, Clin. Cancer Res. 1 998, 4(1 0): 2463 -7 1; Lin Q. et al, Am J. Pathol. 2005, 1 67(4): 969-80; Tibbies HE. et al, J. Biol. Chem. 200 1, 276 (2 1 ): 1 78 1 5-22 )° It has been found that certain compounds of formula I, in addition to inhibiting JAK3 activity, also inhibit JAK2 kinase to varying degrees, so that the compounds of formula I can also be used for the treatment or prevention. Any disease that is mediated by the AK2 kinase. The disease group of the JAK2 vector is a myeloproliferative disorder including polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, chronic myelogenous leukemia, eosinophilic syndrome, chronic neutrophil Cellular leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloablative metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis, and myelodysplasia (see Text-74-201035095 For example, Geron I. et al, Cancer cell 2008, 13: 321-330; Pardanani A. et al, Leukemia 2007, 2 1 (8): 1 65 8-68; Mathur A. et al, Biochem Pharmacol 2009, 7 8(4): 3 82-9; Manshouri T. et al, Cancer Sci. 200 8, 99(6): 1 265-73; Wernig G. et al, Cancer cell 200 8, 1 3 (4): 3 1 1 -20; Elizabeth O. et al, Blood, 1 1 1 (1 2): 5663 -5 67 1 ). Compounds of formula I which have been found to be particularly useful as TAK2 inhibitors include the compounds of the Q examples lu, lv, 2p, 9b, 11, 13, 14 and 15. Thus, in addition to treating or preventing all of the diseases described in the preceding paragraphs, such compounds are particularly useful for the treatment or prevention of myeloproliferative disorders (MPD). Accordingly, another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease mediated by JAK2, in particular examples lu, lv, 2p, 9b, 11, 13, 14 And 15 compounds. More specifically, the disease caused by JAK2 is a myeloproliferative disease. Another aspect of the invention pertains to the manufacture of a compound of formula I or a pharmaceutically acceptable salt thereof (particularly the compounds of the examples lu, lv, 2p, 9b, 11, 13, 14 and 15) for the treatment or prophylaxis The use of drugs for the disease of JAK2 media. More specifically, the disease caused by JAK2 is a myeloproliferative disease. Another aspect of the invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a myeloproliferative disorder, in particular Example 1 u, 1 V, 2p, 9b, 1 1 ' 1 3, 1 4 and 1 5 compounds. In a preferred system, the myeloproliferative disorder is selected from the group consisting of true polycythemia, primary-75-201035095 thrombocythemia, idiopathic myelofibrosis, chronic myelogenous leukemia, eosinophilia syndrome , chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloablative metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis or spinal cord development Bad syndrome. Another aspect of the invention pertains to the manufacture of a compound of formula I or a pharmaceutically acceptable salt thereof (particularly the compounds of the examples lu, lv, 2p, 9b, 11, 13, 14 and 15) for the treatment or prevention of myeloproliferation The use of drugs for sexually transmitted diseases. In a preferred system, the myeloproliferative disorder is selected from the group consisting of polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis, chronic myelogenous leukemia, eosinophilic syndrome, chronic hooliganism Sexual cell leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloablative metaplasia, chronic basophilic leukemia, chronic eosinophilic leukemia, systemic mastocytosis or myelodysplastic syndrome. Bioassays that can be used to determine the ability of a compound to inhibit AK (especially AK3 and: ΓΑΚ2) are well known in the art. For example, as described in the assay methods of Examples 17 and 18, respectively, the test compound can be incubated in the presence of J [AK3 or JAK2 to determine whether or not the enzymatic activity of inhibiting JALA3 or AK2 occurs. Other in vitro assays that can be used to determine JAK3 inhibitory activity include cellular assays, such as proliferation of human T lymphocytes by IL-2. The immunosuppressive activity of the compounds of the invention can be tested using standard in vivo animal models of the immunological and autoimmune diseases known in the art. For example, the following assay method can be used: delayed type oversensitivity (DTH) (see Example-76-201035095 as documented by Kudlacz E. et al, Am J. Transplant 2004, 4 (1): 5 1 - 7 Methods of disclosure [the contents of which are incorporated herein by reference), rheumatoid arthritis patterns (such as arthritis caused by collagen) (see, for example, the literature Holmdahl R et al, APMIS, 1989, 97(7): 575 -84 The method of detection disclosed in this document is incorporated herein by reference), multiple sclerosis patterns (such as experimental autoimmune encephalomyelitis (EEE)) (see, for example, the literature Gonzdlez-Rey et al, Am J. Q Pathol. 2006, 1 68(4): 1 1 79-8 8 methods, the contents of which are incorporated herein by reference) and the graft rejection mode (see, for example, the references listed above) A variety of different animal models are disclosed which are associated with the treatment of graft rejection, the contents of which are incorporated herein by reference. Bioassays which can be used to determine the toxicity profile of the compounds of the invention are well known in the art. Several in vitro toxicity tests can be performed on a live disk such as a different cell line (e. g., HepG2). In order to select an active compound against JAK3, in the Q test described in Example 17, the test at 10 μΜ must achieve an activity of more than 50% inhibition of JAK3 activity. Preferably, the compound should have more than 50% inhibition at 1 μΜ when tested in this assay and more preferably these compounds should have more than 50% inhibition at 0.1 μΜ. In order to select the active compound for > 2, the assay described in Example 18 must have an activity of more than 50% inhibition of JAK2 activity at 10 μΜ. Preferably, the compound should have more than 5 % inhibition at 1 when tested in this assay and more preferably the compound should have greater than 50% inhibition at 0. 5 μΜ. The invention also relates to a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt or solvate thereof) and one or more pharmaceutically acceptable excipients. Such excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient of the composition. The compounds of the present invention can be administered in the form of any of the pharmaceutical modulators, the nature of which is conventionally dependent upon the nature of the active compound and the route of administration. Any administration route can be used, such as oral, parenteral, nasal, ocular, rectal, and topical administration. Solid compositions for oral administration include tablets, granules and capsules. In any case, the manufacturing process is based on simple mixing, dry granulation or wet granulation of the active compound with the excipient. Such excipients can be, for example, diluents (such as lactose, microcrystalline cellulose, mannitol or dibasic calcium phosphate), binding agents (such as, for example, starch, gelatin or polyvinylpyrrolidone), disintegrating agents (such as Sodium carboxymethyl starch or croscarmellose sodium) and a lubricant such as, for example, magnesium stearate, stearic acid or talc. The tablet may be additionally coated with a suitable excipient by using conventional techniques for the purpose of delaying the disintegration and absorption of the tablet in the gastrointestinal tract and thereby providing a sustained action for a longer period of time or simply improving the tablet. Special sensibility or stability. The active compound can also be loaded by application to a natural or synthetic film coating using a natural or synthetic film coating agent. Soft gelatin capsules may also be employed in which the active compound is mixed with water or an oily base such as coconut oil, mineral oil or olive oil. By mixing the active compound with a dispersing or wetting agent, a suspending agent and a preservative, a powder for the preparation of an oral suspension by addition of water and -78-201035095 granules can be obtained. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. Liquid forms for oral administration include emulsions, solution 'suspensions, syrups and elixirs, and such liquid forms contain conventional inert diluents such as purified water, ethanol, sorbitol, glycerol, polyethylene glycol, and propylene glycol. The compositions may also contain co-adjuvants such as wetting agents, suspending agents, sweetening agents, perfuming agents, preservatives, and buffering agents. The injectable preparation for parenteral administration of the present invention comprises a sterile solution, suspension or emulsion in a water-soluble or water-insoluble solvent such as propylene glycol, polyethylene glycol or vegetable oil. These compositions may also contain co-adjuvants such as wetting agents, emulsifying agents, dispersing agents and preservatives. These compositions may be sterilized by any conventional method or such compositions may be prepared as a sterile solid composition which will dissolve in water or any other sterile injectable base immediately prior to use. It can also be initiated from sterile materials and kept in sterile condition throughout the manufacturing process. 〇 For rectal administration, the active compound is preferably formulated as a suppository for oily substrates such as, for example, vegetable oils or solid semi-synthetic glycerides or hydrophilic substrates such as polyethylene glycol. The compounds of the invention may also be formulated for topical administration to treat or prevent the appearance of lesions in areas or organs accessible through such topical routes of administration, such as the eye, skin and intestines. Modulators include creams, lotions, gels, powders, solutions, and patches, wherein the compound is dispersed or dissolved in a suitable vehicle. For nasal or inhalation administration, the compound can be formulated as an aerosol and can be conveniently released using a suitable propellant at -79-201035095. The dosage and frequency of administration will depend, inter alia, on the nature and severity of the condition to be treated, the age, general condition and weight of the patient, and the particular compound and route of administration being administered. A representative example of a suitable dosage range is from about 0.01 mg/Kg/day to about 100 mg/Kg/day. The dose can be administered in a single dose or in divided doses. The following examples will illustrate the scope of the invention. [Embodiment] The following abbreviations have been used in the examples:

AcN: B. BINAP: 2,2,-bis(diphenylphosphine)binaphthalene DBU: 1,8-diazabicyclo [5.4.0] deca-carbon DME: 1,2-dimethoxy B Alkyl DMF: N,N-dimethylformamide imine EDC : N-[3-(dimethylamino)propyl]_N,·Ethyl EDAPA: ethyldiisopropylamine

Et20: diethyl ether

EtOAc: ethyl acetate EtOH: ethanol HOBT: 1-hydroxybenzotriazole HPLC: high performance liquid chromatography Κ: ΟιΒιι: tertiary potassium pentoxide LC-MS: liquid chromatography-mass spectrometry -80- 201035095

MeOH: methanol

NaC^Bu: three-stage sodium butoxide oxide NMP: N-methylpyrrolidone

Pd2(dba)3: tris(dibenzylideneacetone)dipalladium (〇) TBAF: tetrabutylammonium fluoride TEA: triethylamine THF: tetraammine oxime 0 TMSI: 1-(trimethyldecyl) Imidazole tR: residence time 邛11〇3:2-dicyclohexylphosphino-2|,4',6'-triisopropyl-biphenyl LC-MS spectra were carried out using the following chromatographic method: Method 1 : Waters Acquity UPLC BEH C18 column (1·7 μηι, 2· 1 χ 50 mm ), temperature 40 ° C, flow rate: 0.5 ml / min, eluent: AcN (A) / ammonium bicarbonate 10 mM (B ), Gradient: 0 minutes 1% A-3.7 5 minutes 90% A. 〇Method 2: YMC column, 3 μηη (50 mm χ 4.6 mm), temperature: 30 °C, flow rate: 2.6 ml/min, solution Α = Η20 (0.1% HCOOH) B = AcN (0.1% HCOOH ), gradient: 0 minutes 5 % B; 4.8 minutes 9 5 % B; 6 minutes 9 5 % B. Reference Example 1 3-(6-Fluoropyridin-2-yl)pyrazolo[i,5-a]pyridine 6-fluoro-2-pyridylboronic acid under argon (1.80 g, 1 2.7 7 Mol), Pd(PPh3)4 (1.40g, 1.21 millimolar) and K2C03 ( 3.70g, -81 - 201035095 2 6.8 millimolar) water (7 ml) solution was added to 3-bromopyrazole And [1,5-a] pyridine (2.40 g, 12.17 mmol) in DME (54 ml). Let the resulting mixture be at 85. It was heated for 5 hours at C, cooled and concentrated to dryness. The obtained crude product was subjected to silica gel chromatography (yield of hexane/EtOAc mixture as a solvent) to give the desired compound (1·2 1 g, 47% yield). LC-MS (method 2): tR = 3.00 min; m/z = 2 1 4 (MH+). Reference Example 2 2 - Ethyl-6-fluoroindole ratio π a) 6-Fluoro-2 - (trimethylsilylethynyl)pyridine ethynyl trimethyl decane under argon (4.0 ml , 28.4 mmol) added to 2-bromo-6-fluoropyrazine (5.0 g, 28.4 mmol), Pd(PPh3)4 (1.64 g, 1.42 mmol), Cul (0.27 g, 1.42 mil) Mole) and EPIPA (5_3 ml, 36.9 mmol) in toluene (115 ml). The resulting mixture was stirred at room temperature for 18 hours. The resulting crude product was filtered through a Celite salt C e 1 i t e ® . The filtrate was diluted with a saturated aqueous solution of n Η 4 C1 and extracted three times with CHW12. The organic layer was dried over Na 2 S 4 and concentrated to dryness. The obtained crude product was subjected to silica gel chromatography (yield of hexane/CH2C12 mixture as a solvent) to give the desired compound (5.28 §, 96% yield). LC-MS (method 2): t = 3.62 min; m/z = 200 (MH+). b) The standard compound -82- 201035095 will be 8-8 under -78乞? 1]^7'1^ solution (7.93 1111, 7.93 mmol) was slowly added to a solution of the compound obtained in the previous step (5 · 2 8 g, 2 7.3 mmol) in Et20 (70 ml). The mixture was stirred at -78 °C for 1 hour and then diluted with E t Ο A c and rinsed 3 times with water. The organic layer was dried over MgS 4 and concentrated to dryness. The obtained crude product was subjected to silica gel chromatography (yield of hexane/CH2C12 mixture as a solvent) to give the desired compound (2.34 g, 70% yield). LC-MS (method 2): tR = 2.10 min; m/z = i22 (MH+). Following the procedure similar to that described in Reference Example 2 but using the corresponding starting materials, the following compounds were obtained: Reference Examples Compound Name Starting Materials HPLC Method tR (minutes) m/z 2a 6-bromo-2-acetylene Pyridine 2,6-dibromopyridine 2 2.42 182 Reference Example 3 5-cyano-3-(6-fluoropyridin-2-yl)pyrazolo[l,5-a]pyridine O a) 2,4 , 6-trimethylbenzenesulfonic acid 1-amino-4-cyanopyridine key o--2,4,6-trimethylbenzenesulfonylhydroxylamine (1.5 〇g, 6.97 m) at 〇 ° C The CH2C12 (20 ml) solution of MeOH was slowly added to a solution of 4-cyanopyridine (0.72 g, 6-97 mmol) in CH2C12 (10 ml). After the addition, the resulting solution was stirred at room temperature for 2 hours and then Et2 Ο (3 2 0 m 1 ) was added. The precipitate was filtered and dried in a vacuum oven to give the desired compound (1500 g, 7% yield). LC-MS (Method 2): tR=l_52 min; m/z = 120 (MH+). -83- 201035095 b ) The title compound was slowly added to a solution of DBU ( 1.24 ml, 8.26 mmol) in AcN (7 ml) at 〇 ° C to the compound obtained in the previous step (1.45 g, 4.54 mmol) and reference Example 2 (0.50 g, 4.13 mmol) in AcN (20 mL). The resulting mixture was heated at 50 ° C for 18 hours and then cooled and concentrated to dryness. The crude product obtained was subjected to a silica gel chromatography (yield of hexane/EtOAc mixture with </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> LC-MS (method 2): tR = 3.03 min; m/z = 239 (MH+). Reference Example 4 3 - (6-Bromopyridin-2-yl)pyrazolo[1,5-a]pyridine was replaced by a method similar to that described in Reference Example 3 but using iodine j-aminopyridinium instead of 2,4,6-Trimethylbenzenesulfonate oxime-amino-4-ylcyanopyridine key and reference example 2a was substituted for Reference Example 2 to give the desired compound (49% yield). LC-MS (method 2): tR = 3.45 min; m/z = 274 (MH+). Reference Example 5 3-Aminoethoxycarbonylpiperidine a) 3 -(tertiary butoxycarbonylamino)-1 -ethoxycarbonylpiperidine TEA (1.05 ml, 7_49 mmol) and ethyl chloroformate (〇·48 ml, 4.99 mmol) was added to a solution of 3-tris-butoxycarbonylaminopiperidine (5 mg, 2.49 m) in CH2CI2 (15 ml). The resulting -84-201035095 mixture was stirred at room temperature for 12 hours and then concentrated to dryness, diluted with EtOAc and washed three times with water. The organic layer was dried over Na 2 SO 4 and concentrated to dryness to give the desired compound in quantitative yield. b) Standard compound The compound obtained in the previous step and a 4 M solution of HCl in dioxane (8 ml) were mixed in a flask. The resulting mixture was stirred at room temperature for 2 hours and concentrated to dryness. The resulting crude product was purified on a SCX-2 column eluted with MeOH/NH3 mixture of </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> LC-MS (Method 2): m.s. Reference Example 6 Trans-4-ethylaminocyclohexanol KOH (200 mg, 3.56 mmol) and acetic acid (0.25 ml)

A solution of va (5 ml) was added to a solution of EtOAc (EtOAc) Acetaldehyde (0.13 ml, 2.31 mmol) and NaBH3CN (176 mg, 2.8 mmol) were then added. The resulting mixture was stirred at room temperature for 18 hours and then concentrated to dryness <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </ RTI> </ RTI> 4M HCl in dioxane (5 ml) and the volatile compound was concentrated to dryness. The crude product obtained was purified on a SCX-2 column eluted with MeOH/NH3 mixture of </ RTI> </ RTI> </ RTI> to afford the desired compound (72 mg, 30% yield). LC-MS (method 2): tR = 0.53 5 min; m/z = 144 (MH+) -85 - 201035095 Example 1 3 - [ 6 - ( 1 - hydroxymethylcyclopentylamino) pyridine - 2 Pyridyl[1,5-a]pyridine added hydroxymethylcyclopentylamine (173 mg, 1.5 mM millimolar) and EDIPA (0.13 ml, 0.75 mmol) to Reference Example 1. Compound (40 mg, 0.18 mmol) in NMP (1.5 ml) solution. The reaction mixture was heated at 1 90 ° C for 6 days and cooled, then diluted with EtOAc EtOAc and washed three times with NaH. The organic layer was dried over MgS04 and concentrated to dryness. The crude product obtained was subjected to silica gel chromatography (yield of hexane/EtOAc mixture with </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> LC-MS (method 2): tR = 1.77 min; m/z = 309 (MH+). The following compounds were obtained following the procedure described in Example 1 but using the corresponding starting materials in each case: Example Compound name Starting material HPLC method tR (min) m/z la H6-(4 Hydroxymethylpiperidin-1-yl)pyridin-2-yl]indolozolo[1,5-a]pyridine 4-hydroxymethylpiperidine 2 1.82 309 lb 3-[6-(3-hydroxy ring Hexylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine 3-aminocyclohexanol 2 1.77 309 lc trans-3-[6-(4-hydroxycyclohexyl-N-A Amino)pyridinyl-2-pyridylpyrazolo[l,5-a]pyridine trans-4-methylaminocyclohexanol 2 1.97 323 Id 3-[6-(1-ethoxycarbonylpiperidine- 4-ylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine 4-amino-1-ethoxycarbonylpiperidine 2 2.73 351 le trans-3-[6-(4- Aminocyclohexylamino)pyridine~2-yl]pyrido[l,5-a]pyridine trans-1,4-diaminocyclohexane 2 0.97 308 -86 - 201035095

If trans-3·[6-(4-carbylcyclohexylamino)pyridin-2-ylfoxazolo[1,5-a]pyridine trans-4-aminocyclohexanol hydrochloride 2 1.43 309 ig 3-[6-(tetrahydro-4H-piperazin-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine 4-aminotetrahydro-4H-pyran Hydrochloride 2 2.22 295 lh 3-[6-(N-methylcyclohexylamino)pyridin-2-yloxazolo[l,5-a]pyridine N-cyclohexylmethylamine 2 3.73 307 li 3-[6-(3-Hydroxymethylcycloazin-1-yl)pyridin-2-yl]indolozolo[1,5-a]pyridine 3-hydroxymethylpiperidine 2 1.90 309 lj 3 -[6-(1-methyl-encephalin-4**-amino-amino)pyrene is 0疋-2-yl](d) sits and [l,5-a]pyridine 4-amino-1-methylper Acridine 2 1.02 308 lk 3-[6-(2,2,6,6-tetramethylpiperidin-4-ylamino)pyridin-2-yl]-pyrazolo[1,5-a-acridin 4 -amino-2,2,6,6-tetramethylpiperidine 2 1.35 350 11 3-[6-(2-phenylpropan-2-aminopyridin-2-yl)pyrazolo[l, 5-a]pyridine 2-phenylpropan-2-amine 2 2.48 329 lm (S)-3-[6-(l-phenylethylamino acyl-2-yl)pyrazolo[1,5 -a] pyridinium (S)-l-phenylethylamine 1 2.53 315 In 3-[6·(1-pyramino)pyridin-2-yl]-pyrazolo[1,5-a]pyridine Benzylamine 2 2.20 301 lo (S) -3-[6-(li^hexylethyl § female) D ratio D疋_ 2-yl]pyridino[l,5-a]pyridine (S)-l-cyclohexylethylamine 2 2.58 321 Ip (S)-3-[6-(l-methoxypropan-2-ylamino)pyridin-2-yl]azolo[l,5-a]pyridine(S)-2-amino- 1-methoxypropane 2 1.60 283 iq 3-[6-(methylamino)pteridine-2-ylpyrazolo[1,5-a]pyridinamide 2 1.26 225 lr 3-[6-( Phenylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridaniline 2 3.12 287 Is 3-[6-(alridin-3-ylamino)[1pyridin-2-yl Pyrazolo[l,5-a]pyridine 3-aminopyridine 2 1.75 288 it 3-[6-(alridin-4-ylamino)pyridin-2-yl]pyrazolo[l,5- a] Pyridine 4-aminopyridine 2 1.63 288 Following the procedure described in Example 1 but using the compound of Reference Example 3 in place of the compound of Reference Example 1 and in each case -87-201035095 The starting material gave the following compound: Example Compound name Starting material HPLC method tR (min) m/z lu trans-5-cyano-3·[6-(4-hydroxycyclohexylamino) Pyridyl-2-3⁄4 pyrazolo[l,5-a]pyridine trans-4-aminocyclohexanol hydrochloride 2 1.87 334 lv trans -5-cyano-3-[6-(4-hydroxycyclohexyl.N-methylamino)pyridin-2-yl] azozolo[l,5-a]pyridine trans-4-A Aminocyclohexanol 2 2.92 348 lw trans-3-[6-(4-aminocyclohexylamino)pyridin-2-yl]-5-cyanopyrrino[l,5-a]pyridine Trans-1,4-diaminocyclohexane 2 1.42 333 lx 5-cyano-(S)-3-[6-(l-phenylethylamino)pyridin-2-yl]pyrazole [1,5-a]pyridine (S)-l-phenylethylamine 2 3.50 340 Example 2 5-cyano-3 - [ 6 - ( 4 -hydroxybutylamino)pyridine-2-yl] Pyrazolo[1,5-a]pyridine 4-Ethyl-1-butanol (45 mg, 0.50 mmol) and EDIPA (0.09 ml, 0.50 mmol) were added to the compound of Reference Example 3 ( 40 mg, 0.17 mmoles in NMP (1.5 ml) solution. The reaction mixture was heated in a single mode microwave oven (250 w) at 140 °C for 1 hour and cooled, then diluted with EtOAc and washed three times with NaHC03 solution. The organic layer was dried on MgS04 and concentrated to dryness. The crude product thus obtained was subjected to silica gel chromatography using a hexane/acetone mixture of increasing polarity as a solvent to give the title compound (2 1 m g, 41% yield). LC-MS (method 2): tR = 2.47 min; m/z = 308 (MH+). Following the procedure similar to that described in Example 2, but using the corresponding starting materials in each case, the following compounds were obtained: -88- 201035095 Example Compound name Starting material HPLC method tR (minutes) xn/z 2a 5-Akyl-3-[6-(N-methyl-(3-propylpropyl)amino)pyridin-2-yl]pyrazolo[l,5-a]pyridine 3-methylamino -1-propanol 2 2.68 308 2b 3_[6_(3·aminosuccinylamino) 卩 卩 -2- -2- -2-yl]-5-cyanopyrazolo[l,5-a]pyridine 1, 3-diaminocyclohexane 2 2.25 333 2c 5-cyano-3-[6-(N-methyl-N-(2-methylamino)ethylamino)pyridin-2-yl]pyridinium Zoxa[l,5-a]pyridinium, Ν'-dimethylethyl-1,2-diamine 2 2.28 307 2d 5-cyano-3-[6-((l-ethoxycarbyl)piperidin D--3-Aminoamino)Calidine-2-Base D and [1,5-a]pyridine Reference Example 5 2 3.13 391 2e 3-[6-(2-Aminoethylamino) Pyridin-2-yl]-5-cyanopyrrole l "1.5-a]pyridine 1,2-ethanediamine 2 1.93 279 2f (S)-5-cyano-3-[6-(2-hydroxyl) (pyridyl steep-1 -yl)-dehydrazino-2-yl]pyrazolo[1,5-a]pyridine (S)-2-hydroxymethylpyrrolidine 2 2.87 320 2g (R)-5-cyano- 3-[6-(2-hydroxymethylpyrrole d-1 - Pyridox-2-yl]pyridin[1,5-a]pyridinidine (R)-2-hydroxymethyl-tertidine 2 2.87 320 2h 5_gasyl-3-[6_(3- Base D ratio ΰ疋-1-yl) pyridin-2-yl]pyrazolo[l,5-a]pyridine 3-hydroxypyrrolidine 2 2.55 306 2i 5-cyano-3-[6-(3- (N,N-dimethylamino) pyrrolidin-1 -yl)pyridin-2-yl]pyrazolo[1,5-a]pyridine 3-(N,N-dimethylamino)pyrrolidine 2 2.98 333 2k 5-cyano-3-[6-(N-ethyl-N-(4-hydroxybutyl)amino)pyridinylpyryl]pyrazolo[1,5-a] 4-4- Ethylamino-1-butanol 2 3.03 336 21 5-cyano-3-[6-(3-hydroxypropylamino)pyran-2-yl]pyrazolo[1,5-a]pyridine 3-Amino-1-propanol 2 2.33 294 2m(1) 3-[6-(3-Aminopyrrolidin-1-yl)-dean-2-yl]-5-cyanopyridinium [1,5- a]pyridine 3-(tertiary butoxycarbonylamino) thiazolidine 2 2.30 305 2n amino-3-[6-(3_exiyl fluoren-1-yl)ylpyridin-2-yl] Pyrazolo[l,5-a]pyridine 3-hydroxypiperidine 2 2.65 320 -89- 201035095 2〇5-Cyano-3-[6-(4-piperidyl-1 -yl)pyridine-2 -基基卩卩[[,5-a]pyridine 4-hydroxypiperidine 2 2.53 320 2p trans-5-cyano-3-[6-(N-ethyl-N-(4-hydroxyl) Hexyl) Pyridin-2-yl]pyrazolo[l,5-a]pyridine Reference Example 6 2 3.17 362 2q 3-[6-(3-Ethylaminopiperidin-1-yl)[] ratio Π定-2-yl]-5-cyanopyrazolo[1,5-a]pyridine 3-ethinylaminopiperidine 2 2.50 361 2r (S)-5-cyano-3·[6· (1-(Ethoxycarbonyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine Ms)-Amino-1-ethoxycarbonylpiperidine 2 3.13 394 (1) The reaction is carried out at 10 ° C instead of 140 ° C. Example 3 trans-3-(6-(4-Ethylaminocyclohexylamino)pyridin-2-yl]oxazolo[l,5-a]pyridine acetic acid (0.013 ml, 0_23) Mol), EDC (45 mg, 0.023 mmol), HOBT (31 mg, 0.23 mol) and EDIPA (0.074 ml, 0.42 mmol) were added to the compound of Example le (65 mg, 0.21 mmol) Ear) in DMF (2 ml) solution. The resulting mixture was stirred at room temperature for 18 hours. The resulting crude reaction was concentrated to dryness and diluted with EtOAc EtOAc &EtOAc. The organic layer was dried over MgS04 and concentrated to dryness. The obtained crude product was subjected to silica gel chromatography (yield with a mixture of increasing polarity of CH 2 C12 / M e Ο 为) to give the title compound (34 mg, 46% yield). LC-MS (method 2): tR = 1.53 min; m/z = 350 (MH+). Example 4 trans-3-[6-(4-Methanesulfonylaminocyclohexylamino)pyridin-2-yl]pyrazole-90- 201035095 and [1,5-a]pyridine in 〇〇C Methionine chloride (0.017 ml, 0.21 mmol) was added to a solution of the compound of Example le (65 mg, 0.21 mmol) and TEA (0.030 ml, 0.21 mmol) in DMF (2 ml) . The resulting mixture was stirred at 〇 ° C for 1 hour and then at room temperature for 18 hours. The crude product obtained was concentrated to dryness and purified by silica gel eluting with CH2Cl2/MeOH mixture of </ RTI> </ RTI> </ RTI> to afford the title compound (26 mg, 32% yield). LC-MS (Method 2): m.s. Example 5 3-[6-(3-(2-Sideoxypyrrolidinyl)phenylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine at room temperature and argon K2C03 (55 mg, 0.40 mmol), 乂-Phos ( 8.70 mg, 0.018 mmol), Pd2 (dba) 3 ( 8.35 mg, Q 0.0092 mmol) and 1-( 3-aminobenzene) Pyrrolidin-2-one (35 mg, 0.2 mM millimolar) was added to a solution of the compound of Reference Example 4 (50 mg, 0.18 mmol) in tert-butanol (2 ml). The mixture was heated at 10 (TC) for 18 hours. The crude reaction was diluted with MeOH and filtered over Celite®. The filtrate was concentrated to dryness and chromatographic chromatography / EtOAc mixture as a solution to give the title compound (4 9 mg, 7.2% yield) LC-MS (Method 2): tR = 2.73 min; m/z = 3 70 (MH+). The method described in Example 5, but in each case, using -91 - 201035095 with the corresponding starting material, gave the following compound: Example Compound name Starting material HPLC method tR (min) m/z 5a 3- [6-(N-cyclohexylfee)]11-2-yl]bendo[l,5-a]pyridinecyclohexylamine 2 2.22 293 5b 3-[6-(N-(2-methyl) Cyclohexyl)amine B _ 2-3⁄4 pyrazolo[1,5-a]pyridine 2-methylcyclohexylamine 2 2.90 307 5c 3-[6-(4-Ethylaminophenyl phenylamine Pyridin-2-yl]pyrazolo[l,5-a]pyridine N-(4-aminophenyl)acetamidine 2 2.12 344 5d 3-[6-(3-Ethylaminophenyl) Amino)pyridin-2-yl]pyrazolo[1,5-a]pyridine N-(3-aminophenyl)acetamidamine 2 2.12 344 5e 3-[6-((3-methylamine) Carbocarbonyl) Phenylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine 3·methylaminocarbonylphenylamine 2 2.34 344 Example 6 3-[6·(3-hydroxyphenyl- N-methylamino)pyridin-2-yl]pyrazolo[l,5-a] lycopene a) 3-[6-(N-methyl-3-methoxyphenylamino)pyridine 2-yl]pyrazolo[l,5-a]pyridine followed the procedure described in Example 5 but using N-methyl-3-methoxyaniline instead of 1-(3-aminophenyl) Pyrididine-2-one, to give the desired compound (73% yield). LC-MS (Method 2): tR = 3 - 98 min; m/z = 331 (MH+) b) A CH2C12 solution of BBr3 (〇·35 ml, 0_35 mmol) was added to a solution of the compound obtained in the previous step (60 mg, 〇 17 mmol) in CHC13 (3 ml). The reaction mixture was heated at -65-201035095 for 18 hours at 65 °C. The resulting crude reaction was concentrated to dryness and purified by silica gel eluting with hexane/hexane mixture of </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> to afford the title compound (43 mg, 76% yield). LC-MS (method 2): tR = 3.07 min; m/z = 317 (MH+). Example 7 3-[6-(N-Cyclopropylcarbonylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine pa) 3-[6-(N-diphenylmethyl) Aminopyridin-2-yl]pyrazolo[l,5-a]pyridine NaOlBu (58 mg, 0.60 mmol), BINAP (2 1 mg, 0.034 mmol), argon at room temperature P d 2 (dba) 3 (1 5 mg, 0 · 0 1 7 halo; mol) and benzophenonimine (0.11 ml, 0.65 mmol) were added to the compound of Reference Example 4 ( 118 mg, 0.43 mmoles in toluene (8.6 ml). The reaction mixture was stirred at 85 ° C for 7 hours. The resulting crude reaction is concentrated to a dry Q state and subjected to silica gel chromatography using a hexane/EtOAc mixture of increasing polarity to give the desired compound (1 3 〇mg, 8 1 %) rate). b) 3-(6-Aminopyridin-2-yl)pyrazolo[1,5-a]pyridine will be hydroxylamine hydrochloride (120 mg, 1.73 mmol) and DIPEA (0.302 ml, 173 To a solution of the compound obtained in the previous step (130 mg, 0.35 mmol) in MeOH (17 ml). The reaction mixture was allowed to stir at room temperature for 18 hours. The resulting crude reaction is concentrated to dryness and subjected to silica gel chromatography (yield of hexane-93-201035095 / EtOAc mixture as a solvent) to give the desired compound (65 mg, 8% yield) rate). LC-MS (Method 2) ·· tR = 1.14 min; m/z = 211 (MH+). c) Standard compound TEA (0.018 ml, 0.135 mmol) was added to a solution of the compound obtained in the previous step (19 mg, 0.09 mmol) in anhydrous THF (1 ml), and then slowly added to hexane at ot. Acid chloride (0.010 ml, 0.1 13 mmol). The reaction mixture was allowed to stir at room temperature for 4 days. The resulting crude reaction was concentrated to dryness and purified by silica gel eluting with EtOAc EtOAc (EtOAc: EtOAc) LC-MS (method 2): tR = 2.73 min; m/z = 279 (MH+). Example 8 (S) - 3 - [ 6 - ( 1 -Phenylethylamino)pyridin-2-yl]-5-hydroxymethylpyrazolo[1,5-a]pyridine a) 2,4 -Dinitrophenolic acid 1-amino-4-ethoxycarbonylpyridine iron 0-(2,4-dinitrophenyl)hydroxylamine (1.45 g, 7.28 mmol) was added to ethyl isocyanate (lg, 6.62 mmol) in AcN (4_41 ml) solution. The reaction mixture was allowed to stir at 40 ° C for 18 hours. The resulting crude reaction was concentrated to dryness and extracted 3 times with Et.sub.2 (3.times. The resulting solid was filtered and dried to give the desired compound (l. -94- 201035095 b) 5-ethoxycarbonyl·3·(6-fluoropyridin-2-yl)pyrazolo[l,5-a]pyridine followed the method described in step b of Reference Example 3 but The compound obtained by the previous step was used in place of 1-amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate to give the desired compound (46% yield). LC-MS (method 2): tR = 3.48 min; m/z = 286 (MH+). 0 c ) 5·carboxy-3-(6-fluoropyridin-2-yl)pyrazolo[丨,5-a]pyridine Adding LiOH, H20 (22 mg, 0.526 mmol) to the compound obtained in the previous step (50 mg, 0.175 mmol) in a DME / water 2:1 mixture (1 · 5 ml) solution. The reaction mixture was allowed to stir at room temperature for 8 hours. The resulting crude reaction was diluted with E10 A c and extracted three times with a NaHC.sub.3 solution. The aqueous layer was acidified to pH i by in HCbj solution and extracted three times with CH2CI (3 x 10 ml). The combined organic layer was dried over Na 2 S 〇 4 and concentrated to dryness to give the desired compound (4 1 m g, 9 % yield 〇). LC-MS (method 2): tR = 2.48 min; m/z = 25 8 (MH+). d) (S)·5-carboxy-3-[6-(1-phenylethylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine is as described in Example 1. The method of using the compound obtained in the foregoing step in place of the compound of Reference Example 1 and (s)-fluorenyl-phenylethylamine in place of 1-hydroxymethylcyclopentylamine to obtain the desired compound (1 〇0) %Yield). -95- 201035095 e) (S)-3-(6-(1-Phenylethylamino)pyridin-2-yl)-5-methoxycarbonylpyrazolo[1,5-a]pyridine will be SOCl2 (0.0023 ml, 0.032 mmol) was added to a solution of the compound (57 mg, 0.16 m. The reaction mixture was allowed to stir at room temperature for 18 hours. The resulting crude reaction was concentrated to dryness, then purified by &lt;&lt;&gt;&gt;&lt;&gt;&gt; State to give the desired compound (2 8 mg, 46% yield). LC-MS (method 2): tR = 3.17 min; m/z = 3 73 (MH+). LiAlH4 (5 mg, 0.15 mmol) was added to a solution of the compound obtained in the previous step (28 mg, 0.075 mmol) in anhydrous THF (2 ml). The reaction mixture was allowed to stir at room temperature for 18 hours. The crude reaction was diluted with EtOAc and washed with EtOAc EtOAc. The combined organic layer was dried over Na 2 SO 4 and the solvent was evaporated to dryness. The resulting crude reaction was subjected to EtOAc (EtOAc) eluted eluted elution LC-MS (method 2): tR = 1.90 min; m/z = 3 45 (MH+). Example 9 -96- 201035095 3 - [ 6 -(piperidin-4-ylamino)pyridine-2-yl]pyrazolo[丨,5 _ a ]pyridine a ) 3 - [ 6 - ( ;1 - Ethoxycarbonylpiperidine-4-ylaminopyridin-2-ylpyrazolo[l,5-a]pyridine followed the procedure described in Example 但 but using i-ethoxycarbonyl-4-amine The cisplatidine was given 'the desired compound (49% yield). LC-MS (Method 2): tR = 2 〇〇 min; m/z = 366 (MH+). 0 b ) The title compound was added to a solution of the compound obtained in the previous step (127 mg, 0.350 mmol) in Et0H (3 ml) and heated at 1 ° C. 8 hours. The crude reaction was allowed to cool, concentrated to dryness and purified eluting eluting eluting with EtOAc LC-MS (method 2): tR=l. 〇 2 min; m/z = 294 (MH+). Following the procedure described in Example 9, but using the corresponding starting materials in each case, the following compounds were obtained: Example Compound name Starting material HPLC method tR (min) m/z 9a(1) 3_[6 - (Pulsation D疋_4·ylamino) gadine 2·yl]-5-carboxypyrazolo[l,5-a]pyridine Reference Example 3 2 1.40 338 9b(2) 5-Chloro group· 3-[6-(峨D定-4·-ylamino)pyrene than π-but-2-yl]pyrazolo[l,5-a]pyridine Reference Example 3 2 1.98 319 (1) Before purification The crude product was acidified by a solution of 4 river 11 (: 1 in dioxane (21111). (2) obtained as in step c of Example 11. -97 - 201035095 Example 1 〇3 - [6 · (1 -Ethyl piperidin-4-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine will be acetic acid (0.014 ml, 0.245 mmol), EDC (46 mg, 0.245 mmol) Ears, H〇Bt (33 mg, 0.245 mmol) and EDIPA (0,071 ml, 0,408 mmol) were added to the compound of Example 9 (60 mg, 0·2〇4 mmol) of DMF (2) Ml) in solution. The resulting mixture was stirred at room temperature for 18 hours. Then, the solvent was concentrated to dryness and then produced. The crude reactants were distributed in a saturated aqueous solution of CH2C12 and NaHCO3. The phase layer was separated and the aqueous layer was extracted twice with CH2C12. The combined organic layer was dried over MgSO4 and concentrated to dryness. Chromatography (using a hexane/acetone mixture of increasing polarity as the eluent) to give the title compound (25 mg, 7% yield) LC-MS (Method 2): tR = 1 '47 min ;m/z = 3 3 6. Example 1 1 5-cyano-3-[6-(methyl(piperidin-4-yl)amino)pyridin-2-yl]pyrazolo[1,5 - a ] 卩 Π a a) 5 -Cyano-3 - [ 6 -(( ethoxylated)piped-4 _ylamino)pyridin _ 2-yl]pyrazolo[l, 5-a]pyridine Following the procedure described in Example 1 but using the compound of Reference Example 3 and 4-amino-1-ethoxycarbonylpiperidine afforded the desired compound (48% yield). -98- 201035095 b) 5-cyano-3-[6-(N-methyl(1-ethoxycarbonyl)piperidin-4-dipyridin-2-yl]pyrazolo[l,5-a]pyridinium lBuOK (1 1 6 mg, 〇, 384 mmol) and 1^1 (0.64 mmol/mole) were added to a solution of the compound obtained in the previous step (0.25 mmol) in THF (2 ml). The mixture was stirred for 18 hours at room temperature and concentrated. The crude residue was taken from EtOAc (EtOAc: EtOAc) c) The title compound was added TMSI (40 μM, 0,272 mmol) to the aforementioned compound (22 mg, 0,054 mmol) of AcN (2 ml). The reaction mixture was stirred at 50 ° C for 18 hours. The residue was purified by SCX chromatography to give the title compound (5.8 mg, ), EtOAc (m.). Example 1 2 5 -Cyano-3 -[ 6 - ((1-ethoxy)piperidin-3-ylamino)pyrazole[l,5-a]pyridine a ) 5-cyano- 3 - [ 6 -(piperidin-3-ylamino)pyridin-2-yl]pyridinium i is determined to follow the method described in Step C of Example 11 for the initiation of the compound of Example 2d. And 4 μH of C1 bisthylene lysine) 2.27 ml, 100 mg, and the mixture was chromatographed ( ) to form the solution obtained in the step. . The crude residue 3 2% yield: 2-yl]pyridinium [1,5- but using a solid solution to give the desired compound (65% yield) of -99-201035095. b) The title compound was added acetic anhydride (12 μM, 0.126 mmol) and TEA (28 μM, 0.189 mmol) to the compound obtained in the previous step (2 mg, 〇.063 mmol) of DMF (1 Mi) in solution. The reaction mixture was allowed to stir at room temperature for 18 hours and concentrated to remove solvent. The reaction mixture was quenched with aq. EtOAc EtOAc. The combined organic phase was dried over anhydrous Mg 2 S04, filtered and concentrated. The crude residue was chromatographed eluted with EtOAc (hexanes: hexanes: hexanes) to afford the title compound (20 mg, 85% yield). LC-MS (method 2): tR = 2.52 min; m/z = 361. Example 1 3 5 -Cyano-3 -[ 6 -( 1 -( 2 -cyanoethyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[l,5-a The pyridine was subjected to a procedure similar to that described in the step b of Example 12, but using 2,5-di- oxypyrrolidine-bromo-2-cyanoacetate to give the title compound (55% yield). LC-MS (method 2): tR = 2.63 min; m/z = 386. Example 1 4 (R) -5 -Cyano-3- [6-(Bu(2·cyanoethyl)-thromid-3-ylamino)pyridin-2-yl]pyrazolo[l, 5-a]pyrrole-100-201035095 Following the procedure described in Example 13 but using 3 _(R)-amino-1-ethoxycarbonylpiperidine as starting material, the title compound (6 2 % produced τΛ-s \ 半)〇LC-MS (method 2): tR = 2,63 minutes; m/z = 386. Following the procedure similar to that described in Example 14 but using the corresponding starting materials, the following compounds were obtained: 〇 Example Compound Name 14a (5)-5-Cyano-indole 6-(ι-(2-cyanoacetamidine) Base) piperidinylamino-acridin-2-yl]pyrazolo[l,5-a]pyridine HS)-amino-1-ethoxycarbonylpiperidine starting material HPLC method tR (minutes) m/ z 2 2.63 386 Example 1 5 (R) -5-Cyano-3-[6-(N-methyl-1-(2-cyanoethyl)piperidinyl-3-aminocarbyl) -2 -yl] 卩 哩 [ [1,5 - a ] 卩 ratio steep a) (R) -5 -cyano-3-(6-(N-methyl-1-(ethoxycarbonyl)) piperidine -3·ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridinidine is similar to the method described in Example 2 and in step b of Example 11 but using 3 - ( respectively) R )-Amino-1 -ethoxycarbonylpiperate and (r ) - 5 -cyano-3 -[ 6 -( 1 -(ethoxycarbonyl)piperidin-3-ylamino)pyridine _ 2 yl ] Pyr π sits and [1,5 - a ] is used as the starting material to give the desired compound (9 9 % yield). b) (R) ·5-cyano-3 -[ 6 -(piperidin-3-yl(N-methyl)amino)pyridin-2-yl]pyrazolo[l,5-a]pyridine Similar to the method described in the step c of Example 11 but using the compound obtained in the previous step -101-201035095, the desired compound was obtained. C) The title compound ί 彳 类似于 类似于 类似于 类似于 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 LC-MS (method 2): tR = 2.92 min; m/z = 400. Example 1 6 (S ) - 5 -Cyano-3 -[ 6 -(piperidin-3-ylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine Following a similar example The method described in the step c of 1 1 but the compound of Example 2 r was used as the starting material to give the title compound (74% yield). LC-MS (method 2): tR = 2.20 min; m/z = 319. Example 1 Inhibition of JAK3 activity The kit-Tyr 6 peptide (Supply of Invitrogen: product number PV41 22) was assayed using Z'-Lyte® kinase and the amount of microdroplets was determined in 3 84 wells according to the manufacturer's instructions. The inhibition of JAK3 kinase activity was determined on the plate. In the final volume of 10 μΐ/well, the product to be tested (2.5 μΐ) was dissolved in 4 % DMS Ο (the final concentration of the product to be tested was 0.1 to 1 0 0 0 η Μ ) and 0.3 pg/ml human JAK3 The enzyme catalytic domain (amino acid sequence 281 to 1124), 2 μΜ of the peptide Z,-Lyte® Tyr 6 and 4 μΜ ATP, all components are dissolved in 5〇1111^116068?117.5 buffer, 1〇« 1\1 Magnesium Chloride-102- 201035095 (II), 1111 River £0 Ding Ba and 〇.〇1%31^4 35. The reaction was initiated by the addition of 4卩1 ATP; after incubation for 1 hour at 25 °C, the development reagent (5 μM) was added to Z,-Lyte® Tyr 6 and incubated at 25 °C. 1 hour. Phosphorylation in each well was quantified using a Safire 2® luminometer (Tecan). In this test, all of the compounds of the examples showed an inhibitory effect on JAK3 activity of more than 50% at 10 μΜ. In this assay, compounds 1 c, If, lm, 1 〇, lu, lv, 2p, 9b, 13, 14 and 15 exhibited an inhibitory effect on JAK3 activity of more than 50% at 0.1 μΜ. Example 1 Inhibition of JAK2 activity The kit-Tyr 6 peptide was assayed using Z'-Lyte® kinase (Invitrogen supplied: product number PV4 122) and the amount of microdroplets was determined in 3 84 wells according to the manufacturer's instructions. The inhibition of JAK2 kinase activity was determined on the plate. In the final volume μ/well, let the product to be tested (2.5 μΐ) dissolve in 4% DMS Ο (the final concentration of the product to be tested is 0.1 to 1 0 0 0 ηΜ) and the person with 0.5 Mg/hole : FAK2 enzyme catalytic domain, 2 μΜ receptor peptide Ζ'-Lyte® Tyr 6 and 16 μΜ ,, all components are dissolved in 50 mM Hepes pH 7.5 buffer, 10 mM magnesium chloride (π), 1 mM EGTA and 0.01% Brij® 35. The reaction was initiated by the addition of 16 μM ATP; after incubation for 1 hour at 25 ° C, the development reagent (5 μM) was added to 2'-Lyte® Tyr 6 and the mixture was allowed to stand at 25 ° C. It was incubated for 1 hour. The -103-201035095 phosphorylation in each well was quantified using a Safire2® Fluorescent Microplate Reader (TeCan). In this assay, 'Compounds 1 U, 1 v, 2p, 9b, 1 1 , 1 3, 14 and 15 exhibited an inhibitory effect on JAK2 activity of more than 50% at 0.5 μΜ. -104-

Claims (1)

201035095 VII. Patent application scope: 1. A compound of formula I Or a salt thereof, wherein Ri represents hydrogen, C, _4 alkyl 'halo Ci4 alkyl, hydroxy d. 4 alkyl, aryl 'halogen, _CN, __c〇Nr4R4, —c〇R5, —C02R5, —OR4, -S02R5, _S02NR4r4, a Nr4r4, _NR6c〇r4, -NR6CONR4R4, -NR6C02R5, _NR6S〇2R5 or Cyi, wherein the Cyi is optionally substituted by one or more R8; R2 represents hydrogen '¢^-4 alkyl, haloCl_4 alkyl, hydroxyCi-4 alkyl, RrCu alkyl or Cy2, wherein Cy2 is optionally substituted by one or more r8, R3 represents an ind-4 alkyl group, Halogen C^.4 alkyl, hydroxycyalkyl, Rh-Ch, /CONR9R9, -CORio, -CO2R10, _S〇2Ri, -SO2NR9R9 or Cy3, wherein Cy3 is optionally via one or more R12 Substituted» or 112 and 113 may be bonded to a nitrogen atom to form a Cy4 group, wherein Cy4 is optionally substituted by one or more R, 2; each R4 represents hydrogen or R5; -105 - 201035095 per r5 Each represents Ci-4, the Ci-4, the Ci-4, the Ci-4-alkyl, the hydroxyCh alkyl, the cyanoCl·4 alkyl, the cyi_Cl·4 alkyl or C y] Wherein C y ! is optionally substituted by one or more R 8 ; R 6 represents hydrogen or alkyl; R 7 ft ^ -CN ' -CONR 4 R 4 ' -COR 5 ' -CO 2 R 5 ' -OR 4 ' -SO 2 R 5 , -SO 2 NR 4 R 4 ' -NR 4 R 4 '-NR6COR4, -NR6CONR4R4, -NR6C02R5, -NR6S02R5 or Cy!, wherein Cyi is optionally substituted by - or multiple R8; each R8 represents 匕^alkyl, halogen C] _4 alkyl, cumane Oxyl C^-4 alkyl, hydroxy Cw alkyl, cyano Cu alkyl, halogen or Each R9 represents hydrogen or R10; each Rlc represents Cl_4 alkyl, sec. Cl.4 alkyl, hydroxyCl_4 alkyl, Rn-Ci-4 alkyl or Cy5, wherein Cy5 is optionally Substituted by one or more r13; Rii represents halogen, -CN, -CONRI4RI4, -COR]5, -C02Ri5, -or14 '-〇conr14r14, -so2r15, -so2nr14r14, -NR14Ri4 '-NR6COR14 &gt; -NR6CONRi4Ri4 ' - NR6C02Ri5 '-NR6S02R15 or Cy5, wherein Cy5 is optionally substituted by one or more Rn; each R12 represents Cm alkyl, halo Cm alkyl, hydroxy CL4 alkyl, Rm-Cm alkyl, or Rl2 represents Any meaning described by Rll; each R13 represents 匕^alkyl, halo Cm alkyl, Cm alkoxy Cm alkyl, hydroxy C1-4 alkyl, cyano C1-4 alkyl, halogen, -cm , -CONR16Ri6, -COR17, -C02Ri7, -〇Ri6, -0C0NR16Ri6 -106- 201035095, -S02Ri7, -S02NR16R16, -NR16R16, -NR6COR16, -NR6CONRi6Ri6, -nr6co2r17 or -NR6S02R17 ; each Rm represents hydrogen or R15 ; each R15 represents a mountain-4 alkyl group, a halogen Cm alkyl group, a Cm alkoxy group Ci-4 alkyl group, a hydroxyl group c, a 4-alkyl group, a cyano Cm alkyl group, a Cys-C alkyl group Or Cy5, wherein Cy5 is optionally substituted by one or more R13; each R16 represents hydrogen or R17; q each Rl7 represents C, _4 alkyl, haloalkyl, Cw alkoxy Ci- 4 yard base, base 1.4 base or oxy 1-4 base; Cyi represents a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic carbocyclic ring, optionally containing 1 to 3 a heteroatom independently selected from N, S or oxime, wherein the ring is bonded to the remainder of the molecule via any C or N atom available, and wherein one or more C or S ring atoms are optionally Oxidized to form a CO, SO or S02 group; Cy2 represents a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic carbon Q ring optionally containing from 1 to 3 independently selected from N, S or 0. a hetero atom, wherein the ring is bonded to the remainder of the molecule via any C atom available, and wherein one or more of the C or S ring atoms are optionally oxidized to form a CO, so or so2 group Cy3 represents a saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic or 8 to 12 membered bicyclic carbocyclic ring optionally having from 1 to 4 independently selected from N, S. a hetero atom of 0, wherein the ring is bonded to the remainder of the molecule via any C atom available, and wherein one or more of the &lt;^ or 3 ring atoms are optionally oxidized to form CO, so Or so2 group; -107- 201035095 Cy4 represents a saturated or partially unsaturated 3 to 7 membered monocyclic heterocyclic ring's which are optionally thickened with a saturated, partially unsaturated or aromatic 5 or 6 membered carbocyclic or heterocyclic ring. Wherein Cy4 optionally contains a total of from 1 to 4 heteroatoms independently selected from N, S or hydrazine; and wherein one or more C or S atoms of Cy4 are optionally oxidized to form CO, SO or a so2 group; and a Cy5R-saturated, partially unsaturated or aromatic 3 to 7 membered monocyclic or 8 to 12 membered bicyclic carbocyclic ring optionally having from 1 to 4 independently selected from N, L, or 0. a hetero atom, wherein the ring is bonded to the remainder of the molecule via any C or N atom available, and wherein one or more of the C or S ring atoms are optionally oxidized to form c 0, S 0 Or S 0 2 base. 2. A compound as claimed in claim 1, wherein R! represents hydrogen or -CN. 3. A compound as claimed in claim 2, wherein R 1 represents -C N . 4. A compound according to any one of claims 1 to 3, wherein Κ·2 represents hydrogen, Ci-4, a halogen Ci-4, a base, a Ci-4, or a R7-Ci- 4 alkyl. 5. A compound as claimed in claim 4 wherein R 2 represents hydrogen, Cl 4 alkyl, halo d-4 alkyl or hydroxy CL 4 alkyl. 6. A compound according to claim 5, wherein R2 represents hydrogen or Ci-4 alkyl. 7. A compound as claimed in claim 6 wherein R2 represents hydrogen, methyl or ethyl. 8. A compound according to claim 7 wherein R2 represents hydrogen. 9. The compound of claim 7, wherein R 2 represents methyl-108-201035095 1 ο. The compound of claim 7 wherein R 2 represents ethyl 0 1 1 · as claimed in claim 1 The compound of any one of the preceding claims, wherein R3 represents Cy3, wherein the 〇丫3 is optionally substituted with one or more Ri2. 1 2 · A compound as claimed in claim 11 wherein Cy3 represents a 5 or 6 membered saturated monocyclic carbocyclic ring optionally containing 1 or 2 heteroatoms independently selected from N, U s or fluorene. The ring is bonded to the remainder of the molecule via any available c atom, wherein one or more (or 3 ring atoms are optionally oxidized to form a CO, SO or 502 group, and wherein the Cys system Alternatively, substituted by one or more Ri 2 .. 13. The compound of claim 12, wherein Cys represents cyclohexyl, 3-piperidinyl or 4-oxaridinyl, wherein Cy3 is optionally passed through a Or a plurality of R12 substitutions. 14. A compound according to claim 12, wherein C y3 represents a cyclohexyl group which may be optionally substituted by one or more R 12 . 1 5 . The compound 'wherein C y3 represents a 4-piperidinyl group optionally substituted by one or more R 12 . 1 6. The compound of claim 12, wherein C y 3 represents optionally one or more a R12-substituted 3-piperidinyl group. 1 7 · A compound according to claim 12, wherein Cy 3 represents a formula Cy3a Cy3b the group: -109-201035095 Wherein R12a represents -COR15; and wherein additionally C y 3 a and C y 3 b are independently and optionally substituted by one or more R 1 2 18. The compound of claim 12, wherein Cy3 represents formula C y 3 a base: Cy3a; wherein R12a represents -COR15; and wherein additionally Cy3a is optionally substituted with one or more R12. 19. A compound according to claim 12, wherein Cy3 represents a group of formula C y 3 b: 〇Rl4 Cy3b; and wherein additionally Cy3b is optionally substituted with one or more Ri 2 . The compound according to any one of claims 17 to 19, wherein each R12 is independently selected from a Cm alkyl group, a halogen Cm alkyl group, a hydroxyl group Cm-110-201035095 alkyl group or R! -Cu alkyl group. 2 1. A compound of claim 12, wherein Cy3 represents a group of formula C y 3 a: Wherein R12a represents -COR15. 2 2. The compound of claim 12, wherein Cy3 represents the base of the formula Cy3b: OR14 Cy3b. The compound of any one of claims 17, 19 and 22, wherein R 1 4 represents hydrogen. The compound of any one of claims 1 to 7, 18 and 21, wherein R15 represents C, _4 alkyl or cyano C, _4 alkyl. 25. A compound according to claim 24, wherein R15 represents a cyanomethyl group. 2 6. A compound according to claim 1 which is selected from the group consisting of: trans-5-amino-3-[6-(4-carbocyclohexylamino)-indenyl-1-yl]pyridinium Oxazo[1,5-a]pyridine; trans-5-cyano-3-[6-(4-hydroxycyclohexyl-N-methylamino)pyridin-2-yl]pyrazolo[l, 5-a]pyridine; -111 - 201035095 trans-5-cyano-3-[6-(N-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2-yl]pyrazole [l,5-a]pyridine; 5-cyano-3 -[ 6 -(piperidin-4-ylamino)pyridin-2-yl]pyrazolo[1,5 - a ] -Cyano-3-[6-(methyl(piperidin-4-yl)amino)pyridin-2-yl]pyrazolo[1 ,5 - a ]pyridine; 5-cyano-3-[6 - (1-(2-cyanoethyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine; (R)-5-cyano-3 -[6-(1-(2-cyanoethenyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[1,5-a]pyridine; and (11)-5- Cyano-3-[6-(1methyl-1-(2-cyanoethenyl)piperidin-3-ylamino)pyridin-2-yl]pyrazolo[l,5-a]pyridine , or the salt of the other. 27. A compound according to claim 1 which is selected from the group consisting of: trans-5-cyano-3.[6-(4-hydroxycyclohexyl-N-methylamino)pyridin-2-yl] Pyrazolo[1,5-a]pyridine; trans-5-cyano-3-[6·(N-ethyl-N-(4-hydroxycyclohexyl)amino)pyridin-2-yl]pyridinium Zoxa[1,5-a]pyridine; 5-cyano-3-[6-(1-(2-cyanoethyl)piperidin-3-ylamino)pyridin-2-yl]pyrazole [1,5-a]pyridine; (R) -5-cyano-3- [6-(1-(2-cyanoethyl) fluorenyl-3-ylamino)pyridine-2-yl] Pyrazolo[1,5-a]pyridine; and (1〇-5-cyano-3-[6-(1methyl-1-(2-cyanoethyl)piperidin-3-ylamine) Pyridin-2-yl]pyrazolo[l,5-a]pyridine, -112-201035095 or a salt thereof. 2 8 · A pharmaceutical composition comprising, as claimed in claims 1 to 27 A compound of the formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The compound of any one of claims 1 to 27, It is used to treat or prevent diseases caused by JAK3. 3 0. If the scope of patent application is 1 The compound according to any one of the 27, wherein the Q is used for the treatment or prevention of at least one disease selected from the group consisting of a graft rejection, an immune, an autoimmune or inflammatory disease, a neurodegenerative disease or a proliferative disease. The compound of claim 30, which is used for treating or preventing a hair loss caused by graft rejection, rheumatoid arthritis, psoriatic arthritis, psoriasis, type I diabetes, diabetes Symptoms, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, allergic reactions to mast cell media, leukemia, lymphoma or thromboembolic and allergic complications associated with leukemia and lymphoma. The compound of any one of claims 1 to 27, which is for use in the treatment or prevention of a disease which is mediated by JAK2. It is used to treat or prevent myeloproliferative diseases. • 3 4 · The compound of claim 3, which is used for the treatment or prevention of polycythemia vera, primary thrombocytopenia Disease, idiopathic myelofibrosis, chronic myelogenous leukemia, eosinophilic syndrome, chronic neutrophilic leukemia, chronic myelomonocytic leukemia, myelofibrosis with myeloablative metaplasia, chronic hobby Alkali cell white blood-113- 201035095 Disease, chronic eosinophilic leukemia, systemic mastocytosis or diseases of the spinal cord dysplasia syndrome. 35. A method of preparing a compound of formula I according to claim 1 which comprises: (a) reacting a compound of formula VIII with a compound of formula IX Wherein R1, R2 and 3 are as defined in claim 1 and X represents halogen; or (b) in a step or a plurality of steps, converting a compound of formula XII to a compound of formula I \v-NH2 wherein R1 is as defined in claim 1 of the patent application; or (c) in one or more steps, the compound of formula I is converted to another compound of formula I. -114- 201035095 IV. Designation of representative drawings: (1) The representative representative of the case is: None (2) The symbol of the symbol of the representative figure is simple: No 201035095 V. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: Formula I