Tricyclic compounds, pharmaceutical composition containing them and using them for treating immunological and oncological compounds

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a heterocyclic compound of formula and to its pharmaceutically acceptable salts, stereoisomers and isomers, wherein T: N, U: N, X: CR3 and Y: N; or T: CR6, U: CR4, X: CR3 and Y: N; or T: CR6, U: N, X: NR3 and Y: C; or T: O, U: N, X: CR3 and Y: C; or T: NR6, U: N, X: CR3 and Y: C; and R1, R2 and R5: H, heteroaryl substituted by 1-2 substitutes; or T: CR6, U: N, X: CR3 and Y: N; or T: N, U: CR4, X: CR3 and Y: N; and R1 and R2: H, heteroaryl substituted by 1-2 substitutes; R5: heteroaryl substituted by 1-2 substitutes; R3: H, bridging (C7-C10)cycloalkyl; (C1-C8)alkyl optionally substituted by 1 substitute; (C3-C10)cycloalkyl optionally substituted by 1 substitute; (C6-C8)cycloalkenyl substituted by two (C1-C6)alkyl; (C6)aryl optionally substituted by 1-2 substitutes; heteroaryl optionally substituted by (C1-C6)alkyl; heterocyclyl optionally substituted by (C1-C6)alkyl or heteroaryl; or R3: -A-D-E-G, wherein: A: a bond or (C1-C6)alkylene; D : (C1-C2)alkylene optionally substituted by (C1-C6)alkyl, bridging (C6-C10)cycloalkylene optionally substituted by (C1-C6)alkyl, (C3-C10)cycloalkylene optionally substituted by 1-2 substitutes, (C4-C6)cycloalkenylene optionally substituted by (C1-C6)alkyl, (C6)arylene, heteroarylene or heterocyclylene optionally substituted by one (C1-C6)alkyl; E: a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)O-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-N(Ra)C(O)ORe- or -Re-N(Ra)S(O)2-Re-; wherein in each case, E is bound to either a carbon atom, or a nitrogen atom in D; G: H, -N(Ra)(Rb), halogen, -ORa, S(O)2Ra, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -C(O)Ra, -CF3, N(Ra)S(O)2Rb, -(C1-C6)alkyl optionally substituted by 1-3 substitutes; -(C3-C6)cycloalkyl optionally substituted by CN; -heteroaryl optionally substituted by 1-2 halogens, CN, -C(O)NH2 or -CF3; -heterocyclyl optionally substituted by 1-5 substitutes, -(C6-C10)aryl optionally substituted by 1-3 substitutes; wherein in a fragment containing -N(Ra)(Rb), nitrogen, Ra and Rb can form a ring so that -N(Ra)(Rb) represents (C3-C6)heterocyclyl optionally substituted by 1 substitute, wherein said (C3-C6)heterocyclyl is bound through nitrogen; R4 and R6: H, (C1-C4)alkyl optionally substituted by -OH, -COOH; (C3-C8)cycloalkyl, phenyl, optionally substituted by -SO2CH3 or -NHSO2CH3, halogen or -J-L-M-Q; wherein: J: (C2-C6)alkenylene; L: a bond; M: a bond; Q: -C(O)ORa; Ra and Rb: H, (C1-C4)alkyl optionally substituted by cyano, -CF3 or cyclopropane; (C6)aryl optionally substituted by halogen or -O(C1-C4)alkyl; and Re: a bond, (C1-C4)alkylene or (C3)cycloalkylene. Besides, the invention refers to specific compounds, a pharmaceutical composition based on the compound of formula I, using the compound of formula I for treating and using the compounds of formulas 2-6

for preparing the compound of formula I.

EFFECT: prepared are the new compounds effective in treating a condition mediated by Jak1, Jak3 or Syk protein kinase activity.

51 cl, 34 tbl, 44 ex

 

Cross-reference to related applications

The present application claims priority on provisional application U.S. No. 61/131599 filed June 10, 2008, provisional application U.S. No. 61/131602 filed June 10, 2008, provisional application U.S. No. 61/190159, filed August 26, 2008, and provisional application U.S. No. 61/201064, filed December 5, 2008, the contents of which are incorporated herein.

The level of technology

In the present invention proposed a new class of compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of Jak1, Jak2, Jak3, Tyk2, KDR, Flt-3, CDK2, CDK4, TANK, Trk, FAK, Abl, Bcr-Abl, cMet, b-RAF, FGFR3, c-kit, PDGF-R, Syk, PKC kinase or Aurora kinases.

Protein kinases represent a large family of proteins that play a Central role in the regulation of a wide range of cellular processes and in maintaining cellular functions. Partial, non-limiting list of these kinases include: preceptory tyrosine kinase inhibitors, such as the family of Janus kinases (Jak1, Jak2, Jak3 and Tyk2); hybrid kinases, such as BCR-Abl, focal adhesion kinase (FAK), Fes, Lck and Syk; receptor tyrosine kinase inhibitors such as CI�basics receptors of growth factors, derived from platelets (PDGF-R), the receptor kinase for stem cell factor, c-kit, receptor growth factor hepatocyte, c-Met, receptor fibroblast growth factor FGFR3; and serine/threonine kinases such as b-RAF, mitogen-activated protein kinases (for example, MKK6) and SAPK2β. Aberrant kinase activity was observed in many disease conditions, including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune and nervous systems. The new compounds of the present invention inhibit the activity of one or more of the protein kinases and therefore are expected to be useful in the treatment mediated by kinases diseases.

Summary of the INVENTION

In the first embodiment of the present invention provides a compound of formula (I)

Formula (I)

its pharmaceutically acceptable salt, prodrug, biologically active metabolites, stereoisomers and isomers, where

T is N, U is an N X represents CR3and Y represents N; or

T is a CR6U represents N and X represents CR3and Y represents N; or

T is N, U represents CR4, X represents CR3and Y represents N; or

T is a CR6U represents CR4, X represents CR3and Y represents N; or

T is a CR6U represents N and X represents NR3and Y is C; or

T represents O, U represents N and X represents CR3and Y is C; or

T represents NR6U represents N and X represents CR3and Y is C; or

T is a CR6U represents CR4, X represents NR3and Y is C; or

T represents S, U represents N and X represents CR3and Y is C;

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -C(OH)RaRb, -N(Ra)S(O)2-Rb, -S(O)2N(Ra)(Rb), -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)GE�Eroare, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R3represents hydrogen, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted bridged (C2-C10)heterocyclyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl; or

R3is a-A-D-E-G, where A is attached to X and;

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra )-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

E is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-OC(O)-Re-, -Re-N(Ra)C(O)N(Rb)-R e-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

E represents,

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -OC(O)N(Ra), -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, optionally substituted -(C6-C10)aryl, optionally substituted -(C1-C6)alkyl-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkyl-(C6-C10)aryl, optionally substituted -(C1-C6)alkyl-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)and�Kil-(C 1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R4and R6each independently represents hydrogen, halogen, deuterium, an optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl or-J-L-M-Q;

where:

J is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Rsup> e-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

L is a bond, optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

M is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, -Re-OC(O)-Re-, -Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Rsup> e-S(O)2N(Ra)-Re-; or

M represents;

where in all cases, M associated with either a carbon atom or a nitrogen atom in L;

Q represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkyl-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkyl-(C1-C10)heterocyclyl;

where in the fragment, containing�eat-N(R a)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

Raand Rbeach independently represents hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkyl-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl; and

Rein each case, independently is a bond, optionally substituted (C1-C10)alkylene, optionally substituted (C2-C10)alkanine needed�optionally substituted (C 2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkylenes group, an optionally substituted C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl;

provided that if the compound is a

R3has the above significance, and R6not linked to the pyrazole ring via a nitrogen atom or oxygen; and

provided that if the compound is a

if R3represents H, CH3or-C(O)OH, then R4represents H, -C(O)OCH2CH3, -C(O)NH-optionally substituted phenyl, -NHC(O)-optionally substituted phenyl or-S(O)2-phenyl.

In the second embodiment of the present invention provides a compound of formula (II)

Formula (II)

its pharmaceutically acceptable salt, prodrug, biologically active metabolites, stereoisomers and isomers, where

if T represents NR6U represents N and X represents CR3and there is a double bond between U and X;

if T represents O, U represents N and X represents CR 3and there is a double bond between U and X;

if T is a CR6U represents N and X represents NR3and there is a double bond between T and U;

if T is a CR6U represents CR4, X represents NR3and there is a double bond between T and U;

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -N(Ra)S(O)2-, -S(O)2N(Ra)-, -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl, linked through a nitrogen;

R3represents an optionally substituted bridge�on (C 5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted adamantyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl or-A-D-E-G;

where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optional�individual substituted (C 1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

E is a bond, -Re-, -C(O)-Re-, -C(O)C(O)-Re-, -C(O)O-Re-, -C(O)C(O)N(Ra)-Re-, -O-Re-, -S(O)2-Re-, -S(O)-Re-, -S-Re-, -N(Ra)-Re-, -N(Ra)C(O)-Re-, -C(O)N(Ra)-Re-, -OC(O)N(Ra)-Re-, -OC(O)-Re-, -N(Ra)C(O)N(Rb)-Re-, -N(Ra)S(O)2-Reor-S(O)2N(Ra)-Re-; or

E represents;

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)RbN(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted�th (C 1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkyl-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment comprising-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb), is an optionally substituted C2-C10)heterocyclyl, linked through a nitrogen;

R6represents hydrogen, deuterium, an optionally substituted bridged (C3-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted adamantyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl; or R6the performance�t a-J-L-M-Q, where:

J is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -C(O-Ra)(Rb)-Re-, or-S(O)2N(Ra)Re-;

L is a bond, optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl; or

L represents;

M is a bond, -Re-, -C(O)-Re-, -C(O)C(O)-Re-, -C(O)O-Re-, -C(O)C(O)N(Ra)-Re-, -O-Re-, -S(O)2-Re-, -S(O)-Re-, -S-Re-, -N(Ra)-Re-, -N(Ra)C(O)-Re-, -C(O)N(Ra)-Re-, -OC(O)N(Ra)-Re-, -OC(O)-Re-, -N(Ra)C(O)N(Rb)-Re-, -N(Ra)S(O)2-Re- or-S(O)2N(Ra)-Re-;

Q made�is hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkyl-(C1-C10)heteroaryl or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment comprising-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl, which is connected through a�from;

R4represents hydrogen, deuterium, an optionally substituted bridged (C3-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted adamantyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl; or

R4is a-V-W-Y-Z, where:

V is a bond, -C(O)-, optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -C(O-Ra)(Rb)-Re-, or-S(O)2N(Ra)Re-;

W is a bond, optionally substituted (C1-C8)alkyl, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally someseni� (C 1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl; or

W is a

Y represents a bond, -Re-, -C(O)-Re-, -C(O)C(O)-Re-, -C(O)O-Re-, -C(O)C(O)N(Ra)-Re-, -O-Re-, -S(O)2-Re-, -S(O)-Re-, -S-Re-, -N(Ra)-Re-, -N(Ra)C(O)-Re-, -C(O)N(Ra)-Re-, -OC(O)N(Ra)-Re-, -OC(O)-Re-, -N(Ra)C(O)N(Rb)-Re-, -N(Ra)S(O)2-Re- or-S(O)2N(Ra)-Re-;

Z represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, S(O)2Ra, -NO2, -C(O)ORb, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Rb, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterotic�Il, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkyl-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment comprising-N(Ra)(Rb), the nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl, linked through a nitrogen;

Raand Rbeach independently represents hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6 -C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl; and

Reis a bond or is independently selected from optionally substituted C1-C10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)Allenova group, an optionally substituted C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl;

provided that if the compound is a

R6not linked to the pyrazole ring via a nitrogen atom or oxygen; and

provided that if the compound is a

where if R3represents H, CH3or-C(O)OH, then R4represents H, -C(O)OCH2CH3, -C(O)NH-optionally substituted phenyl, -NHC(O)-optionally substituted phenyl or-S(O)2-phenyl.

In the third embodiment of the present invention offers sedimentary (Ig)

Formula (Ig)

its pharmaceutically acceptable salt, prodrug, biologically active metabolites, stereoisomers and isomers, where

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -N(Ra)S(O)2-, -S(O)2N(Ra)-, -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, or optionally substituted -(C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl, linked through a nitrogen;

R3represents an optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, niobate�till then substituted adamantyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl; or R3is a-A-D-E-G, where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or not�certainly substituted (C 2-C10)heterocyclyl;

E is a bond, -Re-, -C(O)-Re-, -C(O)C(O)-Re-, -C(O)O-Re-, -C(O)C(O)N(Ra)-Re-, -O-Re-, -S(O)2-Re-, -S(O)-Re-, -S-Re-, -N(Ra)-Re-, -N(Ra)C(O)-Re-, -C(O)N(Ra)-Re-, -OC(O)N(Ra)-Re-, -OC(O)-Re-, -N(Ra)C(O)N(Rb)-Re-, -N(Ra)S(O)2-Re- or-S(O)2N(Ra)-Re-;

or

E represents

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10) heterocyclyl, optionally substituted -(C6-C 10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl, linked through a nitrogen;

R4represents hydrogen, deuterium, an optionally substituted bridged (C3-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted adamantyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl; or

R4represents-J-L-M-Q where:

J is a bond, -C(O)-, optionally substituted (C1-C6)alkylen, neobythites�but substituted (C 2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -C(O-Ra)(Rb)-Re-, or-S(O)2N(Ra)Re-;

L is a bond or optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

or L is a

M is a bond, -Re-, -C(O)-Re-, -C(O)C(O)-Re-, -C(O)O-Re-, -C(O)C(O)N(Ra)-Re-, -O-Re-, -S(O)2-Re-, -S(O)-Re-, -S-Re-, -N(Ra)-Re-, -N(Ra)C(O)-Re-, -C(O)N(Ra)Re-, -OC(O)N(Ra)-Re-, -OC(O)-Re-, -N(Ra)C(O)N(Rb)-Re-, -N(Ra)S(O)2-Re-, or-S(O)2N(Ra)-Re-;

Q represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl, linked through a nitrogen;

Raand Rbindependently represent hydrogen, deuterium, not necessarily samewe�tion (C 1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkylen-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl; and

Reis a bond, optionally substituted (C1-C10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkylenes group, an optionally substituted C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl;

In the fourth�ω embodiment of the present invention provides a compound of formula (III)

Formula (III)

its pharmaceutically acceptable salt, prodrug, biologically active metabolites, stereoisomers and isomers, where

X represents CR6orN; Y represents CR4or N;

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -C(OH)RaRb, -N(Ra)S(O)2-Rb, -S(O)2N(Ra)(Rb), -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl, linked through a nitrogen;

R3presents with�fight optionally substituted bridged (C 5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl; or R3is a-A-D-E-G, where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C 5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

E is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-N(Ra)C(O)ORe-, -Re-C(O)ORe-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

E represents

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(R b)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, optionally substituted -(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R6represents hydrogen, deuterium, an optionally substituted bridged (C5-C12)cycloalkyl group, �obazatelno substituted bridged (C 2-C10)heterocyclyl group, an optionally substituted C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl or R6represents-J-L-M-Q where:

J is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

L is an optionally substituted C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

M is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, -Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -ReC(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-N(Ra)C(O)ORe-, -Re-C(O)ORe-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

M represents;

where in all cases, M associated with either a carbon atom or a nitrogen atom in L;

Q represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O) 2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10) heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R4represents hydrogen, deuterium, an optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, neobyazatel� substituted (C 1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl; or R4is a-U-V-W-Z where:

U is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

V is an optionally substituted C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, �obazatelno substituted (C 1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

W is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, Re-C(O)C(O)N(Ra)-Re-, Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, Re-C(O)N(Ra)Re-, Re-OC(O)N(Ra)-Re-, Re-N(Ra)C(O)ORe-, -Re-N(Ra)C(O)ORe-, -Re-C(O)ORe-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Reor Re-S(O)2N(Ra)-Re-; or

W is a;

where in all cases, W associated with either a carbon atom or a nitrogen atom in V;

Z independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rb optionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

Raand Rbeach independently represents hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkylen-O-(C1 -C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl; and

Rein each case, independently is a bond, optionally substituted (C1-C10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkylenes group, an optionally substituted C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl or optionally substituted (C1-C10)heterocyclyl;

In the fifth embodiment of the present invention provides a compound of formula (Ia)

Formula (Ia)

its a pharmaceutically premliminary, prodrugs of biologically active metabolites, stereoisomers and isomers, where

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -N(Ra)S(O)2-, -S(O)2N(Ra)-, -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl, linked through a nitrogen;

R3represents an optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted adamantyl, optionally substituted (C1-C8)alkyl, NeoMaster�of substituted (C 3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl; or R3is a-A-D-E-G, where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

E represents�Oh bond, -Re-, -C(O)-Re-, -C(O)C(O)-Re-, -C(O)O-Re-, -C(O)C(O)N(Ra)-Re-, -O-Re-, -S(O)2-Re-, -S(O)-Re-, -S-Re-, -N(Ra)-Re-, -N(Ra)C(O)-Re-, -C(O)N(Ra)Re-, -OC(O)N(Ra)-Re-, -OC(O)-Re-, -N(Ra)C(O)N(Rb)-Re-, -N(Ra)S(O)2-Re- or-S(O)2N(Ra)-Re-; or

E represents;

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, optionally substituted -(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C 3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl, linked through a nitrogen;

Raand Rbindependently represent hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkylen-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1-C6)alkyl-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally Thames�nny -(C 1-C6)alkylene-(C1-C10)heterocyclyl; and

Rein each case, independently is a bond, optionally substituted (C1-C10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkyl group, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl.

In the sixth embodiment of the present invention provides a compound in accordance with the first embodiment, where R1, R2and R5each independently represents hydrogen, deuterium, halogen, -ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -CF3, -OCF3optionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, -(C1-C10)heterocyclyl or optionally substituted -(C6-C10)aryl.

In the seventh embodiment of the present invention provides a compound in accordance with�tvii with the first embodiment, where T represents N, U represents N and X represents CR3, Y represents N and forms a compound of formula (Ia)

Formula (Ia)

In the eighth embodiment of the present invention provides a compound in accordance with the first embodiment, where T is a CR6U represents N and X represents CR3andY represents N and forms a compound of formula (Ib)

Formula (Ib)

In the ninth embodiment of the present invention provides a compound in accordance with the first embodiment, where T is a N, U represents CR4, X represents CR3and Y represents N and forms a compound of formula (Ic)

Formula (Ic)

In the tenth embodiment of the present invention provides a compound in accordance with the first embodiment, where T is a CR6U represents CR4, X represents CR3and Y represents N and forms a compound of formula (Id)

Formula (Id)

In the eleventh embodiment of the present invention provides a compound in accordance with the first embodiment, where T is a CR6, U is an N X n�ecstasy a NR 3and Y is C and forms a compound of formula (Ie)

Formula (Ie)

In the twelfth embodiment of the present invention provides a compound in accordance with the first embodiment, where T represents O, U represents N and X represents CR3and Y is C and forms a compound of formula (If)

Formula (If)

In the thirteenth embodiment of the present invention provides a compound in accordance with the first embodiment, where T represents NR6U represents N and X represents CR3and Y is C and forms a compound of formula (Ig)

Formula (Ig)

In the fourteenth embodiment of the present invention provides a compound in accordance with the first embodiment, where T is a CR6U represents CR4, X represents NR3and Y is C and forms a compound of formula (Ih)

Formula (Ih)

In the fifteenth embodiment of the present invention provides a compound in accordance with the first embodiment, where T represents S, U represents N and X represents CR3and Y is C and forms a compound of formula� (Ii)

Formula (Ii)

In the sixteenth embodiment of the present invention provides a compound in accordance with the first embodiment, where R3represents hydrogen, optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted C1-C6)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl.

In the seventeenth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, wherein R3represents hydrogen, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted adamantyl, optionally substituted azetidine, optionally substituted bicyclo[2.1.1]hexyl, optionally substituted bicyclo[2.2.1]heptyl, optionally substituted bicyclo[2.2.2]octyl, optionally substituted bicyclo[3.2.1]octyl, optionally substituted bicyclo[4..1]decyl, optionally substituted bicyclo[3.3.1]nonyl, optionally substituted bornyl, optionally substituted of borneil, optionally substituted norbornyl, optionally substituted of norbornanyl, optionally substituted bicyclo[3.1.1]heptyl, optionally substituted tricyclazole, optionally substituted asangroni, optionally substituted quinuclidinyl, optionally substituted isoquinolinyl, optionally substituted Trapani, optionally substituted azabicyclo[3.2.1]octenyl, optionally substituted azabicyclo[2.2.1]heptenyl, optionally substituted 2-azabicyclo[3.2.1]octenyl, optionally substituted azabicyclo[3.2.1]octenyl, optionally substituted azabicyclo[3.2.2]nonanal, optionally substituted azabicyclo[3.3.0]nonanal, optionally substituted azabicyclo[3.3.1]nonanal, optionally substituted bicyclo[2.2.1]hept-2-enyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl or optionally substituted tetrahydrofuranyl.

In the eighteenth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, wherein R3represents an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, neobythites�but substituted phenyl, optionally substituted adamantyl, optionally substituted azetidine, optionally substituted bicyclo[2.1.1]hexyl, optionally substituted bicyclo[2.2.1]heptyl, optionally substituted bicyclo[2.2.2]octyl, optionally substituted bicyclo[3.2.1]octyl, optionally substituted bicyclo[3.1.1]heptyl, optionally substituted azabicyclo[3.2.1]octenyl, optionally substituted azabicyclo[2.2.1]heptenyl, optionally substituted 2-azabicyclo[3.2.1]octenyl, optionally substituted azabicyclo[3.2.2]nonanal, optionally substituted bicyclo[2.2.1]hept-2-enyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl or optionally substituted tetrahydrofuranyl.

In the nineteenth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, wherein R3represents A-D-E-G.

In the twentieth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where A is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

In �badcat the first embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where D represents optionally substituted azetidine, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C5-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl, or optionally substituted (C2-C10)heterocyclyl.

In the twenty-second embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where E is a bond, -Re-, -Re-C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)-Re-, -Re-N(Ra)S(O)2-Re-, -Re-N(Ra)C(O)N(Rb)-Reor Re-S(O)2N(Ra)-Re-.

In the twenty-third embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where G represents-ORa, CN, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), optional Deputy�ers (C 1-C6)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl or optionally substituted phenyl.

In the twenty-fourth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, wherein R3represents A-D-E-G and A is A bond, -C(O)-, optionally substituted (C1-C6)alkylene, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-, -N(Ra)-, -S-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-, -N(Ra)S(O)2- or-N(Ra)C(O)N(Rb)-.

In the twenty-fifth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where D represents optionally substituted azetidine, optionally substituted bicyclo[2.2.2]hoktanyan, optionally substituted bicyclo[2.2.1]heptylene, optionally substituted bicyclo[2.1.1]hexylen, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted bicyclo[2.2.1]hept-2-Anilin, optionally substituted piperidine, or optionally substituted pyrrolidin.

In the twenty-sixth embodiment, be implemented thr�of the present invention provides a compound in accordance with any of the preceding embodiments, where E is a-Re-C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-N(Ra)S(O)2-Reor Re-S(O)2N(Ra)Re.

In the twenty-seventh embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where G represents-ORa, -CN, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), optionally substituted (C1-C6)alkyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted phenyl, optionally substituted pyridazine, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrazole, optionally substituted pyrrolidine, optionally substituted hinzelin, optionally substituted pyridine, optionally substituted, thiazolidin or optionally substituted triazole.

In the twenty-eighth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where A represents A bond or optionally substituted (C1-C6)alkylen.

In the twenty-ninth embodiment �of sushestvennee the present invention provides a compound in accordance with any of the preceding embodiments, where D represents optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted azetidine, optionally substituted bicyclo[2.2.1]heptylene, optionally substituted bicyclo[2.1.1]hexylen, bicyclo[2.2.2]hoktanyan, optionally substituted piperidine, or optionally substituted pyrrolidin;

E is a-Re-C(O)-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)S(O)2-Re-, -Re-S(O)2-Reor Re-S(O)2N(Ra)-Re- where Rein each case represents independently a bond, optionally substituted (C1-C6)alkylene or optionally substituted (C3-C6)cycloalkyl; and

G represents-CN, optionally substituted (C1-C6)alkyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted phenyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrimidinyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted thiazolidines or optionally substituted triazolyl.

In the thirtieth embodiment of the present invent�tion offers a connection in accordance with any of the preceding embodiments, where D represents optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted azetidine, optionally substituted piperidine, optionally substituted bicyclo[2.2.1]heptylene, or bicyclo[2.2.2]hoktanyan.

In the thirty-first embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where G represents-CN, optionally substituted (C1-C6)alkyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted phenyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, optionally substituted pyrazolyl, or optionally substituted pyridinyl.

In the thirty-second embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where A is a bond, D represents optionally substituted cyclopentyl, optionally substituted bicyclo[2.2.2]octenyl, optionally substituted azetidine, or optionally substituted piperidine;

E is a-Re-C(O)-Re-, -Re-N(Ra)-Re-, -Re-S(O)2N(Ra)-Re-, -Re -S(O)2-Reor Re-N(Ra)S(O)2-Re-;

where Rein each case independently represents a bond or optionally substituted (C1-C6)alkylene; and

G represents-CN, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted phenyl, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted pyrazole or optionally substituted pyridine.

In the thirty-third embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where G represents-CN, optionally substituted cyclopropyl or optionally substituted cyclopentyl.

In the thirty-fourth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, wherein R1, R2, R4, R5and R6if present, each independently represents hydrogen or optionally substituted -(C1-C4)alkyl.

In the thirty-fifth embodiment of the present invention provides the compound according to the first, second, fourth, fifth, seventh and sixteenth to thirty-third embodiments, where the specified connection p�ecstasy a compound of formula (Ia)

Formula (Ia)

In the thirty-sixth embodiment of the present invention provides the compound according to the first, fourth, eighth and sixteenth to thirty-third embodiments, where the compound is a compound of formula (Ib)

Formula (Ib)

In the thirty-seventh embodiment of the present invention provides the compound according to the first, fourth, ninth, sixteenth to thirty-third embodiments, where the compound is a compound of formula (Ic)

Formula (Ic)

In the thirty-eighth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where T is a N, U represents N and X represents CR3andY represents N.

In the thirty-ninth embodiment of the present invention provides the compound according to the first, fourth, fifth, sixteenth to thirty-third embodiments, where the compound is a

In a fortieth embodiment of the present invention provides the compound according to the first, fourth, fifth, sixteenth to thirty-third embodiments, where the Union representative�possessing a

In the forty-first embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where the compound is a

In the forty-second embodiment of the present invention provides the compound according to the first to fourteenth embodiments, where A is a bond, D represents optionally substituted cyclopentyl or optionally substituted piperidine, E is a-Re-N(Ra)-Re-, -Re-S(O)2N(Ra)-Re-, -Re-C(O)-Re-, -Re- S(O)2-Re- or-Re-N(Ra)S(O)2-Re-; and G represents-CN, optionally substituted phenyl, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted pyrazole, or optionally substituted pyridine.

In the forty-third embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where T is a CR6.

In the forty-fourth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where U represents N.

In the forty-fifth embodiment of the present invent�their offers connection in accordance with any of the preceding embodiments, where X represents CR3.

In the forty-sixth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where Y represents N.

In the forty-seventh embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where T is a CR6U represents N and X represents CR3and Y is N.

In the forty-eighth embodiment of the present invention provides the compound according to the first to the fourth, eighth, sixteenth to thirty-third, thirty-sixth and forty-second to forty-seventh embodiments of the implementation, where the compound is a

In the forty-ninth embodiment of the present invention provides a compound in accordance with any of the preceding embodiments, where G is an optionally substituted phenyl, optionally substituted pyrazine, optionally substituted pyrazole, optionally substituted pyridazin or optionally substituted pyridine.

In a fiftieth embodiment of the present invention provides the compound according to the first to sixteenth embodiments, wherein R2and R5each independently represents odor�d, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -C(OH)RaRb, -N(Ra)S(O)2-Rb, -S(O)2N(Ra)(Rb), -CF3, -OCF3optionally substituted -(C1-C6)alkyl, optionally substituted -(C3-C6)cycloalkyl, optionally substituted benzo(b)thienyl, optionally substituted benzimidazol, optionally substituted benzofuran, optionally substituted benzoxazolyl, optionally substituted benzothiazole, optionally substituted benzothiadiazole, optionally substituted furan, optionally substituted imidazole, optionally substituted of indolin, optionally substituted indole, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted isoindoline, optionally substituted morpholine, optionally substituted oxadiazole, optionally substituted phenyl, optionally substituted piperazine, optionally substituted piperidine, optionally substituted PYRAN, optionally substituted pyrazole, optionally substituted pyrazolo[3,4-d]pyrimidine, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyrrolidine, optionally substituted �Errol, optionally substituted imidazo[2,3-d]pyrimidine, optionally substituted quinoline, optionally substituted thiomorpholine, optionally substituted tetrahydropyran, optionally substituted tetrahydrofuran, optionally substituted tetrahydroindole, optionally substituted thiazole, or optionally substituted thienyl.

In the fifty-first embodiment of the present invention provides the compound according to the first to sixteenth and forty-seventh embodiments, wherein R1is an optionally substituted C6-C10)aryl or optionally substituted (C1-C10)heteroaryl.

In the fifty-second embodiment of the present invention provides the compound according to the first to sixteenth, forty-seventh and fiftieth options, where R2represents hydrogen, halogen, -CN, -C(O)NRaRb, -CF3optionally substituted (C1-C6)alkyl, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C1-C10)heterocyclyl.

In the fifty-third embodiment of the present invention provides the compound according to the first to fifteenth, forty-seventh and COP�to ninth embodiments, where R1represents an optionally substituted azaindole, optionally substituted benzofuran, optionally substituted benzothiazole, optionally substituted benzoxazolyl, optionally substituted dihydropyrimido, optionally substituted furan, optionally substituted imidazole, optionally substituted imidazolate, optionally substituted imidazopyridine, optionally substituted imidazopyridine, optionally substituted indazol, optionally substituted indole, optionally substituted isoquinoline optionally substituted isothiazole, optionally substituted isoxazole, optionally substituted oxadiazole, optionally substituted oxazole, optionally substituted pyrazole, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyrazolopyrimidine, optionally substituted pyrrole, optionally substituted quinoline, optionally substituted hinzelin, optionally substituted thiazole, or optionally substituted thiophene.

In the fifty-fourth embodiment of the present invention provides the compound according to the first to fifteenth and forty-seventh to fifty-second embodiments, wherein R5represents hydrogen, halogen, NH2or N(Ra)(Rb).

In the fifty-fifth embodiment is�the implementation of the present invention provides the compound according to the first to fifteenth and forty-seventh to fifty-third embodiments, where T represents CH, U represents N, Y represents N and X represents CR3where R3is a (C1-C6)optionally substituted alkyl, (C3-C12)optionally substituted cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl.

In the fifty-sixth embodiment of the present invention provides the compound according to the first to fifteenth and forty-seventh to fifty-fourth embodiments, where R3represents an optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted, azetidin, optionally substituted (C6-C10)aryl, or optionally substituted (C1-C10)heterocyclyl.

In the fifty-seventh embodiment of the present invention provides the compound according to the first to fifteenth and forty-seventh to fifty-fourth embodiments, where T represents CH, U represents N, Y represents C and X represents NR3where R3is a (C1-C6)optionally substituted alkyl, (C3-C10)optionally substituted cycloalkyl, not�certainly substituted (C 6-C10)aryl, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl.

In the fifty-eighth embodiment of the present invention provides the compound according to the first to fifteenth and forty-eighth to fifty-seventh embodiments, wherein R3represents an optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted, azetidin, optionally substituted (C6-C10)aryl, or optionally substituted (C1-C10)heterocyclyl.

In the fifty-ninth embodiment of the present invention provides the compound according to the first to fifteenth and forty-eighth to fifty-eighth embodiments, where T is a N, U represents N, Y represents N and X represents CR3where R3is a (C1-C6)optionally substituted alkyl, (C3-C12)optionally substituted cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl.

In the sixtieth embodiment of the present invention provides a compound in accordance with feathers�first to fifteenth and forty-eighth to fifty-ninth embodiments, where R3represents an optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted, azetidin, optionally substituted (C6-C10)aryl, or optionally substituted (C1-C10)heterocyclyl.

In the sixty-first embodiment of the present invention provides use of a compound of formula 2:

Formula 2

to obtain the compound of formula (Ia)

Formula (Ia)

its pharmaceutically acceptable salt, prodrug, biologically active metabolites, stereoisomers and isomers, where

Rprepresents hydrogen, -SO2N(CH3)2, -SO2(2,4,6-trimethylphenyl), -SO2-phenyl, -SO2(4-butylphenyl), -SO2(4-methylphenyl), -SO2(4-methoxyphenyl), -C(O)OCH2CCl3, -C(O)OCH2CH2Si(CH3)3, -C(O)OC(CH3)3, -C(O)OC(CH3)2(CCl3), -C(O)O-1-adamantyl, -CH=CH2, -CH2CH2Cl, -CH(OCH2CH3)CH3, -CH2CH2-2-pyridyl, -CH2CH2-4-pyridyl, -Si(C(CH3)3)(CH3)2, -Si(CH(CH3)2)3, -CH2-phenyl, -CH2(4-CH3O-phenyl), -CH2(3,4-dimethoxyphenyl), -CH2(2-nitrophenyl), -(2,4-dinitrophenyl), -CH2C(O)Hairdryer�l, -C(phenyl)3, -CH(phenyl)2, -C(phenyl)2(4-pyridyl), -N(CH3)2, -CH2OH, -CH2OCH3, -CH(OCH2CH3)2, -CH2OCH2CH2Cl, -CH2OCH2CH2Si(CH3)3, -CH2OC(CH3)3, -CH2OC(O)C(CH3)3, -CH2OCH2-phenyl, -(2-tetrahydropyranyl), -C(O)H, or-P(S)(phenyl)2;

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra- (IT)RaRb, -N(Ra)S(O)2-Rb, -S(O)2N(Ra)(Rb)-, -, -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl linearization substituted (C 2-C10)heteroaryl connected through the nitrogen;

R3represents hydrogen, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted bridged (C2-C10)heterocyclyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl or optionally substituted (C2-C10)heterocyclyl; or

R3is a-A-D-E-G, where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)-Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12/sub> )cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

E is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, Re-C(O)C(O)N(Ra)-Re-, Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-OC(O)-Re-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

E represents

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN,- C(O)N(R a)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb-, -OC(O)N(Ra)-, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, optionally substituted -(C6-C10)aryl, optionally substituted -(C1-C6)alkyl-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

Raand Rbindependent performance�control a hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkylen-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl; and

Rein each case, independently is a bond, optionally substituted (C1-C10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkyl group, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or the optional�individual substituted (C 1-C10)heterocyclyl;

In sixty-second embodiment of the present invention provides use of a compound of formula 3:

Formula 3

to obtain the compound of formula (Ib)

Formula (Ib)

its pharmaceutically acceptable salt, prodrug, biologically active metabolites, stereoisomers and isomers, where

Rprepresents hydrogen, -SO2N(CH3)2, -SO2(2,4,6-trimethylphenyl), -SO2-phenyl, -SO2(4-butylphenyl), -SO2(4-methylphenyl), -SO2(4-methoxyphenyl), -C(O)OCH2CCl3, -C(O)OCH2CH2Si(CH3)3, -C(O)OC(CH3)3, -C(O)OC(CH3)2(CCl3), -C(O)O-1-adamantyl, -CH=CH2, -CH2CH2Cl, -CH(OCH2CH3)CH3, -CH2CH2-2-pyridyl, -CH2CH2-4-pyridyl, -Si(C(CH3)3)(CH3)2, -Si(CH(CH3)2)3, -CH2-phenyl, -CH2(4-CH3O-phenyl), -CH2(3,4-dimethoxyphenyl), -CH2(2-nitrophenyl), -(2,4-dinitrophenyl), -CH2C(O)phenyl, -C(phenyl)3, -CH(phenyl)2, -C(phenyl)2(4-pyridyl), -N(CH3)2, -CH2OH, -CH2OCH3, -CH(OCH2CH3)2, -CH2OCH2CH2Cl, -CH2OCH2CH2Si(CH3)3, -CH2OC(CH3)3, -CH2OC(O)C(CH 3)3, -CH2OCH2-phenyl, -(2-tetrahydropyranyl), -C(O)H, or-P(S)(phenyl)2;

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -C(OH)RaRb, -N(Ra)S(O)2-Rb, -S(O)2N(Ra)(Rb), -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R3represents hydrogen, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted bridged (C2-C10)heterocyclyl, optional�tive substituted (C 1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10) heterocyclyl; or

R3is a-A-D-E-G, where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen optionally substituted (C 1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

E is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, Re-C(O)C(O)N(Ra)-Re-, Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-OC(O)-Re-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Reor Re-S(O)2N(Ra)-Re-; or

E represents;

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -OC(O)N(Ra)-, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rbnot necessarily samewe�tion -(C 1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, optionally substituted -(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R6represents hydrogen, halogen, deuterium, an optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, not�certainly substituted (C 3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl or-J-L-M-Q;

where:

J is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

L is a bond, optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl�h or optionally substituted (C 2-C10)heterocyclyl;

M is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, -Re-OC(O)-Re-, -Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

M represents;

where in all cases, M associated with either a carbon atom or a nitrogen atom in L;

Q represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, NeoMaster�of substituted (C 3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

Raand Rbeach independently represents hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkylen-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optional�individual substituted (C 1-C10)heterocyclyl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl; and

Rein each case, independently is a bond, optionally substituted (C1-C10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkylenes group, an optionally substituted C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl;

In sixty-third embodiment of the present invention provides use of a compound of formula 4:

Formula 4

to obtain the compound of formula (Ic)

Formula (Ic)

or its pharmaceutically acceptable salt, prodrug, biologically active metabolites, stereoisomers and isomers, where

Rsup> p1represents hydrogen, -SO2N(CH3)2, -SO2(2,4,6-trimethylphenyl), -SO2-phenyl, -SO2(4-butylphenyl), -SO2(4-methylphenyl), -SO2(4-methoxyphenyl), -C(O)OCH2CCl3, -C(O)OCH2CH2Si(CH3)3, -C(O)OC(CH3)3, -C(O)OC(CH3)2(CCl3), -C(O)O-1-adamantyl, -CH=CH2, -CH2CH2Cl, -CH(OCH2CH3)CH3, -CH2CH2-2-pyridyl, -CH2CH2-4-pyridyl, -Si(C(CH3)3)(CH3)2, -Si(CH(CH3)2)3, -CH2-phenyl, -CH2(4-CH3O-phenyl), -CH2(3,4-dimethoxyphenyl), -CH2(2-nitrophenyl), -(2,4-dinitrophenyl), -CH2C(O)phenyl, -C(phenyl)3, -CH(phenyl)2, -C(phenyl)2(4-pyridyl), -N(CH3)2, -CH2OH, -CH2OCH3, -CH(OCH2CH3)2, -CH2OCH2CH2Cl, -CH2OCH2CH2Si(CH3)3, -CH2OC(CH3)3, -CH2OC(O)C(CH3)3, -CH2OCH2-phenyl, -(2-tetrahydropyranyl), -C(O)H, or-P(S)(phenyl)2;

Rp2represents hydrogen, -C(O)O-C(CH3)3, -C(O)OCH2-phenyl, -C(O)O-fluoren-9-yl, -C(O)CH3, -C(O)CF3, -C(O)-CH(CH3)2, -CH2-phenyl, -CH2-(4-methoxyphenyl), -S(O)2-phenyl, or-S(O)2-(4-methylphenyl);

R1, R2and R5each independently represents hydrogen, datari�, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -C(OH)RaRb, -N(Ra)S(O)2-Rb, -S(O)2N(Ra)(Rb), -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R3represents hydrogen, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted bridged (C2-C10)heterocyclyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optional Deputy�ers (C 6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl; or

R3is a-A-D-E-G, where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2 -C10)heterocyclyl;

E is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-OC(O)-Re-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

E represents;

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -OC(O)N(Ra), -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, not�certainly substituted -(C 3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, optionally substituted -(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R4represents hydrogen, halogen, deuterium, an optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)hetero�aryl, optionally substituted (C2-C10)heterocyclyl or-J-L-M-Q;

where:

J is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

L is a bond, optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

M is a bond, -Re-, -Re-C(O)-Re-, -Re -C(O)C(O)-Re-, -Re-C(O)O-Re-, -Re-OC(O)-Re-, -Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

M represents;

where in all cases, M associated with either a carbon atom or a nitrogen atom in L;

Q represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroarm�l, optionally substituted (C1-C10)heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

Raand Rbeach independently represents hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkylen-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1 -C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl; and

Rein each case, independently is a bond, optionally substituted (C1-C10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkylenes group, an optionally substituted C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl.

In the sixty-fourth embodiment of the present invention provides use of a compound of formula 5

Formula 5

to obtain the compound of formula (Id)

Formula (Id)

its pharmaceutically acceptable salt, prodrug, biologically active metabolites, stereoisomers and isomers, where

Rprepresents hydrogen, -SO2N(CH3)2, -S 2(2,4,6-trimethylphenyl), -SO2-phenyl, -SO2(4-butylphenyl), -SO2(4-methylphenyl), -SO2(4-methoxyphenyl), -C(O)OCH2CCl3, -C(O)OCH2CH2Si(CH3)3, -C(O)OC(CH3)3, -C(O)OC(CH3)2(CCl3), -C(O)O-1-adamantyl, -CH=CH2, -CH2CH2Cl, -CH(OCH2CH3)CH3, -CH2CH2-2-pyridyl, -CH2CH2-4-pyridyl, -Si(C(CH3)3)(CH3)2, -Si(CH(CH3)2)3, -CH2-phenyl, -CH2(4-CH3O-phenyl), -CH2(3,4-dimethoxyphenyl), -CH2(2-nitrophenyl), -(2,4-dinitrophenyl), -CH2C(O)phenyl, -C(phenyl)3, -CH(phenyl)2, -C(phenyl)2(4-pyridyl), -N(CH3)2, -CH2OH, -CH2OCH3, -CH(OCH2CH3)2, -CH2OCH2CH2Cl, -CH2OCH2CH2Si(CH3)3, -CH2OC(CH3)3, -CH2OC(O)C(CH3)3, -CH2OCH2-phenyl, -(2-tetrahydropyranyl), -C(O)H, or-P(S)(phenyl)2;

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -C(OH)RaRb, -N(Ra)S(O)2-Rb, -S(O)2N(Ra)(Rb), -CF3, -OCF3optionally substituted (C1 6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R3represents hydrogen, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted bridged (C2-C10)heterocyclyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl; or

R3is a-A-D-E-G, where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optional someseni� (C 2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

E is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, - e-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-OC(O)-Re-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

E represents;

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -OC(O)N(Ra), -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10)heterocyclyl, optionally substituted -(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cyclo�lcil, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkyl-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R4and R6each independently represents hydrogen, halogen, deuterium, an optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl or-J-L-M-Q;

where:

J is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optional samisen�th (C 2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

L is a bond, optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

M is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, -Re-OC(O)-Re-, -Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re -, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

M represents;

where in all cases, M associated with either a carbon atom or a nitrogen atom in L;

Q represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkyl-(C6 -C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbcan form a ring, so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

Raand Rbeach independently represents hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkylen-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C )alkylene-(C1-C10)heterocyclyl; and

Rein each case, independently is a bond, optionally substituted (C1-C10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkylenes group, an optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl.

In the sixty-fifth embodiment of the present invention provides use of a compound of formula 6

to obtain compounds of formula (Ig) or formula (If) or formula (Ii)

their pharmaceutically acceptable salts, prodrug, biologically active metabolites, stereoisomers and isomers, where

Rprepresents hydrogen, -SO2N(CH3)2, -SO2(2,4,6-trimethylphenyl), -SO2-phenyl, -SO2(4-butylphenyl), -SO2(4-methylphenyl), -SO2(4-methoxyphenyl), -C(O)OCH2CCl3, -C(O)OCH2CH2Si(CH3)3, -C(O)OC(CH3)3, -C(O)OC(CH3)2(CCl3), -C(O)O-1-adamant�l, -CH=CH2, -CH2CH2Cl, -CH(OCH2CH3)CH3, -CH2CH2-2-pyridyl, -CH2CH2-4-pyridyl, -Si(C(CH3)3)(CH3)2, -Si(CH(CH3)2)3, -CH2-phenyl, -CH2(4-CH3O-phenyl), -CH2(3,4-dimethoxyphenyl), -CH2(2-nitrophenyl), -(2,4-dinitrophenyl), -CH2C(O)phenyl, -C(phenyl)3, -CH(phenyl)2, -C(phenyl)2(4-pyridyl), -N(CH3)2, -CH2OH, -CH2OCH3, -CH(OCH2CH3)2, -CH2OCH2CH2Cl, -CH2OCH2CH2Si(CH3)3, -CH2OC(CH3)3, -CH2OC(O)C(CH3)3, -CH2OCH2-phenyl, -(2-tetrahydropyranyl), -C(O)H, or-P(S)(phenyl)2;

Rxrepresents hydrogen, fluorine, chlorine, bromine, iodine, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2phenyl, or-OS(O)2(4-methylphenyl);

R1, R2and R5each independently represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)(Rb), -C(O)Ra, -C(OH)RaRb, -N(Ra)S(O)2-Rb, -S(O)2N(Ra)(Rb), -CF3, -OCF3optionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (Csub> 2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, or optionally substituted (C6-C10)aryl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R3represents hydrogen, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted bridged (C2-C10)heterocyclyl, optionally substituted (C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl; or

R3is a-A-D-E-G, where:

A represents A bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, neoblast�flax substituted (C 3-C12)cycloalkyl, optionally substituted (C2-C6)heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

D represents optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

E is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra )-Re-, -Re-N(Ra)C(O)ORe-, -Re-OC(O)-Re-, -Re-N(Ra)C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

E represents;

where in all cases, E is associated with either a carbon atom or a nitrogen atom in D;

G represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -OC(O)N(Ra), -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted -(C1-C6)alkyl, optionally substituted -(C2-C6)alkenyl, optionally substituted -(C2-C6)alkynyl, optionally substituted -(C3-C10)cycloalkyl, optionally substituted -(C1-C10)heteroaryl, optionally substituted -(C1-C10) heterocyclyl, optionally substituted -(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted-(C 1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

R6represents hydrogen, halogen, deuterium, an optionally substituted bridged (C5-C12)cycloalkyl group, optionally substituted bridged (C2-C10)heterocyclyl group, an optionally substituted C1-C8)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C8)cycloalkenyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C2-C10)heterocyclyl or-J-L-M-Q;

where:

J is a bond, -C(O)-, optionally substituted (C1-C6)alkylene, optionally substituted (C2-C6)alkanine, optionally substituted (C2-C6)akinyan, optionally substituted (C3-C12)cycloalkyl, optionally substituted (C2-C6)�heterocyclyl, -C(O)N(Ra)-Re-, -N(Ra)C(O)-Re-, -O-Re-, -N(Ra)-Re-, -S-Re-, -S(O)2-Re-, -S(O)Re-, -C(O-Ra)(Rb)-Re-, -S(O)2N(Ra)-Re-, -N(Ra)S(O)2-Re- or-N(Ra)C(O)N(Rb)-Re-;

L is a bond, optionally substituted (C1-C8)alkylene, optionally substituted bridged (C5-C12)cycloalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted bridged (C5-C10)cycloalkenyl, optionally substituted (C3-C10)cycloalkenyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, optionally substituted bridged (C2-C10)heterocyclyl or optionally substituted (C2-C10)heterocyclyl;

M is a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)C(O)-Re-, -Re-C(O)O-Re-, -Re-OC(O)-Re-, -Re-C(O)C(O)N(Ra)-Re-, -Re-N(Ra)-C(O)C(O)-ORe-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-S(O)-Re-, -Re-S-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-OC(O)N(Ra)-Re-, -Re-N(Ra)C(O)ORe-, -Re-N(Ra )C(O)N(Rb)-Re-, -Re-N(Ra)S(O)2-Re- or-Re-S(O)2N(Ra)-Re-; or

M represents;

where in all cases, M associated with either a carbon atom or a nitrogen atom in L;

Q represents hydrogen, deuterium, -N(Ra)(Rb), halogen, -ORa, -SRa, -S(O)Ra, -S(O)2Ra, -NO2, -C(O)ORa, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -N(Ra)C(O)ORb, -N(Ra)C(O)N(Rb)2, -C(O-Ra)(Rb)2, -C(O)Ra, -CF3, -OCF3, -N(Ra)S(O)2Rb, -S(O)2N(Ra)(Rb), -S(O)2N(Ra)C(O)Rboptionally substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10) heterocyclyl, optionally substituted (C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C )alkylene-(C1-C10)heterocyclyl;

where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted C2-C10)heterocyclyl or optionally substituted (C1-C10)heteroaryl connected through the nitrogen;

Raand Rbeach independently represents hydrogen, deuterium, an optionally substituted C1-C10)alkyl, optionally substituted (C2-C10)alkenyl, optionally substituted (C2-C10)alkynyl, optionally substituted (C1-C10)alkyl-O-(C1-C10)alkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C6-C10)aryl, optionally substituted (C1-C10)heteroaryl, optionally substituted (C1-C10)heterocyclyl, optionally substituted -(C1-C6)alkylene-(C3-C10)cycloalkyl, optionally substituted -(C1-C6)alkylene-(C6-C10)aryl, optionally substituted -(C1-C6)alkylene-(C1-C10)heteroaryl, or optionally substituted -(C1-C6)alkylene-(C1-C10)heterocyclyl; and

Rein each case, independently is a bond, optionally substituted (C1C 10)alkylene, optionally substituted (C2-C10)alkanine, optionally substituted (C2-C10)akinyan, optionally substituted -(C1-C10)alkylen-O-(C1-C10)alkylenes group, an optionally substituted C3-C10)cycloalkyl, optionally substituted (C6-C10)Allen, optionally substituted (C1-C10)heteroaryl, or optionally substituted (C1-C10)heterocyclyl.

In the sixty-sixth embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to claim 1

Formula (I)

pharmaceutically acceptable carrier and excipient and a second therapeutic agent selected from the group consisting of a cytokine-suppressing anti-inflammatory drugs, antibodies to other human cytokines or antagonists of other human cytokines or growth factors, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, PDGF, CTLA or their ligands including D154, HUMIRA™, REMICADE™, SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571, and soluble p55 or p75 TNF receptors, ENBREL™, lenercept, inhibitors of TNFα-converting enzyme inhibitors, IL-1, interleukin 11, antagonists of IL-18 antagonists, IL-12, antibodies against IL-12, soluble receptors of IL-12 proteins that bind L-12, sustainable anti-CD4 inhibitors FK506, rapamycin, of mycophenolate mofetil, Leflunomide, NSAID, ibuprofen, corticosteroids, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, inhibitors of complement, adrenergic agents, inhibitors of IL-11β-converting enzyme inhibitors signaling system T-cells, inhibitors of metalloproteinases, sulfasalazine, 6-mercaptopurine derived p75TNFRIgG, sIL-1RI, sIL-1RII, sIL-6R, celecoxib, hydroxylaminsulphate, rofecoxib, infliximab, naproxen, valdecoxib, sulfasalazine, meloxicam, acetate, nutritional gold, aspirin, triaminobenzene, propoxyphene napsylate/Arar (acetaminophen), folate, nabumetone, diclofenac, piroxicam, etodolac, diclofenac-sodium, oxaprozin, oxycodone HCl, the hydrocodone bitartrate/apap, diclofenac sodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronate sodium, martinslife, lidocaineydrocortisone, indomethacin, glucoseinsulin/chondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, VX-740, roflumilast, IC-485, CDC-801, S1P1 agonists, FTY720, inhibitors of the PKC family, ruboxistaurin, AEB-071, mesopram, methotrexate, Leflunomide, corticosteroids, �adenoid, dexamethasone, sulfasalazine, 5-aminosalicylic acid, olsalazine, inhibitors of IL-1β - converting enzyme, IL-1ra, inhibitors of the signaling system T-cells, the tyrosine kinase inhibitors, 6-mercaptopurine, IL-11, mesalamine, prednisone, azathioprine, mercaptopurine, infliximab, metilprednisolona sodium, Diphenoxylate/atrop such as atropine sulfate, loperamidesee, omeprazole, folate, ciprofloxacin/dextrose-water, hydrocodone, bitartrate/apap, tetracyclinetoprol, fluocinonide, metronidazole, thimerosal/boric acid, cholestyramine/sucrose, ciprofloxacinciprofloxacin, histaminergic, piperidinedione, midazolam.hydrocodone, oxycodone HCl/acetaminophen, promethazineodeine, nutrifaster, sulfamethoxazole/trimethoprim, polycarbophil, propoxyphenyl, hydrocortisone, multivitamins, dinitrobenzoate, codeinefosfaat/apap, colesevelam HCl, cyanocobalamin, folic acid, levofloxacin, natalizumab, gamma interferon, methylprednisolone, azathioprine, cyclophosphamide, cyclosporine, methotrexate, 4-aminopyridine, tizanidine, interferon-β1a, AVONEX®, interferon-β1b, BETASERON®, interferon α-n3, interferon-α, interferon β1A-IF, peginterferon α 2b, copolymer 1, COPAXONE®, hyperbaric oxygen, intravenous immunoglobulin, cladribine, cyclosporine, FK506, mycophenolate mofetil, Leflunomide, NSAID, corticosteroids, prednisolone, inhibitors of f�spadester, the adenosine agonists, antithrombotic agents, inhibitors of complement, adrenergic agents, anti-inflammatory cytokines, interferon-β, IFNβ1a, IFNβ1b, Copaxone, corticosteroids, caspase inhibitors, inhibitors of caspase-1, antibodies to CD40 ligand and CD80, alemtuzumab, dronabinol, impact, mitoxantrone, calyptomeridae, Fampridine, latinamerica, natalizumab, cannabidiol, α-immunogen NNSO3, ABR-215062, AnergiX.MS, antagonists of chemokine receptors, BBR-2778, calaguala, CPI-1189, incorporated in liposomes mitoxantrone, THC.CBD, agonists cannabinoid, MBP-8298, mesopram, MNA-715, an antibody against IL-6 receptor, neurovax, perpendicular 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, diplomatic, antagonists of VLA-4 antagonists, gamma-interferon, agonists of IL-4, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, methotrexate, azathioprine, minocycline, prednisone, etanercept, rofecoxib, sulfasalazine, naproxen, Leflunomide, acetylaminophenol, indomethacin, hydroxylaminsulphate, prednisone, sulindac, betamethasone diprop (dipropionate) (reinforced), infliximab, methotrexate, folate, triamcinolone, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, Ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluorine�ID, glucoseinsulin, nutritionalist gold, hydrocodonebitartrat/apap, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, efalizumab, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin, COX2 inhibitors, rofecoxib, valdecoxib, hydroxychloroquine, steroids, prednisone, budenoside, dexamethasone, cytotoxic drugs, azathioprine, cyclophosphamide, of mycophenolate mofetil, PDE4 inhibitors, the inhibitor of the synthesis of purine, sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®, CTLA-4-IgG, antibodies against B7 family antibodies against the family of PD-1, anti-cytokine antibodies, fontolizumab, antibody against IFNg, antireceptor antibodies, antibodies against the receptor of IL-6, antibodies against surface molecules on B-cells, LJP 394, rituximab, an antibody against CD20 and lymphostat-B.

A DETAILED DESCRIPTION of the INVENTION

Protein kinases represent a large and diverse class of more than 500 enzymes, which includes oncogenes, receptors of growth factors, the intermediate signal transduction associated with apoptosis kinase and cyclin-dependent kinases. They are responsible for transferring a phosphate group to specific tyrosine, serine or treningowy amino acid residues, and, in General, are classified as tyrosine and serine/threonine kinase, as a result of their substrate specificity.

To�called the Jak family (Jak1, Jak2, Jak3 and Tyk2) are zitoplazmaticeski tyrosine kinase, which is associated with associated with membranes of cytokine receptors. The binding of cytokines to their receptors triggers the activation of Jak kinases by the processes of TRANS - and autophosphorylation. The activated Jak kinases fosfauriliruet balances on cytokine receptors, creating binding sites of phosphotyrosine for SH2 domain containing proteins, such as activators of signal transduction of transcription factors (STAT) and other regulators of signal transduction, such as SOCS proteins and phosphatase SHIP. Activation of STAT factors at the expense of such processes leads to their dimerization, nuclear translocation and new mRNA transcription, which leads to the expression of the proliferation of immunocytes and survival factors, as well as additional cytokines, chemokines and molecules that facilitate cell traffic (seeJournal of Immunology,2007, 178, p. 2623). Jak kinase transducer signals for many different families of cytokines and therefore potentially play a role in diseases with widely differing pathologies, including, but not limited to, the following examples. And Jak1 and Jak3 regulate signaling pathways of the so-called common gamma-chain cytokines (IL2, IL4, IL7, IL9, IL15 and IL21), therefore, simultaneous inhibition, or inhibition or Jak1 or Jak3 can cause contribute forecast�s effect on Th1-mediated diseases, such as rheumatoid arthritis, because of the blockade of the signaling system IL2, IL7 and IL15. On the other hand, it has recently been shown that signaling system IL2 is essential for the development and homeostasis of T-regulatory cells (Malek T R et. al.,Immunity,2002, 17(2), p. 167-78). Thus, on the basis of genetic data suggest that the blockade only IL2 signaling system affect immunity (Yamanouchi J, et al.,Nat. Genet.,2007, 39(3), p. 329-37, and Willerford D M et al.,Immunity,1995, 3(4), p. 521-30). Th2 mediate diseases, such as asthma or atopic dermatitis, due to the blockade of the signaling system IL4 and IL9. Jak1 and Tyk2 mediate signals IL13 (see Int. Immunity, 2000, 12 p. 1499). Therefore, one can assume that their blockade will exert its therapeutic effect in the case of asthma. Consider also that these two kinases mediate the signals of interferon type I; therefore, they suggest that their blockade will reduce the severity of systemic lupus erythematosus (SLE). Tyk2 and Jak2 mediates the signals of IL12 and IL23. Indeed, blockade of these cytokines using monoclonal antibodies have been effective in the treatment of psoriasis. We can therefore assume that the blockade of this scheme using inhibitors of these kinases will be effective in the treatment of psoriasis. In the end, in the present invention discloses low molecular weight compounds that inhibit, regulate and/or modulate the activity of CIN�W Jak family, which are the basis of several mechanisms, which are considered critical for the development of autoimmune diseases, including, but not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Crohn's disease, psoriasis and asthma.

Some pathologically significant cytokines carry signals only via Jak1 (Guschin D, et al.,EMBO J.1995 Apr. 3; 14(7):1421-9; Parganas E, et al.,Cell.1998 May 1; 93(3):385-95; Rodig, S. J., et al.,Cell.1998 May 1; 93(3):373-83). It has been shown that the blockade of one of them, IL6, using neutralizing IL6R antibody, significantly improves the performance of the disease in patients with rheumatoid arthritis (N. Nishimoto et al.,Ann Rheum Dis.,2007, 66(9), p. 1162-7). Similarly, blockade of the signaling system GCSF, which are also mediated only one Jak1, using neutralizing monoclonal antibodies or nesenevich gene deletions protects mice against experimentally induced arthritis (K. E. Lawlor et al.,Proc Natl Acad Sci U. S. A.,2004, 101(31), p. 11398-403). Accordingly, identification of low molecular weight compounds that inhibit, regulate and/or modulate the signal transduction of kinases, such as Jak1, is a desirable tool for the prevention or treatment of autoimmune diseases or other disorders associated with aberrant function of Jak1.

Jak2 also are activated by a wide range of cancer Soboleva�th person such as prostate cancer, rectal cancer, ovarian and breast cancers, melanoma, leukemia and other hematopoietic malignancies. In addition, it was found that somatic point mutations Jak2 gene is closely related to classical myeloproliferative disorders (MPD) and rarely with other myeloid disorders. Constitutive activation of Jak2 activity is also called chromosomal translocation in hematopoietic malignancies. It was also shown that the inhibition of the way Jak/STAT, and especially the inhibition of the activity of Jak2 leads to anti-proliferative and Pro-apoptotic effects largely through inhibition of STAT phosphorylation. Moreover, pharmacological modulation or inhibition of Jak2 activity is able to effectively block tumor growth and induce apoptosis by reducing STAT phosphorylation in cell culture and in the case of tumor xenografts in humansin vivo. Accordingly, identification of low molecular weight compounds that inhibit, regulate and/or modulate the signal transduction of kinases, particularly Jak2, it may be desirable as a means of treatment or prophylaxis of diseases and conditions associated with cancer.

Jak kinases also carry signals, adjusting�tion of important physiological processes, the inhibition of which may be undesirable. For example, Jak2 mediates signaling system erythropoietin (Epo) and the factor stimulating granulocyte/monocyte-colony. In individuals with genetic, congenital or acquired defects with the schemes of signal transmission can develop potentially life-threatening complications, such as anemia and neutrophil dysfunction. Accordingly, one non-limiting aspect of the present invention also relates to a method of identifying compounds that can have a favorable security profile as a result of the fact that they selectively avoid inhibition of Jak2.

A family of protein kinases C is a group of serine/threonine kinases, which includes twelve related isoenzymes. Its members are encoded by different genes, and are divided into subclasses according to their requirements in relation to activation. Classic enzymes (cPKC) to require activation of diacylglyceride (DAG), phosphatidylserine (PS) and calcium. New PKC (nPKC) require DAG and PS, but are calcium-independent. Atypical PKC (aPKC) do not require calcium or DAG.

Rxdata is a member of the nPKC subfamily (Baier, G., et al.,J. Biol. Chem.,1993, 268, 4997). He has limited scheme expression, found primarily in T-cells and skeletal muscle (Mischak, H. et al.,FEBS Lett.,1993, 326, p. 51, and reported some expression in fat cells (Liu, Y. et al.,J. Leukoc. Biol.,2001, 69, p. 831) and endothelial cells (Mattila, P. et al.,Life Sci.,1994, 55, p. 1253).

After the activation of T-cells supramolecular activation complex (SMAC) forms at the site of contact between T cells and antigen-presenting cells (APC). Rxdata is the only PKC isoform, which is detected, localized at SMAC (Monks, C. et al.,Nature,1997, 385, 83), bringing it closer to other signaling enzymes, which mediate the activation of T-cells.

In another study (Baier-Bitterlich, G. et al.,Mol. Cell. Biol.,1996, 16, 842) confirmed the role of Rxdata in the activation of AP-1, transcription factor, which plays an important role in the activation of the IL-2 gene. In restimulating T-cells constitutive active Rxdata stimulate AP-1 activity, whereas in cells with dominant negative Rxdata, AP-1 activity is not induced after activation through PMA.

In other studies demonstrated that Rxdata, due to the activation of IκB kinase beta, mediates the activation of NF-κB caused by stimulation of the T cell receptor/CD28 (N. Coudronniere et al.,Proc. Nat. Acad. Sci. U. S. A.,2000, 97, p. 3394; and Lin, X. et al.,Mol. Cell. Biol.,2000, 20, p. 2933).

Proliferation of peripheral T cells from Rxdata knock-out mice in response to stimulation of the T cell receptor(TCR)/CD28 markedly reduced by �compared with stimulation to T cells from wild type mice. In addition, also significantly reduced the amount of IL-2, isolated from T cells (Sun, Z. et al.,Nature,2000, 404, p. 402). It was also shown that Rxdata-deficient mice show attenuated inflammation of the lungs and reduced airway hyperreactivity (AHR) in the model of Th2-dependent asthma in mice, in the absence of defects in viral clearance and functions of Th1-dependent cytotoxic T-cells (Berg-Brown, N. N. et al.,J. Exp. Med.,2004, 199, p. 743; Marsland, B. J. et al.,J. Exp. Med.,2004, 200, p. 181). Attenuated Th2 cell responses lead to low levels of IL-4 and immunoglobulin E (IgE), which contributes to AHR and pathophysiology of inflammation. In other respects, Rxdata knock-out mouse seemed to be healthy and fertile.

There is also evidence that Rxdata participate in mediated IgE receptors (FcεRI) reaction of mast cells (Liu, Y. et al.,J. Leukoc. Biol.,2001, 69, p. 831). It was demonstrated that in cultured human fat cells (HCMC), the activity of PKC kinase quickly is localized on the membrane with subsequent cross-linking FcεRI (Kimata, M. et al.,Biochem. Biophys. Res. Commun.,1999, 257(3), p. 895). Recent studies in vitro activity of mast cells bone marrow (BMMC), obtained from wild type mice and Rxdata-deficient mice showed that after cross-linking with FceRI, BMMC Rxdata-deficient mice reduced the levels of IL-6, factor-alpha �of krosa tumors (TNFα) and IL-13 compared with BMMC in mice wild-type, that suggests the potential role of Rxdata in the generation of cytokine fat cells, in addition to activation of T cells (Ciarletta, A. B. et al., poster presentation at conference 2005 American Thoracic Society International Conference).

The above-cited study, like other studies confirm the critical role of Rxdata in the activation of T-cells and in the signal system mast cells (MC). Thus, inhibitors of Rxdata can provide therapeutic benefits in the treatment of immunological disorders and other diseases mediated by inappropriate activation of T cells and signal MC.

It was discovered that many kinases, whether receptor or preceptories tyrosine kinase, or a S/T kinase involved in cellular pathways signaling is involved in numerous pathological conditions, including immunomodulation, inflammation, or proliferative disorders such as cancer.

Many autoimmune diseases and diseases associated with chronic inflammation as well as acute reactions are associated with excessive or disordered production or activity of one or more cytokines.

Compounds of the present invention can also be used to treat cardiovascular disorders such as acute myocardial infarction, acute coronary syndrome, chronic heart failure, INF�of LV myocardium, atherosclerosis, viral myocarditis, cardiac rejection and cardiac allograft dysfunction associated with sepsis. In addition, the compounds of the present invention can also be used for treating disorders of the Central nervous system, such as meningococcal meningitis, Alzheimer's disease and Parkinson's disease.

Compounds of the present invention can also be used in the treatment of eye diseases, cancer, solid tumors, sarcomas, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, hypersensitivity reactions, hyperkinetic movement disorders, hypersensitivity pneumonitis, hypertension, hypokinetic disorders of movement, aortic aneurysm and peripheral aneurysms, to assess the hypothalamic-pituitary-adrenal axis, dissections of the aorta, arterial hypertension, arteriosclerosis, arteriovenous fistula, ataxia, spinocerebellar degenerations, streptococcal myositis, structural ulcers cerebellum, subacute sclerosing panencephalitis, syncope, syphilis of the cardiovascular system, systemic anaphylaxis, systemic inflammatory response syndrome, the occurrence of systemic juvenile rheumatoid arthritis, T-cell or FAB ALL, telangiectasia, thromboangitis (thromboangitis obliterans), when a transplant�the Nations, with bleeding injuries, when hypersensitivity reactions type III, type IV hypersensitivity, unstable angina, for the treatment of uremia, urosepsis, urticaria, diseases of the heart valves, varicose veins, vasculitis, venous diseases, venous thrombosis, ventricular atrial, viral and fungal infections, vital encephalitis/aseptic meningitis, a life-threatening hemophagocytic syndrome, Wernicke-Korsakov, Wilson's disease, rejection of the xenograft any organs or tissues, rejection of the transplanted heart, hemachromatosis, hemodialysis, for treatment of syndrome hemolytic uremia/thrombolytic thrombocytopenia purpura, bleeding, for the treatment of idiopathic pulmonary fibrosis, antibody-mediated cytotoxicity, asthenia, infantile spinal muscular atrophy, inflammation of the aorta, influenza A, when exposed to ionizing radiation for the treatment of iridocyclitis/uveitis/optic neuritis, juvenile spinal muscular atrophy, lymphoma, myeloma, leukemia, malignant ascites, hematopoietic cancers, diabetic conditions, such as insulin-dependent glaucoma associated with diabetes, diabetic retinopathy or microangiopathy, for the treatment of sickle-cell anaemia, chronic inflammation, glomer�of anerica, transplant rejection, Lyme disease, disease von Hippel-Lindau, pemphigoid, Paget's disease, fibrosis, sarcoidosis, cirrhosis, tirodite, of hyperviscosity syndrome, disease Osler-Weber-Rendu, chronic occlusive pulmonary disease, asthma or edema after burns, trauma, radiation, stroke, for the treatment of hypoxia, ischemia, ovarian hyperstimulation syndrome, postperfusion syndrome, postperfusion syndrome, post-MI cardiotonicescoe syndrome, preeclampsia, menometrorrhagia, endometriosis, pulmonary hypertension, infantile hemangioma, or for the treatment of herpes simplex, herpes zoster, in the treatment of diseases, caused by the virus human immunodeficiency, parapoxvirus, protozoa or in the treatment of toxoplasmosis, progressive supranuclear paralysis (progressive supranucleo palsy), for the treatment of primary pulmonary hypertension, radiation therapy, Raynaud's phenomenon, for the treatment of Raynaud's disease, disease Refsum, regular narrow QRS tachycardia, regular narrow QRS tachycardia), renal vascular hypertension, obliterative cardiomyopathy, sarcomas, senile chorea, senile dementia type illness diffuse Taurus Levi, shock, rejection, skin allograft syndrome skin changes, swelling of the eye or macular degeneration, neovascular eye diseases, of scleritis, radial keratotomy for the treatment of uveitis, vitrite, myopia, pits of the optic nerve, chronic retinal detachment, of complications after laser irradiation, conjunctivitis, diseases of Stargardt, disease Ilza, retinopathy degeneration of the corpus luteum, restenosis, ischemia/reperfusion lesions, ischemic stroke, of occlusion, carotid obstructive disease, ulcerative colitis, inflammatory bowel disease, diabetes, diabetes mellitus, insulin-dependent diabetes mellitus, allergic diseases, sclerodermalike dermatitis, graft versus host rejection when transplanted organ (including but not limited to, rejection of bone marrow and solid organs), for the treatment of acute or chronic immune disease associated with organ transplantation, sarcoidosis, diffuse intravascular coagulation, Kawasaki disease, nephrotic syndrome, chronic completeness, granulomatosa granulomatosis, Henoch purpura Is Henoch, microscopic vasculitis of the kidneys, chronic acute hepatitis, septic shock, toxic shock syndrome, sepsis syndrome, cachexia, infectious diseases, parasitic diseases, acquired immunodeficiency syndrome, acute transverse myelitis, Huntington's chorea, stroke, primary biliary cirrhosis, hemolytic anemia, Slokas�governmental entities, Addison's disease, idiopathic Addison's disease, sporadic, polyglandular deficiency type I and polyglandular deficiency type II, Schmidt syndrome, (acute) respiratory distress syndrome in adults, alopecia, circular areata, seronegative arthropathy, arthropathy, Reiter's disease, psoriatic arthropathy, arthropathy ulcerative colitis, enteropathic synovitis, chlamydia, arthropathy associated with Yersinia (yersinia) and Salmonella (salmonella), atheromatous disease/arteriosclerosis, atopic Allergy, autoimmune bullous disease, vulgar pemphigus, pemphigus bubble disease resembling pemphigus, linear IgA disease, autoimmune haemolytic anaemia, Coombs positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious anaemia, peripheral vascular disorders, peritonitis, pernicious anemia, millitesla encephalitis/chronic fatigue syndrome, chronic mucocutaneous candidiasis, giant cell arthritis, primary sclerosing hepatitis, cryptogenic autoimmune hepatitis, acquired immunodeficiency Syndrome, diseases associated with acquired immune deficiency syndrome, hepatitis A, hepatitis B, hepatitis C, arrhythmia related to the bundle of his, HIV infection/HIV neuropathy, usually�CSOs variable immunodeficiency (common variable hypogammaglobulinemia), dilated cardiomyopathy, female infertility, ovulation disorders, premature ovulation disorders, fibrotic lung disease, chronic wound healing, cryptogenic fibrous alveolitis, post-inflammatory interstitial lung disease, interstitial pneumonitis, interstitially plasma cellpneumonia, pneumonia, connective tissue disease-related interstitial lung disease, mixed connective tissue disease associated with lung disease, systemic sclerosis associated with lung disease, rheumatoid arthritis associated with interstitial lung disease, systemic lupus erythematosus-related lung disease, dermatomyositis/polymyositis associated with lung disease, Sjogren's syndrome associated with lung disease, ankylosing spondylitis associated with lung disease, vasculitis diffuse lung disease, hemosiderosis associated with a lung disease caused by medications interstitial lung disease, radiation fibrosis, obliterative broncholitis, chronic eosinophilic pneumonia, lymphocytic infiltrative lung disease, postinfectious interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoid g�patita), type-2 autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, insulinomimetic type B acanthocardia, hypoparathyroidism, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, osteoarthrosis, primary sclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leukopenia, autoimmune neutropenia, renal disease NOS, glomerulonephritis, microscopic vasculitis of the kidneys, Lyme disease, discoid lupus erythematosus, male infertility idiopathic or NOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension secondary to connective tissue disease, acute and chronic pain (different types of pain), goodpasture's syndrome, pulmonary manifestation of polyarteritis arthritis, acute rheumatic fever, rheumatoid spondylitis, still's disease, systemic sclerosis, sjögren's syndrome, Takayasu disease/arthritis, autoimmune thrombocytopenia, toxicity, transplants, and diseases including inadequate vascularization, for example, diabetic retinopathy, premature retinopathy, choroidal neovascularization caused by age-related degeneration of the corpus luteum, and m�edenesque hemangioma in humans. In addition, such compounds may be useful in the treatment of disorders such as ascites, effusions, exudates, including, for example, swelling of the corpus luteum, cerebral edema, acute lung disease, respiratory distress syndrome in adults (ARDS), proliferative disorders such as restenosis, fibrotic disorders, such as cirrhosis and atherosclerosis, proliferative disorders mesangial cells, such as diabetic nephropathy, malignant nephrosclerosis, thrombotic syndrome microangiopathy and glomerulopathy, myocardial angiogenesis, coronary and cerebral collaterals, ischemic angiogenesis limb ischemia/reperfusion injury, peptic ulcers associated withHelicobactercaused by a virus angiogenic disorders, preeclampsia, menometrorrhagia, cat scratch fever, robes, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retrolental p. or age-related macular degeneration. In addition, these compounds can be used as active agents against hyperproliferative disorders such as thyroid hyperplasia (especially grave's disease), and cysts (such as hypervascularity ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal) and poly�Istisna kidney disease, as these diseases require cell proliferation of blood vessels for growth and/or metastasis.

Compounds of formula (I) of the present invention can be used alone or in combination with an additional agent, for example, with therapeutic agent, and these additional agents chosen by the person skilled in the art for their intended use. For example, the additional agent can be a therapeutic agent that is known to specialists, can be used for treatment of the indicated subject to treatment of a disease or condition of the compound of the present invention. The additional agent may also be an agent that imparts a favorable therapeutic properties of the composition, for example, an agent that affects the viscosity of the composition.

It should also be understood that combinations that should be included in the present invention, such combinations are useful for their intended use. The following are the agents who are merely illustrative, and should not be limiting. The combinations, which are part of the present invention may comprise compounds of the present invention and at least one additional agent selected from the following. This combination may also VC�ucati more than one additional agent, for example, two or three additional agent, if the specified combination is such that the resulting composition can perform their assigned functions.

Preferred combinations are non-steroidal anti-inflammatory drug, which is also called NSAIDS, which include drugs like ibuprofen. Other preferred combinations are corticosteroids including prednisolone; the well known side effects of steroid use can be reduced or even eliminated, reducing the dose of steroid needed to treat patients, in combination with the compounds of the present invention. Non-limiting examples of therapeutic agents for rheumatoid arthritis with which it is possible to combine the compounds of formula (I) of the present invention include the following: cytokine-overwhelming anti-inflammatory drug (medication) (CSAID); antibodies to other human cytokines or antagonists of other human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. Compounds of the present invention can be combined with antibodies to molecules on the cell surfaces, such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands including CD154 (gp39 or CD40L).

Preferred to�the combination of therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade; preferred examples include TNF antagonists, such a chimeric, humanized or human TNF antibodies, D2E7 (U.S. Pat. No. 6090382 HUMIRA™), CA2 (REMICADE™), SIMPONI™ (golimumab), CIMZIA™, ACTEMRA™, CDP 571, and soluble p55 or p75 TNF receptors, derivatives thereof (p75TNFRIgG (ENBREL™) or p55TNFRIgG (lenercept), and also inhibitors of TNFα converting enzyme (TACE); similar to IL-1 inhibitors (inhibitors of interleukin-1-converting enzyme, IL-IRA, etc.) may be effective for the same reason. Other preferred combinations include interleukin 11. Other preferred combinations are the other key players of the autoimmune reactions, which may act parallel to, dependent or in conjunction with the operation of the IL-18; particularly preferred are antagonists of IL-12, including antibodies to IL-12 or soluble receptors of IL-12, or binding of IL-12 proteins. It has been shown that IL-12 and IL-18 have overlapping but distinct functions, and the combination of both antagonists may be most effective. Still another preferred combination are sustainable anti-CD4 inhibitors. Still other preferred combinations include antagonists of the co-stimulant ways CD80 (B7.1) or CD86 (B7.2) including antibodies, soluble receptors or antagonistic ligands.

The compound of formula (I) of this izobreteny� can also be combined with agents, such as methotrexate, 6-MP, azathioprineallergic, mesalazine, olsalazine the chloroquine/hydroxychloroquine, penicillamine, aurothiomalate (intramuscular and oral), azathioprine, colchicine, corticosteroids (for oral administration, inhalation or local injection), agonists of beta-2 adrenergic receptors (salbutamol, terbutaline, nedocromil), xanthines (theophylline, aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and oxitropium, cyclosporine, FK506, rapamycin, mycophenolate mofetil, Leflunomide, NSAID, such as ibuprofen, corticosteroids such as prednisolone, inhibitors fosfodiesterasa, the adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that inhibit signaling by proinflammatory cytokines such as TNFα or IL-1 (for example, NIK, IKK, p38 or inhibitors of MAP kinase) inhibitors of IL-1β-converting enzyme, inhibitors of the signaling system T-cells, such as kinase inhibitors, inhibitors of metalloproteinases, sulfasalazine, 6-mercaptopurine, angiotensin-converting enzyme, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors and the derivatives p75TNFRIgG (Enbrel™) and p55TNFRIgG (lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines (for example IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid, �hydroxychloroquine, the rofecoxib, etanercept, infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, nutritional gold, aspirin, triaminobenzene, propoxyphene/apap folate, nabumetone, diclofenac, piroxicam, etodolac, nutritional, oxaprozin, oxycodone HCl, hydrocodonebitartrat/apap nutritional/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate, sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, nutrientand, prednisolone, martinslife, lidocaineydrocortisone, indomethacin, glucoseinsulin/chondroitin, amitriptilin HCl, sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol katrinaparker, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12, anti-IL15, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, roflumilast, IC-485, CDC-801, S1P1 agonists (such as FTY720), inhibitors of the PKC family (such as ruboxistaurin or AEB-071) and mesopram. Preferred combinations include methotrexate or Leflunomide and in cases of moderate or severe rheumatoid arthritis cyclosporine and anti-TNF antibodies, as indicated above.

Non-limiting examples of therapeutic agents for the treatment of inflammatory bowel disease with which it is possible to combine the compound of formula (I) of the present invention include: budenoside; epidermal growth factor; to�ticosteroid; cyclosporin, sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine; balsalazide; antioxidants; inhibitors of thromboxane; receptor antagonists of IL-1; anti-IL-1β monoclonal antibodies; anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors; compounds pyridinyl-imidazole; antibodies to other human cytokines or growth factors or their antagonists, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine; FK506; rapamycin; mycophenolate mofetil; Leflunomide; NSAID, such as ibuprofen; corticosteroids such as prednisolone; inhibitors fosfodiesterasa; adenosine agonists; antithrombotic agents; inhibitors of complement; adrenergic agents; agents that disrupt signaling system of proinflammatory cytokines such as TNFα or IL-1 (for example, NIK, IKK, or inhibitors of MAP kinase); inhibitors of IL-1β converting enzyme inhibitors; TNFα-converting enzyme inhibitors; signal system T-cells, such as kinase inhibitors; inhibitors of metalloproteinases; sulfasalazine; azathioprine; 6-mercaptopurine; angiotensin-converting enzyme; soluble cytokine receptors and their production�water (for example, soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines (eg, IL-4, IL-10, IL-11, IL-13 and TGFβ). Preferred examples of therapeutic agents for the treatment of Crohn's disease with which it is possible to combine the compounds of formula (I) include the following: TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S. Pat. No. 6090382, HUMIRA™), CA2 (REMICADE™), CDP 571, design TNFR-Ig, inhibitors (p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™), and PDE4 inhibitors. The compound of formula (I) can be combined with corticosteroids, for example, budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents that disrupt the synthesis or functioning of proinflammatory cytokines, such as IL-1, for example, inhibitors of IL-1β-converting enzyme and IL-Ira; inhibitors of the signaling system T-cells, for example, tyrosine kinase inhibitors 6-mercaptopurine; IL-11; mesalamine; prednisone; azathioprine; mercaptopurine; infliximab; nitrosoglutathione; Diphenoxylate/atrop sulfate; loperamidedepakote; methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodonebitartrat/apap; tetracyclinehydrochloridefish; fluocinonide; metronidazole; thimerosal/boric acid; cholestyramine/sucrose; ciprofloxacinciprofloxacin; hyoscyaminesulfate; meperidinehydrochloride; midazolam.hydrocodone;oxycodone HCl/acetaminophen; promethazineodeine; nutrifactor; sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenyl; hydrocortisone; multivitamins; dinitrobenzamide; codeinefosfaat/apap; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin; methylprednisolone; natalizumab and gamma-interferon.

Non-limiting examples of therapeutic agents for the treatment of multiple sclerosis with which it is possible to combine the compound of formula (I) include the following: corticosteroids; prednisolone; methylprednisolone; azathioprine; cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-β1a (AVONEX®; Biogen); interferon-β1b (BETASERON®; Chiron/Berlex); interferon α-n3) (Interferon Sciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferon β1A-IF (Serono/Inhale Therapeutics), peginterferon α2b (Enzon/Schering-Plough), copolymer 1 (Cop-1; COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen; immunoglobulins for intravenous administration; cladribine; antibodies to other human cytokines or antagonists of other human cytokines or growth factors and their receptors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF. The compound of formula (I) can be combined with antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. The compound of formula (I) can also� be combined with agents, such as methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil, Leflunomide, S1P1 agonist, NSAID, such as ibuprofen, corticosteroids such as prednisolone, inhibitors fosfodiesterasa, adenosine agonists, antithrombotic agents, inhibitors of complement, adrenergic agents, agents that disrupt signaling system of proinflammatory cytokines such as TNFα or IL-1 (for example, NIK, IKK, p38 or inhibitors of MAP kinase) inhibitors of IL-1β-converting enzyme, TACE inhibitors, inhibitors of signaling systems T-cells, such as kinase inhibitors, inhibitors of metalloproteinases, sulfasalazine, azathioprine, 6-mercaptopurine, angiotensin-converting enzyme, soluble cytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines (eg, IL-4, IL-10, IL-13 and TGFβ).

Preferred examples of therapeutic agents for the treatment of multiple sclerosis with which it is possible to combine the compound of formula (I) include interferon-β, for example, IFNβ1a and IFNβ1b; Copaxone, corticosteroids, caspase inhibitors, for example inhibitors of caspase-1 inhibitors, IL-1, TNF inhibitors, and antibodies to CD40 ligand and CD80.

The compound of formula (I) can also be combined with agents, such as alemtuzumab, dronabinol, impact, mitoxantron, xaliproden�of lore, Fampridine, latinamerica, natalizumab, cannabidiol, α-immunogen NNSO3, ABR-215062, AnergiX.MS, antagonists of chemokine receptors, BBR-2778, calaguala, CPI-1189, LEM (encapsulated in the liposome mitoxantron), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, perpendicular 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2, diplomatic, antagonists of VLA-4 (for example, TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), antagonists interferon-gamma agonists and IL-4.

Non-limiting examples of therapeutic agents for the treatment of ankylosing spondylitis with which it is possible to combine the compound of formula (I) include the following: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine, minocycline, prednisone, and anti-TNF antibodies, D2E7 (U.S. Pat. No. 6090382; HUMIRA™), CA2 (REMICADE™), CDP 571, design TNFR-Ig, (p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™)

Non-limiting examples of therapeutic agents for asthma with which it is possible to combine the compound of formula (I) include the following: albuterol, salmeterol/fluticasone, nutrionalist, fluticasonet, budenoside, prednisone, seletracetam, levalbuterol HCl, albuterolsulfatb/ipratropium, prednisolonestore, triaminobenzene, beclomethasone, ipratropium�Rome, azithromycin, pirbuterol, prednisolone, anhydrous theophylline, methylprednisoloneside, clarithromycin, zafirlukast, formaterror, the vaccine of the influenza virus, amoxicillin trihydrate, drug, allergy injection, chromosonally, fexofenadine.pharma, drug/menthol, amoxicillin/clavulanate, levofloxacin, an auxiliary device for inhalation, guaifenesin, dexamethasonee, moxifloxacin HCl, doxycyclinehycl, guaifenesin/d-methorphan, p-ephedrine/code/chlorphenyl, Gatifloxacin, zetiasynthroid, mometasone, seletracetam, benzonatate, cephalexin, PE/hydrocodone/chlorphenyl, cetirizine HCl/pseudoephed, phenylephrine/code/promethazine, codeine/promethazine, cefprozil, dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline, epinephrine, methylprednisolone, an anti-IL-13 antibody and metaproterenol.

Non-limiting examples of therapeutic agents for the treatment of COPD, with which it is possible to combine the compound of formula (I) include the following: albuterol sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol, seletracetam, fluticasonet, prednisone, anhydrous theophylline, methylprednisolone sodium succinate, montelukast sodium, budenoside, formaterror, triaminobenzene, levofloxacin, Huai�enein, azithromycin, beclomethasone, levalbuterol HCl, drug, Ceftriaxone sodium, amoxicillin trihydrate, Gatifloxacin, zafirlukast, amoxicillin/clavulanate, drug/menthol, chlorpheniramine/hydrocodone, metaproterenol, methylprednisolone, mometasone, p-ephedrine/code/chlorphenyl, pirbuterol, p-ephedrine/loratadine, terbutaline, tetrapyrrole, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for the treatment of HCV with which it is possible to combine the compound of formula (I) include the following: Interferon-alpha-2α, Interferon-alpha-2β, Interferon-alpha con1, Interferon-alpha-n1, pegylated interferon-alpha-2α, pegylated interferon-alpha-2β, ribavirin, peginterferon Alfa-2b+ribavirin, ursodeoxycholic acid, glycyrrhizinate acid, thymalfasin, Maximin, VX-497 and any compounds that are used to treat HCV through intervention with the following targets: HCV polymerase, HCV protease, HCV helicase, and HCV IRES (internal binding site of the ribosome).

Non-limiting examples of therapeutic agents for the treatment of idiopathic pulmonary fibrosis with which it is possible to combine the compound of formula (I) include the following: prednisone, azathioprine, albuterol, colchicine, albuterolsulfatb, digoxin, gamma interferon, metilprednisolone�NAT, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone, cyclophosphamide, ipratropium, actinomycin d, alteplase, fluticasonet, levofloxacin, metaproterenol, martinslife, oxycodone HCl, potassium chloride, triamcinolone, anhydrous tacrolimus, calcium, interferon-alpha, methotrexate, mycophenolate mofetil and interferon-gamma-1β.

Non-limiting examples of therapeutic agents for the treatment of myocardial infarction with which it is possible to combine the compound of formula (I) include the following: aspirin, nitroglycerin, metoprololtartrate, enoxaparin, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, isosorbide Mononitrate, digoxin, furosemide, simvastatin, ramipril, tenecteplase, enalapril maleate, torsemide, retavase, losartan potassium, cheaprisperdal/magnesium carbonate, bumetanide, alteplase, enalaprilat, amiodaronesee, tirofiban HCl m-hydrate, diltiazemcream, captopril, irbesartan, valsartan, propranololhydrochlorid, fosinopril sodium, lidocaineydrocortisone, eptifibatide, Cefazolin sodium, atropine sulfate, aminocaproic acid, spironolactone, interferon, cataloguedownload, potassium chloride, docusate sodium, dobutamine HCl, alprazolam, pravastatin sodium, atorvastatin calcium, midazolame�chlorid, piperidinedione, isosorbidedinitrate, epinephrine, dopaminergic, bivalirudin, rosuvastatin, ezetimibe/simvastatin, avasimibe and cariporide.

Non-limiting examples of therapeutic agents for psoriasis with which it is possible to combine the compound of formula (I) include the following: calcipotriene, clobetasone, triaminobenzene, globalatlanta, tazarotene, methotrexate, fluocinonide, betamethasone diprop augumented, fluorenylacetamide, acitretin, tar shampoo, betamethasone, mometasone, ketoconazole, pramoxine/fluocinolone, hydrocortisone, flurandrenolide, urea, betamethasone, clobetasone/emoll, fluticasonet, azithromycin, hydrocortisone, moisturizing formula, folic acid, desonide, pimecrolimus, coal tar, diflorasone diacetate, etanercept, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone, a sunscreen, halcinonide, salicylic acid, anthralin, clocortolone pivalate, coal extract, tar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone, diazepam, emmolient, fluocinonide/emmolient, mineral oil/castor oil/na lact, mineral oil, peanut oil, petrol/isopropyl myristate, psoralen, salicylic acid, soap/tribromsalan, Cimarosa�/boric acid, celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinumab.

Non-limiting examples of therapeutic agents for the treatment of psoriatic arthritis with which it is possible to combine the compound of formula (I) include the following: methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, Leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine, prednisone, sulindac, betamethasone diprop augmented, infliximab, methotrexate, folate, triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, Ketoprofen, meloxicam, methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosamine sulfate, nutritional gold, the hydrocodone bitartrate/apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (U.S. Pat. No. 6090382, HUMIRA™), and efalizumab.

Non-limiting examples of therapeutic agents for the treatment of restenosis with which it is possible to combine the compound of formula (I) include the following: sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578 and acetaminophen.

Non-limiting examples of therapeutic agents for the treatment of sciatica with which it is possible to combine the compound of formula (I), on�prepared as follows: the hydrocodone bitartrate/apap, the rofecoxib, cyclobenzaprine HCl, methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeine phosphate/apap, tramadol HCl/acetaminophen, metaxalone, meloxicam, Methocarbamol, lidocaineydrocortisone, diclofenac sodium, gabapentin, dexamethasone, carisoprodol, Ketorolac tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HCl, diclofenac sodium/misoprostol, propoxyphene n-pap, asa/oxycod/oxycodone ter, ibuprofen/hydrocodone bit, tramadol HCl, etodolac, propoxyphene HCl, amitriptilin HCl, carisoprodol/codeine phos/asa, morphine sulfate, multivitamins, naproxen sodium, orphenadrine citrate and temazepam.

Preferred examples of therapeutic agents for the treatment of systemic lupus erythematosus (SLE (Lupus) with which it is possible to combine the compound of formula (I) include the following: NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib; antimalarial agents, for example, hydroxychloroquine; steroids such as prednisone, prednisolone, budenoside, dexamethasone; cytotoxic agents, such as azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate; inhibitors of PDE4 or inhibitor of the synthesis of purine, such as Cellcept®. The compound of formula (I) can also combine�ü with agents, such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®, and agents that interfere with the synthesis, production or action of proinflammatory cytokines such as IL-1, for example, caspase inhibitors like inhibitors of IL-1β-converting enzyme and IL-1ra. The compound of formula (I) can also be used with inhibitors of the signaling system T cells, for example, tyrosine kinase inhibitors; or molecules that are focused on molecules that activate T-cells, for example, CTLA-4-IgG or antibodies to anti-B7 family antibodies to anti-PD-1 family. The compound of formula (I) can be combined with IL-11 or anti-cytokine antibodies, for example, with fontolizumab (antibody to anti-IFNg), or anti-receptor receptor antibodies, for example, anti-IL-6 receptor antibody and antibodies to surface molecules on B-cells. The compound of formula (I) can also be used with LJP 394 (abetimus), agents that Deplete or inactivate B-cells, for example, rituximab (the antibody to anti-CD20), lymphostat-B (antibody to anti-BlyS), TNF antagonists, for example, antibodies to anti-TNF, D2E7 (U.S. Pat. No. 6090382; HUMIRA™), CA2 (REMICADE™), CDP 571, design TNFR-Ig, (p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™).

In the present invention adopted the following definitions:

The term “therapeutically effective amount” is an amount of a compound of formula (I) �whether combinations of two or more such compounds, which inhibits, totally or partially, the development of the state, or facilitate, at least in part, one or more of the symptoms of the condition. A therapeutically effective amount may also be a quantity that is prophylactically effective. The quantity that is therapeutically effective will depend on the patient's weight and gender to be treated condition, the severity of the condition and desired result. For a particular patient a therapeutically effective amount can be determined by methods known to experts in this field.

The term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are receiving, interacting with inorganic acids, e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or with organic acids such as sulfonic acid, carboxylic acid, phosphorous acid, methanesulfonic acid, econsultancy acid, p-toluensulfonate acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid (for example, (+) or (-)-winnoc�Menno acid or mixtures thereof), amino acids (for example, (+) or (-)-amino acids or mixtures thereof), etc., These salts can be obtained by methods known to experts in this field.

Some compounds of formula (I), which have acidic substituents may exist as salts with pharmaceutically acceptable bases. The present invention includes such salts. Examples of such salts include sodium salt, potassium salt, lysine salt and arginine salts. These salts can be obtained by methods known to experts in this field.

Some compounds of formula (I) and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.

Some compounds of formula (I) and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

Some compounds of formula (I) can have one or more chiral centers, and exist in different optically active forms. If the compound of formula (I) contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both of the enantiomer and mixtures of enantiomers, such as racemic mixtures. These enantiomers can be separated by methods known to those skilled in Danno� region, for example through education diastereoisomeric salts, which can be divided, for example, by crystallization; through education diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example by enzymatic esterification; or using gas-liquid or liquid chromatography in a chiral environment, for example on a chiral substrate, the silica gel which binds the chiral ligand or in the presence of a chiral solvent. It should be understood that if desired enantiomer is converted into another chemical compound with one of the disclosed above procedures of separation, you will need an additional step to release the required enantiomeric forms. Alternatively, specific enantiomers can be synthesized using asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or converting one enantiomer to another, using asymmetric transformation.

If the compound of formula (I) contains more than one chiral center, it may exist then reduced to diastereoisomeric forms. Diastereoisomeric compounds can be divided ways, �known to specialists in this field, for example, using chromatography or crystallization, and individual enantiomers can be separated, as disclosed above. The present invention includes each of the diastereomers of a compound of formula (I) and mixtures thereof.

Some compounds of formula (I) may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each of tautomers and/or geometric isomers of the compounds of formula (I) and mixtures thereof.

Some compounds of formula (I) may exist in different stable conformational forms which may be divided. Torsion the asymmetry due to restricted rotation around the asymmetric simple connection, for example, due to steric problems or stresses in the cycle, can provide the ability to separate the different conformers. The present invention includes each conformational isomer of compounds of formula (I) and mixtures thereof.

Some compounds of formula (I) may exist in the form zwitterions, and the present invention includes each of zwitterionic forms of the compounds of formula (I) and mixtures thereof.

In the sense used here, the term “prodrug”, he refers to the agent that turns into the original drug in vivo as a result of some physiological chemical process (for example, eslin prodrug to bring to physiological values, the prodrug is converted into the required dosage form). Prodrug is used quite often, as in some situations, they may be easier to enter than the original drug. For example, they may be bioavailable by oral administration whereas the original medications. The prodrug may also have improved solubility in pharmaceutical compositions compared to the original drug. For example, but without limitation, the prodrug may be a compound of the present invention, when it is administered as an ester (the“prodrug”) to facilitate penetration through the cell membrane when the solubility in water is not favorable, but it then is metabolically hydrolyzed to the carboxylic acid, already inside the cell where water-solubility is beneficial property.

Prodrugs have many useful properties. For example, you may find that the prodrug is more soluble in water than the ultimate cure, thereby facilitating intravenous medications. The prodrug may also have a higher degree of bioavailability when administered orally than the final cure. After the introduction of the prodrug enzymatically or chemically cleaved, delivering the ultimate cure in blood or tissue.

Examples of the prodrug after split�I highlight the corresponding free acid, and such hydrolyzable forming the ester residues of the compounds of the present invention include, but are not limited to, the Vice-carboxylic acids in which free hydrogen is replaced by (C1-C4)alkyl, (C1-C12)alkanoyloxy, (C4-C9)1-(alkanoyloxy)ethyl, 1-methyl-1-(alkanoyloxy)ethyl, containing 5 to 10 carbon atoms, alkoxycarbonylmethyl containing from 3 to 6 carbon atoms, 1-(alkoxycarbonyl)ethyl containing from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyl)ethyl containing from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl containing from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl, containing from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotononitrile, gamma-butyrolactone-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2-allylcarbamate-(C1-C2)alkyl and piperidino-, pyrrolidino - or morpholino(C2-C3)alkyl.

Other examples of prodrug that produce alcohol of the formula (I), where free hydrogen of the hydroxyl substituent (for example, R1contains hydroxyl) is replaced by (C1-C6)alkanoyloxy, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C )alkanoyloxy)ethyl, (C1-C12)alkoxycarbonylmethyl, N-(C1-C6)alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, arylation and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where said α-aminoaniline fragments represent independently any natural L-amino acids found in proteins, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2or glycoside (the radical resulting from the removal of hydroxyl from Polyacetal or carbohydrate).

In the sense used here, the term “bridged (C5-C12)cycloalkyl group”, it refers to a saturated or unsaturated, bicyclic or bridged polycyclic hydrocarbon group containing two or three C3-C10cycloalkyl ring. Namashikaye cycloalkyl excluded. Bridged cyclic hydrocarbons may include such as bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, berenil, norbornyl, norbornanyl, 6,6-dimethylbicyclo[3.1.1]heptyl, tricyclazole and adamantyl.

In the sense used here, the term “bridged (C2-C10)heterocyclyl”, it refers to a bicyclic or polycyclic Aza-bridged hydrocarbon group and mo�et to include asangroni, hinokitiol, ethanolamine, Trapani, azabicyclo[3.2.1]octenyl, azabicyclo[2.2.1]heptenyl, 2-azabicyclo[3.2.1]octenyl, azabicyclo[3.2.1]octenyl, azabicyclo[3.2.2]nonanal, azabicyclo[3.3.0]nonanal, and azabicyclo[3.3.1]nonanal.

The terms “heterocyclic”, “heterocyclic” or “heterocyclyl”, in the sense used here, include non-aromatic ring system, including, but not limited to, monocyclic, bicyclic, tricyclic and spirocyclic ring which may be completely saturated or which can contain one or more units of unsaturation (and, to avoid doubt, the degree of unsaturation does not lead to an aromatic system), and contain from 5 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen or sulfur. As examples, which should not be construed as limiting the scope of the present invention, it is possible to give the following examples of heterocyclic rings: azepines, azetidine, indolinyl, isoindolyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, hinokitiol, thiomorpholine, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroindole, thiomorpholine and Trapani.

The terms “heteroaryl” or “heteroaryl” in the sense used here, include aromatic ring systems, including, but not �graniteware, monocyclic, bicyclic and tricyclic rings and contain from 5 to 12 atoms including at least one heteroatom, such as nitrogen, oxygen or sulfur. As examples, which should not be construed as limiting the scope of the present invention, include: isoindolyl, benzo[b]thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzoxazolyl, furanyl, imidazolyl, imidazopyridines, indole, indazole, isoxazolyl, isothiazolin, oxadiazolyl, oxazolyl, purinol, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, chinoline, hintline, triazolyl, thiazolyl, thiophenyl, tetrazolyl, thiadiazolyl or thienyl.

The term “heterocytolysine” group in the sense used here, represents a heterocyclic group which is connected with the connection aliphatic group containing from one to about eight carbon atoms. For example, heterocytolysine group is morpholinomethyl group.

In the sense used here, the terms “alkyl”, “alkylene” or symbols such as “(C1-C8) ” include a straight or branched hydrocarbons which are completely saturated. Examples of Akilov are methyl, ethyl, propyl, isopro�Il, butyl, pentyl, hexyl and their isomers. In the sense used here, the terms “alkenyl”, “alkanine”, “akinyan” and “alkynyl” mean C2-C8and include unbranched or branched hydrocarbons that contain one or more units of unsaturation, one or more of the double bonds to alkenyl and one or more triple bonds of alkynyl.

In the sense used here, the term “aromatic” group (or “aryl” or “Allenova” groups) include aromatic carbocyclic ring system (e.g. phenyl) and the condensed polycyclic aromatic ring systems (e.g. naphthyl, biphenyl and 1,2,3,4-tetrahydronaphthyl).

In the sense used here, the terms “cycloalkyl” or “cycloalkyl”, they mean C3-C12monocyclic or polycyclic (e.g. bicyclic, tricyclic, spirocyclic, etc.) hydrocarbons which are completely saturated or contain one or more unsaturated bonds, but this number does not lead to the formation of aromatic groups. Examples cycloalkyl groups represent cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

In the sense used here, many fragments or Deputy or refer to as “substituted” Il� “optionally substituted”. If the fragment is marked as one of these terms, unless otherwise indicated, this means that any part of the specified fragment, which is known to specialists that are available for substitution may be substituted, includes one or more of the substituents, and where there is more than one Deputy, then each of the substituents chosen independently. Such designations to replace well-known to experts in the field and/or adopted in the present description. As examples, which should not be construed as limiting the scope of the present invention, there are some groups that are substituents are: (C1-C8)alkyl group, (C2-C8)alkenyl groups, (C2-C8)alkyline group, (C3-C10)cycloalkyl group, halogen (F, Cl, Br or I), halogenated (C1-C8)alkyl groups (for example but not limited to, -CF3), -O-(C1-C8)alkyl groups, -OH, -S-(C1-C8)alkyl groups, -SH, -NH(C1-C8)alkyl groups, -N((C1-C8)alkyl)2group, -NH2, -C(O)NH2, -C(O)NH(C1-C8)alkyl groups, -C(O)N((C1-C8)alkyl)2group, -NHC(O)H, -NHC(O)(C1-C8)alkyl group, -NHC(O)(C3-C8)cycloalkyl groups, -N((C1-C8)alkyl)C(O)H, -N((C1-C8)alkyls(O)(C 1-C8)alkyl group, -NHC(O)NH2, -NHC(O)NH(C1-C8)alkyl groups, -N((C1-C8)alkyl)C(O)NH2group, -NHC(O)N((C1-C8)alkyl)2groups, -N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2groups, -N((C1-C8)alkyl)C(O)NH((C1-C8)alkyl), -C(O)H, -C(O)(C1-C8)alkyl group, -CN, -NO2, -S(O)(C1-C8)alkyl groups, -S(O)2(C1-C8)alkyl groups, -S(O)2N((C1-C8)alkyl)2group, -S(O)2NH(C1-C8)alkyl groups, -S(O)2NH(C3-C8)cycloalkyl group, -S(O)2NH2group, -NHS(O)2(C1-C8)alkyl groups, -N((C1-C8)alkyl)S(O)2(C1-C8)alkyl group, -(C1-C8)alkyl-O-(C1-C8)alkyl group, -O-(C1-C8)alkyl-O-(C1-C8)alkyl groups, -C(O)OH, -C(O)O(C1-C8)alkyl group, NHOH, NHO(C1-C8)alkyl group, -O-halogenated (C1-C8)alkyl group (for example, but not limited to, -OCF3), -S(O)2-halogenated (C1-C8)alkyl group (for example, but not limited to, -S(O)2CF3), -S-halogenated (C1-C8)alkyl group (for example, but not limited to, -SCF3), -(C1-C6)heterocycles (e.g.�, but not limited to, pyrrolidine, tetrahydrofuran, PYRAN or morpholine), -(C1-C6)heteroaryl (for example but not limited to, tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, -NHC(O)O-(C1-C6)alkyl groups, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl groups, -C(=NH)-(C1-C6)alkyl groups, -C(=NOH)-(C1-C6)alkyl group, or-C(=N-O-(C1-C6)alkyl)-(C1-C6)alkyl group.

in the formula (I) is an aromatic ring.

One or more of the compounds of the present invention can be administered to the patients-people as they are, or in pharmaceutical compositions where they are mixed with a biologically suitable carriers or excipient (excipients) in doses sufficient to treat or alleviate a disease or condition as disclosed here. Mixtures of these compounds can also be administered to the patient in the form of a simple mixture or in the form of appropriately prepared pharmaceutical composition. The concept of a therapeutically effective dose refers to that amount of a compound or compounds which is enough to ensure the prevention or attenuation of a disease or condition as disclosed here. The technology of preparation of medicines and the introduction of the compounds rossmar�Wai applications can be found in the links which are well known to specialists in this field, such as “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition.

Suitable routes of administration may, for example, include oral, using eye drops, rectal, transmucosal, or outer enteric introduction; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.

Alternatively, you can enter the specified connection locally and not systemically, for example, by injection of the compound directly into the edematous region, often in the form of depot formulations or compositions with delayed allocation.

In addition, you can enter a medicament in the form of a directed system of drug delivery, for example, in the form of liposomes covered with the endothelial cell-specific antibody.

Pharmaceutical compositions of the present invention can be prepared by known methods, for example, using processes conventional mixing, dissolving, granulating, the manufacture of pellets, grinding into powder, emulsification, encapsulation, enable, or lyophilization.

Thus, pharmaceutical compositions for use in accordance with the present invent�amount of force can be prepared by conventional methods, using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Suitable forms depend on the selected method of administration.

For injection, the agents of the present invention can be prepared in the form of aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, ringer's solution or saline. For transmucosal injection drugs use penetrants appropriate to overcome the barrier. Such penetrants are generally known to experts in this field.

For oral administration the compounds can be easily prepared by combining the active compounds with pharmaceutically acceptable carriers that are well known to experts in this field. Such media facilitate the acquisition of the compounds of the present invention in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for learning to be patient treatment in oral administration. Pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture, and converting the mixture into pellets after added�of suitable auxiliary substances, if desired, to obtain tablets or internal content drops. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; preparations of cellulose, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, resin tragakant, methylcellulose, hydroxypropylmethyl-cellulose, nutricosmetics and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as crosslinked polyvinylpyrrolidone, agar or alginic acid or salts thereof such as sodium alginate.

The inner content of pellets provided with a proper sheath. For this purpose you can use concentrated solutions of sugars, which can optionally contain gum Arabic, talc, polyvinylpyrrolidone, HPMC gel, polyethylene glycol and/or titanium dioxide, solvents and varnishes suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or shell beans for identification or to indicate different combinations of doses of active compounds.

Pharmaceutical preparations which can be used orally include detachable gelatin capsules as well as soft, sealed capsules made of gelatin and plasti�of icator, such as glycerol or sorbitol. Split the capsules can contain the active ingredients in admixture with fillers, such as lactose, binders, such as starches, and/or lubricating agents such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as liquid oils, liquid paraffin, or liquid polyethylene glycols. It is also possible to add stabilizers. All preparations for oral administration should be prepared in dosages suitable for such administration.

Compositions for buccal administration may be in the form of tablets or lozenges prepared in the usual way.

For administration via inhalation, the compounds for use in accordance with this invention, generally supplied in the form of aerosol sprays, prisoners in containers under pressure, or nebulizers that use of a suitable propellant, e.g. DICHLORODIFLUOROMETHANE, trichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of an aerosol under pressure a single dose can provide a valve, which counts a certain number. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator can be prepared �AK, to contain a mixture of powders of compounds and a suitable base powder, such as lactose or starch.

Compounds of the present invention can be prepared for parenteral administration by injection, for example bolus injection or continuous infusion. Compositions for injection may be in unit dose forms, for example in ampoules or in multi-dose containers with an added preservative. Such compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous carriers, and may include contributing to the creation of forms of agents, such as suspendida, stabilizing and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds can be in the form of suitable oily suspensions for injection. Suitable lipophilic solvents or carriers include liquid oils such as sesame oil, or synthetic fatty acid esters, such as ethyloleate, or triglycerides, or liposomes. Aqueous suspension for injection may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilization�Torah or agents, which increase the solubility of the compounds, giving the opportunity to obtain solutions with high concentration.

Alternatively, the active ingredient may be in powder form for dilution prior to use suitable carrier, e.g. sterile, containing no pyrogen water.

Compounds of the present invention may also be prepared in rectal compositions such as suppositories or retention enemas, e.g. containing conventional bases for suppositories, such as cocoa butter or other glycerides.

In addition to the above preparations, the compounds of the present invention can also be prepared in the form of depot preparations. These long-acting drugs can be entered using implantation (for example subcutaneously or intramuscularly or by intramuscular injection). So, for example, the compounds of the present invention can be prepared in a mixture with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, in the form of slightly soluble salts.

Example of a pharmaceutical carrier for the hydrophobic compounds of the present invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant agent, smeshivayesh� water organic polymer and the aqueous phase. Such a system of co-solvents can be a system of VPD cerastoides. VPD is a solution of 3 wt./vol.% benzyl alcohol, 8 wt./vol.% non-polar surface-active agent Polysorbate 80, and 65 wt./vol.% polyethylene glycol 300, brought to volume in absolute ethanol. System cerastoides VPD (VPD:5W) consists of VPD diluted 1:1 with 5% dextrose in water solution. This system of co-solvents is a good solvent for hydrophobic compounds, and is itself a low toxicity with systemic administration. Naturally, the proportions in the system of co-solvents may vary considerably without breaking its characteristics solubility and toxicity. In addition, the identity of the components of the co-solvent may vary: for example, you can use other non-polar surface active agents with low toxicity instead of Polysorbate 80; may vary size fractions of polyethylene glycol; other biocompatible polymers may replace polyethylene glycol, for example, polyvinylpyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

Alternatively, you can use other delivery system for hydrophobic pharmaceutical compounds. Liposomes and emulsions are well known examples of carriers for shipping or carriers for hydrophobic drugs. You can also �use some organic solvents, such as dimethylsulfoxide, although usually at the cost of more high toxicity. In addition, the compounds of the present invention can be delivered using a system with a slow release, such as semipermeable matrices of solid hydrophobic polymers containing therapeutic agent. Installed various materials which provide sustained release, and they are well known to specialists in this field. Capsule delayed release can, depending on their chemical nature, to isolate the compounds of the present invention in the course of a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of therapeutic reagent, you can use additional approaches to stabilization of proteins.

The pharmaceutical composition may also include suitable carriers or excipient in solid or gel phases. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Many of the compounds of the present invention can be offered in the form of salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be with many acids, including but� not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Compounds in the form of salts are more soluble in aqueous or other protonic solvents than the corresponding form of free bases.

Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an effective amount to achieve the intended target. More specifically, a therapeutically effective amount means an amount that effectively prevents the development or weakens the already existing symptoms in a subject to treatment of a subject. Determination of effective amounts is entirely within the competence of specialists in this field.

For any of the compounds used in the method of the present invention, a therapeutically effective dose can be determined initially on the basis of cellular assays. For example, in cellular analysis or in animal models it is possible to prepare the dose to achieve a circulating concentration in the range that includes IR50as determined in cellular assays(i.e. the concentration of test compound that provides half the maximum inhibition activity of specific protein kinases). In some cases UD�BNO to determine the value of IR 50in the presence of from 3 to 5% serum albumin, as this definition approximates the effects of binding plasma protein. Such information can be used to better define the dose for people. In addition, the most preferred compounds for systemic administration to effectively inhibit protein kinase signals in intact cells at levels that are safely achievable in plasma.

The expression of a therapeutically effective dose refers to that amount of coupling, which leads to relief of symptoms in the patient. Toxicity and therapeutic efficacy of such compounds can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the maximum tolerated dose (MTD) and ED50(effective dose for 50% of the maximum response). The ratio of doses between toxic and therapeutic effects is a therapeutic index, and it can be expressed as the ratio between MTD and ED50. Preferred compounds that exhibit high therapeutic value indexes. The results obtained in the analysis of cell cultures and animal studies, can be used in determining the range of doses that are applicable to humans. Dositeja joints lie, preferably, in the range of circulating concentrations that include the ED50with little toxicity or in its absence. The dose can vary within the specified range depending on the dosage form and the route of administration. Specific composition, method of administration and dosage can choose the attending physician considering the patient's condition (see, for example, Fingl et al., 1975, “The Pharmaceutical Basis of Therapeutics”, Ch. 1 p. 1). In the treatment of crisis States to achieve fast response may need a extra bolus or to achieve rapid response, you may need an infusion, which is close to the maximum tolerated dose (MTD).

The number of doses and intervals between doses can be set individually to create such levels of active agent in the plasma, which is sufficient to maintain the modulating kinase effects, or minimal effective concentration (MEC). The value of the MEC will vary for each of the connections, but it can be set on the basis of in vitro results; for example, the concentration necessary to achieve 50-90% inhibition of protein kinase C using the analyses described here. The dose necessary to achieve the MEC will depend on individual characteristics and route of administration. In addition, to determine plasma concentrations can be HPLC analyses or bioassays.

Dose ranges can also be determined using the values of the MEC. Connections should be entered using this mode, which supports the levels in the plasma is higher than the MEC for 10-90% of the time, preferably from 30 to 90% and most preferably from 50 to 90%, until, until you reach the desired attenuation of symptoms. In cases of local administration or selective engagement, the effective local concentration of the drug may not be related to plasma concentrations.

Enter the amount of the composition, of course, will depend on to an outstanding treatment of the subject, from the weight of the subject, the severity of the lesion, the method of administration and the judgment of the treating physician.

The compositions may, if desired, be presented in the form of packages or metering devices that may contain one or more unit dosage forms containing the active ingredient. The package may, for example, be a metal or plastic foil, for example, can be blister packaging. Such packaging or portioning device may be accompanied by instructions for administration. It is also possible to prepare compositions comprising a compound of the present invention in a pharmaceutically compatible carrier and place them in the appropriate container and labeled for treatment of the specified condition.

In some dosage forms may be advantageous to use compounds of the present invention in the form of particles of very small size, for example, those which receive from hydropower grinding.

The use of the compounds of the present invention in the preparation of pharmaceutical compositions is illustrated by the following description. In this description, the term “active compound” means any compound of the present invention, but more specifically, any compound which is the final product of one of the following examples.

(a) Capsule

In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose ground and mixed. The obtained mixture is filled hard gelatin capsules, each capsule contains a single dose or part of a unit dose of active compound.

b) Tablets

Tablets receive, for example, from the following ingredients.

Weight parts

Active connection10
Lactose190
Corn starch22
Polyvinylpyrrolidone10
Magnesium stearate3

Active compound, lactose and some number�tvo milled starch, stirred, and the resulting mixture was granulated using a solution of polyvinylpyrrolidone in ethanol. Dry granules are mixed with magnesium stearate and the remainder of the starch. Then the resulting mixture is compressed into tablets using a tableting machine, receiving tablets, each containing a unit dose or a part of a unit dose of active compound.

c) Tablets with enteric coating

Tablets can be obtained disclosed above (b) method. Then put on tablets enteric coated in the usual manner using a solution of 20% azettftalat cellulose and 3% in a mixture of diethyl ethanol:dichloro methane (1:1).

(d) Suppositories

To obtain suppositories, for example, 100 parts by weight of active compound include in 1300 parts by weight of a triglyceride base for suppositories, and the resulting mixture is formed in the form of suppositories, each containing a therapeutically effective amount of the active ingredient.

In the compositions of the present invention active compound, if desired, may be combined with other compatible pharmacologically active ingredients. For example, the compounds of the present invention can be administered in combination with another therapeutic agent, which is known cures revealed here, the disease or condition. For example, with one or Bo�it from additional pharmaceutical agents, which inhibit or prevent the production of growth factor vascular endothelial (VEGF=VEGF) or angiopoetines, attenuate intracellular response to VEGF or angiopoietin, block intracellular signaling, inhibit vascular hyperproliferate, reduce inflammation, or inhibit or prevent the formation of edema or neovascularization. Compounds of the present invention can be entered before, after or simultaneously with an additional pharmaceutical agent, depending on which mode of introduction is more appropriate. Additional pharmaceutical agents include, but are not limited to, decongestants, steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines, PAF-antagonists, inhibitors of COX-1, COX-2 inhibitors, NO synthase inhibitors, inhibitors of Akt/PTB, inhibitors of IGF-1R inhibitors of PKC, kinase inhibitors PT3, calcineurin inhibitors and immunosuppressants. Compounds of the present invention and additional pharmaceutical agents operate or additive or synergistic. So, the introduction of this combination of agents that inhibit angiogenesis, vascular hyperproliferate and/or inhibit the formation of edema, can provide greater relief from the harmful effects of hyperproliferative diseases, angiogenesis, vascular hyperprolinemia or edema, h�m introduction of each of these substances separately. In the treatment of malignant disorders combination with protivoprolezhnevyj or cytotoxic chemotherapies or radiation exposure was included in the scope of the present invention.

The present invention also includes the use of a compound of formula (I) as a medicament.

The following aspect of the present invention proposed the use of a compound of formula (I) or salts thereof in the manufacture of medicinal products for the treatment of vascular hyperprolinemia, angiogenesis-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, especially in humans.

The present invention also proposes a method of treatment of vascular hyperprolinemia, inadequate neovascularization, proliferative diseases and/or disorders of the immune system, which includes an introduction to the needy in the mammal, particularly a human, a therapeutically effective amount of a compound of formula (I).

REDUCTION

aaAmino acids
AcOHGlacial acetic acid
ATPAdenosine triphosphate
Boc tert-butoxycarbonyl

t-BuOHtert-butanol
BOP-ClBis(2-oxo-3-oxazolidinyl)phosphinic chloride
BSABovine serum albumin (BSA
BuOHButanol
CbzCarboxybenzoyl
CDI1,1'-Carbonyldiimidazole
CTComputed tomography
CyPFt-Bu1-dicyclohexylphosphino-2-di-tert-butylacetophenone
dDoublet
dbaDibenzylideneacetone
DCCDicyclohexylcarbodiimide
DCEDichloroethane
DCMDichloro methane (methylene chloride)
DDDoublet of doublets
DIBAL-HDiisobutylaluminium
DIEAN,N-diisopropylethylamine
DMADimethylacetamide
DMAPN,N-dimethylaminopyridine
DME1,2-dimethoxyethan
DMEMModified Dulbecco medium eagle
DMFAN,N-dimethylformamide
DMSODimethyl sulfoxide
DNP-HSADinitrophenyl-human serum albumin
DTTDithiotreitol
dppf1,1'-bis(diphenylphosphino)ferrocene

The EDC.HClN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
EDTAEthylenediaminetetraacetic acid
EQ. Equivalent (equivalent)
Et2NHDiethylamine
EtOAcThe ethyl acetate
Et2ODiethyl ether
EtOHEthanol
FBSFetal bovine serum
FLAGpeptide sequence DYKDDDDK
gGram (grams)
GSTGlutathione S-transferase
hHour (time)
HATUO-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium hexaflurophosphate
HEPESN-2-hydroxyethylpiperazine-N'-2-econsultancy acid
HOBtHydroxy-benzotriazole
HPLCHigh performance liquid chromatography
IBCFIsobutylparaben
i.d.Intradermally
IFAIncomplete adjuvant of Franta
IPAIsopropyl alcohol
LC/MSLiquid chromatography/mass spectrometry
LDASitedisability
LHMDSLithium bis(trimethylsilyl)amide

mThe multiplet
MMolar
MeCNAcetonitrile
MeOHMethyl alcohol
minMin (minutes)
mmolMillimole
MOPS3-(N-morpholino)-2-hydroxypropanesulfonic acid
MOPSO3-(N-morpholino)propanesulfonic acid
MSMass spec�romeria
n(unbranched)
nNormal
NaOt-BuTert-butoxide sodium
NH4OAcAmmonium acetate
NMMN-methylmorpholin
NMPN-methylpyrrolidinone
NMRNuclear magnetic resonance
OPThe optical density
o.in.Optical rotation
PBSPhosphate superyoung saline
pHlog[H+]
pNAGNitrophenyl-N-acetyl-β-D-glucosamine
ppmParts per million or M. D.
PrOHPropanol
psiPounds per square inch
rc Relative centrifugal force

RP-HPLCHigh-performance liquid chromatography with reversed phase
RtRetention time
K. T.Room temperature
Singlet
SEM2-(trimethylsilyl)ethoxymethyl
SLMStandard liters per minute
tTriplet
t-tertiary
TBAFTetra-n-butylammonium
TEATriethylamine
Tert--tertiary
TFATriptorelin
TFAATrifluoroacetic anhydride
THFTetrahydrofuran
TIPSTriisopropylsilyl
TLCThin-layer chromatography
TMSTrimethylsilyl
USPThe United States Pharmacopeia
UVUltraviolet
wt.%Weight percent

Tests

In Vitro activity of Jak1 kinase, measured using a homogeneous fluorescence time-resolved (HTRF)

Purified Jak1 enzyme (aa 845-1142; expressively in SF9 cells as GST hybrid and purified using glutathione affinity chromatography) was mixed with 2 μm peptide substrate (Biotin-TYR2, Sequence: Biotin-(Ahx)-AEEEYFFLFA-amide) in various concentrations of inhibitor in reaction buffer: 50 mm MOPSO pH 6.5, 10 mm MgCl2, 2 mm MnCl2, 2.5 mm DTT, and 0.01% BSA, 0.1 mm Na3VO4and 0.001 mm ATP. After about 60 min of incubation at room temperature, the reaction mixture was quenched by adding EDTA (final concentration: 100 mm) and developed by adding revelation reagents (final approximate concentrations: 30 mm HEPES pH 7.0, 0,06% BSA, 0,006% Tween-20, 0,24 M KF, 80 ng/ml PT66K (europium labeled anti-phosphotyrosine antibody, catalog number No. 61T66KL Cisbio, Bedford, MA.) and 3.12 μg/ml SAXL (Phycolink streptavidin-allophycocyanin acceptor, cat. No. PJ52S, Prozyme, San Leandro, CA.). The reaction mixture was incubated in the dark or at about 4°C for about 14 hours, or about 60 min at room temperature, then the readings can be read using a fluorescence detector with a time resolution (Rubystar, BMG) and laser with an excitation wavelength of 337 nm and wavelengths of emission of 620 nm and 665 nm. In the linear analysis interval the ratio of the observed signal at 620 nm and 665 nm is directly linked to the phosphorylated product, and these values are used to calculate IR50.

Carry out analyses of other kinases, using a similar Protocol. Additional purified enzymes Tyk2 (aa 880-1185 with the N-terminal histidinol-tag and C-terminal FLAG tag; peeled yourself by using affinity chromatography with immobilized metal ions), RET (aa 711-1072 with the N-terminal histidinol-tag; purified using affinity chromatography with immobilized metal ions) and KDR (aa 792-1354 with the N-terminal histidinol-tag; peeled yourself by using affinity chromatography with immobilized metal ions) Express in SF9 cells and Aurora 1/B (aa1-344 with the N-terminal histidinol-tag and purified using affinity chromatography with immobilized metal ions) Express inE. coli. Other enzymes used are available and� commercial sources. Enzymes are mixed with biotinylating substrates at different concentrations of inhibitor in different reaction buffers (see table 1). After about 60 min of incubation at room temperature, the reaction was quenched by adding EDTA and develop, adding exhibiting reagents (final approximate concentrations: 30 mm HEPES pH 7.0, 0,06% BSA, 0,006% Tween-20, 0,24 M KF, with varying amounts of donor europium labeled antibody, and acceptor-labeled with streptavidin of allophycocyanin (SAXL)). The reaction mixture was incubated in the dark at about 4°C for about 14 hours, or about 60 min at room temperature, then read the readings using a fluorescence detector with a time resolution (Rubystar, BMG Labtech), as disclosed above.

The reaction buffers:

MOPSO buffer contains: 50 mm MOPSO pH 6.5, 10 mm MgCl2, 2 mm MnCl2, 2.5 mm DTT, and 0.01% BSA, and 0.1 mm Na3VO4

HEPES buffer contains 50 mm HEPES pH of 7.1, 2.5 mm DTT, 10 mm MgCl2, 2 mm MnCl2, and 0.01% BSA, and 0.1 mm Na3VO4

MOPS buffer containing: 20 mm MOPS pH of 7.2, 10 mm MgCl2, 5 mm EGTA, 5 mm Beta-fosfoglitserin, 1 mm Na3VO4, and 0.01% Triton-X-100 and 1 mm DTT.

Substrates:

Biotin-ATF2 peptide sequence: Biotin-(Ahx)-AGAGDQTPTPTRFLKRPR-amide

Biotin-TYR1-peptide sequence: Biotin-(Ahx)-GAEEEIYAAFFA-COOH

Biotin-TYR2-peptide sequence: Biotin-(Ahx)-AEEEYFLFA-amide

Biotin-MBP-peptide sequence: Biotin-(Ahx)-VHFFKNIVTPRTPPPSQGKGAEGQR-amide

The peptide Biotin-polyGluTyr received from Cisbio (cat. No. 61GT0BLA, Bedford, MA.)

Peptides KinEASE S2 and S3 obtained from Cisbio (cat. No. 62ST0PEB, Bedford, MA.)

The detection reagents:

Anti-pATF2-Eu-labeled by individual order Cisbio (Bedford, MA.)

Anti-pMBP-Eu-labeled by individual order Cisbio (Bedford, MA.)

PT66K received from Cisbio (cat. No. 61T66KLB, Bedford, MA.)

SAXL obtained from Prozyme (cat. No. PJ25S, San Leandro, Calif.)

In Vitro activity of Syk kinase, measured using a homogeneous fluorescence time-resolved (HTRF)

1 nm purified, full-length Syk enzyme (obtained from Millipore, Billerica, MA., cat. No. 14-314) is mixed with 0.1 μm peptide substrate (Biotin-TYR1, sequence: Biotin-(Ahx)-GAEEEIYAAFFA-COOH) at different concentrations of inhibitor in reaction buffer: 50 mm MOPSO pH 6.5, 10 mm MgCl2, 2 mm MnCl2, 2.5 mm DTT, and 0.01% BSA, 0.1 mm Na3VO4and 0.01 mm ATP. After about 60 min of incubation at room temperature, the reaction was quenched by adding EDTA (final concentration: 100 mm) and resume by adding exhibiting reagents (final approximate concentrations: 30 mm HEPES pH 7.0, 0,06% BSA, 0,006% Tween-20, 0,24 M KF, 90 ng/ml PT66K (europium labeled anti-phosphotyrosine antibody cat. No. 61T66KLB Cisbio, Bedford, Mass.) and 0.6 μg/ml SAXL (Phycolink streptavidin-allophycocyanin acceptor, cat No. PJ52S, Prozyme, San Leandro, Calif.). The treated reaction mixture �cuberoot in the dark or at about 4°C for about 14 hours, or about 60 min at room temperature, then the readings can be read using a fluorescence detector with a time resolution (Rubystar, BMG) using a laser with an excitation wavelength of 337 nm and wavelengths of emission of 620 nm and 665 nm. In the linear analysis interval the ratio of the observed signal at 620 nm and 665 nm is directly linked to the phosphorylated product, and these values are used to calculate IR50.

Cellular analysis of T-blast IL-2 pSTAT5 man

Materials:

Treated with phytohemagglutinin T-blasts derived from Leukopacks obtained from Biological Specialty Corporation, Colmar, Pa. 18915, and cryopreserved in 5% DMSO/medium prior to analysis. For this analysis, the cells were thawed in a research environment the following composition: RPMI 1640 medium (Gibco 11875093) with 2 mm L-glutamine (Gibco 25030-081), 10 mm HEPES (Gibco 15630-080), 100 μg/ml Pen/Strep (Gibco 15140-122), and 10% thermoinactivation FBS (Gibco 10438026). Other materials used in the analyses: DMSO (Sigma D2650), 96-well plates for dilutions (polypropylene) (Corning 3365), 96-well analytical tablets (white, 1/2 area 96 well) (Corning 3642), D-PBS (Gibco 14040133), IL-2 (R&D 202-IL-10 (10 ug)), the set of Alphascreen pSTAT5 (Perkin Elmer TGRS5S10K) and a set of Alphascreen protein A (Perkin Elmer 6760617M)

Methods:

T-blasts were thawed and cultured for about 24 h without IL-2 prior to analysis. Test compounds or controls dissolved separately and diluted � 100% DMSO. Original solutions in DMSO serially diluted 1:50 in the medium for cell culture to obtain solutions of 4×stock solution of the compounds (containing 2% DMSO). Using white 96-well plates Corning, 1/2 plate area, the cells are placed in wells at a concentration of 2×105/10 μl/well in 10 μl of the medium followed by the addition of 5 μl 4×test compound in duplicate. Cells were incubated with compound for about 0.5 hour at a temperature of about 37°C. Then add 5 μl of IL-2 stock solution to a final concentration of 20 ng/ml IL-2 is stored as the original 4 μg/ml solution, as recommended by the manufacturer, at a temperature of about -20°C in aliquots and diluted 1:50 analytical environment (up to 80 ng/ml) immediately before use. The contents of the wells are mixed by gently tapping the edges of the tablet (tablets) several times, incubated at 37°C for about 15 min Analysis done by adding 5 μl 5×AlphaScreen lisanova buffer and shaking on an orbital shaker for about 10 minutes at room temperature. The mixture balls Alphascreen acceptor reduced in accordance with the Protocol Perkin Elmer. Add 30 ál/well of a mixture of balls recovered Alphascreen acceptor, cover with foil, then shaken on an orbital shaker for about 2 min at high speed, then about 2 hours with low speed�awn. A mixture of donor beads reduced in accordance with Perkin Elmer's Alphascreen Protocol; add 12 ál/well, cover with foil, then shaken for about 2 minutes at high speed, then about 2 hours at a low speed. Results for tablets read using the reader EnVision in accordance with the instructions of the Protocol Perkin Elmer's Alphascreen.

Cellular analysis of TF-1, IL-6 pSTAT3

Materials:

TF-1 cells (ATCC no CRL-2003). Culture medium: DMEM medium (Gibco 11960-044) with 2 mm L-glutamine (Gibco 25030-081), 10 mm HEPES (Gibco 15630-080), 100 μg/ml Pen/Strep (Gibco 15140-122), 1.5 g/l sodium bicarbonate (Gibco 25080-094), 1 mm sodium pyruvate (Gibco 11360-070), 10% thermoinactivation FBS (Gibco 10437-028), and 2 ng/ml GM-CSF (R&D 215-GM-010). Other materials used in the above analysis: DMSO (Sigma D2650), 96-well plates for dilutions (polypropylene) (Corning 3365), 96-well analytical tablets (white, 1/2 area 96 well) (Corning 3642), D-PBS (Gibco 14040133), IL-6 (R&D 206-IL/CF-050 (50 μg)), the set of Alphascreen pSTAT3 (Perkin Elmer TGRS3S10K) and a set of Alphascreen protein A (Perkin Elmer 6760617M).

Methods:

Before analysis, the cells are cultured for about 18 hours in a nutrient medium for cultures without GM-CSF. Test compounds or controls and dissolved separately diluted in 100% DMSO. Original solutions in DMSO serially diluted 1:50 in the culture medium to obtain a 4× stock solution of the compounds (containing 2% DM�About). Using white plates Corning 96-well plate, 1/2 square, the cells are placed in an amount of 2×107/10 μl/well in 10 μl of the medium followed by the addition of 5 μl 4× stock solution of the test compound in duplicate. Cells were incubated with compound for about 0.5 hour at about 37°C followed by the addition of 5 μl of 400 ng/ml IL-6. IL-6 is stored in 10 μg/ml aliquots are using does not contain endotoxin (D-PBS (with 0.1% BSA) at a temperature of about -20°C. Before analysis of IL-6 was diluted to 400 ng/ml in the culture medium and placed (5 μl/well) to all wells, except wells negative control, add 5 μl/well of medium. The contents of the wells gently stirred, tapping on the edges of the tablet several times. The plates were incubated at 37°C for 30 min, the Cells lisarow by adding 5 μl 5× litany Alphascreen buffer cells to all wells, shaken for about 10 min at room temperature, then analyzed. Alternatively, analytical tablets can be frozen at about -80°C, and thaw later at room temperature. Using analytical set of pSTAT3 SureFire Assay (Perkin Elmer No. TGRS3S10K), a mixture of acceptor beads reduced in accordance with the instructions in the Protocol Perkin Elmer's Alphascreen. Add 30 ál into the hole, then the tablet cover with foil and shaken using an orbital shaker for about 2 min at you�Oka speed, then about 2 hours at low speed at room temperature. A mixture of donor beads reduced in accordance with the instructions of the Protocol Perkin Elmer's Alphascreen. To each well was added 12 μl, then cover with foil and shaken using an orbital shaker for about 2 min at high speed, then about 2 hours at low speed at room temperature. The results of the tablets can be read using the reader EnVision in accordance with the instructions of the Protocol Perkin Elmer's Alphascreen at room temperature.

Cellular analysis of UT7/EPO pSTAT5

Materials:

UT7/EPO cells saute with erythropoietin (EPO), split twice a week, and fresh culture medium were thawed and added during the splitting. Culture medium: DMEM medium (Gibco 11960-044) with 2 mm L-glutamine (Gibco 25030-081), 10 mm HEPES (Gibco 15630-080), 100 U/ml Pen/Strep (Gibco 15140-122), 10% thermoinactivation FBS (Gibco 10437-028), EPO (5 ál/ml=7,1 7 ál ág/ml stock solution per ml of medium). Analytical medium: DMEM, 2 mm L-glutamine, 5% FBS, 10 mm HEPES. Other materials used in the analyses: DMSO (Sigma D2650), 96-well plates for dilution (polypropylene) (Corning 3365), 96-well analytical tablets (white, 1/2 area 96 well) (Corning 3642), D-PBS (Gibco 14040133), IL-2 (R&D 202-IL-10 (10 ug)), the set of Alphascreen pSTAT5 (Perkin Elmer TGRS5 S10K) and a set of Alphascreen protein A (Perkin Elmer 6760617M)

Methods:

Cells are cultivated in tech�of about 16 hours without EPO prior to analysis. Test compounds or controls and dissolved separately diluted in 100% DMSO. Original solutions in DMSO serially diluted 1:50 in cell culture medium to obtain 4× the original solutions of compounds (containing 2% DMSO). Using white 96-well plates Corning, 1/2 square, the cells are placed in an amount of 2×105/10 μl/well in 10 μl of the medium followed by the addition of 5 μl 4× stock solution of the test compound in duplicate. Cells were incubated with compound for about 0.5 hour at a temperature of about 37°C. After incubation, add 5 ál of EPO to achieve a final concentration of 1 nm EPO. The contents of the wells are mixed by gently tapping the edges of the plate several times, followed by incubation at a temperature of about 37°C for about 20 min. Add 5 µl of 5× litany AlphaScreen buffer, then shaken using an orbital shaker for about 10 minutes at room temperature. Add 30 ál/well of acceptor beads after the restoration in accordance with the Protocol Perkin Elmer's Alphascreen, cover with foil and shaken using an orbital shaker for about 2 minutes at high speed, then about 2 hours at low speed. Donor beads reduced in accordance with the instructions of the Protocol Perkin Elmer AlphaScreen, followed by the addition of 12 ál/well, cover Volga� and shaken, using the orbital shaker for about 2 min at high speed, and about 2 hours on low speed. Indications tablets read using the reader EnVision in accordance with the instructions of the Protocol Perkin Elmer's Alphascreen.

Caused by antigen degranulation of RBL-2H3 cells:

RBL-2H3 cells maintained in T75 flasks at a temperature of about 37°C and 5% CO2and saute every 3-4 days. To collect cells using 20 ml of PBS, washing out the flask once, then add 3 ml of trypsin-EDTA and incubated at a temperature of about 37°C for about 2 min, the Cells were transferred to a vial with 20 ml of the medium, is rotated at a speed of 1000 rpm at room temperature for about 5 min, and again suspended at a concentration of 1×106cells/ml Cells sensitize, adding DNP-specific mouse IgE to a final concentration of 0.1 μg/ml. Add 50 ál of cells to each well of 96-well plates with flat bottom (50×103cells/well) and incubated overnight at a temperature of about 37°C in 5% CO2. The next day, compounds are prepared in 100% DMSO at a concentration of 10 mm. Each connection is then individually diluted 1:4 six-fold in 100% DMSO. Each of the dilutions of the compounds then diluted 1:20 and then 1:25, both dilution doing in Tyrode's buffer. The medium is aspirated from the plates with cells, and the cells washed twice 100 MK� Tyrode buffer (preheated to 37°C). To each well is added 50 μl of compounds diluted in Tyrode's buffer, and the plates were incubated for about 15 minutes at a temperature of about 37°C in 5% CO2. Then to each well was added 50 μl of 0.2 μg/ml DNP-HSA in Tyrode's buffer, and the plates were incubated for about 30 min at a temperature of about 37°C in 5% CO2. The final concentration of various components in the incubation mixture is of 0.002 to 10 μm compounds of 0.1% DMSO and 0.1 μg/ml DNP-HSA. As a control, 0.2% DMSO (without connections) in Tyrode's buffer is added to the set of holes to determine the maximum stimulated secretions. As a second control Tyrode buffer without DNP-HSA is added to the set of wells containing 0.2% DMSO without compound to determine restimulating selection. Each condition (connections and controls) are repeated in the hole three times. At the end of the 30 minute incubation 50 μl of the supernatant is transferred to a new 96-well plate. Remaining in the supernatant from cells is aspirated, and replaced with 50 μl of 0.1% Triton X-100 in Tyrode's buffer for the implementation of cell lysis. Then add 50 ál of freshly prepared 1.8 mm 4-nitrophenyl N-acetyl-β-D-glucosamine (pNAG) to each well with the supernatant and the cell lysate, and the plates were incubated for about 60 minutes at a temperature of about 37°C in 5% CO2. To each well was added 100 μl of 7.5 mg/ml of bicarbonate NAT�Oia to stop reaction. Readings from the plates read at a wavelength of 405 nm, using the reader for tablets Molecular Devices SpectraMax 250.

Treatment results

1) Background OD value405,received forholes containing Tyrode buffer and pNAG (without supernatant or lysate) is subtracted from the values OP405to be read for each hole containing supernatant or lysate.

2) the Allocation for each hole is expressed as a percentage of the total allocation for the hole where the total allocation exceeds twice the allocation in the case of the supernatant plus the selection in the case of cell lysate. This calculation makes a correction for unequal number of cells in each well.

3) the Maximum response is the average response to the wells containing DNP-HSA, but not containing compound.

4) the Minimum reaction represents the average response for wells that do not contain any DNP-HAS, no connection.

5) Reaction in each hole containing compound, calculated as a percentage of the maximum response (expressed as % of control), where the maximum reaction rate is 100%, and the minimum is 0%.

6) Curve dose-response build for each connection, and IR50for the curve calculated using the software GraphPad Prism and nonlinear regression �method of least squares.

Real in vivo measurement of inhibition of JAK compounds is carried out using:

The production of cytokines in rats induced concavalin A (Con A) in Lewis rats

The test compound is prepared in an inert medium (e.g. but not limited to, 0.5% hydroxypropylmethylcellulose (Sigma, cat. No. H3785)/0,02% Tween 80 (Sigma, cat. No. 470) in water) at a concentration necessary to achieve a dose in the range of from 0.01 to 100 mg/kg Six-week male Lewis rats (125 g-150 g) (Charles River Laboratories) administered oral dose, at time (0 min). After about 30 min the rats by intravenous injection (i.v.) 10 mg/kg concanavalin A (Con A, Amersham Bioscience, cat. No. 17-0450-01) dissolved in PBS (Invitrogen, cat. No. 14190). After about 4 hours in rats away the blood from the heart, and the obtained plasma was analyzed for levels of IL-2 (ELISA kit: R&D Systems cat. No. R2000) and IFN-γ (ELISA kit: R&D Systems cat. No. RIF00).

Real in vivo measurement of inhibition by the compounds of the signal transmission Fcγ receptors are, using:

Reverse passive model Artus court

On day 0 prepared OVA at a concentration of 17.5 mg/ml in PBS, carefully turning until then, until a solution. Then add 2% (Evans Blue) solution of Evans blue (Sigma Aldrich, cat. No. E2129) so as to double the volume to a final concentration of 8.75 mg/ml OVA and 1% of the dye Evans blue. Anti-OVA and�titulo (Abazyme), the initial concentration of 10 mg/ml, thawed, and prepare for a solution of 400 μg/100 μl using PBS. Compounds prepared by adding the medium with 0.5% HPMC with 0.02% Tween 80, and rapidly rotating for about 15 seconds, followed by homogenization for at least about 2 minutes at a speed of 28000 rpm, until, until a fine suspension of particles without lumps connection. Rats weighed, and injected t-max dose compounds, predetermined on the basis of pharmacokinetic studies. Then the animal is given a General anesthesia using a mixture of 5% isoflurane and oxygen, and shave. Using an insulin syringe 1/2 ml perform intradermal injection at two sites; one site was added 100 μl of 400 µg/100 µl of anti-OVA antibodies, and another site was added 100 μl of sterile PBS. Then each site outline indelible marker for follow-up observations. Immediately after intradermal injection animals injected by the injection of 200 μl of OVA (10 mg/kg) and the mixture Evans blue intravenous i.v., using an insulin syringe ½ ml for About 4 hours after injection the animals evtanaziyu, blood is taken using a needle for cardiac puncture, and blood is placed in an ampule emitting plasma. Blood samples stored on ice until centrifugation (within about 2 hours after collection). Each injection site was removed using a single dermatome (Acuderm Acu-Punch Disposable 12 m�), cut into 4 pieces and placed in a 2 ml pre-labeled Eppendorf tubes. One ml of DMF is added to each flask with biopsy and placed in the fuser for about 24 hours at about 50°C. After about 24 hours of incubation add 100 ál of each sample in a 96-well flat-bottomed tablet. Indications tablets read at 620 nm, using reader with a tablet device, using the software Softmax. Background values exclude by subtracting the OP for sites that had implemented PBS injection of OP values for sites, which was carried out by the injection of anti-OVA, for each individual animal.

The precipitated plasma samples in a microcentrifuge for about 5 min at at 16.1 rcf. 200 μl of plasma was placed in a 1.7 ml Eppendorf tube for measuring the level of maintenance medications, and stored at -80°C until measurement.

Measure chronic in vivo effects of the compounds in the model of ankylosing arthritis, using:

Induced adjuvant arthritis (AIA) in rats Lewis

Female Lewis rats (aged 6 weeks, weighing 125 g-150 g from Charles River Laboratories) immunize intradermally (i.d.) in the pad of the right hind paws of 100 μl of a suspension of mineral oil (Sigma, cat. No. M5905) containing 200 mcgM. tuberculosis, H37RA (Difco, cat. No. 231141). Inflammation appears on the opposite (left) hind leg 7 days after immunization. After seven days�th after immunization compound is prepared in an inert medium (for example, but not limited to, 0.5% methylcellulose (Sigma, cat. No. H3785)/0,02% Tween 80 (Sigma, cat. No. 4780) in water) and dose administered orally once or twice daily for at least 10 days. The basic volume of the paw was measured at day (0), using the plethysmograph, based on the displacement of the water (Vgo Basile North America Inc. PA 19473, Model No. 7140). Rats slightly anastasiou inhalation anesthetic (isoflurane) and contra-lateral (left) hind leg immersed in the plethysmograph, and recording the volume of the paw. Rats are estimated through the day, up to 17 days after immunization, and all rats exsanguinated using the needle to puncture the heart under anesthesia with isoflurane, and the left rear paw cut out to assess the impact on bone erosion with the help of micro-CT scans (SCANCO Medical, Southeastern, PA, Model No. μCT 40) when the size of the three-dimensional image 18 μm, with the threshold value of 400, sigma-gauss 0,8, support of 1.0 gauss. The volume of the bone density is determined for 360 µm (200 slices) vertical cross-sections, including predpljusnevye part of paws. Received 360 µm sections were analyzed from the base of the shank to the top of the tibia, and the bottom point is fixed at the point of junction of the tibia and the talus of the joints. The impact of drugs determined in plasma using LC/MS.

or:

Caused by collagen arthritis (CIA) in rats Lewis

In day-1 collagen type II (CII), RAS�warily, from bovine nasal septum (Elastin Products, cat. No. CN276) is weighed for the dose of 600 ág/rat, added 0.01 M acetic acid (150 μl Or USP grade. J. T. Baker, order No. 9522-03, and 250 ml of Milli Q Water) to achieve a concentration of 4 mg/ml Vial covered with aluminum foil and placed on a rocking chair at a temperature of about 4°C overnight. On day 0 of the collagen stock solution was diluted 1:1 with partial adjuvant of franda (IFA) (Difco labs, cat. No. 263910), using a Hamilton glass syringe with a tip of Luera (SGE Syringe Perfection VWR cat. No. 007230), to a final concentration of 2 mg/ml. Female Lewis rats (Charles River Laboratories), acclimatized for 7 days at the time of immunization, weighing approximately 150 g anastasiou in anesthetizing camera using isoflurane (5%) and oxygen. After the rat is fully anesthetized, they are transferred to the protective cone to maintain anesthesia during the injection. Rats shave at the base of the tail, 300 μl of collagen injected injected intradermally (i.d.) in the sacrum rats, n=9 in the group, 100 μl into three site 500 ál syringe with a tip of Luera and needle gauge 27. IFA for the control of rats administered the same way (n=6). IFA is a 1:1 emulsion with 0.01 M acetic acid. Booster injection was performed on day 6 of the study. On this day, the rats don't shave, and the injection is carried out as with immunization. Inflammation appears on both hind legs h�RES 10 days after the initial immunization. 10 days after immunization compound is prepared in an inert medium (e.g. but not limited to, 0.5% methylcellulose (Sigma, cat. No. H3785)/0,02% Tween 80 (Sigma, cat. No. 4780) in water) and dosed orally once or twice daily for at least 9 days. The basic volume of the paw is determined at day 7 using pleythsmograph using water displacement (Vgo Basile North America Inc. PA 19473, Model No. 7140). Rats slightly anastasiou an inhalation anesthetic (isoflurane) and both hind feet are immersed in the plethysmograph, and recording the volume of the paws. Rats estimate 2-3 times a week until 18 days after immunization. On day 18 after immunization of all exsanguinated rats, using a needle to puncture the heart under anesthesia with isoflurane, and the hind legs are cut out to assess the impact on bone erosion with the help of micro-CT scans (SCANCO Medical, Southeastern, PA, Model No. μCT 40) when the size of the three-dimensional image 18 μm, with the threshold value of 400, sigma-gauss 0,8, support of 1.0 gauss. The volume of the bone density is determined for 360 µm (200 slices) vertical sections comprising predpljusnevye part of paws. Received 360 µm sections were analyzed from the base of the shank to the top of the tibia, the lower fixed point at the junction of the tibia and the talus of the joints. The effect of the medication is determined from plasma using LC/MS.

The contents of all references, including Zhu�tional article, patents and published patent applications are incorporated herein by reference in its entirety. The following examples are for illustrative purposes and should not be construed as limiting the scope of the present invention.

The GENERAL SCHEME of SYNTHESIS

Compounds of the present invention can be obtained using the synthetic transformations presented in schemes I-XII. The starting materials are commercially available, they can be obtained revealed here by the methods disclosed in the literature or by methods that are well known to experts in the field of organic chemistry. Methods of obtaining imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine, the compounds of the present invention, is illustrated in scheme I. In scheme I at stage a, commercially available 2-bromo-5H-imidazo[2,3-b]pyrazine (also referred to as 5-bromo-4,7-diakanda, Ark Pharm, Inc) protect as a sulfonamide, using terms such as disclosed in the example of obtaining the No. 1, or by methods known to those skilled in the art (for example, Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndedition”, 1999, Wiley-VCH or Greene, T. W. and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3rdEdition”, 1999, Wiley-Interscience). Alternatively, protected imidazo[2,3-b]pyrazine 2 can be obtained from commercially available 3,5-dibromopyridin-2-amine using the reaction cross combination Sonagachi�and (Sonogashira) (Scheme 1, stage g) to give alkyne 9, which can be cichlisuite (Scheme 1, step (h), receiving pyrrolopyrazine 2, using methods known to those skilled in the art (for example, example No. 7, method B). In scheme I, a b-stage injected substituted hydrazine, interacting with pyrrolopyrazine 2 in conditions of amination of Buchwald-Hartwig (Buchwald-Hartwig) (for example, example No. 2 orAdvanced Synthesis&Catalysis2004, 346, 1599-1626), receiving pyrrolopyrazine 3. If R accepts such values that pyrrolopyrazine 3 contain hydrazide (R"=-C(O)R'") or hydrazon, the material can be directly cilitate to pyrrolotriazine 6, using terms such as disclosed in the General procedure C, in the initial stage of example 1, General procedure G or methods known to those skilled in the art (for example,Bioorganic&Medicinal Chemistry Letters2007, 17(12), 3373-3377 orJournal of Medicinal Chemistry1990, 33(9), 2326-34). In some cases, pyrrolotriazine 6 can be subjected to the interaction in situ, getting pyrrolotriazine 7 (for example, example No. 1 or General procedures B and E). It can also cause further reaction without isolation of the source pyrrolotriazine 6 or 7, as presented in the General procedures D and F. If R is a protective group, removing the protective groups of compound 3 to obtain gegratineerde�of operating 4 can be realized, using conditions, such as disclosed in the General procedure I, in General procedure J, or Greene, T. W. and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3rdEdition”, 1999, Wiley-Interscience. For example, a protective group such as tert-butoxycarbonyl group can be removed with acid, using terms such as disclosed in the example of receiving No. 3, General procedure I, or by methods known to those skilled in the art (for example, in books from Larock, R. C. or Greene, T. W. and Wuts, P. G. M. Cm. the link above). Alternatively, the reaction of pyrrolopyrazine 2 with hydrazine under conditions of amination of Buchwald-Hartwig, as disclosed above, may lead directly to hydrazinopyridazine 4. Getting hydrazides 5 out of hydrazinopyridazine 4 (Scheme I, step d) can be accomplished in various ways known to those skilled in this field, including in situ conditions, such as disclosed in the example 1, General procedure A, or by standard methods of peptide binding, such as disclosed in Larock, R. C. (see link above). The hydrazides 5 can be cilitate to pyrrolotriazine 6, using terms such as disclosed in the example 1, General procedure C, or by methods known to those skilled in the art (for example,Bioorganic&Medicinal Chemistry Letters2007, 17(12), 3373-3377 orJournal of Medicinal Chemistry1990, 33(9), 2326-34). Further functionalization of pyrrolotriazine can be realized, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine or heteroarenes can be obtained from pyrrolotriazine 6 containing primary or secondary amine (for example, examples No. 3 and No. 4 or a General procedure L, M, N or O). Additionally, the removal of the protective groups at pyrrolotriazine 6 can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J. for Example, the protective group, such as benzyloxycarbonyl group, you can delete the protected amine, receiving unprotected amine (for example, in figure 2), and compound 6 with remote protective groups can then be subjected to further interaction, as disclosed above. The removal of sulfonamide protective group at pyrrolotriazine 6 can be performed using conditions such as disclosed in the example 1, General procedure H, or by methods known to those skilled in the art (for example, books from Larock, R. C., or Greene, T. W. and Wuts, P. G. M. (see link above)), getting pyrrolotriazine 7 (Scheme I, step f). Further functionalization of the R'"groups in pyrrolotriazine 7 can be carried out, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link �ove)). For example, amides, urea, sulfonamides, arylamine, or heteroarenes can be obtained from pyrrolotriazine 7, in which R'"has a primary or secondary amine (for example, examples No. 3 and No. 4 or a General procedure L, M, N or O). In addition, removal of the R'"groups in pyrrolotriazine 7 to obtain an unsecured connection can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J. for Example, the protective group, such as benzyloxycarbonyl group can be removed from a protected amine, receiving unprotected amine (for example, example No. 2 or the General procedure (J), 7 and the connection with the remote protective group can then be subjected to further interaction, as disclosed above.

Scheme I

The formation of hydrazones from 10 hydrazinopyridazine 4 (Scheme II, step a) can be accomplished in various ways known to those skilled in this field, including in situ conditions, such as disclosed in the General procedure G. the Hydrazones 10 can be cilitate to pyrrolotriazine 6, using terms such as disclosed in the General procedure G, or methods known to experts in this field. Further functionalization of pyrrolotriazine 6 can be implemented, if desired, using reactions known �the experts in this field (for example, Larock, R. C. (see link above)). Further functionalization of pyrrolotriazine 6, including the hydrolysis of the sulfonamide to obtain pyrrolotriazine 7 (Scheme I, step f) are described above.

Scheme II

Methods of obtaining imidazo[1,2-a]imidazo[2,3-e]pyrazines, compounds of the present invention, is illustrated in scheme III. At stage a, is administered carbamate, interacting of pyrrolopyrazine 2 with tert-BUTYLCARBAMATE in conditions of amination of Buchwald-Hartwig (for example, example # 8, step A; example No. 2, orAdvanced Synthesys&Catalysis2004, 346, 1599-1626), receiving pyrrolopyrazine-2-ylcarbamate 11. The removal of the protective group from compounds 11 to obtain a 2-aminobenzenesulfonamide 12 can be performed using conditions such as disclosed in example # 8, step B; in General procedure I, or Greene, T. W. and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3rdEdition”, 1999, Wiley-Interscience. The formation of imidazopyrimidines 13 substituted in the 7-position can be achieved by interacting 2-aminobenzenesulfonamide 12 with appropriately substituted 2-halogeometricum ways, known to those skilled in the art (for example,Journal of Medicinal Chemistry,1987, 30(11), 2031-2046 or example # 8, step C). Further functionalization of imidazopyrimidines 13 can make�ü, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine or heteroarenes can be obtained from imidazopyrimidines 13 containing primary or secondary amine (for example, examples No. 3 and No. 4 or a General procedure L, M, N or O). In addition, the removal of the protective groups at imidazopyrimidines 13 can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and the connection 13 with remote protective groups can then be subjected to further interaction, as disclosed above. The removal of sulfonamide protective group at imidazopyrimidines 13 can be performed using conditions such as disclosed in example # 8, step D; in General procedure H, or by methods known to those skilled in the art (for example, books from Larock, R. C., or Greene, T. W. and Wuts, P. G. M. (see link above)), getting imidazopyridine 14. Alternatively, the alkylation pyrrolopyrazine-2-ylcarbamate 11 appropriately substituted 2-halogeometricum ways, known to those skilled in the art (for example, example # 9, step A; Tetrahedron Letters, 2006, 47(34), 6113-6115; orJournal of Medicinal Chemistry,2005, 48(14), 4535-4546), yields pyrrolopyrazine 15. The cyclization of pyrrolopyrazine 15 to them�of asopersonerias 16 can be realized ways, known to those skilled in the art (for example, example # 9, step B;European Journal of Medicinal Chemistry,2001, 36(3), 255-264; orBioorganic @ Medicinal Chemistry Letters,2007, 17(5), 1233-1237). Further functionalization of the R'"groups in imidazopyridine 16 can be implemented, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine or heteroarenes can be obtained from imidazopyrimidines 16 with R'"groups containing primary or secondary amines (for example, examples No. 3 and No. 4 or a General procedure L, M, N or O). Also, removal of the R'"groups in imidazopyridine 16 to obtain an unsecured connection 17 can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and unprotected connection 17 can then be subjected to further interaction, as disclosed above. The removal of sulfonamide protective group at imidazopyrimidines 16 can be performed using conditions such as disclosed in example # 9, step C; in General procedure H, or by methods known to those skilled in the art (for example, in books from Larock, R. C., or Greene, T. W. and Wuts, P. G. M. (see link above)), getting imidazopyridine 17.

Scheme III

Methods of obtaining imide�about[1,5-a]imidazo[2,3-e]pyrazines, compounds of the present invention, is illustrated in scheme IV. On a stage, introduce a vinyl group, interacting of pyrrolopyrazine 2 Bronevoy acid in the conditions of cross combinations Suzuki (for example, example No. 10, step A). Oxidative cleavage of alkenes 18, yields of aldehyde 19 (for example, example No. 10, step B). The transformation into the corresponding primary amines can be performed using first condensation with hydroxylamine followed by reduction with zinc, receiving amines 21 (for example, example No. 10, step C). Alternatively, amines 21 can be obtained by restoring aldehydes 19 to the corresponding alcohols (for example, example No. 13, step D) converting the alcohol to the chloride, and replacing the azide to obtain an azide 20 (for example, example No. 13, step E). The restoration of azides leads to the preparation of amines 21 (for example, example No. 13, step F). Alternatively, amines 21 can be obtained as a result of conversion of bromides 2 into the corresponding NITRILES 25 (for example, example No. 28), followed by reduction to an amine 21 (for example, example No. 28). The reaction of a combination of amine 21 with acids yields of amides 22 (for example, example No. 10, step C). The cyclization of amides 22 can be realized by making thioamide with subsequent treatment of an activating agent (such as a salt of mercury, sorcerer or copper salt), getting imidazo[1,5-a]imidazo[2,3-e]pyrazine 23 (for example, example No. 10, step D). The removal of the protective group from compounds 23 to obtain imidazo[1,5-a]imidazo[2,3-e]pyrazines 24 can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3rdEdition", 1999, Wiley-Interscience, in General procedure H, or in example No. 10, in step E. Further functionalization R'"groups in imidazo[1,5-a]imidazo[2,3-e]pyrazino 23 or imidazo[1,5-a]imidazo[2,3-e]pyrazino 24 can be implemented, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine or heteroarenes can be obtained from compounds 23 or 24 with R'"groups containing primary or secondary amines (for example, General procedure L, M, N or O). In addition, removal of the R'"groups in compounds 23 or 24 to receive unsecured connections can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and unprotected compounds can then be subjected to further interaction, as disclosed above.

Scheme IV

Methods of obtaining 3H-dipyrrole[1,2-a:2',3'-e]pyrazines, compounds of the present invention, is illustrated in scheme V. In stage a, the aldehyde 19 is subjected to radio frequency interference�mainstream in terms of the Horner-Emmons (Horner-Emmons), receiving α,β-unsaturated ketones 26 (for example, example No. 11, step A). The restoration of the double bond leads to saturated ketones 27 (for example, example No. 11, step B). The cyclization to tricyclic compounds 28 can be realized by processing the connection 27 activating agent by methods known to those skilled in the art (for example, example No. 11, step C). The removal of the protective group from compounds 28 to receive 3H-dipyrrole[1,2-a:2',3'-e]pyrazines 29 can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. "Protective Groups in Organic Synthesis, 3rdEdition", 1999, Wiley-Interscience; in General procedure H, or in example No. 11, in step D. Further functionalization R'"groups in 3H-dipyrrole[1,2-a:2',3'-e]pyrazino 28 or 29 can be realized, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine, or heteroarenes can be obtained from compounds 28 or 29 with R'"groups containing primary or secondary amines (for example, General procedure L, M, N or O). In addition, removal of the R'"groups in compounds of 28 or 29 to receive unsecured connections can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and unprotected compounds can then be subjected to main�Isamu interaction, as disclosed above.

Scheme V

Methods of obtaining substituted cyclopentanecarbonyl acids 38 for use in obtaining the compounds of the present invention is illustrated in scheme VI. At stage a, a complex of β-ketoamine 31 can condense with methyl 4-chloroacetoacetate 30, receiving cyclic salt of β-catefories 32 (for example, General procedure BB). The removal of the protective group from compounds 32 to obtain α,β-unsaturated ketones 33 is carried out by standard methods known to those skilled in the art (for example, General procedure CC). As shown in stage c, the hydrogenation of α,β-unsaturated ketones 33 yields a saturated ketone 34 (for example, General procedure DD). Reducing amination of ketones 34 dibenzylamine leads to the formation of compounds 35, using conditions such as disclosed in the General procedure EE. Dibenzylamine connection 35 can be realized by hydrogenation, as described in the General procedure FF, to obtain amine 36. Alternative arrangements can be used to obtain amines from 36 34 ketones, for example, as disclosed in Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndedition”, 1999, Wiley-VCH. Amines 36 can be further functionalization, using reactions known to those skilled in the art (e.g.�p, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine, or heteroarenes can be obtained from amines 36 (for example, General procedure L, M, N or O) to give compound 37. Esters of compounds 37 can hydrolyze in aqueous alkaline or acidic conditions, yielding the desired carboxylic acid 38 (for example, General procedure GG or Larock, R. C. (see link above)). If desired, you can make chiral separation of compounds 33, 34, 35, 36, 37 or 38, using methods known to experts in this field, such as chiral preparative HPLC (for example, General procedure (II).

Scheme VI

The methods of obtaining the 4-substituted piperidine-3-carboxylic acid, the compounds of the present invention, is illustrated in scheme VII. At stage a, 4-substituted or unsubstituted nicotinic acid 39 can fully saturate, using methods which are known to those skilled in the art (for example, example No. 13, step G). Received piperidinylcarbonyl acid 40 can be protected with a suitable aminosidine group such as disclosed in Greene, T. W. and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3rdEdition”, 1999, Wiley-Interscience; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndedition”, 1999, Wiley-VCH; or in example No. 13, in step G, getting piperidinecarbonitrile acid 41.

Scheme VII

Methods of obtaining dihydropyrazolo[4,3-d]imidazo[2,3-b]pyridine, compounds of the present invention, is illustrated in scheme VIII. At stage a, the reaction of the aldehyde 42 with the Grignard reagent yields of alcohols 43 when using methods known to those skilled in the art (for example, example No. 23, step A). Obtaining ketones 44 (stage b) can be accomplished by treating the alcohols 43 oxidizing agent by methods known to those skilled in the art (for example, example No. 23, step B). Alternatively, ketones 44 can be obtained through the interaction of heteroaromatic 45 with aldehyde (stage C) to obtain 43 alcohols (for example, example No. 24, step A) followed by oxidation, as disclosed previously. Obtaining ketones 44 can be made directly, through the interaction of heteroaromatic 45 with an appropriately substituted acid chloride by methods known to those skilled in the art (such as disclosed inHeterocycles,2003, 59(1), 369-385). Ketones 44 can then be turned into a hydrazone 46, using the reaction with hydrazine, using terms such as disclosed in example No. 24, for phase C. the Cyclization of hydrazones 46 for receiving dihydropyrazolo[4,3-d]imidazo[2,3-b]pyridines 47 can be done via intramolecular cyclization of Buchwald-Hartwig (for example, example No. 24, phase B, orOrganic Letters 2008, 10(18), 4109-4112). Further functionalization of the R'"groups in dihydropyrazolo[4,3-d]imidazo[2,3-b]pyridine 47 can be done, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine or heteroarenes can be obtained from compounds 47, R'"group, containing primary or secondary amines (for example, in a common procedure L, M, N or O). In addition, the removal of the protective group R'"groups in compounds 47 to obtain an unsecured connection can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and received unprotected compounds can then be subjected to further interaction, as disclosed above.

Scheme VIII

Methods of obtaining isoxazole[4,5-d]imidazo[2,3-b]pyridine, compounds of the present invention shown in scheme IX. Ketones 44 can be subjected to the interaction with hydroxylaminopurine (stage a) to obtain Asimov 48 ways, known to those skilled in the art (for example, in example No. 28, in step A). The cyclization Asimov 48 to obtain the necessary isoxazole[4,5-d]imidazo[2,3-b]pyridines 49 (stage b) is carried out using methods known to those skilled in the art (for example, PR�measures No. 28, stage B orTetrahedron,2007, 63(12), 2695-2711). Further functionalization of the R'"groups in isoxazole[4,5-d]imidazo[2,3-b]pyridine 49 can be done, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine, or heteroarenes can be obtained from compounds 49, R'"group, containing primary or secondary amines (for example, General procedure L, M, N or O). In addition, the removal of the protective group R'in the compounds 49 to receive unsecured connections can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and connect to remote protective groups can then be subjected to further interaction, as disclosed above.

Scheme IX

Methods for obtaining 1,6-dihydropyrazolo[3,4-d]imidazo[2,3-b]pyridine, compounds of the present invention shown in scheme X. Commercially available 4-chloro-1H-imidazo-[2,3-b]pyridine-5-carbaldehyde 50 is subjected to interaction with an appropriately substituted hydrazine or hydrazinecarboxamide (Scheme X, step (a) until the desired 1,6-dihydropyrazolo[3,4-d]imidazo[2,3-b]pyridines 51 ways, known to those skilled in the art (for example, example No. 27). In addition, 1,6-dihydro�irazola[3,4-d]imidazo[2,3-b]pyridine 51 can be protected as sulfonamides (Scheme X, stage (b), using conditions, such as disclosed in the example of obtaining the No. 1 or by methods known to those skilled in the art (for example, Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndedition”, 1999, Wiley-VCH, or Greene, T. W. and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3rdEdition”, 1999, Wiley-Interscience). Secure connection 52 can be laderoute ways, known to those skilled in the art (for example, example No. 42, step C). Halogenated tricyclic compound 53 is subjected to interaction with appropriately substituted Bronevoy acid or ester at a cross combinations Suzuki followed by removal of the protective groups to obtain dihydropyrazolo[3,4-d]imidazo[2,3-b]pyridines 54, using terms such as disclosed in example No. 42, step D. Further functionalization R'"? group in dihydropyrazolo[3,4-d]imidazo[2,3-b]pyridine 54 can be implemented, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine, or heteroarenes can be obtained from compounds 54, R'"group, containing primary or secondary amines (for example, in a common procedure L, M, N or O). In addition, the removal of the protective group R'"groups in compounds 54 to obtain an unsecured connection can be made using conventional�Vija, such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and connect to remote protective groups can then be subjected to further interaction, as disclosed above.

Scheme X

Methods for obtaining 1,6-dihydropyrrolo[2,3-b:2',3'-d]pyridines, compounds of the present invention shown in scheme XI. As can be seen on a stage, heteroarylboronic 55 is subjected to interaction with an appropriately substituted amine using methods such as disclosed in Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparation, 2ndedition”, 1999, Wiley-VCH, getting esters 56 with simultaneous removal of the protective groups. Esters 56 can be converted to the corresponding aldehyde 57 (stage b) and then cilitate to obtain the desired 1,6-dihydropyrrolo[2,3-b:2',3'-d]pyridines 58, using methods known to those skilled in the art (for example, Larock, R. C. (see link above)). Further functionalization of the R'"groups are in a 1,6-dihydropyrrolo[2,3-b:2',3'-d]pyridine 58 can be implemented, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine or heteroarenes can be obtained from compounds 58, R'"group, containing primary or secondary amines (for example, about�ing procedure L, M, N or O). Also, the removal of the protective groups R'"groups in compounds 58 to obtain an unsecured connection can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and connect to remote protective groups can then be subjected to further interaction, as disclosed above.

Scheme XI

Methods of obtaining imidazo[1,5-a]imidazo[2,3-e]pyrazines 66 of the present invention is illustrated in scheme XII. 5-bromo-3-((trimethylsilyl)ethinyl)pyrazine-2-amine 9 can be subjected to the interaction with appropriately functionalized halide to obtain substituted alkynes 59 (Scheme XII, step a) by methods known to those skilled in the art (for example, example No. 20, step B). Alkynes 59 can be subjected to interaction in alkaline conditions to obtain imidazo[2,3-b]pyrazines 60 (as in the sample No. 20, step C). Imidazo[2,3-b]pyrazine 60 can be functionalitywith suitable protective group, such as (2-(trimethylsilyl)ethoxy)methyl, by methods known to those skilled in the art (for example, Greene, T. W. and Wuts, P. G. M. “Protective Groups in Organic Synthesis, 3rdEdition”, 1999, Wiley-Interscience, or in example No. 20, in step D). Imidazo[2,3-b]pyrazine 61 can be converted to the corresponding hydroxymethyl derivative 62 in the result� the introduction of alkene using cross combination Suzuki, followed by oxidative cleavage and recovery of the intermediate aldehyde, using methods known to those skilled in the art (for example, Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndedition”, 1999, Wiley-VCH, or in example No. 20, step E). Methanamine 63 can be obtained from hydroxymethylene connection 62 (step e) by conversion to azide (for example, example No. 20, step F) with subsequent restoration of Staudinger (Staudinger), using methods known to those skilled in the art (for example, Larock, R. C. (see link above) or in example No. 20, step G). Methanamine 63 can be turned into appropriately functionalityand amides 64, using methods known to those skilled in the art (for example, example No. 20, step H). The amides 64 can remove the protective group using methods known to those skilled in the art (for example, Greene, T. W. and Wuts (see link above) or in example No. 20, in step (I) to obtain a functionalized imidazo[2,3-b]pyrazines 65 (stage g). In scheme XII, step h, the cyclization of amides 65 can be realized by making thioamide with subsequent treatment of an activating agent, receiving imidazo[1,5-a]imidazo[2,3-e]pyrazine 66 (for example, example No. 20, step J). Alternatively, the cyclization of amides 64 can be implemented using the disclosed above conditions (Scheme XII, step i) (for example, example No. 22, step B) followed by removal of protective groups imidazo[1,5-a]imidazo[2,3-e]�of Yasinov 67 (Scheme XII, stage j) using methods known to those skilled in the art (for example, Greene, T. W. and Wuts (see link above) or example No. 22, step C). Further functionalization of the R'"group in imidazo[1,5-a]imidazo[2,3-e]pyrazino 66 or 67 can be done, if desired, using reactions known to those skilled in the art (for example, Larock, R. C. (see link above)). For example, amides, urea, sulfonamides, arylamine, or heteroarenes can be obtained from compounds 66 or 67, R'"group, containing primary or secondary amines (for example, General procedure L, M, N or O). In addition, the removal of the protective group R'"groups in compounds 66 or 67 to receive unsecured connections can be performed using conditions such as are disclosed in Greene, T. W. and Wuts, P. G. M. (see link above) or in the General procedures I or J, and connect to remote protective groups can then be subjected to further interaction, as disclosed above.

Scheme XII

GENERAL PROCEDURES AND EXAMPLES

Further schemes 1-39 shows the General scheme of synthesis, which is used for most of the compounds disclosed in the application concerned. These schemes are presented only for illustrative purposes and should not be considered as limiting the present invention.

Scheme 1. Getting hydrazide from ka�oil acid (General procedure (A)

Scheme 2. Getting hydrazide chloride, followed by cyclization and hydrolysis of the sulfonamide (General procedure (B)

Scheme 3. Cyclization of a hydrazide (General procedure (C)

Scheme 4. Cyclization of a hydrazide, followed by hydrolysis of the sulfonamide and removal of the Boc-protective groups (General procedure (D)

Scheme 5. Cyclization of a hydrazide, followed by hydrolysis of the sulfonamide (General procedure E)

Scheme 6. Cyclization of a hydrazide with the loss of the Boc-protective group, followed by hydrolysis of the sulfonamide (General procedure F)

Scheme 7. Getting hydrazone, followed by cyclization and hydrolysis of the sulfonamide (General procedure (G)

Scheme 8. Hydrolysis of the sulfonamide (General procedure (H)

Scheme 9. Acidic cleavage of the Boc-protected amine (General procedure (I)

Scheme 10. The removal of protective groups with Cbz-protected amine (General procedure (J)

Scheme 11. Obtaining an amide of an activated acid and amine (General procedure (K)

b> Scheme 12. Obtaining an amide of carboxylic acid and amine (General procedure (L)

Scheme 13. Obtaining a urea from an amine and carbamylcholine (General procedure (M)

Scheme 14. The receipt of a sulfonamide from an amine (General procedure (N)

Scheme 15. The substitution of helgaleena or heteroarylboronic amine (General procedure O or O. 1)

Scheme 16. The introduction of the Boc-protective group to amine (General procedure P)

Scheme 17. The introduction of the Cbz-protecting groups to amine (General procedure (Q)

Scheme 18. Recovery of pyridine (General procedure (R)

Scheme 19. The recovery of the ester to the alcohol (General procedure (S)

Scheme 20. Oxidation of the alcohol to the aldehyde (General procedure T)

Scheme 21. Getting semicarbazide (General procedure (U)

Scheme 22. Cyclization of semicarbazide(General procedure (V)

Scheme 23. Getting chloride (General procedure W)

Scheme 24. Obtaining urea using CDI (Common p�ocedure X)

Scheme 25. Obtaining ester of carboxylic acid (General procedure Y)

Scheme 26. N-alkylation using alkylhalogenide or α-halogenation (General procedure Z)

Scheme 27. Cyclization of amide using dithiophosphates reagent (General procedure AA)

Scheme 28. Knoevenagel condensation to obtain the substituted cyclopentadiene (General procedure BB)

Scheme 29. Decarboxylation of enolate β-keeeper (General procedure CC)

Scheme 30. Hydrogenation of alkene (General procedure DD)

Scheme 31. Reducing amination of a ketone or aldehyde (General procedure EE)

Scheme 32. Dibenzylamine amine (General procedure FF)

Scheme 33. Hydrolysis of the ester to obtain the carboxylic acid (General procedure (GG)

Scheme 34. The dehydration of amide to nitrile (General procedure HH)

Scheme 35. Separation of stereoisomers by using chiral preparative HPLC (General procedure (II)

Scheme 36. Acid hydrolysis of acetyl-substituted amine (General procedure JJ)

Scheme 37. Cyclopropylamine using chloroiodomethane (General procedure KK)

Scheme 38. Getting promotility of chloride (General procedure (LL)

Scheme 39. The recovery of the α,β-unsaturated ketone to allyl alcohol (General procedure MM)

A LIST of COMMON PROCEDURES

General procedure A: Getting hydrazide carbonic acid

General procedure B: obtain the hydrazide of chloride, followed by cyclization and hydrolysis of the sulfonamide

General procedure C: Cyclization of a hydrazide

General procedure D: Cyclization of a hydrazide, followed by hydrolysis of the sulfonamide and removal of the Boc-protective groups

General procedure E: Cyclization of a hydrazide, followed by hydrolysis of the sulfonamide

General procedure F: Cyclization of a hydrazide with the loss of the Boc-protective group, followed by hydrolysis of the sulfonamide

General procedure G: Getting hydrazon followed by cyclization and hydrolysis of the sulfonamide

General procedure H: Hydrolysis of the sulfonamide

General procedure I: Acidic cleavage of the Boc-protected amine

General procedure J: removal of the protective groups with Cbz-protected�military Amin

General procedure K: Obtaining an amide of an activated acid and amine

General procedure L: Obtaining an amide of carboxylic acid and amine

General procedure M: obtain a urea from an amine and carbamoylated

General procedure N: Obtain the sulfonamide from an amine

General procedure O: the Substitution of allegorised or heteroarylboronic Amin

General procedure P: the introduction of the Boc-protective group to amine

General procedure Q: the introduction of the Cbz-protecting groups to amine

General procedure R: Recovery of pyridine

General procedure S: Restoration of ester to alcohol

General procedure T: Oxidation of alcohol to aldehyde

General procedure U: Receive semicarbazide

General procedure V: Cyclization of semicarbazide

General procedure W: Receiving chloride

General procedure X: Receiving urea using CDI

General procedure Y: Receiving from ether carboxylic acids

General procedure Z: N-alkylation using alkylhalogenide or α-halogenation

General procedure AA: Cyclization of an amide using dithiophosphates reagent

General procedure BB: Knoevenagel Condensation to obtain the substituted cyclopentadiene

General procedure CC: Decarboxylation of enolate β-keeeper

General procedure DD: Hydrogenation of alkene

General procedure EE: Restorative and�inromania ketone or aldehyde

General procedure FF: Dibenzylamine Amin

General procedure GG: Hydrolysis of ester to obtain carboxylic acids

General procedure HH: the Dehydration of amide to nitrile

General procedure II: the Separation of stereoisomers by using chiral preparative HPLC

General procedure JJ: Acid hydrolysis of acetyl-substituted amine

General procedure KK: Cyclopropylamine using chloroiodomethane

General procedure LL: Getting promotility of chloride

General procedure MM: Recovery of α,β-unsaturated ketone to allyl alcohol

The following examples are set in accordance with the ultimate General procedure used for their production. Methods of synthesis of all new intermediate compounds detailed in a subsequent enumeration of common procedures (letter symbols) in parentheses after their names with additional relevant reagents. A working example of this Protocol the following using the example № H. 1.1 as a non-limiting illustration. Example # H. 1.1 represents N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-3-chlorobenzenesulfonamide, which is obtained from 3-chloro-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimide, using General procedure H, as before�tableno in scheme A.

Scheme And

The precursor of example No. H. 1.1, 3-chloro-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimide get method shown in scheme B. 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (example # 9), and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid is subjected to interaction, in accordance with the conditions described in General procedure A, yielding tert-butyl 4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)bicyclo[2.2.2]octane-1-ylcarbamate. The resulting hydrazide cyclist using criteria presented in the General procedure C, to obtain tert-butyl 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]octane-1-ylcarbamate. The resulting carbamate is removed protective group using General procedure I, resulting in 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-amine. The obtained amine sulfonylureas, using the conditions outlined in General procedure N, yielding a precursor of example No. H. 1.1. Detailed above sequence of reactions is repeated in the “examples” section of receipt and examples in expressions like “using A from example receipt No. 9 and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid [Prime Organics], C with TEA, I, N 3-chlorobenzenesulfonic�chloride”.

Analytical methods

Analytical results are included in the following procedures disclosed in illustration of common procedures, or in the tables of examples. Unless otherwise indicated, all results1H NMR was obtained on the instruments Varian Mercury Plus 400 MHz or Varian Inova 600 MHz and chemical shifts are expressed as parts per million (MD). The results of LC/MS and HPLC relate to the conditions of LC/MS and HPLC, as shown in the table and marked in small letters shown below in table 2.

Table 2.
Methods LC/MS and HPLC
MethodConditions
aLC/MS: the Gradient is 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for for 1.2 min (1.3 ml/min flow rate). Mobile phase A: 10 mm NH4OAc, mobile phase B: HPLC purity MeCN. The column used for chromatography: a 4.6×50 mm MAC-MOD Halo C8 column (2.7 µm particles). Methods of detection: diode array (DAD) and evaporative light scattering detector (NT), as well as positive/negative electrospray ionization.
bHPLC: the Gradient is 10-60% B over 40 min (25 ml/min speed �Otok). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase B: HPLC purity MeCN. The column used for chromatography: of 21.2×250

mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=254 nm.
cHPLC: the Gradient is 10-100% B over 40 min, incubated for 5 min at 100% B, 2 min, return to 10% B, 4 min, hold at 10% B (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase B: HPLC purity MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=344 nm.
dLC/MS: the Gradient is 5-60% B over 0,75 min then 60-95% B to 1.15 min, hold at 95% B for 0.75 l min (1.3 ml/min flow rate). Mobile phase A: 10 mm NH4OAc, mobile phase: HPLC purity MeCN. The column used for chromatography: a 4.6×50 mm MAC-MOD Halo C8 column (2.7 µm particles). Methods of detection: diode array (DAD) and evaporative light scattering detector (NT), as well as positive/negative electrospray ionization.
eHPLC: Gradient drawing up�et 5-95% B for 20 min (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=254 nm.

fHPLC: Gradient 0-30% B over 20 min (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=254 nm.
gHPLC: the Gradient is 0-50% B over 20 min (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=254 nm.
hHPLC: Gradient 20-60% B over 40 min (81 ml/min flow rate), mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity MeCN, the column used for chromatography: 25×250 mm Hypersil HS C18 column (10 μm particle), method of detection: UV, λ=315 nm.
i HPLC: the Gradient is 10-80% B over 9 min, then 80-100% B over 0,10 min, hold at 100% B for 1,50 min (22,5 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity MeCN, the column used for chromatography: 19×50 mm Waters Atlantis T3 OBD C18 column (5 μm particles). Methods of detection: Photodiode matrix DAD and mass

the spectrometer Waters ZQ 2000.
jHPLC: the Gradient is 0-40% B over 30 min (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=254 nm.
kHPLC: the Gradient is 25-100% B for 25 min (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity
MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=380 nm.
lLC/MS: the Gradient is 0.1 min at 10% B, 10-100% B for 2.5 min, incubated �ri 100% B within 0.3 min, then to 10% B for 0.1 min Mobile phase A: 0.1% of TFA in water and mobile phase B: HPLC purity MeCN. The column used for chromatography: 2.1 mm×30 mm Phenomenex Luna Combi-HTS C8(2) (5 μm particles). Methods of detection: diode array Waters 996 and Sedere Sedex-75 NT. The mass spectrometer ZMD: in positive mode APCI ionization conditions.
mHPLC: the Gradient is 10-100% B over 50 min (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity

MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=341 nm.
nLC/MS: the Gradient 30-60% B in a over 1,50 min then 60-95% B to 2.5 min, hold at 95% B for for 1.2 min (1.3 ml/min flow rate). Mobile phase A: 10 mm ammonium acetate, mobile phase: HPLC purity MeCN. The column used for chromatography: a 4.6×50 mm MAC-MOD Halo C8 column (2.7 µm particles). Methods of detection: diode array (DAD) and evaporative light scattering detector (NT), as well as positive/negative electrospray ionization.
o LC/MS: the Gradient is 5-60% B in 1.5 min then 60-95% B to 2.5 min, hold at 95% B for for 1.2 min (1.3 ml/min flow rate). Mobile phase A: 10 mm ammonium acetate, mobile phase: HPLC purity MeCN. The column used for chromatography: a 4.6×30 mm Vydac Genesis C8 column (4 μm particles). Methods of detection: diode array (DAD) as well as positive/negative electrospray ionization and MS2the results depend on the scan in the positive mode (45 alsalt energy collisions).
pHPLC: Column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles).

The gradient is 5% to 95% B over 50 min (21 ml/min
the flow rate). Mobile phase A: 0.05 is called a buffer, an aqueous solution of ammonium acetate (pH 4.5) and mobile phase: HPLC purity MeCN. Method of detection: UV, λ=254 nm.
qHPLC: Gradient of 10% to 50% B over 40 min (81 ml/min flow rate). Mobile phase A: 50 mm ammonium acetate in water, mobile phase: HPLC purity MeCN. The column used for chromatography: Microsorb C18, 100 Å, 5 μm, 46×250 mm column. Method of detection:�, λ=310 nm.
rHPLC: the Gradient is 30% to 70% B over 40 min (81 ml/min flow rate). Mobile phase A: 50 mm ammonium acetate in water, mobile phase: HPLC purity MeCN. The column used for chromatography: Microsorb C18, 100 Å, 5 μm, 46×250 mm column. Method of detection: UV, λ=254 nm.
sHPLC: the Gradient is 10-40% B over 50 min, 40-100% for 3 min, incubated for 5 min at 100% B, 2 min, return to 10% B, 3 min, hold at 10% B (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection: UV, λ=326 nm.
tHPLC: Column used for chromatography:

19×50 mm Waters Atlantis T-3 column(5 μm particles). A gradient of 20-25% B in techenie 3.0 minutes then cables 25-95% B to 9.00 min, hold at 95% B within 0,10 min (25 ml/min flow rate). Mobile phase A: 50 mm ammonium acetate, mobile phase: HPLC purity acetonitrile. Methods of detection: Waters 2996 PDA and the Mass spectrometer Waters ZQ 2000 Mass spectra detects, using toggle positive/negative mode APCI ionization.
uHPLC: the Gradient is 5-100% B over 20 min (21 ml/min flow rate). Mobile phase A: 50 mm NH4OAc (pH 4.5) and mobile phase: HPLC purity MeCN. The column used for chromatography: of 21.2×250 mm Hypersil HS C18 column (8 μm particles). Method of detection : UV, λ=254 nm.

Table 3.
Ways chiral HPLC
MethodConditions
1The gradient is 5-60% A in 19 min, incubated at 60% a for 2 min (20 ml/min flow rate). Mobile phase A: ethanol (200 fortress), mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IC, 20×250 mm column (5 μm particles). Methods of detection: evaporative light scattering detector (NT), as well as optical

rotation.
2The gradient is 30-58% A for 12 min (20 ml/min flow rate). Movable �Aza A: HPLC purity isopropanol, mobile phase B: HPLC purity heptane. The column used for chromatography: Daicel IA, 20×250 mm column (5 μm particles). Methods of detection: UV, λ=280 nm, evaporative light scattering detector (NT), and optical rotation.
3Isocratic elution 30% a for 25 min (20 ml/min flow rate). Mobile phase A: ethanol (200 fortress), mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IA, 20×250 mm column (5 μm particles). Methods of detection: evaporative light scattering detector (NT) and optical rotation.
4Isocratic elution with 20% a for 40 min (20 ml/min flow rate). Mobile phase A: ethanol (200 fortress), mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IA, 20×250 mm column (5 μm particles). Methods of detection: evaporative light scattering detector (NT), and optical rotation.
5The gradient is 30-65% a for 18 min (20

ml/min flow rate). Mobile phase A: HPLC purity isopropanol mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IA, 20×250 mm column (5 μm particles). Methods of detection: UV, λ=280 nm, evaporative light scattering detector (NT), and optical rotation.
6The gradient is 10-55% a for 19 min, incubated at 55% for 0.5 min (20 ml/min flow rate). Mobile phase A: 50:50 mixture of HPLC purity of methanol and ethanol (200 fortress), mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IA, 20×250 mm column (5 μm particles). Methods of detection: evaporative light scattering detector (NT), and optical rotation.
7The gradient is 30-70% a for 18 min (20 ml/min flow rate). Mobile phase A: ethanol (200 fortress), mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IC, 20×250 mm column (5 μm particles). Methods of detection: UV, λ=280 nm, evaporative light scattering detector (NT), and optical rotation.
8 Isocratic elution: 20% A for 30 min (20

ml/min flow rate). Mobile phase A: HPLC purity isopropanol mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IA, 20×250 mm column (5 μm particles). Methods of detection: evaporative light scattering detector (NT), and optical rotation.
9Isocratic elution: 50% a for 25 min (20 ml/min flow rate). Mobile phase A: 50:50 mixture of HPLC purity of methanol and ethanol (200 fortress), mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IA, 20×250 mm column (5 μm particles). Methods of detection: evaporative light scattering detector (NT), and optical rotation.
10Isocratic elution: 70% a for 25 min (20 ml/min flow rate). Mobile phase A: ethanol (200 fortress), mobile phase: HPLC purity heptane with the addition of 0.1% diethylamine. The column used for chromatography: Daicel IA, 20×250 mm column (5 μm particles). The ways children�of tiravanija: evaporative light scattering detector (NT), as well as optical rotation.

Examples of receipts and examples

The following are the General methods of synthesis, which are used in each common procedure and which include an illustration of a compound that is synthesized using the indicated General procedure. None of these specific conditions and none of the specific reagents should not be construed as limiting the scope of the present invention, and are presented here for illustrative purposes only. All starting materials are commercially available from Sigma-Aldrich (including Fluka and Discovery CPR) unless otherwise indicated after the chemical name. The names of the reactants are given in accordance with titles on commercial vials or in accordance with the IUPAC nomenclature, CambridgeSoft® Chemdraw Ultra 9.0.7 or AutoNom 2000. Compounds indicated as salts (e.g. hydrochloride, acetate) may contain more than one molar equivalent of a salt.

Example No. 1: 2-bromo-5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine

A solution of 2-bromo-5H-imidazo[2,3-b]pyrazine (5.00 g, of 25.2 mmol, Ark Pharm) in DMF (150 ml) was cooled on an ice bath to about 0°C, and then added NaH (60% dispersion in mineral oil, 1.21 g, to 30.3 mmol). After about 15 minutes, add 4-tert-butylbenzoyl-1-sulphonylchloride (of 6.46 g, 27.8 mmol). Temperature R�shares support between 0 and 10°C for about 2 hours. Then the reaction mixture was diluted with water (200 ml) to give a yellow suspension. The solid product is collected by vacuum filtration, washing with additional water (100 ml), and dried in a vacuum thermostat at a temperature of about 70°C, yielding 2-bromo-5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine (a 9.05 g, 91%): LC/MS (table 2, Method a) Rt=3,05 min; MS m/z: 394/396 (M+H)+.

Example No. 2: tert-butyl 2-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide

The flask was added Pd2(dba)3(of 5.06 g, 5,53 mmol), di-tert-butyl-(2',4',6'-triisopropylsilyl-2-yl)Foshan (4,70 g, 11,06 mmol) and 1,4-dioxane (350 ml). A mixture of the catalyst-ligand Tegaserod using the cycle vacuum/purge with nitrogen (3 times) and heated at a temperature of about 80°C for about 10 min the Reaction mixture was quickly removed from the oil bath, then added 2-bromo-5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine (21.8 g, 55,3 mmol, example No. 1), tert-butyl, hydrazinecarboxamide (36,5 g, 276 mmol), and NaOt-Bu (7,97 g, 83 mmol). After an additional cycle vacuum/nitrogen purge, the reaction mixture is heated at a temperature of about 80°C for about 5.5 hours. The reaction mixture was cooled to room temp�atmospheric temperature and filtered through celite may®, washing with EtOAc (500 ml). The filtrate obtained was washed with a saturated aqueous solution of NH4Cl (3×500 ml), a saturated aqueous solution of NaHCO3(500 ml) and brine (500 ml), dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure, yielding about 55 g of crude brown oil. Brown oil adsorb on silica and purified by column chromatography with silica gel performing a gradient elution with 10-50% EtOAc in heptane, yielding tert-butyl 2-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide (4,51 g, 18% yield) and to 4.68 g of a mixture of tert-butyl 2-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [main regioisomer] and tert-butyl 1-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [secondary regioisomer]: LC/MS (table 2, Method a) Rt=2,68 min; MS m/z: 446 (M+H)+[main regioisomer]; Rt=2,77 min; MS m/z: 446 (M+H)+[secondary regioisomer].

Example No. 3: 5-(4-tert-butylphenylmethyl)-2-hydrazine-5H-imidazo[2,3-b]pyrazine

To a mixture of tert-butyl 2-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide (11,4 g, of 25.2 mmol, example # 2) in 1,4-dioxane (125 ml) was added HCl (4 M in 1,4-dioxane, 125 ml, 500 mmol). The obtained reaction mixture is heated at a temperature of about 60°C for about 1 hour, and then the reaction mixture was cooled to room temperature. The resulting mixture was filtered, washing with Et2O (150 ml), and the solid product is separated between EtOAc (500 ml) and a saturated aqueous solution of NaHCO3(500 ml). The obtained layers are isolated, and the organic layer was washed with a saturated aqueous solution of NaHCO3andbrine (200 ml each), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and dried in a vacuum thermostat at a temperature of about 70°C, yielding 5-(4-tert-butylphenylmethyl)-2-hydrazine-5H-imidazo[2,3-b]pyrazine in a solid yellow-brown color (7,54 g, 87%): LC/MS (table 2, Method a) Rt=2,20 min; MS m/z: 346 (M+H)+.

Example No. 4: 2-methylcyclohexanecarboxylic

To a solution of 2-methylcyclohexanecarboxylic acid (6,00 ml of 42.6 mmol, mixture of CIS - and TRANS-) in DCM (60 ml) was added oxaliplatin (4,80 ml of 55.3 mmol), was then added DMF (0.03 ml, 0.4 mmol). The obtained reaction mixture was stirred at room temperature for about 4 hours before it was concentrated under reduced pressure to constant in�sa to obtain 2-methylcyclohexanecarboxylic (mixture of diastereomers) as a yellow oil (7.0 g, 97%):1H-NMR (400 MHz, CDCl3) δ 2,98-to 2.94 (m, 1H), 2.39 and of 2.35 (m, 1H), 1,91-to 1.82 (m, 1H), 1,79 is 1.72 (m, 1H), 1,69 to 1.60 (m, 2H), 1,57 was 1.47 (m, 2H), 1,42-of 1.36 (m, 1H), 1,34-of 1.26 (m, 1H), 1,04-of 0.96 (m, 3H).

Example No. 5: Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate

Stage A: 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid

To a solution of piperidine-4-carboxylic acid (10.0 g, to 77.4 mmol) and Na2CO3(8,21 g of 77.4 mmol) in water (100 ml) was added a solution of benzyl 2,5-dioxopiperidin-1-ylcarbamate (19,3 g, to 77.4 mmol) in MeCN (100 ml). The obtained reaction mixture was stirred at room temperature for about 16 hours and then concentrated under reduced pressure. The resulting aqueous solution was quenched using NH4Cl and then extracted with EtOAc (2×100 ml). The combined organic extracts dried over anhydrous Na2SO4andconcentrated under reduced pressure, yielding 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid in the form of white solids (4,56 g, 22%): LC/MS (table 2, Method a) Rt=1,93 min; MS m/z: 262 (M-H)-.

Step B: Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate

To a solution of 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid (4,50 g of 17.1 mmol, example No. 5, step A) in DCM (40 ml) at room temperature is added�t oxaliplatin (3,00 ml, to 34.2 mmol) followed by the addition of DMF (0.10 ml, 1.3 mmol). After about 3 hours, the reaction mixture is concentrated under reduced pressure to constant weight to obtain benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate in the form of a yellow oil (3,88 g, 81%):1H-NMR (CDCl3) δ 7,44-7,35 (m, 5H), 5,16 (s, 2H), 4,20-4,10 (m, 2H), 3,03-2,89 (m, 3H), 2,15-of 2.05 (m, 2H), 1,81-of 1.76 (m, 2H).

Example No. 6: Perftoralkil 2-cyanoacetate

To a solution of 2,3,4,5,6-pentafluorophenol (1,08 g, is 5.88 mmol) and 2-tsianuksusnogo acid (0.50 g, 5.9 mmol) in DCM (20 ml) was added DCC (1.21 g, is 5.88 mmol). After stirring for about 4 hours at room temperature the reaction mixture was concentrated under reduced pressure and then purified on silica gel (20 g) using DCM as eluent to obtain perftoralkil 2-cyanoacetate in the form of white solids (1,39 g, 94%):1H NMR (400 MHz, CDCl3) δ 3,85 (s, 2H).

Example No. 7: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

(Method A)

A solution of 2-bromo-5H-imidazo[2,3-b]pyrazine (78,0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 ml) was dropwise added over about 60 min to a stirred suspension of NaH (1.8 g, 532 mmol) in anhydrous DMF (543 ml) at a temperature of about 0-5°C. the Brown reaction solution was stirred for about 30 min at a temperature of about 0-5�C. Then dropwise added a solution of p-toluensulfonate (94,0 g, 492 mmol) in anhydrous DMF (272 ml) for about 60 minutes at a temperature of about 0-5°C. the reaction mixture Obtained is stirred at a temperature of about 0-5°C for about 1 hour, then allowed to warm to room temperature and stirred for about 18 hours at room temperature. The obtained reaction mixture was slowly poured into ice water (6 l) was then added an aqueous solution of 2.5 n NaOH (50,0 ml, 125 mmol). The resulting precipitate was collected by filtration and stirred with cold water (3×200 ml). The solid product is collected by filtration and dried to constant weight in a vacuum oven thermostat at a temperature of about 55°C, resulting in 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (134,6 g, 97%) as a solid pale beige: LC/MS (table 2, Method d) Rt=to 1.58 min; MS m/z: 352/354 (M+H)+.

Example No. 7: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

(Method B)

Stage A: 5-bromo-3-((trimethylsilyl)ethinyl)pyrazine-2-amine

To a solution of 3,5-dibromopyridin-2-amine (40,0 g, 158 mmol), TEA (66,1 ml, 475 mmol) and copper iodide(I) (0,301 g, to 1.58 mmol) in THF (1172 ml) was added PdCl2(PPh3)2(1.11 g, to 1.58 mmol). The obtained reaction mixture was cooled at a temperature of about 0°C. and dropwise added a solution (trimethylsilylacetamide (of 20.8 ml, 150 mmol) in THF (146 ml). The obtained reaction mixture was stirred at a temperature of about 0-10°C for about 7 hours, and then concentrated under reduced pressure. The dark brown residue was dissolved in DCM (600 ml) and filtered through a layer of celite may® (3 cm×9 cm in diameter), elwira with DCM (300 ml). The filtrate obtained was washed with water (2×500 ml) and brine (500 ml), dried over anhydrous MgSO4and filtered through a layer Florisil® (1 cm in height and 9 cm in diameter), rinsing with DCM/MeOH (9:1, 200 ml), and concentrated under reduced pressure, obtaining a solid brown color. Solid product triturated and treated with ultrasound in a warm petroleum ether (boiling point 30-60°C, 250 ml), cooled and collected by washing with petroleum ether (boiling point 30-60°C; 2×100 ml), and dried in a vacuum thermostat at a temperature of about 70°C, yielding 5-bromo-3-((trimethylsilyl)ethinyl)pyrazine-2-amine (34,6 g, 70%): LC/MS (table 2, Method d) Rt=1,59 min; MS m/z: 272 (M+H)+.

Step B: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

To a solution of 5-bromo-3-((trimethylsilyl)ethinyl)pyrazine-2-amine (3.00 g, 11.1 mmol) in DMF (60 ml) at a temperature of about 0°C. is added NaH (60% dispersion in mineral oil, 0,577 g, 14.4 mmol) in three portions. After about 15 minutes add p-toluensulfonate (2.75 g, 14.4 mmol) and the reaction mixture is left �slow to warm to room temperature. After about 16 hours the reaction mixture obtained was poured into ice water (120 ml) and the resulting precipitate collected by vacuum filtration. The crude solid was dissolved in DCM (15 ml) and purified by column chromatography with silica gel, elwira DCM. Contains the product fraction is concentrated under reduced pressure, yielding 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (2,16 g, 52%): LC/MS (table 2, Method d) Rt=to 1.58 min; MS m/z: 352/354 (M+H)+.

Example No. 8: tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide

The flask was added Pd2(dba)3(3,90 g of 4.26 mmol), di-tert-butyl-(2',4',6'-triisopropylsilyl-2-yl)Foshan (3,62 g, 8,52 mmol), and anhydrous 1,4-dioxane (453 ml). A mixture of the catalyst-ligand Tegaserod using the cycle vacuum/purge with nitrogen (3 times) and heated at a temperature of about 80°C for about 10 min the reaction mixture Obtained quickly removed from the oil bath, then added 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (30,0 g, 85 mmol, example No. 7), tert-butylhydroperoxide (16,9 g, 128 mmol) and NaOt-Bu (to 12.28 g, 128 mmol). After an additional cycle vacuum/nitrogen purge, the reaction mixture is heated at a temperature of about 80°C. after About 50 min, the reaction mixture obtained was cooled �about room temperature and filtered through a layer of silica gel (6 cm×6 cm in diameter), with a layer of celite may® top (1 cm×6 cm in diameter), rinsing with EtOAc (3×150 ml). To the filtrate was added water (300 ml) and the organic layer isolated. The aqueous layer was extracted with additional EtOAc (3×200 ml). The combined organic extracts were washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaHCO3and brine (400 ml each), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding a dark brown oil (45 g). The brown oil was dissolved in DCM (250 ml), was added silica gel (200 g), and the resulting mixture was concentrated under reduced pressure. The mixture of silica gel was purified using chromatography on silica gel performing a gradient elution from 25 to 65% EtOAc in heptane, yielding a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [main regioisomer] and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [secondary regioisomer] (18,8 g, 50%): LC/MS (table 2, Method d) Rt=1,47 min; MS m/z: 404 (M+H)+.

Example No. 9: 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine

To a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide (18,8 g of 46.6 mmol, example of getting� No. 8) in 1,4-dioxane (239 ml) was added HCl (4 M in 1,4-dioxane, 86 ml, 345 mmol). The reaction mixture is heated at a temperature of about 60°C for about 1 hour and then cooled to 15-20°C. the Solid product is collected by vacuum filtration, washed with cold 1,4-dioxane (2×20 ml), and then stirred with a saturated solution of NaHCO3and water (1:1, 150 ml). After about 1 hour the evolution of gas ceases, and the solid product collected by vacuum filtration, washed with ice water (3×20 ml), and dried in a vacuum thermostat to constant weight to obtain 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine in a solid light yellowish brown (8,01 g, 50%): LC/MS (table 2, Method d) Rt=1,28 min; MS m/z: 304 (M+H)+.

Example No. 10: (R)-tert-butyl 1-(chlorocarbonyl)pyrrolidine-3-ylcarbamate

The flask is loaded (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.0 g, 5.4 mmol, Lancaster) in DCM (15 ml) to give a colorless solution. Add pyridine (0,89 ml, 10.8 mmol) and the resulting solution cooled to about 0°C, then add triphosgene (0.64 g, 2.1 mmol). The resulting mixture was stirred for about 1 hour while slowly warming to room temperature. To the reaction solution was added DCM (50 ml) and the resulting solution was washed with water (20 ml) and HCl (1 n, 10 ml). The organic portion is isolated, dried over anhydrous MgSO4filter and concentrate the dosa�and under reduced pressure, receiving (R)-tert-butyl 1-(chlorocarbonyl)pyrrolidine-3-ylcarbamate (1.3 g, 98%) as a yellow oil:1H-NMR (DMSO-d6) δ to 7.28 (s, 1H), 4,03 (m, 1H), 3,73-3,20 (m, 4H), of 2.05 (m, 1H), was 1.81 (m, 1H), of 1.39 (s, 9H).

Example No. 11: (1R,2S,4R,5S)-4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylic acid and (1S,2R,4S,5R)-4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylic acid

Stage A: (1R,2S,4R,5S)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate

CIS-ethyl-4-hydroxy-2-Methylcyclopentane-2-enecarboxylate (0.96 g, 5,64 mmol, example No. MM.1) and chloroiodomethane (4,97 g, 28.2 mmol) was subjected to the interaction in accordance with the General procedure KK, yielding (1R,2S,4R,5S)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate (0.59 g, 57%) after purification using flash chromatography on silica gel performing a gradient elution 30-60% EtOAc/heptane:1H NMR (400 MHz, CDCl3) δ 4,60-4,51 (m, 1H), 4,23-4,10 (m, 2H), to 2.74 (DD,J=8,0, to 10.9 Hz, 1H), 2,13 (m, 1H) of 1.51 (m, 1H), 1.46 to of 1.40 (m, 1H), 1.35 and of 1.29 (m, 1H), and 1.28 (m, 6H), 1,09-of 1.04 (m, 1H), 0,37 (DD,J=5,7, and 7.9 Hz, 1H).

Step B: (1R,2S,5S)-ethyl 1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,5R)-ethyl 1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate/p>

A mixture of (1R,2S,4R,5S)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-hydroxy-1-methylbicyclo[3.1.0]hexane-2-carboxylate (0.59 g, 3.2 mmol) was treated according to General procedure T, yielding (1R,2S,5S)-ethyl 1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,5R)-ethyl 1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate (0,38 g, 65%) after purification by chromatographic processing on silica gel performing a gradient elution 20-50% EtOAc/pentane:1H NMR (400 MHz, CDCl3) δ 4,35-4,15 (m, 2H), 3,12 (t,J=9,3 Hz, 1H), 2,60 (DD,J=9,2, with 18.3 Hz, 1H), 2,37, at 2.23 (m, 1H), 1,68 (DD,J=3,4, and 9.2 Hz, 1H), 1,48 (s, 3H), of 1.41 (DD,J=3,4, and 5.2 Hz, 1H), 1,34 (t,J=7,1 Hz, 3H), 1,14 (DD,J=5,3, and 9.2 Hz, 1H).

Step C: (1R,2S,4R,5S)-ethyl 4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylate

To a vial containing (1R,2S,5S)-ethyl 1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,5R)-ethyl 1-methyl-4-oxobicyclo[3.1.0]hexane-2-carboxylate (0,305 g, 1.67 mmol), was added a solution of ammonia (2 Nin EtOH) followed by the addition of isopropoxide titanium(IV) (0.54 ml, 1.8 mmol). The ampoule is closed, and the resulting reaction mixture was stirred at room temperature overnight. Add sodium borohydride (0,095 g, 2.5 mmol) and the reaction mixture alternating�sivut for about 5 hours. Add concentrated NH4OH (5 ml), and the resulting mixture was stirred for about 5 min, the resulting suspension was filtered, and the filter cake washed with EtOAc (60 ml). The obtained filtrate were separated, and the aqueous layer was extracted with EtOAc (30 ml). The pooled aqueous layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated, resulting in (1R,2S,4R,5S)-ethyl 4-amino-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-amino-1-methylbicyclo[3.1.0]hexane-2-carboxylate (0,21 g, 69%). This amine (0,212 g of 1.16 mmol) is subjected to the interaction with cyclopropanesulfonyl (0,244 g, 1.74 mmol) using General procedure N, yielding (1R,2S,4R,5S)-ethyl 4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylate (0.11 g, 33%): LC/MS (table 2, Method (a) Rt=2,06 min; MS m/z: 286 (M-H)-.

Step D: (1R,2S,4R,5S)-4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylic acid and (1S,2R,4S,5R)-4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylic acid.

A mixture of (1R,2S,4R,5S)-ethyl 4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylate (0,109 g, 0,379 mmol) hydrolyzing using General procedure�ur GG, receiving (1R,2S,4R,5S)-4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylic acid and (1S,2R,4S,5R)-4-(cyclopropanesulfonyl)-1-methylbicyclo[3.1.0]hexane-2-carboxylic acid (0,113 g, 100%): LC/MS (table 2, Method a) Rt=1,57 min; MS m/z: 258 (M-H)-.

Example No. 12: (1R,2R,4S)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanone acid and (1S,2S,4R)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanone acid

Stage A: (2R,4S)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclohexanecarboxylic and (2S,4R)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclohexanecarboxylic

To a solution of LDA (1.8 M in THF, of 3.04 ml, were 5.47 mmol) and THF (40 ml) at a temperature of about -78°C is added ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl (1.0 g, 2.7 mmol, example No. EE.1) in THF (4 ml). The obtained reaction mixture was stirred at a temperature of about -78°C for about 1 hour. Add MeI (2,57 ml, to 41.0 mmol) and the reaction mixture was stirred at a temperature of about -78°C for about 1 hour and then heated to about -40°C. is Added DCM (150 ml), followed by the addition of saturated aqueous NH4Cl (50 ml). The layers were separated, and the aqueous layer was extracted with DCM (2×30 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, f�trout and concentrated to dryness under reduced pressure. The obtained residue was purified using flash chromatography on silica gel performing a gradient elution of 0-10% EtOAc in DCM, yielding (2R,4S)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclohexanecarboxylic and (2S,4R)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclohexanecarboxylic (0,864 g, 84%). LC/MS (table 2, Method a) Rt=2,25 min; MS m/z: 380 (M+H)+.

Step B: (2R,4S)-ethyl 4-amino-2-ethyl-1-methylcyclohexanecarboxylic and (2S,4R)-ethyl 4-amino-2-ethyl-1-methylcyclohexanecarboxylic

A mixture of (2R,4S)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclohexanecarboxylic and (2S,4R)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclohexanecarboxylic (0,864 g, 2,28 mmol) dibenzyline using General procedure FF, yielding (2R,4S)-ethyl 4-amino-2-ethyl-1-methylcyclohexanecarboxylic and (2S,4R)-ethyl 4-amino-2-ethyl-1-methylcyclohexanecarboxylic (0.45 g, 100%). LC/MS (table 2, Method a) Rt=1,55 min; MS m/z: 200 (M+H)+.

Stage C: (1S,2R,4S) and (1R,2S,4R)-ethyl 4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclohexanecarboxylic, (1R,2R,4S) and (1S,2S,4R)-ethyl 4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclohexanecarboxylic

A mixture of (2R,4S)-ethyl 4-amino-2-ethyl-1-methylcyclohexanecarboxylic and (2S,4R)-ethyl 4-amino-2-ethyl-1-methylcyclohexanecarboxylic (0,454 g, 2,28 mmol) protect using General procedure P. the Crude reaction mixture was purified using XP�maturational processing on silica gel, performing a gradient elution 0-25% EtOAc/heptane to obtain (1S,2R,4S) and (1R,2S,4R)-ethyl 4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclohexanecarboxylic (0,180 g, 26%):1H NMR (400 MHz, CDCl3) δ 4,46 (s, 1H), 4,12 (kV,J=7,1 Hz, 2H), 4,07-3,93 (m, 1H), 2,65 (DD,J=9,2, and 13.8 Hz, 1H), 2,36 (s, 1H), 2,24-of 2.08 (m, 1H), 1,57 (m, 1H), 1,54-of 1.39 (m, 10H), 1,34-1,17 (m, 4H), of 1.17 and 1.05 (m, 4H), of 0.87 (t,J=7,4 Hz, 3H), (1R,2R,4S) and (1S,2S,4R)-ethyl 4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclohexanecarboxylic (0,430 g, 63%):1H NMR (400 MHz, CDCl3) δ is 5.18 (s, 1H), 4,24-of 4.04 (m, 3H), 2,46-of 2.33 (m, 1H), 1,97 (m, 2H), 1,63-1,50 (m, 2H), 1,48 of 1.34 (m, 9H), 1,3-1,17 (m, 7H) of 1.04 is 0.92 (m, 1H), 0,89 (t,J=7,1 Hz, 3H).

Step D: (1R,2R,4S) and (1S,2S,4R)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanone acid

A mixture of (1R,2R,4S) and (1S,2S,4R)-ethyl 4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclohexanecarboxylic (0,430 g, 1.44 mmol) hydrolyze in accordance with the General procedure GG, yielding (1R,2R,4S) and (1S,2S,4R)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanone acid (0,256 g, 86%): LC/MS (table 2, Method a) Rt=2,22 min; MS m/z: 270 (M-H)-.

Example No. 13: (1S,2R,4S) and (1R,2S,4R)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanone acid

A mixture of (1S,2R,4S) and (1R,2S,4R)-ethyl 4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclohexanecarboxylic (0,180 g, 0,600 mmol) hydrolyzing a suitable�accordance with the General procedure GG, receiving (1S,2R,4S)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanone acid and (1S,2R,4S)-4-(tert-butoxycarbonylamino)-2-ethyl-1-methylcyclopentanone acid (0,083 g, 51%): LC/MS (table 2, Method a) Rt=2,23 min; MS m/z: 270 (M-H)-.

Example No. 14: (1R,2S,4R,5R)-4-(tert-butoxycarbonylamino)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylic acid

Stage A: (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate

To a solution of (1R,4S)-2-azabicyclo[2.2.1]hept-5-ene-3-she (1,50 g, and 13.7 mmol) in THF (100 ml) was added TEA (1.90 ml, and 13.7 mmol) and DMAP (0.27 g, 2.2 mmol). The resulting mixture was stirred for about 5 minutes at a temperature of about 0°C. Then added di-tert-BUTYLCARBAMATE (3,40 ml, 14.4 mmol) in THF (15 ml). The obtained reaction mixture was stirred at room temperature for about 24 hours. The obtained solvent was removed under reduced pressure, and the crude residue is placed in DCM (50 ml) and washed with water (25 ml) and brine (25 ml). The organic layer is dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material is purified by chromatography on silica gel processing, performing a gradient elution of 0-30% EtOAc/heptane to obtain (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxyl�that (2.7 g, 93%) in the form of white solids:1H NMR (400 MHz, DMSO-d6) δ 7,26 is 6.86 (DD, 1H), 6,86-at 6.64 (m, 1H), 5,08-to 4.78 (d, 1H), 3,52-3,21 (DD, 1H), 2,32 is 2.24 (d, 1H), 2,09-2,02 (d, 1H), 1.05 and of 1.36 (s, 9H).

Step B: Tert-butyl ether (1S,2R,4R,5R)-7-oxo-3-trimethylsilyl-6-Aza-tricyclo[3.2.1.0(2,4)]octane-6-carboxylic acid

To a solution of (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate (1.3 g, 6.2 mmol) and palladium acetate(II) (0,070 g, 0,31 mmol) in Et2O (62 ml) was added, dropwise, trimethylsilyldiazomethane (2 M in hexano, 3,00 ml, 11.5 mmol) at room temperature for about 1 hour. The resulting mixture was stirred at room temperature for about 18 hours and filtered through celite may®. The pellet celite washed with Et2O (50 ml), and the filtrate obtained is concentrated under reduced pressure. The crude material is purified by chromatography on silica gel processing, performing a gradient elution of 0-30% EtOAc/heptane to obtain tert-butyl ester (1S,2R,4R,5R)-7-oxo-3-trimethylsilyl-6-azatricyclo[3.2.1.0(2,4)]octane-6-carboxylic acid (1.7 g, 92%).1H NMR (400 MHz, DMSO-d6) δ to 4.37 (s, 1H), 2.70 m (s, 1H), 1,45 (m, 10H), 1,23 (t, 1H), 0,76 (t, 1H), 0,10 (s, 2H), -0,03 (s, 9H).

Step C: (1R,2S,4R,5R)-4-(tert-butoxycarbonylamino)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-carboxylic acid

A mixture of tert-butyl ester (1S,2R,4R5R)-7-oxo-3-trimethylsilyl-6-azatricyclo[3.2.1.0(2,4)]octane-6-carboxylic acid (1.7 g, the 5.7 mmol) and potassium fluoride on alumina (2.10 g, a 14.1 mmol) in THF (38 ml) was heated at about 60°C for about 18 hours. The resulting mixture was cooled to room temperature and filtered through celite may®. A layer of celite washed with EtOAc (50 ml), and the filtrate obtained is concentrated under reduced pressure to obtain (1R,2S,4R,5R)-4-(tert-butoxycarbonylamino)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2 - carboxylic acid (1,82 g, 100%): LC/MS (table 2, Method a) Rt=2,62 min; MS m/z: 312 (M-H)-.

Example No. 15: (1R,2R,4S,5S)-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-amine

To a solution of tert-butyl (1R,2R,4S,5R,)-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)-6-(trimethylsilyl)bicyclo[3.1.0]hexane-2-ylcarbamate (0,780 g of 1.34 mmol, obtained using A from example receipt No. 9 and example of receiving No. 14, HATU, C with TEA) in DCM (20 ml) add triftormetilfullerenov acid (of 0.48 ml, 5.4 mmol). After stirring at room temperature for about 18 hours, add additional triftormetilfullerenov acid (of 0.48 ml, 5.4 mmol), and the resulting mixture was additionally stirred for about 18 hours. The obtained reaction mixture is diluted with DCM (40 ml) and slowly poured into a vigorously stirred suspension in ice-cold water (30 ml). After about 5 minutes the resulting reacciona� the mixture is neutralized, using a saturated aqueous solution of NaHCO3. The layers were separated, and the aqueous layer was extracted with DCM (40 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain (1R,2R,4S,5S)-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-amine in the form of a solid light brown color (0.55 g, 87%): LC/MS (table 2, Method a) Rt=1,75 min; MS m/z: 409 (M+H)+.

Example No. 16: Lithium (R)-4-(tert-butoxycarbonyl)-1-methylpiperazin-2-carboxylate

Stage A: (R)-1-tert-butyl 3-methyl 4-methylpiperazin-1,3-dicarboxylate

To (R)-1-tert-butyl 3-methylpiperazin-1,3-dicarboxylate (1.2 g, 4.9 mmol, ASW Med Chem Inc) in MeCN and MeOH (1:1, 100 ml) was added formaldehyde (37% aqueous, 13,2 ml, 177 mmol), then added triacetoxyborohydride sodium (5,20 g, 24.5 mmol). The resulting mixture was stirred for about 15 min at room temperature. Dropwise added AcOH (5,6 ml, 98 mmol), and the resulting mixture was stirred for about 1 hour. The solvent was removed under reduced pressure and the resulting residue dissolved in DCM (100 ml) and neutralized using aqueous 2 n NaOH. Add saturated aqueous solution of NaHCO3(50 ml) and the layers were separated. The organic layer was washed with a saline solution�ohms (50 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material is purified by chromatography on silica gel processing, performing a gradient elution 20-80% EtOAc/heptane to obtain (R)-1-tert-butyl 3-methyl 4-methylpiperazin-1,3-dicarboxylate (1.1 g, 85%): LC/MS (table 2, Method a) Rt=of 1.91 min; MS m/z: 259 (M+H)+.

Step B: Lithium (R)-4-(tert-butoxycarbonyl)-1-methylpiperazin-2-carboxylate

To a solution of (R)-1-tert-butyl 3-methyl 4-methylpiperazin-1,3-dicarboxylate (1.2 g, 4.6 mmol) in 1,4-dioxane (18 ml) and water (18 ml) was added LiOH.H2O (0,290 g, 6,91 mmol). After heating at a temperature of about 80°C for about 1 hour, the reaction mixture obtained was cooled to room temperature, and the solvent removed under reduced pressure. The solid product was dried in a vacuum thermostat at a temperature of about 65°C for about 18 hours to obtain a lithium (R)-4-(tert-butoxycarbonyl)-1-methylpiperazin-2-carboxylate (1.46 g, quantitative): LC/MS (table 2, Method a) Rt=1,17 min; MS m/z: 245 (M+H)+.

Example No. 17: (1S,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-inkarbaeva acid

To a solution of (1R,4S)-2-azabicyclo[2.2.1]hept-5-ene-3-she (5.0 g, 46 mmol) in water (30,5 ml) was added aqueous HCl solution (2 M, 23,0 ml, 46,0 mmol). After�of revane at a temperature of about 80°C for about 2 hours, the obtained reaction mixture was cooled to room temperature, and the solvent removed under reduced pressure. The solid product was dried in a vacuum thermostat at a temperature of about 70°C and used without further purification. To a solution of hydrochloride (1S,4R)-4-aminocyclopent-2-inkarbaeva acid (9,20 g of 45.8 mmol) in 1,4-dioxane (15 ml) and water (18.3 ml) at a temperature of about 0°C is added DIEA (32.0 ml, 183 mmol). After stirring for about 5 min, a solution of di-tert-BUTYLCARBAMATE (11,7 ml of 50.4 mmol) in 1,4-dioxane (5 ml). The obtained reaction mixture was heated to room temperature and stirred for about 18 hours. The solvent was removed under reduced pressure, and the crude oil was dried in a vacuum thermostat at a temperature of about 65°C for about 3 hours. The crude product is purified by chromatography on silica gel processing, performing a gradient elution 80-100% EtOAc/heptane to obtain (1S,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-inkarbaeva acid (5.2 g, 50% over 2 stages): LC/MS (table 2, Method a) Rt=of 1.81 min; MS m/z: 226 (M-H)-.

Example No. 18: (1S,2R,4S,5R)-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-amine

To a solution of ethyl (1S,2R,4S,5R)-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-ylcarbamate (0,16 �, 0,34 mmol, obtained using GG from the sample receiving no KK.1, A from example receipt No. 9 with HATU and TEA, C with TEA) in DCM (2.3 ml) was added trimethylsilylmethyl (of 0.11 ml, 0.75 mmol). After stirring at room temperature for about 24 hours add additional trimethylsilylmethyl (of 0.11 ml, 0.75 mmol) and the resulting reaction mixture is heated at about 40°C for about 4 days. The obtained reaction mixture was cooled to room temperature, then added to a saturated aqueous solution of NaHCO3(20 ml). The resulting mixture was stirred for about 5 min and the layers were separated. The aqueous layer further extracted with DCM (20 ml). The combined organic layers washed with brine (20 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain (1S,2R,4S,5R)-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-amine, which contains 1 molar equivalent DCM (0.17 g, 100%): LC/MS (table 2, Method a) Rt=1,76 min; MS m/z: 409 (M+H)+.

Example No. 19: (9H-fluoren-9-yl)methyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carboxylate

To a solution of (9H-fluoren-9-yl)methyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)amino)acetyl)-4-demerol-1-carboxylate (0,627 g, 0,836 mmol, obtained with the use of� W from the sample receiving No. 20, LL, Z from example # 8, step A) in DCM (10 ml) was added TFA (1,50 ml, 19.5 mmol) and the resulting mixture was stirred at room temperature in a nitrogen atmosphere for about 1 hour. The resulting solution was concentrated and the resulting residue is divided between a saturated aqueous solution of NaHCO3(25 ml) and EtOAc (25 ml). The organic phase was washed with brine (20 ml), dried over anhydrous MgSO4, filtered and concentrated, resulting in raw (9H-fluoren-9-yl)methyl 4-methyl-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylamino)acetyl)piperidine-1-carboxylate in the form of amorphous solids brown. The crude material was added to a 1,4-dioxane (5 ml), was added a reagent Losson (0,2,3 g, 0,502 mmol) and the resulting suspension is heated at a temperature of about 80°C for about 20 min the Solvent was removed under reduced pressure, and the obtained residue was purified by chromatography on silica gel processing, performing a gradient elution from 0 to 1.5% MeOH/DCM, yielding (9H-fluoren-9-yl)methyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carboxylate in the form of a solid substance is not white (of 0.21 g, 40%): LC/MS (table 2, Method a) Rt=2,68 min; MS m/z 632 (M+H)+.

Example No. 20: 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-demerol-3-carboxylic acid

To dissolve�1-(tert-butoxycarbonyl)-4-demerol-3-carboxylic acid (1.50 g, 6,17 mmol, example No. 13, step (G) in 1,4-dioxane (10 ml) was added an aqueous solution of HCl (4 n in 1,4-dioxane (4,62 ml, 18.5 mmol). The obtained reaction mixture is heated at a temperature of about 60°C for about 16 hours before allowed to cool to room temperature. To this mixture was added NaHCO3(2,07 g, to 24.7 mmol) and water (10.0 ml) was then added (9H-fluoren-9-yl)methyl 2,5-dioxopiperidin-1-ylcarbamate (4,16 g, 12.3 mmol). The obtained reaction mixture was stirred at a temperature of about 25°C for about 16 hours. The reaction mixture was acidified to about pH 1 aqueous solution of 1 n HCl and extracted with EtOAc (75 ml). The organic layer was washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product is purified by chromatography treatment on silica gel (40 g column), performing a gradient elution 1-5% MeOH in DCM, yielding 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-demerol-3-carboxylic acid (0,72 g, 31%) as a clear oil: LC/MS (table 2, Method a) Rt=of 2.44 min; MS m/z: 366 (M+H)+.

Example No. 21: 5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)pyridine-2-sulfonamide

To a solution of 5-bromo-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)Piri�in-2-sulfonamide (0,69 g, 1.1 mmol, obtained using A from (1S,3R)-3-atsetamido-2,2-dimethylcyclobutane acid [Tetrahedron: Asymmetry2008, 19, 302-308] and the example of receiving No. 9 with EDC, C with DIEA, JJ, N from 5-bromopyridin-2-sulphonylchloride [Chem Impex]) in degassed DMF (1.5 ml) was added dilantin (0,321 g, to 2.74 mmol) was then added Pd(Ph3P)4(0,063 g of 0.055 mmol, Strem). The reaction mixture is heated at a temperature of about 80°C for about 16 hours in a nitrogen atmosphere. The obtained reaction mixture is allowed to cool to room temperature before it was diluted with aqueous NaOH (1 n, 10 ml) and extracted with EtOAc (25 ml). The organic layer was washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting product is purified by chromatography treatment on silica gel (12 g), performing a gradient elution 1-10% MeOH in DCM, yielding 5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)pyridine-2-sulfonamide (0.09 g, 14%) as a solid yellow-brown color: LC/MS (table 2, Method a) Rt=2,14 min; MS m/z: 577 (M+H)+.

Example No. 22: 2-acetylamino-5-carboxilate

To the methyl ester hydrochloride (E-2-amino-5-carboxilate (1.0 g, 4.1 mmol, obtained according to the methodOrg. Process Res. Dev., 2008, 12 (6), 1114-1118), and DIEA (2,13 ml, 12.2 mmol) in 1,4-dioxane (15 ml) was added Ac2O (0,576 ml, 6,10 mmol). The obtained reaction mixture was stirred at a temperature of about 25°C for about 3 hours before the addition of aqueous NaOH (2 n, to 8.14 ml, 16.3 mmol). The obtained reaction mixture was stirred at a temperature of about 25°C for about 16 hours before it is divided between EtOAc (100 ml) and aqueous 1 n HCl (50 ml). The organic layer was washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding 2-acetylamino-5-carboxilate (0.47 g, 49%) in the form of white solids: LC/MS (table 2, Method a) Rt=1,43 min; MS m/z: 236 (M-H)-?.

Example No. 23: 6-fluoro-4-methyl nicotine amide

In a round bottom flask is loaded 6-fluoro-4-methylnicotinic acid (1.13 g, to 7.28 mmol, Frontier) and DCM (73 ml), yielding a clear solution. Added dropwise thionylchloride (of 5.32 ml, for 72.8 mmol) and the resulting mixture was stirred at room temperature overnight. The obtained reaction mixture is concentrated to dryness under reduced pressure and the resulting residue dissolved in EtOAc (10 ml) and added dropwise to a rapidly stirred mixture of EtOAc (40 ml) and concentrated aqueous solution of NH4OH (36,9 ml, 947 mmol). The resulting mixture PHE�amerivault for about 1 hour, and the layers were separated. The aqueous layer further extracted with EtOAc (50 ml), and the combined extracts washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure, yielding 6-fluoro-4-methyl nicotine amide (0,69 g, 61%) in the form of white solids: LC/MS (table 2, Method d) Rt=1,03 min; MS m/z 153 (M-H)-.

Example No. 24: Hydrochloride of 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)ethanamine

Stage A: 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)ethanol

To a solution of methylmagnesium (0,232 ml, 0.697 against mmol) in THF (10 ml) at a temperature of about -78°C was added a solution of 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde (0,210 g, 0.697 against mmol, example No. 10, step B) in DCM (10.0 ml). After about 10 min to the resulting reaction mixture is added a saturated aqueous solution of NH4Cl. After heating to room temperature, to the resulting reaction mixture was added EtOAc (30 ml) and the organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified by chromatography on silica gel processing, elwira 20-80% EtOAc/heptane, yielding 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)ethanol (0.050 g, 23%) as a yellow oil. LC/MS (table 2, Method a) Rt=2,04 min; MS m/z: 318 (M+H) +.

Step B: 2-(1-azidoethyl)-5-tosyl-5H-imidazo[2,3-b]pyrazine

To a solution of 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)ethanol (0,600 g of 1.89 mmol) in DCM (10 ml) was added SOCl2(0,690 ml, 9,45 mmol) at room temperature. After about 4 hours the reaction mixture obtained is diluted with EtOAc (50 ml), and saturated aqueous solution of NaHCO3(50 ml) was added to the resulting reaction mixture. After stops rapid gas evolution organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was dissolved in DMF (10 ml), and sodium azide (0,615 g, to 9.45 mmol) was added to the resulting reaction mixture. After about 15 hours to the resulting reaction mixture was added EtOAc (50 ml) and water (50 ml). The organic layer is isolated, concentrated under reduced pressure, and purified by chromatography on silica gel processing, elwira 20-80% EtOAc/heptane, yielding 2-(1-azidoethyl)-5-tosyl-5H-imidazo[2,3-b]pyrazine (0.65 g, 100%) as a colorless solid: LC/MS (table 2, Method a) Rt=2,67 min; MS m/z: 343 (M+H)+.

Step C: Hydrochloride of 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)ethanamine

To a solution of 2-(1-azidoethyl)-5-tosyl-5H-imidazo[2,3-b]pyrazine (0.65 g, 1.9 mmol) in THF (10 ml) and water (5 ml) was added triphenylphosphine (0,598 g, to 2.28 mmol). The obtained reaction mixture is heated to about 45°C, and after about 12 hours the reaction mixture obtained was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in EtOAc (40 ml), and after the resulting solution was bubbled gaseous HCl until pH=1. Slowly add Et2O (40 ml) and the solvent decanted, getting solid. The solid product was dried under vacuum to give the hydrochloride of 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)ethanamine (0.65 g, 97%) as a solid yellow-brown: LC/MS (table 2, Method a) Rt=1,56 min; MS m/z: 317 (M+H)+.

Example No. 25: 2,2-dimethyl-4-oxocyclopentanecarboxylate acid

To a solution of 4,4-dimethylcyclopentene-2-Enon (2.0 g, 18 mmol) in EtOH (50 ml), water (7.5 ml) and AcOH (1.5 ml) was added potassium cyanide (2,36 g of 36.3 mmol). The obtained reaction mixture is heated to about 40°C and after about 15 hours the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with EtOAc (50 ml) and washed with brine. The organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated. The remaining residue is dissolved in aqueous HCl (6 n, 50 ml) and heated at reflux. After about 3 days the obtained reaction CME�ü cooled to room temperature and concentrated under reduced pressure, getting 2,2-dimethyl-4-oxocyclopentanecarboxylate acid (3.7 g, 90%, ~70% pure by1H NMR), which is used without further purification: LC/MS (table 2, Method a) Rt=1,30 min; MS m/z: 155 (M-H)-.

Example No. 26: 4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid

Stage A: 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid

To a solution of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (2.00 g, in 9.44 mmol, according to the methodAust. J. Chem.,1985, 38, 1705-18) in MeOH (47 ml) was added KOH (0,475 g, is 8.46 mmol) and water (2.5 ml). The obtained reaction mixture was stirred at reflux for about 16 hours and then cooled to room temperature and concentrated to dryness under reduced pressure. The remaining residue was added water (25 ml), and the resulting mixture was extracted with Et2O (2×25 ml). The aqueous layer acidified to about pH 4 using aqueous solution of 6 n HCl, and extracted with DCM (3×20 ml). The combined DCM extracts were dried over anhydrous MgSO4, filtered and concentrated yielding 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid in the form of a solid substance is not white (1.19 g, 71%):1H NMR (400 MHz, DMSO-d6) δ 12,19 (s, 1H), 3,61 (s, 3H), 1,92 (d, J=6,6 Hz, 4H), and 1.76 (s, 2H), 1.65 V and a 1.54 (m, 4H).

Step B: Methyl 4-(tert-b�oxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylate

To a solution of 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (2,01 g, 10.1 mmol) in toluene (30 ml) was added diphenylphosphoryl (2,20 ml, 10.2 mmol) and TEA (1.60 ml, 11.5 mmol). The resulting mixture was stirred at room temperature for about 1 hour, then heated at a temperature of about 50°C for about 3 hours, and then heated at a temperature of about 70°C for about 2 hours. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The obtained residue was diluted in tert-butanol (10.0 ml, 105 mmol) and the resulting mixture was heated at a temperature of about 80°C for about 16 hours. The obtained reaction mixture was cooled to room temperature and dissolved in Et2O (50 ml). The organic layer was washed with water, an aqueous solution of 1 M NaOH, water and brine (25 ml each). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated, yielding methyl 4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylate in the form of a solid substance is not white (2.22 g, 81%):1H NMR (400 MHz, DMSO-d6) δ of 7.03 (s, 1H) and 3.59 (s, 3H), 1,95-of 1.74 (m, 6H), 1,60 (s, 4H), and 1.37 (s, 9H).

Stage C: 4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid

To a solution of methyl 4-(tert-butoxycarbonyl�but)bicyclo[2.2.1]heptane-1-carboxylate (2,21 g, 8,20 mmol) in THF (27 ml) and MeOH (14 ml) was added aqueous NaOH (1 n, 20.0 ml, 20.0 mmol). The resulting mixture was stirred at room temperature for about 16 hours and concentrated to dryness under reduced pressure. The remaining residue was added water (25 ml), and the resulting mixture was extracted with Et2O (2×25 ml), and Et2O the extracts were decanted. The aqueous layer acidified to about pH 4 using aqueous solution of 6 n HCl and extracted with Et2O (3×10 ml). The combined organic layers dried over anhydrous MgSO4, filtered and concentrated to dryness under reduced pressure, yielding 4-(tert-butoxycarbonylamino)bicyclo[2.2.1]heptane-1-carboxylic acid in the form of a solid substance is not white (1,69 g, 81%):1H NMR (400 MHz, DMSO-d6) δ 12,07 (s, 1H), 7.00 x (s, 1H), 2.00 in to 1.69 (m, 6H), 1,67-of 1.45 (m, 4H), and 1.37 (s, 9H).

Example No. 27: 6-chloro-4-(trifluoromethyl)nicotinamide

6-chloro-4-(trifluoromethyl)nicotinic acid (1.0 g, 4.4 mmol, Oakwood) was dissolved in DCM (44 ml), yielding a clear solution, was added, dropwise, SOCl2(3.2 ml, 44 mmol) and the resulting reaction mixture was stirred at room temperature overnight and then at reflux for about 16 hours. The resulting mixture was concentrated under reduced pressure, yielding a yellow oil that was dissolved in EtOAc (10 ml). Get�nny solution was added dropwise to a rapidly stirred mixture of EtOAc (20 ml) and concentrated aqueous solution of NH 4OH (22 ml, 580 mmol). The obtained turbid mixture was stirred for about 2 hours and separated. The aqueous layer further extracted with EtOAc (30 ml). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding 6-chloro-4-(trifluoromethyl)nicotinamide (0.85 g, 85%) as a solid substance is not white: LC/MS (table 2, Method a) Rt=the 1.62 min; MS m/z: 223 (M+H)+.

Example No. 28: Hydrochloride (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine

A 5-liter reactor was charged with 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (98,8 g, 281 mmol, example No. 7), zinc dust (3.50 g, 53,3 mmol), triptorelin palladium (II) (4.0 g, 12 mmol), racemic-2-(di-tert-butylphosphino)-1,1'-binaphthyl (9.8 g, to 24.7 mmol). The flask supply device for adding a powder, in which is placed the zinc cyanide (10.0 g, 157 mmol) to add it at the last stage. The reactor was purged with argon for no longer than about 30 min, and then added to the reactor DMA (2 l), the spray argon. The resulting mixture was stirred and heated at about 50°C while continuing to maintain the argon sputtering. The obtained dark brown solution is continued to be heated at about 95°C, adding the cyanide of zinc from the device to add powder, Porz�s for about 15 min. After reaching about 95°C, the brown mixture was stirred for about 16 more hours. The obtained reaction mixture was cooled to room temperature, yielding salts in the sludge. The resulting mixture was filtered through a Buchner funnel containing a filter agent, and the filter cake washed with DMA (20 ml). A solution of crude product in the DMA is added to a cold (<10°C) water (16 l), and stirred for about 30 min, the resulting suspension was filtered, and the filter cake washed again with water (1 l). The obtained wet cake was dried in a vacuum thermostat at a temperature of about 50°C. the Crude solid was dissolved in DCM (1.5 l) and dried over anhydrous MgSO4. After filtration, the resulting solution is passed through a layer of silicon dioxide (140 g), washing with additional solvent until, until only a predetermined impurity will not be detected as eluruumina from the layer. The obtained solvent was removed and the crude solid triturated with MeOH/DCM (4:1, 10 volumes of solvent per gram of wet solids) at room temperature for about 5 hours. The solid product was filtered and washed with MeOH (300 ml). The product is dried in a vacuum thermostat, receiving 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbonitrile (58.8 g, 70%) as colorless solids:1H NMR (40 MHz, CDCl3) δ 8,67 (s, 1H), 8,21 (d, J=4.2 Hz, 1H), 8,07 (l,J=8.4 Hz, 2H), 7,34 (l,J=8,1 Hz, 2H), 6,89 (l,J=4.2 Hz, 1H), 2,42 (s, 3H). In a 2-liter reactor made of 316 stainless steel pressure load of 5% Pd/C (15,4 g of 63.6 wt % water, wet material, 5.6 g based on dry weight, Johnson Matthey A503032-5), 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbonitrile (55 g, 184 mmol), THF (1.1 l), deionized water (165 ml), aqueous HCl (37 wt %, 30 ml, 369 mmol) and quinoline (1.1 ml, 9.0 mmol). The reactor was purged, sealed and support the pressure of 275 kPa of hydrogen supplied from the reservoir under high pressure. The resulting mixture was intensively stirred at a temperature of about 25°C. after 5 hours, the reactor is opened and purged with nitrogen to remove most of the dissolved hydrogen, and the resulting reaction mixture was filtered to remove the catalyst. The reactor and the catalyst pellet is washed with a mixture of THF:H2O (1:1, 2×40 ml). The combined filtrate and washing was concentrated, and added EtOH (500 ml). After two additional substitutions of solvent of EtOH (2×500 ml), the crude residue was concentrated, yielding a residue (76 g) suspended in EtOH (550 ml) and stirred at room temperature for about 4 hours. The solid product is collected by filtration and washed with cold EtOH (50 ml). The wet cake was dried in a vacuum thermostat, getting hydrochloride (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)meth�Namin (51,2 g, 82%) as a colorless solid: LC/MS (table 2, Method a) Rt=1,44 min; MS m/z: 303 (M+H)+.

General procedure A: Getting hydrazide carbonic acid

To a mixture of 2-hydrazinolysis[2,3-b]pyrazine (preferably 1 equivalent) and carboxylic acid (1-2 equivalents, preferably 1.1 to 1.3 equivalent) in a solvent such as DCM or THF, preferably DCM, add linking agent, such as EDC.HCl or HATU (1.0 to 2.0 equivalents, preferably 1.2 to 1.6 equivalent) with an organic base (or not) such as TEA or DIEA (2-5 equivalents, preferably 3-4 equivalent). After about 1-72 hours, preferably 2-6 hours) at a temperature of about 20-60°C (preferably about room temperature), the reaction mixture was treated using one of the following methods. Method 1: Add water and the layers were separated. Not necessarily the resulting mixture was filtered through celite may® to form separate layers. The aqueous layer was then extracted with an organic solvent, such as EtOAc or DCM. The combined organic layers are optionally washed with brine, dried over anhydrous Na2SO4orMgSO4, filtered or decanted, and concentrated under reduced pressure. Method 2: the Reaction mixture is diluted with an organic solvent, such as EtOAc or DCM and washed with water, or saline solution�m or both. The aqueous layer is then extracted with optional organic solvent, such as EtOAc or DCM. Then the organic layer or the combined organic layers are optionally washed with brine, dried over anhydrous Na2SO4or MgSO4, filtered or decanted, and concentrated under reduced pressure. Method 3: the Reaction mixture is diluted with an organic solvent, such as EtOAc or DCM and water was added. The layers were separated, and the organic layer directly purified using chromatography. In all cases the raw material is optionally purified by precipitation, crystallization and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure A

Example No. 1: Tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentanecarbonyl

To a mixture of 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (2,50 g, 8,24 mmol, example No. 9) and (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g, 9,07 mmol, Peptech) in DCM (30 ml) was added EDC.HCl (1.90 g, of 9.89 mmol). After about 4.5 hours at room temperature, add water (30 ml) and the layers were separated. The aqueous layer was then extracted with EtOAc (15 ml). The combined organic layers industrial�up with saline, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DCM (15 ml) and purified by chromatography on silica gel processing, performing a gradient elution 40-100% EtOAc in heptane, yielding tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentylamine (4.20 g, 97%): LC/MS (table 2, Method a) Rt=2,27 min; MS m/z: 515 (M+H)+.

General procedure B: obtain the hydrazide of chloride, followed by cyclization and hydrolysis of the sulfonamide

To a solution of 5-sulfonyl-2-hydrazine-5H-imidazo[2,3-b]pyrazine (preferably 1 equivalent) and TEA or DIEA (1-10 equivalents, preferably 4 equivalents) in 1,4-dioxane at a temperature of about 0-25°C (preferably room temperature) was added the acid chloride (1-1,5 equivalents, preferably 1 equivalent). After completion of the addition, the reaction mixture is allowed to warm to room temperature, if at first it was cooled. After about 0.5-2 hours (preferably about 1 hour), add SOCl2(1-10 equivalents, preferably 3 equivalents) and the reaction mixture is heated at a temperature of about 60-100°C (preferably about 80-90°C) for about 0.25 to 8 hours (preferably about 1 hour). The reaction mixture is allowed to cool to room temperature, and then added water�th solution of the base (such as aqueous solution of Na 2CO3oraqueous NaOH solution, preferably aqueous NaOH) followed by an optional, but preferred, the addition of MeOH (5-50% of the reaction volume, preferably 50%). The reaction mixture is heated at a temperature of about 50-90°C for about 1-96 hours (preferably about 3 hours at a temperature of about 60°C, when using aqueous NaOH, or about 3 days at a temperature of about 90°C, if an aqueous solution of Na2CO3). The reaction mixture was concentrated under reduced pressure and then divided between an organic solvent (such as EtOAc or DCM, preferably EtOAc) and water, a saturated aqueous solution of NaHCO3and/or salt solution, preferably a saturated aqueous solution of NaHCO3. The organic layer is isolated, and optionally washed with water and/or brine, dried over anhydrous Na2SO4or MgSO4, filtered or decanted, and concentrated under reduced pressure. The raw material is optionally purified by precipitation, crystallization, and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure B

Example No. 1.1 1-(2-methylcyclohexyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

K R�the target 5-(4-tert-butylphenylmethyl)-2-hydrazine-5H-imidazo[2,3-b]pyrazine (0.40 g, 1,2 mmol, example No. 3) and DIEA (0.20 ml, 1.2 mmol) in 1,4-dioxane (12 ml) at a temperature of about 0°C was added 2-methylcyclohexanecarboxylic (0.19 g, 1.2 mmol, example No. 4). After completion of the addition, the bath with ice is removed, and the reaction mixture is allowed to warm to room temperature. After about 1 hour, add SOCl2(0.42 ml, 5.8 mmol) and the reaction mixture is heated at a temperature of about 90°C for about 1 hour. The reaction mixture was allowed to cool to room temperature and then added 2 M aqueous solution of Na2CO3(2 n, with 11.6 ml of 23.2 mmol) and MeOH (12 ml). The reaction mixture is heated at a temperature of about 90°C for about 3 days. The reaction mixture was concentrated under reduced pressure and then separated between EtOAc (50 ml) and a saturated aqueous solution of NaHCO3(40 ml). The organic layer was isolated and dried over anhydrous Na2SO4, filtered and the solvent concentrated under reduced pressure. The obtained residue is purified on silica gel (12 g) using EtOAc as eluent, and then further purified using HPLC with reversed phase (table 2, Method b). The combined product containing fractions concentrated under reduced pressure to remove MeCN and the resulting precipitate collected by vacuum filtration to obtain 1-(2-methylcyclohexyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine � the form of white solids (0.10 g, 35%): LC/MS (table 2, Method a) Rt=a 1.84 min; MS m/z: 256 (M+H)+.

General procedure C: Cyclization of a hydrazide

To a solution of 2-hydrazine-5H-imidazo[2,3-b]pyrazine (preferably 1 equivalent) in an organic solvent (such as 1,4-dioxane) is added a base such as TEA or DIEA (1-5 equivalents, preferably 2-4 equivalents) and SOCl2(1-5 equivalents, preferably 1-2 equivalents). The resulting mixture was heated at a temperature of about 60-100°C (preferably about 80°C) for about 1 to 16 hours (preferably about 1-2 hours). The obtained reaction mixture was cooled to room temperature and treated using one of the following methods. Method 1: Add an organic solvent (such as EtOAc or DCM) and water. The layers were separated, and the aqueous layer extracted with optional additional organic solvent. The combined organic layers are optionally washed with an aqueous solution of a base (such as NaHCO3and/or brine, dried over anhydrous Na2SO4or MgSO4then decanted or filtered prior to concentrating under reduced pressure. Method 2: Add an organic solvent (such as EtOAc or DCM) and the organic layer is optionally washed with brine and water, dried over anhydrous MgSO4or Na2SO4shown�comfort or decanted, and concentrated under reduced pressure. Method 3: the Obtained reaction mixture was separated between an organic solvent (such as EtOAc or DCM) and a saturated aqueous solution of NaHCO3or saline solution, dried over anhydrous Na2SO4or MgSO4then decanted or filtered prior to concentrating under reduced pressure. The raw material is optionally purified by precipitation, crystallization, and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure C

An example of receiving no C. 1: Tert-butyl-(1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine

To a solution of tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentylamine (9,30 g of 18.1 mmol, example No. A. 1) in 1,4-dioxane (100 ml) was added TEA (10.0 ml, of 72.3 mmol) and SOCl2(2,11 ml of 28.9 mmol). The resulting mixture was heated at a temperature of about 80°C for about 1.5 hours. The obtained reaction mixture was cooled to room temperature, add EtOAc and water (200 ml each) and the layers were separated. The aqueous solution was extracted with EtOAc (2×100 ml) and the combined organic layers washed with a saturated aqueous solution of NaHCO3and brine (100 ml each). About�egy for organic extracts dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The crude material is purified by chromatography on silica gel processing, performing a gradient elution 25 to 100% EtOAc in DCM, yielding tert-butyl-(1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (7,65 g, 85%): LC/MS (table 2, Method a) Rt=2,37 min; MS m/z: 497 (M+H)+.

General procedure D: Cyclization of a hydrazide, followed by hydrolysis of the sulfonamide and removal of the Boc-protective groups

In a round bottom flask is loaded 5-sulfonyl-2-hydrazine-5H-imidazo[2,3-b]pyrazine (preferably 1 equivalent), an organic solvent (such as 1,4-dioxane or THF, preferably 1,4-dioxane), SOCl2(2-5 equivalents, preferably 2 equivalents) and an organic base, such as DIEA or TEA (0-5 equivalents, preferably 3 equivalents). The resulting mixture was stirred at a temperature of about 25-120°C (preferably about 90°C) for about 0.25 to 5 hours (preferably about 1 hour and then allowed to cool to room temperature. To the resulting reaction mixture is added an aqueous solution of a base (such as aqueous solution of Na2CO3oraqueous NaOH, 1 to 30 equivalents, preferably 1-2 equivalents of aqueous NaOH, preferably 15 to 20 equivalents of an aqueous solution of Na2CO3 ) and the resulting mixture was heated at a temperature of about 60-120°C (preferably about 90°C) for about 1-10 hours (preferably about 5 hours) then leave to cool to room temperature. MeOH (5-50% of the reaction volume, preferably 20-30%) is added to the obtained reaction mixture, and the resulting solution is heated at a temperature of about 60-120°C (preferably about 90°C) for about 5-24 hours (preferably about 16 hours) and then allowed to cool to room temperature. The layers were separated, and the organic solvent was concentrated under reduced pressure. To the resulting residue was added an organic solvent (such as 1,4-dioxane or THF, preferably 1,4-dioxane) then HCl solution, such as 4 M HCl in 1,4-dioxane (20-40 equivalents, preferably, 25 equivalents). The resulting suspension was stirred at a temperature of about 20-80°C (preferably about 60°C) for about 1 to 16 hours (preferably about 1 hour and then allowed to cool to room temperature. The solid product is collected by vacuum filtration, washed with an organic solvent (such as 1,4-dioxane, EtOAc and/or Et2O, preferably, 1,4-dioxane and then Et2O), resulting in the crude product as HCl salt. The raw material is optionally purified by precipitation, crystallization, or grind thoroughly with COO�appropriate solvent or solvents, or by chromatography, obtaining the target compound.

Illustration of General procedure D

Example # D. 1.1 Hydrochloride CIS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine and CIS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine

In a round bottom flask is loaded CIS-tert-butyl-4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclohexylcarbamate (0,415 g, 0,785 mmol, obtained using A from CIS-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid [AMRI] and the example of receiving No. 9), 1,4-dioxane (9 ml) and SOCl2(0,115 ml of 1.57 mmol). The resulting mixture was heated at a temperature of about 90°C for about 1 hour, and then allowed to cool to room temperature. To the resulting reaction mixture is added an aqueous solution of Na2CO3(5 n, the 7.85 ml of 15.7 mmol) and the resulting reaction mixture is heated at a temperature of about 90°C for about 5 hours. MeOH (5 ml) was added to the obtained reaction mixture, and the mixture was heated at a temperature of about 90°C for about 16 hours and then allowed to cool to room temperature. The layers were separated, and the organic layer was concentrated under reduced pressure. To the resulting residue was added 1,4-dioxane (10 ml) then HCl (4 M in 1,4-dioxane, 5 ml, 20.0 mmol). The resulting suspension is heated at a temperature of about 60°C in techinical 1 hour and then allowed to cool to room temperature. The solid product is collected by vacuum filtration, washed first 1,4-dioxane (1 ml), then Et2O (50 ml), resulting in the crude product, the hydrochloride of the CIS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (0.42 g, 98%, 84% purity). Part of the crude HCl salt (0.075 g) then purified using HPLC with reversed phase (table 2, Method g) to give CIS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (0,044 g) with 3 equivalents of NH4OAc as excipient. LC/MS (table 2, Method a) Rt=0,92 min; MS m/z: 257 (M+H)+.

TABLE D. 1
Examples of the preparation using General procedure D
HydrazideProductExample No.Rtmin (Tab.2, Method)m/z ESI+ (M+H)+
tert-butyl (1R,3S)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentanecarbonyl
(obtained using A from (1S,3R)-3-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid [PepTech] and the example of receiving No. 9)
hydrochloride (1R,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamineD. 1.20,47 (d) 243
tert-butyl TRANS-4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclohexylcarbamate
(obtained using A from TRANS-4-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid [AMRI] and the example of receiving No. 9)
hydrochloride TRANS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamineD. 1.30,44(d)257
tert-butyl (1R,3R)-3-(2-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)-cyclopentylamine (obtained using A from (1S,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid [Acros] and the example of receiving No. 3)hydrochloride (1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamineD. 1.40,46(d)243

General procedure E: Cyclization of a hydrazide, followed by hydrolysis of the sulfonamide

To a solution of 5-sulfonyl-2-hydrazine-5H-imidazo[2,3-b]pyrazine (preferably 1 equivalent) in a solvent such as 1,4-dioxane, was added SOCl2(1-5 equivalents, preferably 1-2 equivalents). Optionally, an organic base such as TEA or DIEA, (1-5 EQ�valenton, preferably 2-4 equivalents) is added, before SOCl2especially for Boc-protected substrates. The reaction mixture is heated at a temperature of about 60-100°C (preferably about 80°C). After about 0.5-6 hours (preferably about 1-2 hours), adding an aqueous solution of a base (such as aqueous solution of Na2CO3oraqueous NaOH, 1-90 equivalents, preferably 15 to 20 equivalents of an aqueous solution of Na2CO3or1-2 equivalents of aqueous NaOH), and resume heating at a temperature of about 60-90°C. (preferably about 80°C) for about 1-72 hours (preferably about 1 to 16 hours). Optionally, but preferably, the reaction mixture was cooled to room temperature for a time period of 5 minutes to 72 hours, at which time MeOH and/or additional aqueous solution of a base (such as saturated solution of Na2CO3or1 n of NaOH) can be added, and heating is optional resume at a temperature of about 60-90°C (preferably about 80°C) for about 1-72 hours (preferably about 1 to 16 hours). This cycle optional cooling to room temperature and addition of the base can occur up to four times. The reaction mixture is treated using one of the following methods. Method 1: an Organic solvent, such as EtOAc �whether DCM are added with the optional addition of water, salt solution or a saturated aqueous solution of NH4Cl (preferably water), and the layers were separated. The water layer is then optionally extracted with additional organic solvent, such as EtOAc or DCM. The combined organic layers are optionally washed with brine and water, dried over anhydrous MgSO4orNa2SO4, filtered or decanted, and concentrated under reduced pressure. Method 2: the Obtained reaction mixture is decanted and the insoluble material is washed with an organic solvent such as EtOAc. The combined organic layers are concentrated under reduced pressure. Method 3: the Obtained reaction mixture was concentrated under reduced pressure to remove solvent. Water was added, and the aqueous layer was extracted with organic solvent such as EtOAc or DCM. The combined organic layers are optionally washed with brine and water, dried over anhydrous MgSO4orNa2SO4, filtered or decanted, and concentrated under reduced pressure. Method 4: the Reaction mixture containing the precipitate was filtered to collect the target compound, optionally rinsing with water. The obtained filtrate was concentrated and optionally purified, resulting in additional target compound. Method 5 the pH of the obtained reaction mixture was adjusted to neutral values, using an additional quantity of a suitable aqueous acid (such as aqueous HCl solution) before extraction with an organic solvent, such as EtOAc or DCM. The combined organic layers are optionally washed with brine and water, dried over anhydrous MgSO4orNa2SO4, filtered or decanted, and concentrated under reduced pressure. In all cases the raw material is optionally purified by precipitation, crystallization and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure E

Example # E. 1: Tert-butyl (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine

To a solution of tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentylamine (4,73 g, 9,19 mmol, example No. A. 1) in 1,4-dioxane (50 ml) was added TEA (5,10 ml, 36.8 mmol) and SOCl2(1.34 ml, 18.4 mmol). The obtained reaction mixture is heated at a temperature of about 80°C. after About 1.5 hours, add a saturated aqueous solution of Na2CO3(100 ml) and heating was resumed at a temperature of about 80°C for about 6 hours. The reaction mixture was cooled to room temperature for about 3 days, and for�eat is heated at a temperature of about 80°C for about 16 hours. Add water and EtOAc (100 ml each) and the layers were separated. The aqueous layer was then extracted with additional EtOAc (2×100 ml). The combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Wet the solid is triturated with petroleum ether (boiling point 30-60°C; 30 ml) and collected by vacuum filtration, washing with additional petroleum ether (boiling point 30-60°C; 20 ml) to give tert-butyl (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine in a solid light brown color (2,86 g, 86%): LC/MS (table 2, Method (a) Rt=1,75 min; MS m/z: 343 (M+H)+.

General procedure F: Cyclization of a hydrazide with removal of the Boc-protective group, followed by hydrolysis of the sulfonamide

To a solution of 5-sulfonyl-2-hydrazine-5H-imidazo[2,3-b]pyrazine (preferably 1 equivalent) and TEA or DIEA (0-6 equivalents, preferably 1 equivalent) in 1,4-dioxane, was added SOCl2(2.0 to 6.0 equivalents, preferably 3 equivalents). The reaction mixture is heated at a temperature of about 60-120°C (preferably about 80-90°C) for about 1-8 hours, preferably about 1-4 hours). The reaction mixture is allowed to cool to room t�of mperature, then optionally, but preferably, diluted with aristotelem (such as MeOH or EtOH, preferably MeOH) using 5-50% of the reaction volume (preferably 50%). Add an aqueous solution of a base (such as aqueous solution of Na2CO3oraqueous NaOH, 1 to 30 equivalents, preferably 1-2 equivalents of aqueous NaOH, preferably 15 to 20 equivalents of an aqueous solution of Na2CO3) and the reaction mixture is heated at a temperature of about 40-90°C (preferably about 60°C) for about 1-24 hours (preferably about 2 hours before it was concentrated under reduced pressure. The raw material is optionally purified by precipitation, precipitation of the salt obtained, crystallization, and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure F

Example N ° F. 1.1: Hydrochloride ((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methanamine

To a solution of tert-butyl((1R,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentyl)methylcarbamate (of 0.60 g, 1.1 mmol, obtained using A from (1R,3R)-3-((tert-butoxycarbonylamino)methyl)cyclopentanecarboxylic acid [AFID] and the example of receiving No. 9) and DIEA (0.79 ml, 4.5 mm�l) in 1,4-dioxane (5 ml) add SOCl 2(0,166 ml of 2.27 mmol). The obtained reaction mixture is heated at a temperature of about 80°C for about 1 hour before it is allowed to cool to room temperature. Aqueous NaOH (2 n, 4 ml, 8 mmol) was added to the obtained reaction mixture and it is heated at a temperature of about 60°C for about 2 hours. The obtained reaction mixture is allowed to cool to room temperature before it was concentrated under reduced pressure. To the resulting residue was added HCl (4 n in 1,4-dioxane (20 ml). The organic solution was decanted from the resulting precipitate to obtain hydrochloride ((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methanamine in a solid yellow color (0.11 g, 33%): LC/MS (table 2, Method a) Rt=1,01 min; MS m/z: 257 (M+H)+.

TABLE F. 1
Examples of receipts using General procedure F
HydrazideProductExample No.Rtmin (Tab.2, Method)m/z ESI+ (M+H)+
Tert-butyl-TRANS-3-(2-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclohexylcarbamate, (obtained using the example of obtaining the No. 3 and TRANS-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid [AMRI], EDC•HCl, and TEA)The acetate of TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamineF. 1.21,07(a)257
Tert-butyl-CIS-3-(2-(5-(4-tert-butylphenylmethyl)-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclohexylcarbamate, (obtained using A from example receipt No. 3 and CIS-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid [AMRI], EDC•HCl, and TEA)Hydrochloride CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamineF. 1.31,18(a)257

General procedure G: Getting hydrazone, followed by cyclization and hydrolysis of the sulfonamide

To a solution of 2-hydrazine-5-sulfonyl-5H-imidazo[2,3-b]pyrazine (preferably 1 equivalent) in an organic solvent or solvents, such as MeOH or MeOH/DCM (preferably MeOH) is added a solution of aldehyde (1.0 to 1.3 equivalents, preferably 1.0 equivalent) in an organic solvent such as DCM. The obtained reaction mixture was stirred at a temperature of about 15-30°C (preferably at room temperature) for about 1-8 hours, preferably about 2 hours) before adding the diacetate of iodobenzoic�and (1-3 equivalents, preferably 1 equivalent). The reaction mixture was stirred at a temperature of about 15-30°C (preferably at room temperature) for about 15-60 minutes (preferably about 30 minutes before it was concentrated to constant weight. To the resulting residue was added an organic solvent, such as 1,4-dioxane, THF, MeOH or EtOH (preferably 1,4-dioxane), then the aqueous solution of base, such as aqueous solution of Na2CO3orNaOH (2-50 equivalents), preferably NaOH (2 equivalent). The reaction mixture is heated at a temperature of about 40-80°C (preferably about 60°C) for about 1-24 hours (preferably about 2 hours). The crude product is optionally purified by precipitation, crystallization, and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure G

Example # G. 1.1: 1-(tetrahydro-2H-PYRAN-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (0,100 g, 0,330 mmol, example No. 9) in MeOH (2 ml) was added tetrahydro-2H-PYRAN-4-carbaldehyde (0,038 g, 0,330 mmol, J&W PharmLab) in DCM (1 ml). The obtained reaction mixture was stirred at room temperature for about 2 hours before add�represent the diacetate of iodobenzene (0,106 g, 0,330 mmol). The obtained reaction mixture was stirred at room temperature for about 15 min before it was concentrated to constant weight. To the resulting residue was added MeOH (2 ml) then aqueous NaOH (2 n, 0,330 ml, 0,659 mmol). The obtained reaction mixture is heated at a temperature of about 60°C for about 1 hour. The crude reaction mixture was purified using HPLC with reversed phase (table 2, Method f). The combined product containing fractions concentrated under reduced pressure to remove MeCN, and then lyophilizer to obtain 1-(tetrahydro-2H-PYRAN-4-yl)-6H-imidazo[2,3-e][1,2,4]-triazolo[4,3-a]pyrazine in the form of white solids (0,028 g, 35%): LC/MS (table 2, Method a) Rt=1,25 min; MS m/z: 244 (M+H)+.

TABLE G. 1
Examples of receipts from 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (Example No. 9) using General procedure G
AldehydeProductExample No.Rtmin (Tab.2, Method)m/z ESI+ (M+H)+
2,6-dimethylcyclohex-2-interbanded1-(2,6-dimethylcyclohex-2-enyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine/td> G. 1.21,97(a)268
4-(4-hydroxy-4-methylpentyl)cyclohex-3-interbanded5-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohex-1-enyl)-2-methylpentan-2-olG. 1.3of 1.82(a)340
Bicyclo[2.2.1]hept-5-ene-2-carbaldehyde1-(bicyclo[2.2.1]hept-5-EN-2-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.41,72(a)252
Cyclooctadiene (Oakwood)1-cyclooctyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.52,02(a)270
4-o-toiletries-2H-PYRAN-4-carbaldehyde (ASDI)1-(3-o-toiletries-2H-PYRAN-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.61,84(a)334
Benzaldehyde1-phenyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.71,83(a) 236
6-methylcyclohex-3-interbanded (ASDI)1-(6-methylcyclohex-3-enyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.81,83(a)254
4-(thiophene-2-yl)tetrahydro-2H-PYRAN-4-carbaldehyde (ASDI)1-(4-(thiophene-2-yl)tetrahydro-2H-PYRAN-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.91,31(a)326
2-(pyridin-4-yl)cyclopropanecarboxaldehyde (ASDI)1-(2-(pyridin-4-yl)cyclopropyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.101,04(d)277
p-tolualdehydeTriptorelin 1-p-tolyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.111,28(d)250

CyclohexenecarboxaldehydeTriptorelin 1-cycloheptyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.121,32(d)256
2-cyclopropylacetylenetriptorelin 1-(cyclopropylmethyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.131,19(d)214
2-cyclopentylacetylTriptorelin 1-(cyclopentylmethyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.141,29(d)242
CyclopentanecarboxaldehydeTriptorelin 1-cyclopentyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.151,24(d)228
3-(triptoreline)benzaldehydeTriptorelin 1-(3-(triptoreline)phenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.161,34(d)320

3,5-bis(trifluoromethyl)benzaldehydeTriptorelin 1-(3,5-bis(trifluoromethyl)phenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.171,73(l) 372
o-tolualdehydeTriptorelin 1-o-tolyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.181.26 in(d)250
2-chinainternationalBestrefiratecom 1-(quinolin-2-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.191,41(l)287
5-methyl-2-thiophenecarboxaldehydetriptorelin 1-(5-methylthiophene-2-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.201,27(d)256
4-fluoro-2-(trifluoromethyl)benzaldehydeTriptorelin 1-(4-fluoro-2-(trifluoromethyl)phenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.211,31(d)322

3,4-dimethylbenzaldehydeTriptorelin 1-(3,4-dimethylphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.221,31(d)264
4-N-butoxybenzaldehydeTriptorelin 1-(4-butoxyphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.231,40(d)308
3-methoxybenzaldehydeTriptorelin 1-(3-methoxyphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.241,25(d)266
Trimethylacetaldehydetriptorelin 1-tert-butyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.251.22 m(d)216
4-methoxybenzaldehydeTriptorelin 1-(4-methoxyphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.261,24(d)266
4-benzyloxybenzaldehydeTriptorelin 1-(4-(benzyloxy)phenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.271,38(d)342
4-(trifluoromethyl)benzaldehydeTriptorelin 1-(4-(trifluoromethyl)FeNi�)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine G. 1.281,34(d)304
4-phenoxybenzaldehydeTriptorelin 1-(4-phenoxyphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.291,38(d)328
m-tolualdehydeTriptorelin 1-m-tolyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.301,28(d)250
4-ethoxybenzaldehydeTriptorelin 1-(4-ethoxyphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.311,29(d)280
4-N-propoxybenzaldehydeTriptorelin 1-(4-propoxyphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.321,35(d)294

4-isopropylbenzaldehydeTriptorelin 1-(4-isopropylphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.33 278
4-acetamidobenzaldehydeTriptorelin N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)phenyl)acetamideG. 1.341,16(d)293
3-(trifluoromethyl)benzaldehydeTriptorelin 1-(3-(trifluoromethyl)phenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.351,33(d)304
3-methylthiophene-2-carboxaldehydeTriptorelin 1-(3-methylthiophene-2-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.361,24(d)256
CyclopropanecarboxaldehydeTriptorelin 1-cyclopropyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.371,17(d)200

3,3-dimethylbutyramideTriptorelin 1-neopentyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.381.26 in(l) 230
2,3-dimethylbenzaldehydetriptorelin 1-(2,3-dimethylphenyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineG. 1.391,29(d)264

General procedure H: Hydrolysis of the sulfonamide

Into a flask containing a sulfonamide, for example, sulfonyl-protected pyrrole, (preferably 1 equivalent) in an organic solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, preferably 1,4-dioxane) was added an aqueous solution of a base (such as aqueous solution of Na2CO3oraqueous NaOH, 1 to 30 equivalents, preferably 1-2 equivalents of aqueous NaOH, preferably 15 to 20 equivalents of an aqueous solution of Na2CO3). The resulting mixture was stirred at a temperature of about 25-100°C (preferably about 60°C) for about 1-72 hours (preferably about 1 to 16 hours). In that case, if according to TLC, LC/MS or HPLC, the reaction is not fully completed, adding additional aqueous solution of a base (such as aqueous solution of Na2CO310-20 equivalents, preferably 10 equivalents or aqueous NaOH, 1-5 equivalents, preferably 1-2 equivalents) and the reaction continued at a temperature of about 25-100°C (preferably about 60°C) for about 0.25-3 hours(preferably, about 1-2 hours). The reaction mixture is treated using one of the following methods. Method 1. The organic solvent is optionally removed under reduced pressure, and the aqueous solution is neutralized by adding an aqueous solution of the appropriate acid (such as aqueous HCl solution). Add a suitable organic solvent (such as EtOAc or DCM) and water, the layers were separated, and the organic solution is dried over anhydrous Na2SO4orMgSO4, filtered and concentrated to dryness at reduced pressure, obtaining the target compound. Method 2. The organic solvent is optionally removed under reduced pressure, adding a suitable organic solvent (such as EtOAc or DCM) and water, the layers were separated, and the organic solution is dried over anhydrous Na2SO4orMgSO4, filtered and concentrated to dryness at reduced pressure, obtaining the target compound. Method 3. The obtained reaction mixture was concentrated and directly purified by one of the following ways. The crude material obtained by any of the preceding methods, optionally purified by precipitation, crystallization and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure H

Example # H. 1.1: N-(4(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-3-chlorobenzenesulfonamide

In a 100 ml round bottom flask is loaded 3-chloro-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimide (0,14 g, 0.22 mmol, obtained using A from example receipt No. 9 and 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], C with TEA, I and N from 3-chlorobenzenesulfonamide) and 1,4-dioxane (5 ml), yielding a suspension of yellow-brown color, and then added aqueous NaOH (1 n, 0.45 ml, 0.45 mmol, J. T. Baker). The resulting suspension is heated at a temperature of about 60°C for about 3 hours. The obtained reaction mixture was cooled to room temperature, and the solvents were removed under reduced pressure. After addition of NH4OAc (50 mm water superyoung solution), solid precipitate, which is collected by vacuum filtration, washed with water and dried, yielding N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-3-chlorobenzenesulfonamide in the form of white solids (0,088 g, 86%): LC/MS (table 2, Method a) Rt=1,88 min; MS m/z: 457 (M+H)+.

Rtmin (table 2, Method)
TABLE H. 1
Examples of receipts using General procedure H
The sulfonamideProductExample No.m/z ESI+ (M+H)+
1-(piperidine-1-yl)-6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Example No. V. 1)1-(piperidine-1-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineH. 1.21,64(a)243
N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (Prime Organics), HATU, and TEA, C with TEA; I; and N benzosulphochloride and TEA)N-(4-(6H-imidazo[2,3-e]-[1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimideH. 1.31,73(a)423
2-cyano-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)acetamide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (Prime Organics), HATU, and TEA, C with TEA; I; and L 2 tsianuksusnogo acid, HATU and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-2-cyanoacetamideH. 1.4 1,40(a)350
1-cyano-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanecarboxamide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (Prime Organics), HATU, and TEA, C with TEA; I; and L 1-cyanocyclohexane acid, HATU and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-1-cyanocyclohexaneH. 1.51,60(a)376
N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanecarboxamide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (Prime Organics), HATU, and TEA, C with TEA; I; and K cyclopropanecarbonitrile and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanecarboxamideH. 1.61,52(a)351
N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-methanesulfonamide (obtained using A from example receipt No. 9, 4-(tertbutoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (Prime Organics), HATU, and TEA, C with TEA; I; and N methanesulfonanilide and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl) methanesulfonamideH. 1.71,44(a)361
3-cyano-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (Prime Organics), HATU, and TEA, C with TEA; I; and N 3-cyanobenzoyl-1-sulphonylchloride and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-3-cyanobenzenesulfonylH. 1.81,71(a)448

N-(((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methyl)-cyclopropanesulfonyl (obtained using A from example receipt No. 9, an example of obtaining the No. 1 and P. EDC•HCl; C with TEA; I; and N cyclopropanesulfonyl [Matrix])N-(((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methyl)-cyclopropanesulfonylH. 1.91,56(a)361
6-(((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methylamino)nicotinamide (obtained using A from example receipt No. 9, an example of obtaining the No. 1 and P. EDC•HCl, C with TEA; I; and O 6-chloronicotinoyl)6-(((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methylamino)-nicotinamideH. 1.101,72(a)359
6-((1R,3S)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)nicotinamide (obtained using A from example receipt No. 9, (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentane-carboxylic acid [Peptech] and EDC•HCl, C with TEA, I, and O 6-chloronicotinoyl)6-((1R,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-nicotinamideH. 1.111,67(a)345
6-(((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methylamino)nicotinamide (obtained using A from example receipt No. 9, (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentane-carboxylic acid [Peptech] and EDC•HCl, C with TEA, I, and M with pyrrolidin-1-carbonylchloride)N-((1R,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)pyrrole�in-1-carboxamide H. 1.121,51(a)340
4-chloro-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, N 4-chlorobenzene-1-sulphonylchloride and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-4-chlorobenzenesulfonamideH. 1.131,87(a)457
4-cyano-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, N with 4-cyanobenzoyl-1-sulphonylchloride [Maybridge] and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-4-cyanobenzenesulfonylH. 1.141,73(a)448
3-chloro-4-fluoro-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzolamide�Mead (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, N with 3-chloro-4-torbenson-1-sulphonylchloride [Lancaster] and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-3-chloro-4-formentionedH. 1.151,90(a)475
3,4-debtor-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzosulfimide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, N with 3,4-differenza-1-sulphonylchloride [Maybridge] and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-3,4-diftorbenzofenonomH. 1.161,83(a)459
N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzo[c][1,2,5]oxidiazol-4-sulfonamide (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, N with benzo[c][1,2,5]oxidiazol-4-sulphonylchloride [Maybridge] and TEA) N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzo[c][1,2,5]-oxadiazol-4-sulfonamideH. 1.171,78(a)465
N-methyl-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, N cyclopropanesulfonyl [Matrix] and TEA, Z with methyliodide)N-(4-(6H-imidazo[2,3 - e][1,2,4]triazolo[4,3 - a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)-N-methylcyclopentanoneH. 1.181,70(a)401
N-(3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclobutanemethanamine (obtained using N from the sample receiving no FF.1 and cyclobutanemethanamine [Hande], GG with NaOH, a with example receipt No. 9, HATU, and TEA, C with TEA)N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclobutanemethanamine and N-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclobutanemethanamine (1:1)H. 1.19 1,75(a)389
N-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopentanemethanol (obtained using N from the sample receiving no FF.1 and cyclopentanemethanol, GG with NaOH, a with example receipt No. 9, HATU, and TEA, C with TEA)N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo-[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopentanecarbonyl and N-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopentanemethanol (1:1)N. 1.20of 1.82(a)403

6-(-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)nicotinamide (obtained using P from the sample receiving no FF.1 and di-tert-butyl of dicarbonate, GG with NaOH, a with example receipt No. 9, HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, O 6-fornicationem [Matrix])6-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-nicotinamide and 6-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-nicotinamide (1:1)N. 1.211,85(a)373
N-(3-these�-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclobutanemethanamine (obtained using N from the sample receiving no FF.1 icollaboratory [Hande], GG with NaOH, a with example receipt No. 9, HATU, and TEA, C with TEA)N-((1S,3R,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclobutanemethanamine and N-((1R,3S,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclobutanemethanamine (1:1)N. 1.221,75(a)389
6-(-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)nicotinamide (obtained using P from the sample receiving no FF.1 and di-tert-butyl of dicarbonate, GG with NaOH, a with example receipt No. 9, HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, O 6-fornicationem [Matrix])6-((1S,3R,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-nicotinamide and 6-((1R,3S,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-nicotinamide (1:1)N. 1.231,79(a)373

5-chloro-6-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)nicotinamide (obtained using C from the sample receiving no A. 1 with TEA, I with 4 n HCl in 1,4-dioxane, O with 5,6-dichloroacetonitrile)6-((1S,3R)-3-(6H-imidazo[2,3-e][1,,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-5-chloronicotinamide N. 1.241,96(a)379
6-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-4-(trifluoromethyl)nicotinamide (obtained using C from the sample receiving no A. 1, I with 4 N HCl in 1,4-dioxane, O with an example of receiving No. HH.1)6-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-4-(trifluoromethyl)nicotinamideN. 1.252,05(a)413
N-((1S,2R,4S,5R)-5-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-yl)cyclopropanesulfonyl benzosulfimide and N-((1R,2S,4R,5S)-5-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-yl)cyclopropanesulfonyl benzosulfimide (obtained using A from example receipt No. 9 and example of receiving No. 11, HATU, and TEA, C with TEA)N-((1S,2R,4S,5R)-5-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-yl)cyclopropanecarboxamide and N-((1R,2S,4R,5S)-5-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-yl)cyclopropanesulfonylN. 1.261,51(a)373
N-((1S,3S,4R)-4-ethyl-3-methyl-3-(tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl and N-((1R,3R,4S)-4-ethyl-3-methyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl) (received using A from example receipt No. 9 and example of receiving No. 13, HATU, and TEA, C with TEA)N-((1S,3S,4R)-4-ethyl-3-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N- ((1R,3R,4S)-4-ethyl-3-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonylN. 1.271,74(a)387
4-Methoxy-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using A from example receipt No. 9, (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC-HCl, C with TEA, I with 4n HCl in 1,4-dioxane, N with 4-methoxybenzoyl-1-sulphonylchloride and DIEA)N-((1S,3R)-3-(6H-Imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-methoxybenzenesulfonamideN. 1.281,75(a)413
4-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using A from example receipt No. 9, (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC-HCl, C with TEA, I with 4N HCl in 1,4-dioxane, N 4-methylbenzol-1-sulphonylchloride and DIEA)N-((1S,3R)-3-(6H-pyrrol�[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-methylbenzenesulfonamide N. 1.29of 1.82(a)397
2-chloro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using A from example receipt No. 9, (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC•HCl, C with TEA, I with 4N HCl in 1,4-dioxane, N 2-chlorobenzene-1-sulphonylchloride [Lancaster] and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2-chlorobenzenesulfonamideN. 1.30of 1.82(a)417
2,3-dichloro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using A from example receipt No. 9, (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], and EDC•HCl, C with TEA, I with 4N HCl in 1,4-dioxane, N with 2,3-dichlorobenzene-1-sulphonylchloride [Lancaster] and DIEA)N-((1S,3R)-3-(6H-Imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,3-dichlorobenzenesulfonateN. 1.311,93(a)450
1-cyano-N-(((1S,3R)-3-(6-tosyl-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methyl)-cyclopropane�Samid (obtained using A from example receipt No. 9, the example of receiving no P. 1, and EDC•HCl, C with TEA, I with 4 n HCl in 1,4-dioxane, L 1-cyanocyclohexane acid and DIEA)N-(((1S,3R)-3-(6H-Imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methyl)-1-cyanocyclohexaneN. 1.321,57(a)350
3-cyano-4-fluoro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using A from example receipt No. 9, (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC•HCl, C with TEA, I with 4 n HCl in 1,4-dioxane, N, 3-cyano-4-torbenson-1-sulphonylchloride and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-cyano-4-formentionedN. 1.331,84(a)426
3,4-debtor-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using A from example receipt No. 9, (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentane carboxylic acid [Chem-Impex], EDC•HCl, C with TEA, I with 4n HCl in 1,4-dioxane, N with 3,4-differenza-1-sulphonylchloride [Maybridge] and DIEA)N-((1S,3R)-3-(6H-Imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3,4-�aftermentioned N. 1.341,86(a)419
5-(-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile (obtained using O from example 18, step M and 5-chloropyrazine-2-carbonitrile [Ark Pharm])
5-((1S,3R,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile and 5-((1R,3S,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)the pyrazine-2-carbonitrileN. 1.351,76(a)374
N-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, I with 4 n HCl in 1,4-dioxane, and N cyclopropanesulfonyl [Matrix] and TEA, Z with methyliodide)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-N-methylcyclopentanoneN. 1.361,64(a)361
N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.1]heptane-1-yl)C�chlorobenzenesulfonamide (obtained using A from example receipt No. 9, example No. 26, and HATU, C with TEA, I with 4 n HCl in 1,4-dioxane, N cyclopropanesulfonyl [Matrix] and TEA)N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.1]heptane-1-yl)cyclopropanesulfonylN. 1.371,56(a)373
6-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.1]heptane-1-ylamino)nicotinamide (obtained using A from example receipt No. 9, sample receipt No. 26, and HATU, C with TEA, I with 4 n HCl in 1,4-dioxane, O 6-fornicationem [Matrix] and DIEA)6-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.1]heptane-1-ylamino)nicotinamideN. 1.381,86(a)371
N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzo[d]oxazol-2-amine (obtained using O. 1 from example No. 7, step B and 2 - chlorobenzo[d]oxazol [TCI])N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzo[d]oxazol-2-amineN. 1.39of 1.82(a)400
N-((1R,2R,4S,5S)-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-mlziklopentolat (obtained using N from the sample receiving No. 15 with cyclopropanesulfonyl and TEA) N-((1R,2R,4S,5S)-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-yl)cyclopropanesulfonylN. 1.401,72(a)359
N-((1S,2R,4S,5R)-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-yl)cyclopropanesulfonyl (obtained using N from the sample receiving No. 18 with cyclopropanesulfonyl and TEA)N-((1S,2R,4S,5R)-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[3.1.0]hexane-2-yl)cyclopropanesulfonylN. 1.411,58(a)359

3,4-dichloro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (from C in example No. 6, phase A with TEA, I with 4 n HCl in 1,4-dioxane, N, 3,4-dichlorobenzene-1-sulphonylchloride)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3,4-dichlorobenzenesulfonateN. 1.422,00(a)451
3,5-dichloro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (receiving�tion C of example No. 6, Stage A with TEA, I with 4 n HCl in 1,4-dioxane, N, 3,5-dichlorobenzene-1-sulphonylchloride)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3.5-dichlorobenzenesulfonateN. 1.432,03(a)451
N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)piperidine-1-sulfonamide (from C in Example No. 6, phase A with TEA, I with 4 n HCl in 1,4-dioxane, N of the piperidine-1-sulphonylchloride)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)piperidine-1-sulfonamideN. 1.441,75(a)390
N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)morpholine-4-sulfonamide (from C in Example No. 6, phase A with TEA, I with 4 n HCl in 1,4-dioxane, N of the morpholine-4-sulphonylchloride)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)morpholine-4-sulfonamideN. 1.451,53(a)392
6-((1R,3S)-3-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentylamine)nicotinamide (obtained used�eat C from example No. 6, Stage A with TEA, I with 4 n HCl in 1,4-dioxane, O from 5-cyano-2-herperidin [Matrix])6-((1R,3S)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentylamine)-nicotinamideN. 1.46of 1.82(a)344
N-(CIS-3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopentanemethanol (obtained using GG from Example No. 14, step E, P, A from Example receipt No. 9, and HATU, C with TEA, N cyclopentanecarbonitrile [Matrix] and DIEA)N-(CIS-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopentanecarbonylN. 1.471,75(a)389
5-(CIS-3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)picolinate (obtained using GG from example No. 14, step E, P, A from example receipt No. 9, and HATU, C with TEA, d with 5-ftorpirimidinam and DIEA)5-(CIS-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-picolinateN. 1.481,73(a)359
N-(CIS-3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclops�Teal)cyclobutanemethanamine (obtained using GG from example No. 14, Stage E, P, A from example receipt No. 9, and HATU, C with TEA, N cyclobutanemethanamine [Hande] and DIEA)N-(CIS-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclobutanemethanamineN. 1.491,67(a)375
5-(CIS-3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile (obtained using GG from example No. 14, step E, P, A from example receipt No. 9, and HATU, C with TEA, d with 5-chloropyrazine-2-carbonitrile and DIEA)5-(CIS-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrileN. 1.501,74(a)360
N-(3a-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)octahydrophenanthrene-2-yl)cyclopropanesulfonyl (obtained using EE from ethyl 2-oxooctanoate-3a-carboxylate (Tetrahedron Letters(1995), 36(41), 7375-8), FF, K with Acetic anhydride, GG, A from sample receipt No. 9, and HATU, C with TEA, JJ with 6 N HCl, N cyclopropanesulfonyl [Matrix] and DIEA)N-(3a-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)octahydrophenanthrene-2-yl)cyclopropanesulfonylN. 1.511,6(a) 387
N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl and N-((1R,3S,4R)-3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (1:1) (obtained using GG from example No. 14, step F with LiOH, A from sample receipt No. 9, HATU, and TEA, C with TEA)N-((1S,3R,4S)-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N-((1R,3S,4R)-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl (1:1)N. 1.521,65(a)361
N-3,3-dimethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (obtained using EE from the sample receiving No. 25 with N,N-dibenzylamino, Y with EtOH, FF, N cyclopropylacetylene, GG with LiOH, with A sample receipt No. 9, HATU, and TEA, C with TEA)N-((1R,4S)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N- ((1S,4R)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl (1:1)N. 1.531,76(a)375
N-3,3-dimethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (obtained using EE from the sample receiving No. 25 with N,N-dibenzylamino, Y with EtOH, FF, N cyclopropylacetylene, GG with LiOH, A sample receipt No. 9, HATU, and TEA, C with TEA)N-((1R,4R)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N-((1S,4S)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl (1:1)N. 1.541,65(a)375
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl and N-((1R,3S,4R)-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (1:1) (obtained using GG from example No. 15, step F with LiOH, A sample receipt No. 9, HATU, and TEA, C with TEA)N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl (1:1)N. 1.551,75(a)375
N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]imidazo[23-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl and N-((1R,3S,4R)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (1:1) (obtained using GG from example No. 14, Stage F with LiOH, L with example No. 13, step F, HATU, and TEA, C with TEA)N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-methylcyclopentene)-cyclopropanesulfonyl and N-((1R,3R,4S)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-methylcyclopentene)-cyclopropanesulfonyl (1:1)N. 1.561,83(a)360
N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl and N-((1R,3S,4R)-3-ethyl-4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (1:1) (obtained using GG from example No. 15, step F with LiOH, L with example No. 13, step F, HATU, and TEA, with AA reagent Belleau)N-((1S,3S,4R)-3-6H-Imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-ethylcyclopentane)-cyclopropanesulfonyl and N-((1R,3R,4S)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-ethylcyclopentane)-cyclopropanesulfonyl (1:1)N. 1.571,93(a)374
N-3-isopropyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (obtained using BB from ethyl 4-methyl-3-oxopentanoate with methyl 4-chloro-3-oxobutanoate, CC of sodium iodide, DD, EE, N,N-dibenzylamino, FF, N cyclopropylacetylene, GG with LiOH, Primera receipt No. 9, HATU, and TEA, C with TEA)N-((1S,3S,4R)-3-isopropyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N- ((1R,3R,4S)-3-isopropyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl (1:1)N. 1.581,79(a)389

N-3-isopropyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (obtained using BB from ethyl 4-methyl-3-oxopentanoate with methyl 4-chloro-3-oxobutanoate, CC of sodium iodide, DD, EE, N,N-dibenzylamino, FF, N cyclopropylacetylene, GG with LiOH, A sample receipt No. 9, HATU, and TEA, C with TEA)N-((1S,3R,4S)-3-isopropyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N-((1R,3S,4R)-3-isopropyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl (1:1)N. 1.591,87(a)389
N-3-isopropyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (obtained using BB from ethyl 4-methyl-3-oxopentanoate with methyl 4-chloro-3-oxobutanoate, CC of sodium iodide, DD, EE SP,N-dibenzylamino, FF, N cyclopropylacetylene, GG with LiOH, A sample receipt No. 9, HATU, and TEA, C with TEA)N-((1S,3S,4S)-3-isopropyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N-((1R,3R,4R)-3-isopropyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonylN. 1.601,90(a)389
N-((1S,3R,4S)-3-ethyl-4-(3-methyl-6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl and N-((1R,3S,4R)-3-ethyl-4-(3-methyl-6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (1:1) (obtained using N from the sample receiving no FF.1 and cyclopropylacetylene with TEA, GG with LiOH, L sample receipt No. 24, HATU, and TEA, AA with Lawesson reagent)N-((1S,3R,4S)-3-ethyl-4-(3-methyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N-((1R,3S,4R)-3-ethyl-4-(3-methyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl (1:1)N. 1.611,93(a)388
Cyclopropanesulfonyl acid {(3R,7S)-5-[6-(tosyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl]-adamantane-2-yl}-amide (obtained using A from example obtaining � 9 and example of receiving No. 22, C with DIEA, JJ, N cyclopropylacetylene [Matrix] and DIEACyclopropanesulfonyl acid [(3R,7S)-5-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)-adamantane-2-yl]amideN. 1.621,70(a)413
4-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)benzosulfimide (obtained using A from (1S,3R)-3-atsetamido-2,2-dimethylcyclobutane acid [obtained as described in Tetrahedron: Asymmetry 2008, 19, 302-308] and example No. 9 with EDC, C with DIEA, JJ, N with 4-cyanobenzoyl-1-sulphonylchloride [Maybridge] and DIEA)4-(N-((1R,3S)-2,2-Dimethyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)sulfamoyl)-benzamideN. 1.631,57(a)440

5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)pyridine-2-sulfonamide (example No. 21)6-(N-((1R,3S)-2,2-Dimethyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)sulfamoyl)-nicotinamideN. 1.641,45(a)441
5-cyan�-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)pyridine-2-sulfonamide (example No. 21) 5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)pyridine-2-sulfonamideN. 1.651,81(a)423
2-cyano-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using I from the sample receiving no C. 1, N 2-cyanobenzenesulfonyl and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2-cyanobenzenesulfonylN. 1.661,24(d)408
3-(deformedarse)-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using I from the sample receiving no C. 1, N 3-(deformedarse)benzosulphochloride and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-(deformedarse)-benzosulfimideH. 1.671,32(d)449
3,4,5-Cryptor-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with N 3,4,5-triterpenols�vanilloids and DIEA) N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3,4,5-tripersonalityN. 1.681,34(d)437

5-chloro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)thiophene-2-sulfonamide (obtained using the I in the example of obtaining the No. 1 C., with N 5-chlorothiophene-2-sulphonylchloride and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-5-chlorothiophene-2-sulfonamideN. 1.691,33(d)423
5-(Dimethylamino)-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)naphthalene-1-sulfonamide (obtained using the I in the example of obtaining the No. 1 C., and N cancellaria and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-5-(dimethylamino)naphthalene-1-sulfonamideN. 1.701,36(d)476
2,2,4,6,7-Pentamethyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,3-dihydrobenzofuran-5-sulfonamide (obtained used�I eat from the example of obtaining the No. 1 C., N 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulphonylchloride and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-sulfonamideN. 1.711,41(d)495
4-(deformedarse)-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-(deformedarse)benzosulphochloride and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-(deformedarse)-benzosulfimideH. 1.721,32 (d)449
4-bromo-3-fluoro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using I from premenapause No. C. 1, N with 4-bromo-3-forbindelsesfanebladet and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-bromo-3-formentionedH. 1.731,33(d)479
3-chloro-2-fluoro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclops�Teal)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 3-chloro-2-forbindelsesfanebladet and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-chloro-2-formentionedH. 1.741,31(d)435
3-methoxy-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with N 3-methoxybenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-methoxybenzenesulfonamideN. 1.751,29 (d)413
4-acetyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-acetylbenzenesulfonyl and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-acetylbenzenesulfonylN. 1.761.26 in (d)425
3-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N � m-toluensulfonate and DIEA) N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-methylbenzenesulfonamideH. 1.771,30 (d)397
3.5-debtor-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 3.5-differentialthreshold and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3.5-diftorbenzofenonomN. 1.781,31 (d)419
3-chloro-2-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with N 3-chloro-2-methylbenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-chloro-2-methylbenzenesulfonamideH. 1.791,35(d)431
3,5-dimethyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 3.5-dimethylbenzenesulfonamide�m and DIEA) N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3.5-dimethylbenzenesulfonamideN. 1.801,31 (d)411

N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,5-dichlorobenzenesulfonate 1,31(d)
3-fluoro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with N 3-forbindelsesfanebladet and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-formentionedH. 1.811,29(d)401
3-chloro-4-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with N 3-chloro-4-methylbenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-chloro-4-methylbenzenesulfonamideH. 1.821,34(d)431
2,4-dichloro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using I from the sample receiving�Oia No. 1 C., N with 2,4-dichlorobenzenesulfonyl and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,4-dichlorobenzenesulfonicN. 1.831,35 (d)451
2,5-debtor-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with 2.5 N-differentialthreshold and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,5-diftorbenzofenonomN. 1.841,29 (d)419
4-bromo-3-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-bromo-3-methylbenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-bromo-3-methylbenzenesulfonamideH. 1.851,36 (d)475
2,3,4-Cryptor-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using I from example p�radiation No. 1 C., N with 2,3,4-triftormetilfullerenov and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,3,4-tripersonalityN. 1.861,31 (d)437
2,6-debtor-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., and N is 2,6-differentialthreshold and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,6-diftorbenzofenonomN. 1.871,28 (d)419
4-(methyl-sulfonyl)-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-(methyl-sulfonyl)benzosulphochloride and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-(methyl-sulfonyl)-benzosulfimideH. 1.881,23 (d)461
N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)econsultant (obtained using I from when�EPA's receiving No. 1 C., N ethanolammonium and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-econsultantH. 1.891,20 (d)335
2,4-debtor-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-i][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 2,4-differentialthreshold and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,4-diftorbenzofenonomN. 1.901,30(d)419
N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)propane-1-sulfonamide (obtained using I from the sample receiving no C. 1, N 1-propanesulfonate and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)propane-1-sulfonamideH. 1.911,23 (d)349
2,5-dichloro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with 2.5 N-dichlorobenzenesulfonate and DIEA)N. 1.921,35 (d)451
1-phenyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methanesulfonamide (obtained using the I in the example of obtaining the No. 1 C., N with α-toluensulfonate and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-1-phenylmethanesulfonylN. 1.931,28(d)397
4-chloro-3-nitro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-chloro-3-nitrobenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-chloro-3-nitrobenzenesulfonamideN. 1.941,33 (d)462
4-nitro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-nitrobenzenesulfonamide and DIEA)N-((1S,3R)-3-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-nitrobenzenesulfonamide N. 1.951,32 (d)428
N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)thiophene-2-sulfonamide (obtained using the I in the example of obtaining the No. 1 C., N with thiophene-2-sulphonylchloride and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)thiophene-2-sulfonamideN. 1.961.26 in(d)389
5-fluoro-2-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with N 5-fluoro-2-methylbenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-Imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-5-fluoro-2-methylbenzenesulfonamideH. 1.971,32(d)415
3-nitro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with N 3-nitrobenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-nitrobenzenesulfonamide N. 1.981,29 (d)428
N-(4-(N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)sulfamoyl)phenyl)acetamide (obtained using the I in the example of obtaining the No. 1 C., N, N-acetylsulfapyridine and DIEA)N-(4-(N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)sulfamoyl)-phenyl)acetamideN. 1.991,19(d)440
2-fluoro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using I from the sample receiving no C. 1, N 2-forbindelsesfanebladet and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2-formentionedH. 1.1001,25(d)401
5-chloro-2-fluoro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 5-chloro-2-forbindelsesfanebladet and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-5-chloro-2-formentionedH. 1.101435
3-fluoro-4-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., with N 3-fluoro-4-methylbenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-fluoro-4-methylbenzenesulfonamideH. 1.1021,30(d)415
4-fluoro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-forbindelsesfanebladet and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-formentionedH. 1.1031,27(d)401
N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)naphthalene-1-sulfonamide (obtained using I from the sample receiving no C. 1, N 1-naphthalenesulfonate and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)naphthalene-1-sulfonamideH. 1.1041,30(d) 433
N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)naphthalene-2-sulfonamide (obtained using I from the sample receiving no C. 1, N 2-naphthalenesulfonate and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)naphthalene-2-sulfonamideN. 1.1051,31(d)433
4-chloro-2-fluoro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-chloro-2-forbindelsesfanebladet and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-chloro-2-formentionedH. 1.1061,31(d)435
4-fluoro-2-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using the I in the example of obtaining the No. 1 C., N with 4-fluoro-2-methylbenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-fluoro-2-methylbenzenesulfonamideH. 1.1071,29(d) 415
2-fluoro-5-methyl-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimide (obtained using I from the sample receiving no C. 1, N 2-fluoro-5-methylbenzenesulfonamide and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2-fluoro-5-methylbenzenesulfonamideH. 1.1081,28(d)415
2,5-chloro-N-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)thiophene-3-sulfonamide (obtained using the I in the example of obtaining the No. 1 C., with 2.5 N-dichlorothiophene-3-sulphonylchloride and DIEA)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2,5-dichlorothiophene-3-sulfonamideH. 1.1091,34(d)457

General procedure I: Acidic cleavage of the Boc-protected amine

To a solution of Boc-protected amine (preferably 1 equiv) in an organic solvent (such as DCM, 1,4-dioxane or MeOH) was added TFA or HCl (preferably 4 n HCl in 1,4-dioxane, 2-35 equivalents, preferably 2 to 15 equivalents). The reaction mixture was stirred at a temperature of about 20-100°C (preferably at room temperature �about 60°C) for about 1-24 hours (preferably about 1-6 hours). Optional additional amount of TFA or HCl (preferably 4 n HCl in 1,4-dioxane, 2-35 equivalents, preferably 2-15 equivalents) can be added to the obtained reaction mixture in cases where according to TLC, LC/MS, or HPLC, the reaction is not completed. Then the reaction continued at room temperature or optionally heated up to about 100°C (preferably heated at a temperature of about 60°C) for about 1-24 hours (preferably about 1-6 hours). If the resulting reaction mixture is present in the solid product obtained reaction mixture can be filtered, and the obtained solid product is washed with an organic solvent, such as 1,4-dioxane or Et2O. the resulting solid portion is then optionally dried under reduced pressure. Alternatively, the filtered material can be divided between an organic solvent (such as EtOAc, DCM, or 1,4-dioxane) and an aqueous solution of a base (such as saturated aqueous solution of NaHCO3ora saturated aqueous solution of Na2CO3preferably, a saturated aqueous solution of NaHCO3). The resulting mixture was stirred for about 1-5 hours (preferably about 1 hour). All insoluble material is collected by filtration and washed with a suitable solvent (such as cold water and/or Et2O) then the optional�individual dried under reduced pressure. The organic layer is optionally washed with brine, dried over anhydrous Na2SO4or MgSO4then decanted or filtered, before concentrating under reduced pressure, obtaining the target compound. Alternatively, the reaction mixture was separated between alkaline aqueous solution such as a solution of Na2CO3, NaHCO3or NaOH, preferably NaOH) and an organic solvent (such as EtOAc or DCM). The water layer is then optionally extracted with additional organic solvent, such as EtOAc or DCM. The combined organic layers are optionally washed with brine, dried over anhydrous Na2SO4or MgSO4then decanted or filtered, before concentrating under reduced pressure, obtaining the target compound. Optionally, the crude material is purified using chromatography, thorough trituration with an appropriate solvent or crystallization of one or more solvents, obtaining the target compound.

Example No. I. 1.1 Hydrochloride (R)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

In a round bottom flask is loaded (R)-tert-butyl 3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate (0.92 g, 2.68 mmol; obtained using A from example receipt No. 9, (R)-1-(t�et-butoxycarbonyl)piperidine-3-carboxylic acid [CNH Technologies], EDC and TEA and E, using SOCl2TEA and a saturated aqueous solution of Na2CO3), HCl (4 n in 1,4-dioxane, a 2.9 ml, 11.5 mmol), and 1,4-dioxane (20 ml). The obtained reaction mixture is heated at a temperature of about 60° C for about 3 hours. The obtained reaction mixture was cooled to room temperature, then filtered under vacuum and washed with Et2O (35 ml). The solid product is then dried for about 16 hours in a heated vacuum oven (at a temperature of about 70°C), obtaining hydrochloride (R)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine in a solid brown color (0,69 g, 82%): LC/MS (table 2, Method a) Rt=0,45 min; MS m/z 243 (M+H)+.

0,67(a)
TABLE I. 1
Examples of the preparation using General procedure I
Boc-protected amineProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
tert-butyl (1S,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine, (obtained using A from (1S,3S)-3-(tert-butoxycarbonylamino)cyclopentane-carboxylic acid [Acros] and the example of receiving No. 9, (E)hydrochloride (1S,3S)--(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine I. 1.20,50 (d)243
(S)-tert-butyl 3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate, (obtained using A from example receipt No. 3 and (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, EDC•HCl, and TEA, C with DIEA, and H)hydrochloride (S)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineI. 1.30,86(a)243
tert-butyl TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutylmethyl, (obtained using A 3-(tert-butoxycarbonylamino)CYCLOBUTANE-carboxylic acid [AMRI] and the example of receiving No. 9, (E)TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutanoneI. 1.40,70(a)229
(R)-tert-butyl 3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)pyrrolidin-1-carboxylate, (obtained using A from (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-carboxylic acid [Astatech] and the example of receiving No. 9, (E)hydrochloride (R)-1-(pyrrolidin-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineI. 1.5229
tert-butyl 4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate, (obtained using Y from 4-methylnicotinic acid, R, P, S, T and G in the example of obtaining the No. 9)hydrochloride of 1-(4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineI. 1.61,01(a)257
(S)-tert-butyl 3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)pyrrolidin-1-carboxylate, (obtained using A from example receipt No. 9, (S)-1-(tert-butoxycarbonyl)pyrrolidin-3-carboxylic acid [CHEM-IMPEX] and EDC•HCl, E with TEA and NaOH)hydrochloride (S)-1-(pyrrolidin-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineI. 1.70,85 (a)227
tert-butyl 2-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)ethylcarbamate, (obtained using L from example No. 13, step F and 3-(tert-butoxycarbonylamino)propane acid with HATU and TEA, with AA reagent Belleau, H, I with HCl (g))hydrochloride of 2-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)ethanamineI. 1.80,84(d)202

tert-butyl-2-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate, (obtained using R from ethyl 2-methylnicotinate, P, S, T, G in the example of obtaining the No. 9)hydrochloride of 1-(2-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineI. 1.90,81(a)257tert-butyl 3-methyl-5-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate, (obtained using R from methyl 5-methylnicotinate [Alfa], P, S, T, G in the example of obtaining the No. 9)hydrochloride of 1-(5-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineI. 1.101,05(a)257

General procedure J: removal of the protective groups with Cbz-protected amine

A mixture of O-benzylcarbamoyl (preferably 1 equivalent) and 10% Pd-on-carbon (0.05 to 0.30 equivalent, preferably 0.10 equivalent) in proton solvent (such as MeOH, EtOH, AcOH, preferably EtOH) is shaken or stirred in an atmosphere of hydrogen at about 103-690 kPa (preferably about 414 kPa) for about 4-48 hours, preferably, about 4-16 hours) at room temperature. The reaction mixture was filtered through celite may® and concentrate� to dryness under reduced pressure. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure J

Example # J. 1.1: 1-(piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Benzyl 4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate (0,34 g of 0.90 mmol, example # 2, step A) and 10% Pd-on-charcoal (0.10 g, 0.09 mmol) in MeOH (30 ml) is shaken in an atmosphere of hydrogen at about 414 kPa for about 5 hours at room temperature. The reaction mixture was filtered through celite may® and concentrated under reduced pressure to constant weight to obtain 1-(piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine in a solid yellow color (0.18 g, 77%): LC/MS (table 2, Method a) Rt=0,70 min; MS m/z: 243 (M+H)+.

TABLE J. 1
Examples of the preparation using General procedure J
Cbz-protected amineProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
Benzyl 4-methyl�-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate (obtained using R from 4-methylnicotinic acid, Q, W and B from the sample receiving No. 3)1-(4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine [main product]J. 1.21,03 (a)257
Benzyl 4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate (obtained using R from 4-methylnicotinic acid, Q, W and B from the sample receiving No. 3)1-(1,3-dimethylpiperidin-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pertinacity [secondary product]J. 1.30,71(a)271

Benzyl CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutylmethyl, (obtained using the Q of the hydrochloride of 3-aminocyclohexanecarboxylic acid [enamin], A from sample receipt No. 9, (E)CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutanoneJ. 1.40,56(a)229

General procedure K: Obtaining an amide of an activated acid and amine

In a round bottom flask containing the amine or amine salt (preferably 1 equiv) in an organic solvent(such as DCM, DMF or 1,4-dioxane, preferably DCM or DMF), added an organic base, such as DIEA or TEA (0-5 equivalents, preferably 3 equivalents). The obtained reaction mixture is optionally homogenized by heating or treating with ultrasound (preferably processing ultrasound). To the resulting reaction mixture was added the activated acid (such as a derivative performancemore ester or acid chloride). The resulting mixture was stirred at room temperature for about 1-24 hours (preferably about 16 hours). The obtained reaction mixture was directly purified using chromatography. Alternatively, the solvent was concentrated under reduced pressure, or add a suitable organic solvent (such as EtOAc or DCM) and the resulting solution washed with water or saline. The layers were separated, and optional organic solution is dried over anhydrous Na2SO4orMgSO4, filtered or decanted, and concentrated to dryness under reduced pressure. The raw material is optionally purified by precipitation, crystallization, and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure K

Example N ° K. 1.1: N-(CIS-4-(6H-imidazo[2,3-e][1,2,4]triazo�about[4,3-a]pyrazine-1-yl)cyclohexyl)-2-cyanoacetamide

To a suspension of the hydrochloride of the CIS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (0,106 g, 0,206 mmol, Example # D. 1) in DCM (4 ml) was added TEA (0,086 ml of 0.62 mmol). The obtained reaction mixture was treated with ultrasound until then, until the reaction mixture becomes homogeneous. To the reaction solution was added perftoralkil 2-cyanoacetate (0,078 g, 0,31 mmol, example No. 6). The resulting solution was stirred at room temperature for about 16 hours. The crude reaction mixture was purified using a chromatographic treatment on silica gel (40 g), performing a gradient elution of 0-20% EtOAc in DCM and then further purified using HPLC with reversed phase (table 2, Method e) to give N-(CIS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)-2-cyanoacetamide with 3 equivalents of NH4OAc as excipient (0.025 g, 22%). LC/MS (table 2, Method a) Rt= 1,33 min; MS m/z: 324 (M+H)+.

/tr>
TABLE K. 1
Examples of the preparation of perftoralkil 2-cyanoacetate (Example No. 6) using General procedure K
AminProductExample No.Rtmin (table 2, Method) m/z ESI+ (M+H)+
hydrochloride (1R,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (example No. D. 1.2)N-((1R,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2-cyanoacetamideK. 1.2of 1.27 (a)310
hydrochloride TRANS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (example No. D. 1.3)N-(TRANS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)-2-cyanoacetamideK. 1.31,35(a)324
hydrochloride (1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (example No. D. 1.4)
N-((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2-cyanoacetamideK. 1.41,39(a)310
hydrochloride ((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (example # 6, step C)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2-cyanoacetamideK. 1.51,38(a)310
hydrochloride (1S,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (example No. I. 1.2)N-((1S,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-2-cyanoacetamideK. 1.61,05(d)310

General procedure L: Obtaining an amide of carboxylic acid and amine

To the solution or suspension of the carboxylic acid (1-5 equivalents, preferably 1.5 equivalents) and amine (1-5 equivalents, preferably 1 equivalent) in an organic solvent (such as DCM, DCE, THF, or 1,4-dioxane, preferably DCM) is added binding peptide reagent (such as BOP-Cl, IBCF, HATU or EDC.HCl, preferably EDC.HCl, 1-10 equivalents, preferably 1 equivalent), a base (such as TEA, DIEA, or pyridine, preferably TEA, 0 to 20 equivalents, preferably 2 equivalents) and HOBt (0-5 equivalents, preferably 0-1 equivalent if they use EDC.HCl). The obtained reaction mixture was then stirred at room temperature for from about 15 minutes to 24 hours (preferably about 16 hours). The obtained reaction mixture is then treated using one of the following methods. Method 1: the reaction mixture Obtained is diluted with water or a saturated aqueous solution of NaHCO3. The layers were separated. Water with�Oh optionally extracted with additional organic solvent, such as EtOAc or DCM. The organic layer (or merged layers) optionally washed with water, a saturated aqueous solution of NaHCO3and/or brine, dried over anhydrous MgSO4or Na2SO4, filtered or decanted, and concentrated under reduced pressure. Method 2: the Crude reaction mixture was filtered through a layer of silica gel, washing with an appropriate solvent (such as EtOAc, MeOH or DCM, preferably MeOH) and concentrated under reduced pressure. Method 3: the Crude reaction mixture was directly purified using chromatography without treatment. In all cases the raw material is optionally further purified by precipitation, crystallization and/or grind thoroughly with a suitable solvent or solvents, and/or using chromatography, obtaining the target compound.

Illustration of General procedure L

Example No. L. 1.1: (R)-3-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)-3-oxopropanenitrile

To a suspension of the hydrochloride of (R)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (to 0.074 g, 0,265 mmol; example No. I. 1.1) and 2-tsianuksusnogo acid (0,034 g, 0,398 mmol) in DMF (3 ml) was added HOBt (0,041 g, 0,265 mmol), EDC.HCl (0,051 g, 0,265 mmol) and DIEA (0,093 ml of 0.531 mmol). The obtained reaction mixture was stirred at room temperature for about 16 hours. Sy�th reaction mixture was purified, using HPLC with reversed phase (table 2, Method f). The appropriate fraction was concentrated in vacuo and lyophilizer to obtain (R)-3-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)-3-oxopropanenitrile in the form of white solids (0,052 g, 63%): LC/MS (table 2, Method a) Rt=1,30 min; MS m/z: 310 (M+H)+.

TABLE L. 1
Examples of the preparation of (R)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.1) using General procedure L
Carboxylic acidProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
3,3,3-triterpenovy acid(R)-1-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)-3,3,3-cryptochrome-1-itL. 1.21,53 (a)353
1-cyanocyclohexane-carboxylic acid(R)-1-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carbonyl)cyclopropanecarbonitrileL. 1.31,48(a) 336
(R)-2-oxothiazolidine-4-carboxylic acid
(R)-4-((R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carbonyl)thiazolidin-2-heL. 1.4of 1.33(a)372
4-cyanobenzoic acid(R)-4-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carbonyl)benzonitrileL. 1.51,53(a)372

TABLE L. 2
Examples of the preparation of CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (obtained using A from example receipt No. 3 and CIS-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid [AMRI]; (F) using General procedure L
Carboxylic acidProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
2-tsianuksusnym acidN-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)-2-cyanoacetamide L. 2.11,40 (a)324

Acetic acidN-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)acetamideL. 2.21,32(a)299

TABLE L. 3
Additional examples of the preparation of 2-tsianuksusnogo acid using General procedure L
AminProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
(S)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.3)(S)-3-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)-3-oxopropanenitrileL. 3.11,34 (a)310
1-(4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # J. 1.2)
3-(4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)-3-oxopropanenitrile L. 3.21,42(a)342
CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutanone (example No. J. 1.4)N-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)-2-cyanoacetamideL. 3.31,23(a)296
hydrochloride TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutanone (example No. I. 1.4)N-(TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)-2-cyanoacetamideL. 3.41,05(a)296
hydrochloride (R)-1-(pyrrolidin-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Example # I. 1.5)(R)-3-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)pyrrolidin-1-yl)-3-oxopropanenitrileL. 3.51,00(a)296
hydrochloride (S)-1-(pyrrolidin-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Example # I. 1.7)(S)-3-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)pyrrolidin-1-yl)-3-oxopropanenitrileL. 3.61,19(a) 296

(R)-1-(piperidine-3-yl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine, (obtained using L from example No. 13, step F and (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, HATU and TEA, with AA reagent Belleau, H, I with 4 n HCl in 1,4-dioxane)(R)-1-(3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)piperidine-1-carbonyl)-cyclopropanecarbonitrileL. 3.7to 1.61(a)335
hydrochloride of 2-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)ethanamine (example No. I. 1.8)N-(2-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)ethyl)-1-cyanocyclohexane-carboxamideL. 3.81,39(a)295
hydrochloride of 1-(5-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.10)3-(3-methyl-5-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)-3-oxopropanenitrileL. 3.91,52(a)324
hydrochloride of 1-(4-demerol-3-yl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (example # 13, step (K)3-(3-(6H-imidazo[1,5-a]imidazo[2,3-e]PI�Azin-1-yl)-4-demerol-1-yl)-3-oxopropanenitrile L. 3.101,42(a)323

TABLE L. 4
Examples of the preparation of 1-cyanocyclohexane acid using General procedure L
AminProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
hydrochloride ((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methanamine (example n ° F. 1.1)N-(((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methyl)-1-cyanocyclohexaneL. 4.11,56 (a)350
hydrochloride of 1-(4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.6)
1-((3S,4S)-4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carbonyl)cyclopropanecarbonitrileL. 4.2to 1.61(a)350
hydrochloride of 1-(4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I..6) 1-((3R,4R)-4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carbonyl)cyclopropanecarbonitrileL. 4.3to 1.61(a)350
hydrochloride of 1-(4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.6)1-((3S,4R)-4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carbonyl)cyclopropanecarbonitrileL. 4.4to 1.61(a)350
hydrochloride of 1-(4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.6)1-((3R,4S)-4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carbonyl)cyclopropanecarbonitrileL. 4.5to 1.61(a)350

8-((3S,4S)-4-demerol-3-yl)-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine and 8-((3R,4R)-4-demerol-3-yl)-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine (obtained using H from example receipt No. 19)3-((3S,4S)-3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)-4-demerol-1-yl)-3-oxopropanenitrile and -((3R,4R)-3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-yl)-4-demerol-1-yl)-3-oxopropanenitrile L. 4.61,35(a)323
hydrochloride of 1-(2-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.9)1-(2-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carbonyl)cyclopropanecarbonitrileL. 4.71,57(a)350

TABLE L. 5
Examples of preparation of TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (Example n ° F. 1.2) using General procedure L
Carboxylic acidProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
2-tsianuksusnym acidN-(TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)-2-cyanoacetamideL. 5.11,42 (a)324
Acetic acidN-(TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)acetamide L. 5.2of 1.33(a)299

TABLE L. 6
An example of getting out of the hydrochloride of (R)-1-(1-methylpiperazin-2-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (obtained using A from example receipt No. 9 and example of receiving No. 16, C with TEA, H, I with 4 n HCl in 1,4-dioxane) using General procedure L
Carboxylic acidProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
2-tsianuksusnym acid(R)-3-(4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperazine-1-yl)-3-oxopropanenitrileL. 6.11,30 (a)325

General procedure M: obtain a urea from an amine and carbamoylated

The flask containing the amine or amine salt (1 equivalent) in an organic solvent (such as THF or 1,4-dioxane, preferably THF) is added a base (such as DIEA or TEA, preferably TEA (3-5 equivalents, preferably 3 equivalents) and stirred at room temperature for about 0-30 minutes (preferably�and is only about 5 minutes) then add carbamoylated (0.5 to 2 equivalent, preferably 0.75 equivalent). The resulting mixture was stirred at a temperature of about 0-90°C (preferably about 60-65°C) for about 2-24 hours (preferably about 16 hours). The obtained reaction mixture is allowed to cool to room temperature. The organic solvent is optionally removed under reduced pressure. The raw material is divided between an organic solvent (such as EtOAc or DCM) and water, an aqueous solution of a base (such as saturated aqueous solution of NaHCO3) or saline. The layers were separated, and the organic layer is optionally washed with water, an aqueous solution of a base (such as saturated aqueous solution of NaHCO3and/or brine, dried over anhydrous Na2SO4orMgSO4, filtered and concentrated under reduced pressure, obtaining the target compound. The raw material is optionally purified by precipitation, crystallization or grind thoroughly with a suitable solvent or solvents, or by chromatography, obtaining the target compound.

Illustration of General procedure M

Example No. 1.1: N-((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)pyrrolidin-1-carboxamide

In a round bottom flask was charged hydrochloride (1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclops�of nanamin (0,150 g, 0,62 mmol, example # D. 1.4) and TEA (of 0.26 ml, 1.9 mmol) in THF (5.7 ml). The obtained reaction mixture was stirred for about 5 minutes at room temperature before adding pyrrolidin-1-carbonylchloride (0,052 ml, 0.46 mmol). The reaction mixture is heated at a temperature of about 60°C for about 16 hours, cooled to room temperature, and concentrated under reduced pressure. The crude product was dissolved in DCM (40 ml) and washed with a saturated aqueous solution of NaHCO3(20 ml), brine (20 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting material was purified using HPLC with reversed phase (table 2, Method i). The appropriate fractions were pooled, the resulting solvent was mostly removed under reduced pressure, and the solid product was filtered and dried by lyophilization, yielding N-((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)pyrrolidin-1-carboxamide (0,018 g, 8%): LC/MS (table 2, Method a) Rt=1,40 min; MS m/z 340 (M+H)+.

TABLE M. 1
Examples of the preparation of pyrrolidin-1-carbonylchloride using General procedure M
AminProductExample No.Rtmi� (table 2, Method)m/z ESI+ (M+H)+
hydrochloride (R)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.1)(R)-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)(pyrrolidin-1-yl)methanonM. 1.21,44 (a)340
hydrochloride (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (example # 6, step C)N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)pyrrolidin-1-carboxamideM. 1.31,47(a)340

General procedure N: Obtain the sulfonamide from an amine

To a mixture or solution (preferably a solution) amine or amine salt (preferably 1 equivalent) in a solvent such as THF, DCM or DMF (preferably DMF) is added an organic base such as TEA or DIEA (1-10 equivalents, preferably 2-4 equivalents) or an aqueous solution of a base such as saturated aqueous solution of NaHCO3(5 to 20 equivalents, preferably 5 to 10 equivalents) (preferably, an organic base) and sulphonylchloride (0.85 to 3 equivalents, preferably 1-1 .5 equivalents). The reaction mixture per�mesilat in-10-80°C (preferably, at room temperature) for about 0.5-72 hours (preferably about 1-2 hours). Optional add additional base (1-10 equivalents) and/or sulphonylchloride (0,4-2 equivalent) at any time during the reaction time. The reaction mixture is treated using one of the following methods. Method 1: the Reaction mixture was diluted with water and extracted with an organic solvent such as DCM or EtOAc. The combined organic layers are optionally washed with brine, dried over anhydrous Na2SO4orMgSO4, filtered or decanted, and concentrated under reduced pressure. Method 2: the Crude reaction mixture was purified directly using preparative HPLC or after addition of an organic solvent, such as MeOH or DMF or water superyoung solution, such as 50 mm NH4OAc with preliminary concentration (or without) the resulting mixture under reduced pressure. Method 3: the Reaction mixture is diluted with an organic solvent such as DCM or EtOAc, and washed with water and/or saline solution. The organic layer is optionally dried over anhydrous Na2SO4orMgSO4, filtered or decanted, and concentrated under reduced pressure. Method 4: the Reaction mixture was diluted with water and the resulting solid material �fleecing by vacuum filtration. In all cases the raw material is optionally purified by precipitation, crystallization and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure N

Example No. No. 1.1: N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

To a mixture of the hydrochloride salt of (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (0.300 g, 0,952 mmol, example # 6, step C) in DMF (9 ml) was added TEA (0,462 ml of 3.33 mmol) and cyclopropanesulfonyl (0,097 ml, 0.95 mmol). After about 1.5 hours at room temperature the reaction mixture was diluted with water (10 ml) and extracted with DCM (3×15 ml). The combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Raw material is added MeOH (~50 ml) and a small number of nerastvorimogo material (<0.01 g) was removed by filtration. To the filtrate was added a silica gel (2 g), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was purified by chromatography on silica gel processing, carrying out stepwise gradient elution, DCM/MeOH/NH4OH 990:9:1 to 980:18:2, receiving the solid is not quite �logo color, which is dried in a vacuum thermostat at a temperature of about 70°C. the Solid product was dissolved in hot MeOH, filtered hot to remove rainfall, and then the resulting filtrate was treated with ultrasound during cooling, getting thin slurry, which was concentrated under reduced pressure and dried in a vacuum thermostat at a temperature of about 100°C, yielding N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (0,21 g, 64%): LC/MS (table 2, Method a) Rt=1,51 min; MS m/z: 347 (M+H)+.

TABLE N. 1
Examples of the preparation using cyclopropanesulfonyl and General procedure N
AminProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
(R)-1-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)pyrrolidin-3-amine (obtained using U from the sample receiving No. 9 and example of receiving No. 10, V, H)(R)-N-(1-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)pyrrolidin-3-yl)cyclopropanesulfonylN. 1.21,42 (a)348
hydrochloride TRANS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (Example No. D. 1.3)N-(TRANS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)-cyclopropanesulfonylN. 1.31,24(a)361
hydrochloride CIS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (Example No. D. 1.1)N-(CIS-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)cyclopropanesulfonylN. 1.41,54(a)361
hydrochloride (1R,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (Example No. D. 1.2)N-((1R,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonylN. 1.51,20(a)347
hydrochloride (1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (Example No. D. 1.4)N-((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonylN. 1.61,48(a)347
N-((1S,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonylN. 1.71,11(d)347
the acetate of TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (Example n ° F. 1.2)N-(TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)cyclopropanesulfonylN. 1.81,34(a)361
Hydrochloride (R)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Example # I. 1.1)(R)-1-(1-(cyclopropylmethyl)piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 1.91,51(a)347
1-(4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Example # J. 1.2)1-(1-(cyclopropanesulfonyl)-4-demerol-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 1.101,62(a)361
CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-operatin-1-yl)cyclobutanone (Example No. J. 1.4) N-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)cyclopropanesulfonylN. 1.111,43(a)333
TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutylamine hydrochloride (Example No. I. 1.4)N-(TRANS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)cyclopropanesulfonylN. 1.121,25(a)333
hydrochloride (R)-1-(pyrrolidin-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Example # I. 1.5)(R)-1-(1-(cyclopropanesulfonyl)pyrrolidin-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 1.131,37(a)333
hydrochloride ((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methanamine (Example n ° F. 1.1)N-(((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)methyl)-cyclopropanesulfonylN. 1.141,59(a)361
hydrochloride (S)-1-(pyrrolidin-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Example # I. 1.7) (S)-1-(1-(cyclopropanesulfonyl)pyrrolidin-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 1.151,49(a)333
(1S,3R,4R)-4-ethyl-3-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone and (1R,3S,4S)-4-ethyl-3-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (obtained using A from example receipt No. 9 and example of receiving No. 12, HATU, and TEA, C with TEA)N-((1S,3R,4R)-4-ethyl-3-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-cyclopropanesulfonyl and N-((1R,3S,4S)-4-ethyl-3-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonylN. 1.161,68(a)389
hydrochloride (R)-1-(1-methylpiperazin-2-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (obtained using A from example receipt No. 9 and example of receiving No. 16, HATU, and TEA, C with TEA, H, I with 4 n HCl in 1,4-dioxane)(R)-1-(4-(cyclopropanesulfonyl)-1-methylpiperazin-2-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 1.171,55(a)362
(S)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (Example # I. 1.3) (S)-1-(1-(cyclopropylmethyl)piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 1.181,57(a)347

TABLE N. 2
Examples of the preparation of the hydrochloride salt of (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (example # 6, step C) using General procedure N
SulphonylchlorideProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
Cyclobutanemethanamine [Hande]N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclobutanemethanamineN. 2.11,68 (a)361
CyclopentanophenanthreneN-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopentanemethanolN. 2.21,65(a)375
4-(trifluoromethyl)benzene-1-sulphonylchloride [Lancaster] N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-(trifluoromethyl)benzosulfimideN. 2.31,95(a)451
3-(trifluoromethyl)benzene-1-sulphonylchlorideN-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-(trifluoromethyl)benzosulfimideN. 2.41,93(a)451
4-chlorobenzenesulfonamideN-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-chlorobenzenesulfonamideN. 2.51,88(a)417
3-chlorobenzenesulfonamideN-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-chlorobenzenesulfonamideN. 2.61,85(a)417
BenzosulphochlorideN-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)benzosulfimideN. 2.71,71(a)383
Cyclohexanesulfonic�chlorid N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclohexanesulfonicN. 2.81,28(d)389

4-cyanobenzoyl-1-sulphonylchloride [Maybridge]N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-4-cyanobenzenesulfonylN. 2.91,78(a)408
3-cyanobenzoyl-1-sulphonylchloride [Maybridge]N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-cyanobenzenesulfonylN. 2.101,74(a)408
3-chloro-4-torbenson-1-sulphonylchloride [Lancaster]N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)-3-chloro-4-formentionedN. 2.111,91(a)435

TABLE N. 3
Examples of the preparation of the hydrochloride of (S)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (derived from the IP�altanium A from the example of getting # 3 and (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, EDC•HCl, and TEA, C, H, and I) using General procedure N
SulphonylchlorideProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
Propane-1-sulphonylchloride(S)-1-(1-(propylsulfonyl)piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 3.1to 1.61 (a)349
Benzosulphochloride(S)-1-(1-(Phenylsulfonyl)piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 3.21,76(a)383
4-cyanobenzoyl-1-sulphonylchloride
(S)-4-(3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-ylsulphonyl)benzonitrileN. 3.31,78(a)408
Acanaloniidae(S)-1-(1-(ethylsulfonyl)piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 3.41,49(a)335
Methanesulfonanilide(S)-1-(1-(methyl-sulfonyl)piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineN. 3.51,43(a)321

TABLE N. 4
Examples of the preparation of the hydrochloride of the CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (Example n ° F. 1.3) using General procedure N
SulphonylchlorideProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
CyclopropanesulfonylN-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)cyclopropanesulfonylN. 4.11,45 (a)361

BenzosulphochlorideN-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)benzosulfimideN. 4.21,68(a)397
4-cyanobenzoyl-1-�levonelle N-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)-4-cyanobenzenesulfonylN. 4.31,70(a)422
AcanaloniidaeN-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl) cyclohexyl)econsultantN. 4.41,47(a)349
Propane-1-sulphonylchlorideN-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)propane-1-sulfonamideN. 4.51,51(a)363
MethanesulfonanilideN-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)methanesulfonamideN. 4.61,41(a)335

TABLE N. 5
Examples of the preparation of CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutanone (Example No. J. 1.4) using General procedure N
SulphonylchlorideProduct Example No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
4-cyanobenzoyl-1-sulphonylchloride [Maybridge]N-((1S,3S)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)-4-cyanobenzenesulfonylN. 5.11,76 (a)394

General procedure O: Replacement aryl - or heteroarylboronic Amin

In a reactor were placed amine or amine salt (preferably 1 equivalent), aryl - or heteroarylboronic (1-10 equivalents, preferably 1.5 equivalents), a solvent such as MeCN, n-PrOH, n-BuOH, toluene, DMSO or EtOH (preferably EtOH), and a base, such as K2CO3, NaCO3, TEA or DIEA, preferably TEA or DIEA (1-5 equivalents, preferably 2-4 equivalents). The obtained reaction mixture is heated through microwave radiation at a temperature of about 100-200°C (preferably about 130-150°C) for about 0.5-8 hours (preferably about 1-2 hours). In cases where according to TLC, LC/MS or HPLC, the reaction is not completed, the reaction mixture can be subjected to irradiation at a temperature of about 120-200°C (preferably about 130-150°C) for further 1-8 hours (preferably about 1-2 hours), accompanying it �by adding additional quantities aryl - or heteroarylboronic (1-10 equivalents, preferably, 1.5 equivalent) and/or base, such as K2CO3, Na2CO3, TEA or DIEA, preferably TEA or DIEA (1-5 equivalents, preferably 2-4 equivalents). This process is repeated as long as the reaction is not terminated. After cooling to room temperature, the reaction mixture was treated using one of the following methods. Method 1: the Reaction mixture is concentrated under reduced pressure. Method 2: Reaction mixture containing the precipitate was filtered to collect the target compound, optionally washing with an organic solvent (or solvents) such as Et2O, DCM and/or petroleum ether. Method 3: the reaction mixture Obtained is diluted with an organic solvent, such as MeOH, was added a silica gel, and the resulting mixture was concentrated under reduced pressure to prepare for the selection using chromatography. Method 4: the Obtained reaction mixture was concentrated under reduced pressure before adding the organic solvent, such as EtOAc or DCM, and then optionally washed with water and/or brine, dried over anhydrous Na2SO4orMgSO4, filtered or decanted, and concentrated under reduced pressure. Method 5: Added an organic solvent such as EtOAc or DCM, with optional add in�water or saline, and the layers were separated. The water layer is then optionally extracted with additional organic solvent, such as EtOAc or DCM. The combined organic layers are optionally washed with brine and water, dried over anhydrous MgSO4or Na2SO4, filtered or decanted, and concentrated under reduced pressure. In all cases, the raw material is optionally purified by precipitation, crystallization, and/or grind thoroughly with a suitable solvent or solvents and/or using chromatography, obtaining the target compound.

Illustration of General procedure O

Example # O. 1.1: 6-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)nicotinamide

In a microwave reactor adds hydrochloride (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (0,0979 g, 0,311 mmol, example # 6, step C), EtOH (2 ml), 6-chloronicotinamide (0,057 g, 0.41 mmol), and TEA (0,130 ml, 0,932 mmol). The obtained reaction mixture is heated using microwave CEM™ at a temperature of about 130°C for about 1 hour (1724 kPa maximum pressure, 5 min to the maximum output mode, 300 max Watts). After cooling to room temperature the reaction mixture was concentrated under reduced pressure and purified by chromatographic treatment �and silica gel, elwira DCM/MeOH/Et2NH (970:27:3) to give 6-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)nicotinamide (of 0.027 g, 25%): LC/MS (table 2, Method a) Rt=1,24 min; MS m/z: 345 (M+H)+.

TABLE O. 1
Examples of the preparation of the hydrochloride salt of (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (example # 6, step C) using General procedure O
Aryl - or heteroarylboronicProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
6-chloropyridazine-3-carbonitrile (Ark Pharm)6-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo-[4,3-a]pyrazine-1-yl)cyclopentylamine)pyridazin-3-carbonitrilO. 1.21,56 (a)346
4-perbenzoate4-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)benzonitrileO. 1.31,79(a)344
2-chlorinationN-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triaz�lo[4,3-a]pyrazine-1-yl)cyclopentyl)hinzelin-2-amine O. 1.41,72(a)371
2-chloro-5-(trifluoromethyl)pyridinN-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo-[4,3-a]pyrazine-1-yl)cyclopentyl)-5-(trifluoromethyl)pyridin-2-amineO. 1.51,98(a)388
6-chloro-5-fornicationis6-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-5-fornicationisO. 1.61,88(a)363
6-chloro-5-methylnicotinamide6-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-5-methylnicotinamideO. 1.71,78(a)359

TABLE O. 2
Examples of the preparation of the hydrochloride of (R)-1-(piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (example # I. 1.1) and heteroarylboronic using General procedure O
Aryl - or heteroarylboronicProductExample No. Rtmin (table 2, Method)m/z ESI+ (M+H)+
6-chloronicotinamide(R)-6-(3-(6H-imidazo[2,3-e][1,2,4]triazolo-[4,3-a]pyrazine-1-yl)piperidine-1-yl)nicotinamideO. 2.11,76 (a)345
6-chloropyridazine-3-carbonitrile [Ark Pharm](R)-6-(3-(6H-imidazo[2,3-e][1,2,4]triazolo-[4,3-a]pyrazine-1-yl)piperidine-1-yl)pyridazin-3-carbonitrilO. 2.21,57(a)346
2-chloro-5-(trifluoromethyl)pyridin(R)-1-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-3-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazineO. 2.32,04(a)388

m/z ESI+ (M+H)+
TABLE O. 3
Examples of the preparation of the hydrochloride salt of (1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (example No. D. 1.4) using General procedure O
Aryl - or heteroarylboronicProductExample No.Rtmin (table 2, Method)
6-chloronicotinamide6-((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)nicotinamideO. 3.11,65 (a)345
6-chloropyridazine-3-carbonitrile6-((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyridazin-3-carbonitrilO. 3.21,53(a)346
4-perbenzoate4-((1R,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)benzonitrileO. 3.31,81(a)344

TABLE O. 4
An example of obtaining hydrochloride from CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (example n ° F. 1.3) using General procedure O
HeteroarylboronicProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
2-chloro-5-trifluoromethyl)-pyridine N-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)-5-(trifluoromethyl)-pyridin-2-amineO. 4.11,66 (a)402

TABLE O. 5
An example of obtaining from 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-amine (obtained using A from example receipt No. 9, 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid [Prime Organics], HATU, and TEA, C with TEA, I with HCl in 1,4-dioxane) and heteroarylboronic, using General procedure O
HeteroarylboronicProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
6-fornicationis [Matrix]6-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]octane-1-ylamino)nicotinamideO. 5.11,48 (a)385

TABLE O. 6
An example of obtaining hydrochloride from (1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazole,3-a]pyrazine-1-yl)cyclopentylamine (obtained using C from the sample receiving no A. 1 with TEA, I with 4 n HCl in 1,4-dioxane) using General procedure O
Aryl - or heteroarylboronicProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
6-fluoro-4-methylnicotinamide (obtained using HH from the sample receiving No. 23)6-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)-4-methylnicotinamideO. 6.11,81 (a)359

TABLE O. 7
An example of obtaining hydrochloride from (1R,4S)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine hydrochloride and (1S,4R)-3,3-dimethyl-4-(6H-imidazo[2,3 - e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (obtained using the method of producing EE from the sample receiving No. 25 and N,N-dibenzylamine, Y with MeOH, FF, P, GG with LiOH, A from sample receipt No. 9 with HATU and TEA, C with TEA, H, I with 4 n HCl in 1,4-dioxane) using General procedure O
Aryl - or heteroarylboronicProductExample No.Rtmin(table 2, Method)m/z ESI+ (M+H)+
5-chloropyrazine-2-carbonitrile(1R,4S)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone and (1S,4R)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)CyclopentanoneO. 7.10,92 (d)271

TABLE O. 8
An example of getting out of the hydrochloride of (R)-1-(1-methylpiperazin-2-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (obtained using A from example receipt No. 9 and example of receiving No. 16, C, H, I) using General procedure O
HeteroarylboronicProductExample No.Rtmin (table 2, Method)m/z ESI+ (M+H)+
6-chloronicotinamide(R)-6-(4-methyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperazine-1-yl)nicotinamideO. 8.11,70 (a)360

General procedure O. 1: replacement of the aryl - or heteroarylboronic amine (thermal conditions)

In round�bottom flask is placed a mixture of amine or amine salt (preferably 1 equivalent), aryl - or heteroarylboronic (1-10 equivalents, preferably 1.5 equivalents), a solvent such as MeCN, toluene, DMSO, EtOH or DMF, preferably DMF) and a base, such as K2CO3, Na2CO3, TEA or DIEA, preferably TEA or K2CO3(1-5 equivalents, preferably 2-4 equivalents). The obtained reaction mixture is heated at a temperature of about 40-220°C (preferably about 65°C) for about 0.5 to 16 hours (preferably about 8.5 hours). In cases where according to TLC, LC/MS, or HPLC, the reaction is not completed, it can be continued by heating at a temperature of about 40-220°C (preferably about 65°C) for about 1 to 12 hours (preferably about 1-2 hours) with the optional addition of aryl - or heteroarylboronic (1-10 equivalents, preferably 1.5 equivalents) and/or base, such as K2CO3, Na2CO3, TEA or DIEA, preferably TEA or K2CO3(1-5 equivalents, preferably 2-4 equivalents). This process is repeated until until the reaction ends. After cooling to room temperature, the reaction mixture obtained is treated in the following ways. Method 1: the Reaction mixture is concentrated to dryness under reduced pressure. Method 2: Reaction mixture containing the precipitate was filtered to collect the target with�organisations, having washing with an organic solvent (or solvents), such as Et2O, DCM and/or petroleum ether. Method 3: the Obtained reaction mixture is diluted with an organic solvent (such as MeOH), and add silica gel, and the resulting mixture was concentrated under reduced pressure to prepare for the selection using chromatography. Method 4: the Obtained reaction mixture was concentrated under reduced pressure before adding the organic solvent, such as EtOAc or DCM and then optionally washed with water and/or brine, dried over anhydrous Na2SO4orMgSO4, filtered or decanted, and concentrated under reduced pressure. Method 5: Added an organic solvent such as EtOAc or DCM, with the optional addition of water or salt solution, and the layers were separated. The water layer is then optionally extracted with additional organic solvent, such as EtOAc or DCM. The combined organic layers are optionally washed with brine and water, dried over anhydrous MgSO4orNa2SO4, filtered or decanted, and concentrated under reduced pressure. In all cases, the raw material is optionally purified by precipitation, crystallization and/or grind thoroughly with a corresponding dissolve�eat (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure O. 1

Example No. O. 1.1: N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzo[d]oxazol-2-amine

In pear-shaped flask load 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-amine (0.20 g, 0.46 mmol, example # 7, step B) and 2-chlorobenzo[d]oxazol (0.18 g, 1.1 mmol, TCI) in DMF (5.0 ml). To the resulting suspension is added K2CO3(0.16 g, 1.1 mmol), and the resulting mixture was heated at about 65°C for about 8.5 hours. The resulting mixture was cooled to room temperature and the solvent removed under reduced pressure. The obtained residue was dissolved in EtOAc (25 ml) and washed with water and brine (25 ml each). The organic solution is dried over anhydrous MgSO4, filtered and concentrated to dryness under reduced pressure, yielding N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)benzo[d]oxazol-2-amine (0.26 g, 95%, 95% purity according to NT): LC/MS (table 2, Method d) Rt=of 1.48 min; MS m/z: 554 (M+H)+.

General procedure P: Boc-protection of the amine

To a solution of amine (preferably 1 equiv) in an organic solvent (such as MeCN, 1,4-dioxane or THF, preferably THF) optionally adding an aqueous solution of base, such as Na 2CO3, NaOH, K2CO3or NaHCO3(2 to 20 equivalents, preferably 10 equivalents of Na2CO3), or an organic base such as TEA or DIEA (1-5 equivalents, preferably 1-2 equivalents) followed by the addition of di-tert-BUTYLCARBAMATE (1-1,5 equivalents, preferably 1.2 equivalents). The reaction mixture was stirred at a temperature of about 10-40°C (preferably at room temperature) for about 2-24 hours (preferably about 2-6 hours) and treated using one of the following methods. Method 1: Add an organic solvent (such as Et2O, EtOAc or DCM) and water, and the layers were separated. The aqueous layer was extracted with additional organic solvent, and the combined organic layers are optionally washed with brine, dried over anhydrous Na2SO4or MgSO4and then decanted or filtered before concentrating under reduced pressure. Method 2: the Obtained reaction mixture was separated between an organic solvent (such as Et2O, EtOAc or DCM) and an aqueous solution of acid (such as HCl). The acidic layer was extracted with additional organic solvent, and the combined organic layers are optionally washed with brine. The organic layer is optionally dried over anhydrous Na2SO4/sub> orMgSO4and then decanted or filtered before concentrating under reduced pressure. Method 3: Add an organic solvent (such as Et2O, EtOAc or DCM) and water, and the layers were separated. The aqueous layer was acidified with using an acid such as AcOH), which causes the formation of sludge, which is then decanted or filtered, optionally washed with excess amount of water. The raw material is optionally purified by precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure P

An example of receiving no P. 1: (1R,3S)-3-((tert-butoxycarbonylamino)methyl)cyclopentanecarbonyl acid

To a solution of (1R,3S)-3-(aminomethyl)cyclopentanecarboxylic acid (0.500 g, 3,49 mmol, AFID) in THF (4 ml) and water (4 ml) was added Na2CO3(1.11 g, 10.5 mmol) and di-tert-BUTYLCARBAMATE (0,915 g, 4,19 mmol). The reaction mixture was stirred at room temperature for about 4 hours. Add EtOAc (15 ml) and aqueous HCl solution (1 n, 15 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 ml) and the combined organic layers washed with brine (10 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and conc�Ute under reduced pressure, receiving (1R,3S)-3-((tert-butoxycarbonylamino)methyl)cyclopentanecarbonyl acid (0.300 g, 35% yield).1H NMR (DMSO-d6) δ 11,97 (s, 1H), 6,83 (s, 1H), 2,87 (t,J=6,4, 2H), 2,73-of 2.58 (m, 1H), 2,04-to 1.87 (m, 2H), 1,82 to 1.68 (m, 2H), 1,68-to 1.58 (m, 1H), and 1.37 (s, 9H), 1,34-1,19 (m, 2H).

General procedure Q: Cbz-protected amine

To a solution of amine (preferably 1 equiv.) and bases (for example, Na2CO3, 1-3 equiv., preferably, 3 equiv.) in water or in an aqueous organic solvent (for example, a mixture of water/MeCN) was added a solution of benzyl 2,5-dioxopiperidin-1-yl carbonate (1-2 equiv., preferably, 1.3 equiv.) in an organic solvent such as MeCN. The reaction mixture was stirred at room temperature for about 8-24 hours (preferably about 16 h) and then concentrated under reduced pressure. The resulting aqueous solution acidified by adding acid, such as aqueous solution of NH4Cl or HCl and then extracted with an organic solvent (such as EtOAc or DCM). The combined organic extracts are optionally washed with water and/or brine, dried over anhydrous Na2SO4orMgSO4, filtered or decanted, and concentrated under reduced pressure. The raw material is then optionally purified by precipitation, crystallization, and/or thorough rubbing in the solvent (or solvents) and/or� using chromatography, obtaining the target compound.

Illustration of General procedure Q

Example No. 1 Q.: 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid

To a solution of piperidine-4-carboxylic acid (10.0 g, to 77.4 mmol) and Na2CO3(8,21 g of 77.4 mmol) in water (100 ml) was added a solution of benzyl 2,5-dioxopiperidin-1-ylcarbamate (19,3 g, to 77.4 mmol) in MeCN (100 ml). The reaction mixture was stirred at room temperature for about 16 hours and then concentrated under reduced pressure. The resulting aqueous solution was quenched using an aqueous solution of NH4Cl and then extracted with EtOAc (2×100 ml). The combined organic extracts dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding 1-(benzyloxycarbonyl)piperidine-4-carboxylic acid in the form of white solids (4,56 g, 22%): LC/MS (table 2, Method a) Rt=1,93 min; MS m/z: 262 (M-H)-.

General procedure R: Recovery of pyridine

Substituted pyridine (preferably 1 equiv.) and platinum oxide(IV) (0,05-0,20 equiv., preferably, a 0.09 equiv.) in AcOH shaken in a hydrogen atmosphere at a pressure of about 103-620 kPa (preferably, about 414 kPa) for about 1-10 days (preferably about 3-5 days). The reaction mixture was filtered through celite may® and then concentrated under reduced pressure and then� not necessarily clear, using precipitation, crystallization and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure R

Example No. R. 1: Acetate 4-demerol-3-carboxylic acid

4-methylnicotinic acid (2.00 g, 14.6 mmol) and platinum oxide (IV) (0.30 g, 1.3 mmol) in AcOH (70 ml) is shaken in a hydrogen atmosphere at a pressure of about 414 kPa for about 3 days. The reaction mixture was filtered through celite may® and then concentrated under reduced pressure to obtain acetate 4-demerol-3-carboxylic acid as an oil (2.9 g, 98%): LC/MS (table 2, Method a) Rt=0,55 min; MS m/z: 144 (M+H)+.

General procedure S: Restoration of ester to alcohol

The reducing agent (2.0 to 2.5 equiv., preferably, 2.1 equiv.), such as a solution of DIBAL-H was added, dropwise, to a solution of ester (preferably 1 equiv.) in an organic solvent (such as THF or Et2O, preferably THF) at a temperature of about 0-25°C (preferably about 0°C). The reaction mixture was stirred for about 1-3 hours (preferably about 1 hour) before the reaction was quenched using 10% aqueous solution of potassium sodium tartrate, pH 5.5. The reaction mixture is left under stirring about.� 1 hour before how concentrated under reduced pressure. The obtained residue was separated with an organic solvent (such as EtOAc or DCM, preferably EtOAc) and then washed with saline. The organic layer was dried over anhydrous Na2SO4orMgSO4, filtered and concentrated to constant weight. The raw material is optional then cleaned, using precipitation, crystallization, and/or thorough rubbing with an appropriate solvent (or solvents) and/or chromatography, obtaining the target compound.

Illustration of General procedure S

Example no 1: Tert-butyl 3-(gidroximetil)-4-demerol-1-carboxylate

DIBAL-H (1 M in toluene, and 27.3 ml, 27.3 mmol) was added, dropwise, to a solution of 1-tert-butyl 3-methyl 4-demerol-1,3-dicarboxylate (3,35 g, 13,02 mmol, obtained using R from the example of obtaining the No. 1 and Y. P) in THF (40 ml) at a temperature of about 0°C. the reaction mixture Obtained is stirred for about 1 hour before it was quenched using 10% aqueous solution of potassium sodium tartrate (50 ml). The obtained reaction mixture is left under stirring for about 1 hour before it was concentrated under reduced pressure. The resulting residue was separated using EtOAc (200 ml) and brine (3×100 ml). The organic layer was dried �hell anhydrous Na 2SO4, filtered and concentrated to constant weight to obtain tert-butyl 3-(gidroximetil)-4-demerol-1-carboxylate as a clear oil (2,58 g, 86%): LC/MS (table 2, Method a) Rt=2,10 min; MS m/z: 230 (M+H)+.

General procedure T: Oxidation of alcohol to aldehyde

To a solution of alcohol (preferably 1 equiv.) in DCM is added periodinane Dess-Martin (1.0-1.5 equiv., preferably, 1.2 equiv.). The reaction mixture was stirred at room temperature for about 4-24 hours (preferably about 8-16 hours). The reaction mixture is divided between an organic solvent such as EtOAc or DCM (preferably EtOAc) and an aqueous solution of base such as saturated aqueous solution of NaHCO3or Na2CO3(preferably, Na2CO3). The organic layer is isolated, filtered through celite may®, and washed with an aqueous solution of a base such as saturated aqueous solution of NaHCO3orNa2CO3(preferably, Na2CO3). The organic layer was dried over anhydrous Na2SO4orMgSO4, filtered and concentrated under reduced pressure to constant weight. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, receiving TSE�Evoe connection.

Illustration of General procedure T

Example no. 1: Tert-butyl 3-formyl-4-demerol-1-carboxylate

To a solution of tert-butyl 3-(gidroximetil)-4-demerol-1-carboxylate (2,58 g and 11.2 mmol, example of receiving no. 1) in DCM (50 ml) was added periodinane Dess-Martin (5,73 g, 13.5 mmol). The reaction mixture was stirred at room temperature for about 16 hours before it is divided between EtOAc (150 ml) and a saturated aqueous solution of NaHCO3(150 ml). The organic layer was filtered through celite may®, then washed with a saturated aqueous solution of Na2CO3(2×150 ml). The organic layer was isolated and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to constant weight to obtain tert-butyl 3-formyl-4-demerol-1-carboxylate as a clear oil (1,49 g, 58%): LC/MS (table 2, Method a) Rt=2,39 min; MS m/z: 228 (M+H)+.

General procedure U: Receive semicarbazide

Into a flask containing hydrazine (preferably 1 equiv.) in an organic solvent (such as CHCl3, THF, or DCM, preferably, CHCl3) add an organic base (1-3 equiv., preferably, 1 equiv.), such as TEA, DIEA, NMM, or pyridine (preferably TEA). The obtained reaction mixture is optionally cooled to about-10-10°C (preferably about�olo 0°C) and add carbamoylated (pure or in the form of a solution in a suitable organic solvent, such as listed above, preferably in the form of a solution in a suitable organic solvent) (1-2 equiv., preferably, 1.2 equiv.). The obtained reaction mixture was stirred at a temperature of about 0-60°C (preferably about 45°C) for about 1-24 h (preferably about 16 h). Add an appropriate organic solvent (such as EtOAc or DCM) and the resulting solution was washed with water and brine. The layers were separated, and the organic solution is dried over anhydrous Na2SO4orMgSO4, filtered and concentrated to dryness at reduced pressure, obtaining the target compound. The raw material is optional then cleaned, using deposition, crystallization, or grind thoroughly with a suitable solvent (or solvents) or using chromatography, obtaining the target compound.

Illustration of General procedure U

Example No. U. 1: N'-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)piperidine-1-carbohydrazide

A 25 ml round bottom flask was placed 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (0.075 g, 0.25 mmol, example # 9), and TEA (0,041 ml, 0.29 mmol) in CHCl3(1.2 ml) to give a brown suspension. Add piperidine-1-carbonylchloride (0,040 g, 0.27 mmol) and the reaction mixture was stirred at room temperature for OK�lo 3 hours. The obtained reaction mixture was heated at about 45°C for about 16 hours. The resulting mixture was cooled to room temperature, was added DCM (25 ml) and the resulting solution was washed with water and saline solution (about 5 ml each). The layers were separated and the organic solution is dried over anhydrous MgSO4, filtered and concentrated to dryness under reduced pressure, yielding N'-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)piperidine-1-carbohydrazide (0.11 g, 100%): LC/MS (table 2, Method a) Rt=of 2.09 min; MS m/z: 415 (M+H)+.

General procedure V: Cyclization of semicarbazide

The flask containing semicarbazide (preferably 1 equiv.) add POCl3(10-100 equiv., preferably, 50 equiv.). The obtained reaction mixture was stirred at a temperature of about 25-120°C (preferably about 70-100°C) for about 1-10 hours (preferably about 2-4 hours). Optionally, the reaction mixture obtained was stirred at room temperature for about 1-48 hours, preferably, about 24-36 hours). If the resulting mixture is heated at an elevated temperature, it was cooled to room temperature before pouring over ice or in ice water. To this mixture was added a suitable organic solvent (such as EtOAc or DCM) and an aqueous solution of a base (such as Na2CO3, NaHCO3or NaOH), and the organic layer isolated. Neo�satalino, the resulting aqueous solution is then extracted with a suitable organic solvent (such as EtOAc or DCM). The combined organic extracts dried over anhydrous Na2SO4or MgSO4, filtered and concentrated to dryness at reduced pressure, obtaining the target compound. The raw material is not necessarily clear, using deposition, crystallization, or grind thoroughly with a suitable solvent (or solvents), or using chromatography, obtaining the target compound.

Illustration of General procedure V

Example No. V. 1: 1-(piperidine-1-yl)-6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

The flask was placed N'-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)piperidine-1-carbohydrazide (0.18 g, 0.43 mmol, example No. U. 1) followed by the addition of POCl3(2.0 ml, 21.5 mmol). The resulting mixture was heated at about 100°C for about 2 hours. The obtained reaction mixture was cooled to room temperature and stirred for about 36 hours at room temperature. The resulting mixture was slowly poured over ice (about 15 g), followed by the addition to the resulting suspension DCM (50 ml) and saturated aqueous solution of Na2CO3(25 ml). The layers were separated, and the organic solution is dried over anhydrous MgSO4, filtered and concentrated to dryness at lower�rated pressure, getting 1-(piperidine-1-yl)-6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.11 g, 63%) as brown solids colors: LC/MS (table 2, Method a) Rt=2,36 min; MS m/z: 397 (M+H)+.

General procedure W: Receiving chloride

To a solution of carboxylic acid (preferably 1 equiv.) in an organic solvent (preferably DCM) is added oxaliplatin (1.2 to 2.0 equiv., preferably, 2 equiv.) followed by the addition of DMF (0,01-0,10 equiv., preferably, about 0.05 equiv.). The reaction mixture was stirred at a temperature of about 0-40°C (preferably at room temperature) for about 3-6 hours (preferably about 4 hours before it was concentrated under reduced pressure to constant weight, yielding the target compound.

Illustration of General procedure W

Example No. W. 1: 2-methylcyclohexanecarboxylic

To a solution of 2-methylcyclohexanecarboxylic acid (6,00 ml of 42.6 mmol, mixture of CIS - and TRANS-) in DCM (60 ml) was added oxaliplatin (4,80 ml of 55.3 mmol) followed by the addition of DMF (0.03 ml, 0.4 mmol). The reaction mixture was stirred at room temperature for about 4 hours before it was concentrated under reduced pressure to constant weight, to obtain 2-methylcyclohexanecarboxylic (mixture of diastereomers) in the form � / oils yellow (7.0 g, 97%):1H NMR (400 MHz, CDCl3) δ 2,98-to 2.94 (m, 1H), 2.39 and of 2.35 (m, 1H), 1,91-to 1.82 (m, 1H), 1,79 is 1.72 (m, 1H), 1,69 to 1.60 (m, 2H), 1,57 was 1.47 (m, 2H), 1,42-of 1.36 (m, 1H), 1,34-of 1.26 (m, 1H), 1,04-of 0.96 (m, 3H).

General procedure X: Receiving urea using CDI

The flask containing the amine or amine salt (preferably 1 equiv.) added CDI (1-2 equiv., preferably, 1.10 equiv.) and an organic solvent (such as 1,4-dioxane, THF, DCM, DMF or pyridine, preferably pyridine). If using salt and amine, pyridine is used as solvent. The obtained reaction mixture was stirred at room temperature for about 2-24 hours (preferably about 16 h). Then to this mixture was added a second portion amine (1-3 equiv., preferably, 1.10 equiv.), and the mixture was stirred at room temperature for about 2-24 hours (preferably about 16 h). The organic solvent is optionally removed under reduced pressure. The raw material is divided between an organic solvent (such as EtOAc or DCM) and water, an aqueous solution of a base (such as saturated aqueous solution of NaHCO3) or saline. The layers were separated, and the organic solution is optionally washed with water, an aqueous solution of a base (such as saturated aqueous solution of NaHCO3and/or brine, dried over anhydrous Na2SO4orMgSO4shown�comfort and concentrated under reduced pressure, obtaining the target compound. The raw material is not necessarily clear, using deposition, crystallization, or grind thoroughly with a suitable solvent (or solvents) or using chromatography, obtaining the target compound.

Illustration of General procedure X

Example No. X. 1.1: N-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)pyrrolidin-1-carboxamide

The flask containing the hydrochloride CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexanamine (0.050 g, 0,171 mmol, example # F. 1.3) was added CDI (0.030 g, 0,188 mmol) and pyridine (2 ml). The obtained reaction mixture was stirred at room temperature for about 16 hours. To the resulting reaction mixture was added pyrrolidine (0,016 ml 0,188 mmol), and stirred for about 16 hours. The solvent was removed under reduced pressure, and the crude material purified using HPLC with reversed phase (table 2, Method j). The appropriate fractions were pooled, most of the solvent was removed under reduced pressure, and the solid product was filtered and dried using lyophilization, yielding N-(CIS-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclohexyl)pyrrolidin-1-carboxamide (0,010 g, 16%): LC/MS (table 2, Method a) Rt=1,45 min; MS m/z 354 (M+H)+.

General procedure Y: obtain the ester of carboxylic acid�you

A solution of carboxylic acid (preferably 1 equiv.) and mineral acids (such as H2SO4or HCl, preferably, 0.2 to 3 equiv. H2SO4preferably, a saturated solution of HCl in alcohol (such as MeOH or EtOH, preferably MeOH) was stirred at a temperature of about 0-80°C (preferably at about 60°C, when using H2SO4,orpreferably, at room temperature if using HCl) for about 8-24 hours (preferably about 16 h). The reaction mixture was concentrated under reduced pressure, and then separated using EtOAc or DCM (preferably EtOAc) and a saturated aqueous solution of NaHCO3. The organic layer was dried over anhydrous Na2SO4orMgSO4, filtered and concentrated under reduced pressure to constant weight. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure Y

Example No. y 1 Methyl 4-methylnicotinate

A solution of 4-methylnicotinic acid (2.00 g, 14.6 mmol) and concentrated H2SO4(of 4.66 ml, to 87.6 mmol) in MeOH (50 ml) is heated at a temperature of about 60°C for about 16 h�S. The reaction mixture was concentrated under reduced pressure, and then separated using EtOAc (150 ml) and saturated aqueous solution of NaHCO3(200 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to constant weight to obtain methyl 4-methylnicotinate in the form of a transparent liquid (2.30 g, 94%): LC/MS (table 2, Method a) Rt=to 1.67 min; MS m/z: 152 (M+H)+.

General procedure Z: N-alkylation using alkylhalogenide or α-halogenation

In a round bottom flask was placed a base (such as NaH, 60% dispersion in mineral oil), K2CO3or Cs2CO3preferably, NaH (60% dispersion in mineral oil), 1-1,5 equiv., preferably, 1.2 equiv.) and an organic solvent (such as DMF or NMP, preferably DMF). The resulting mixture was cooled to about-10-10°C (preferably about 0°C) and add a solution of appropriately substituted amine (preferably 1 equiv.) in an organic solvent (such as DMF). The obtained reaction mixture was stirred for about 5-90 minutes (preferably about 15 min) at a temperature of about -10°C to room temperature (preferably about 0°C) followed by the addition of alkylhalogenide or α-halogenation (1-2 equiv., preferably, 1.5 equiv.). The obtained reaction mixture alternating�sivut at a temperature of about -10°C to room temperature (preferably, about 0°C.) for about 0.5-2 h (preferably about 0.5 hour), and then heated to room temperature (in cases where the resulting mixture was cooled throughout the reaction). The obtained reaction mixture was stirred at room temperature for about 1-20 hours (preferably about 2 h). The organic solvent was removed under reduced pressure, and the resulting mixture was purified in the following ways. Method 1) the resulting mixture is diluted with water and organic solvent (such as EtOAc or DCM). The layers were separated, and the aqueous solution extracted with an organic solvent (such as EtOAc and/or DCM). The combined organic layers are optionally washed with brine, dried over anhydrous MgSO4, filtered and concentrated to dryness under reduced pressure. Method 2) the Raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents), and/or using chromatography, obtaining the target compound.

Illustration of General procedure Z

Example No. z 1: N-methyl-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl

In a round bottom flask was placed sodium hydride (60% dispersion in mineral oil, 0.013 g, 0,33 mmol�) and DMF (1 ml), getting the suspension white. The resulting suspension was cooled to about 0°C. followed by the addition of a solution of N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanecarboxamide (0.15 g, 0.27 mmol, example # 7, step C) in DMF (2 ml). The obtained reaction mixture was stirred for about 15 min and add iodomethane (0.06 g, 0.41 mmol). The obtained reaction mixture was stirred at a temperature of about 0°C for about 30 min, warmed to room temperature and stirring was continued for about 2 hours. The solvent was removed under reduced pressure. The obtained residue was dissolved in DCM (5 ml), then purified using flash chromatography on silica gel using EtOAc as eluent, yielding N-methyl-N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl (0,068 g, 45%) as a solid yellow: LC/MS (table 1, Method a) Rt=2,35 min; LC/MS m/z 555 (M+H)+.

General procedure AA: Cyclization of an amide using dithiadiphosphetane reagent

To a solution of amide (preferably 1 equiv.) in an organic solvent (preferably 1,4-dioxane) was added tielrooy reagent, such as a Lawson Reagent or reagent Belleau (2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide) (preferably, a Lawson Reagent (0.5 to 2.0 equiv., preferably, 0.6 equiv.). The reaction mixture is heated at a temperature of about 25-120°C (preferably about 80°C) for about 0.5-10 hours (preferably about 1 hour). The obtained reaction mixture is allowed to cool to room temperature and add a Lewis acid, such as diacetoacetate, the dichloride of mercury, nitrate of silver, copper bromide (preferably, diacetoacetate) (1-3 equiv., preferably, 1 equiv.). The obtained reaction mixture was stirred at a temperature of about 20-60°C (preferably at room temperature) for about 0.5-4 hours (preferably about 1 hour). Optional add an additional amount of a Lewis acid (preferably, diacetoacetate) (0.2 to 1.0 equiv., preferably, 0.5 equiv.) and the reaction was continued for about 10 minutes to 3 hours (preferably about 15 min). The obtained reaction mixture was added to an organic solvent (preferably EtOAc) and filtered, preferably through a layer of celite may®. The filtrate obtained is concentrated under reduced pressure, obtaining the target compound. Optionally the product obtained is purified using crystallization or grind thoroughly with a suitable solvent (or solvents), or using chromatography, obtaining the target compound.

Illustration of General procedure AA

Example No. 1: Tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-methyl-3-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 83 mmol, example No. 13, phase (H) in 1,4-dioxane (500 ml) was added a Reagent Lawson (20.2 g, a 50.0 mmol). The reaction mixture is heated at a temperature of about 80°C for about 1 hour. The reaction mixture is allowed to cool to room temperature followed by the addition of diacetoacetate (26,6 g, 83,0 mmol). After about 1 hour add a further amount of diacetoacetate patients (13.3 g, 42.0 mmol). After about 15 minutes, the reaction mixture was poured into a stirred EtOAc (2 l). After about 15 min the reaction mixture was filtered through celite may® and the filtrate concentrated under reduced pressure. The obtained residue was triturated with EtOAc (500 ml) and filtered. The filtrate obtained is concentrated under reduced pressure and purified by column chromatography with silica gel (330 g column), performing a gradient elution with 10-50% EtOAc in heptane, yielding tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)piperidine-1-carboxylate (19 g, 44%) in the form of white solids: LC/MS (table 2, Method a) Rt=2,57 min; MS m/z: 510 (M+H)+.

General procedure BB: Knoevenagel Condensation to obtain the substituted cyclopentadiene

In a round bottom flask was placed dissolve organic�ü (for example THF or dimethyl ether of diethylene glycol; preferably, THF), followed added in portions sodium hydride (60% dispersion in mineral oil) (preferably 1 equiv.). Optional add organic solvent. The obtained reaction mixture was cooled to about -10°C to 0°C (preferably about 0°C). β-ketoester (preferably 1 equiv.) added dropwise at such a speed as to maintain the internal temperature is lower than about 10°C. the resulting mixture was stirred at a temperature of about 0-25°C (preferably about 25°C) for about 0.5-2 h (preferably about 0.5 hour), followed by dropwise addition of α-halogenation (preferably, 0,45-0,55 equiv.). The resulting mixture was heated at about 40-80°C (preferably about 50°C) for about 3-24 hours (preferably about 19 hours). The organic solvent was removed under reduced pressure and the resulting crude material was treated with water bath and placed on ice. The resulting suspension was filtered after about 1-3 hours (preferably about 2 h), and the filter cake washed with water and dried under vacuum for about 1 to 3 hours (preferably about 1 hour). The resulting solid material suspended in an organic solvent (preferably, Et2O) and collected by vacuum filtration, washed with an organic solvent (preferably, Et2O), and dried in �akoume, getting the right product in the form of the sodium salt of enolate.

Illustration of General procedure BB

An example of receiving no BB.1: Sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-Dienst

In a round bottom flask was placed THF (1.5 l), followed added in portions sodium hydride (60% dispersion in mineral oil, 70,0 g, 1.75 mol). Add an additional amount of THF (500 ml), and the resulting mixture was cooled to about -10° C and added dropwise to ethylbromoacetate (250 ml, of 1.80 mol) over about 1 hour in order to maintain its internal temperature is lower than about 10°C. the resulting mixture was stirred at room temperature for about 0.5 hour, yielding a clear yellow solution, and added dropwise methyl 4-chloroacetoacetate (100 ml, 0.88 mol) for about 5 min the resulting mixture was heated at a temperature of about 50°C for about 19 h, receiving a suspension of red-orange color. The obtained reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting liquid is transferred to a beaker and diluted with water (350 ml). The resulting mixture was stirred bath and placed on ice for about 2 hours. The solid product is collected by vacuum filtration and the filter cake was washed with water (150 ml) and dried in a vacuum� for about 1 hour. Solid product suspended in Et2O (1.5 l), filtered, washed with Et2O (1.5 l) and dried in vacuum. The resulting solid material azeotropic distillation with toluene (1 l) to obtain a solid material, which is again suspended in Et2O (1 l) and collected by vacuum filtration. The filter cake was washed with Et2O (500 ml) and dried under vacuum to give sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-Dienst (204,2 g, 89%) as a solid beige color:1H NMR (DMSO-d6) δ 3,94 (kV,J=7,1 Hz, 2H), and 3.46 (s, 3H), of 3.04 (q,J=7,2 Hz, 2H), 2,66 (s, 2H), and 1.13 (t,J=7,1 Hz, 3H), 0.99 (no t,J=7.3 Hz, 3H).

General procedure CC: Decarboxylation enolate complex of β-keeeper

In a round bottom flask place the corresponding complex of β-ketoester or nutrionist (preferably 1 equiv.), organic solvent (for example dimethyl ether of diethylene glycol) and AcOH (2-5 equiv., preferably, 2.5 equiv.). To this mixture was portionwise added sodium iodide (2-5 equiv., preferably, 3.5 equiv.). The reaction mixture is heated at reflux for about 1-5 hours (preferably about 3 hours). The reaction mixture was cooled to room temperature and poured into a mixture of ice and saturated sodium bicarbonate solution. The resulting mixture is extracted with an organic solvent (preferred�Thelen, Et2O). The combined organic layers dried over anhydrous Na2SO4orMgSO4, filtered and concentrated to dryness under reduced pressure. The raw material is optionally purified using vacuum distillation, precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure CC

An example of receiving no CC.1: Ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

In a round bottom flask was placed a sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-Dienst (250 g, 0.94 mole, example No. BB.1) and digim (1.1 l), obtaining a suspension of green, followed by the addition of AcOH (140 ml, 2.4 mol). To this mixture was portionwise added sodium iodide (490 g, 3.3 mole) for about 5-10 min After the addition the temperature rises to about 16°C to about 36°C. the Obtained reaction mixture was then heated at reflux for about 3 h, cooled to room temperature, and was poured onto a mixture of ice (2 l) and saturated aqueous NaHCO3(4 l). The resulting material was extracted with Et2O (4×1.2 l), and combined organic layers dried over anhydrous MgSO4andfiltered. The solvent was removed under �eigendom pressure, getting a brown liquid (250 ml), purified using vacuum distillation (80-92°C, 40 PA) to give ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (95,7 g, 56%) as a yellow syrup:1H NMR (CDCl3) δ of 6.04 (m, 1H), 4,26-4,15 (m, 2H), 3,76-of 3.69 (m, 1H), 2,75-of 2.57 (m, 2H), 2,56 is 2.44 (m, 2H), 1,32-of 1.26 (m, 3H), 1,23-of 1.18 (m, 3H).

General procedure DD: Hydrogenation of alkene

In a round bottom flask was placed 10% palladium-on-charcoal (about 0.02-0.05 equiv., preferably, from 0.02 equiv.). The flask is evacuated, then purged with nitrogen 2-5 times (preferably 3 times), then optionally cooled to about-10-10°C (preferably about 0°C.) before adding the organic solvent (preferably EtOAc) in a nitrogen atmosphere. A cooling bath is removed, and to this mixture was added alken (preferably 1 equiv.) in its pure form or optionally in the form of a solution in an organic solvent (preferably EtOAc). Hydrogen gas was bubbled through the reaction mixture for about 5-20 minutes (preferably about 5 min), and the resulting mixture was stirred under a hydrogen atmosphere for about 12-60 h (preferably about 48 hours). In cases where according to TLC, LC/MS or HPLC, the reaction does not proceed to completion, the hydrogen source is removed, the obtained reaction mixture was bubbled with nitrogen for about 5-20 minutes (preferably about 5 min) and then� was filtered through a layer of celite may®, and the filtrate obtained is concentrated under reduced pressure. The raw material is treated again in the above reaction conditions for about 2-20 hours (preferably about 5 hours). The source of hydrogen is removed, and the resulting mixture was bubbled with nitrogen for about 5-20 minutes (preferably about 5 min) and then filtered through a layer of celite may®. The filter cake is washed with an organic solvent (preferably EtOAc) and the filtrate obtained is concentrated under reduced pressure, yielding the crude product. The raw material is not necessarily clear, using precipitation, crystallization, and/or thorough rubbing with an appropriate solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure DD

Example No. DD.1: Ethyl 2-ethyl-4-oxocyclopentanecarboxylate

In a round bottom flask was placed 10% palladium-on-charcoal (10 g, 9.4 mmol). The flask was cooled to about 0°C. and in a nitrogen atmosphere is added EtOAc (400 ml). A cooling bath is removed and added ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47,8 g, 263 mmol, example No. CC.1). Hydrogen gas was bubbled through the resulting mixture for about 5 min, and then the resulting mixture was stirred under a hydrogen atmosphere for about 48 hours. The source of hydrogen is removed, �must register the mixture was bubbled with nitrogen for about 5 min and filtered through a layer of celite may®. The filter cake was washed with EtOAc (400 ml). The filtrate obtained is concentrated under reduced pressure, yielding ethyl 2-ethyl-4-oxocyclopentanecarboxylate (about 9:1 mixture of CIS:TRANS)(48 g, 99%) as a yellow liquid:1H NMR (CDCl3) δ 4,23-4,10 (m, 2H), up 3.22 (m, 1H), 2,59-of 2.50 (m, 1H), 2,44-to 2.28 (m, 3H), 2.26 and is 2.16 (m, 1H), 1,58-1,46 (m, 1H), 1.41 to 1,30 (m, 1H), 1,30 is 1.23 (m, 3H), 1.02 mm is 0.91 (m, 3H).

General procedure EE: reducing amination of a ketone or aldehyde

In a round bottom flask was placed a ketone or aldehyde (1-40 equiv.; preferably, 1 equiv.) in an organic solvent such as DCE, MeCN, MeOH or MeCN/MeOH; preferably, DCE). The resulting mixture is optionally cooled to about-10-10°C (preferably about 0°C. and dropwise added AcOH (1-3 equiv.; preferably, 1.5 equiv.) and Amin (1-3 equiv., preferably, 1 equiv.), with the subsequent portion by adding a suitable reducing agent, such as triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride, preferably triacetoxyborohydride sodium (1-6 equiv., preferably, 1.5 equiv.). Alternatively, to a solution of amine (1-3 equiv., preferably, 1 equiv.) in an organic solvent such as DCE, MeCN or MeOH; preferably, DCE) was added the ketone or aldehyde (1-40 equiv.; preferably, 1 equiv.) with the subsequent batch addition of the appropriate reducing agent such as triacetoxyborohydride sodium, cyanoborohydride sodium, sodium borohydride, preferably triacetoxyborohydride sodium (1-6 equiv., preferably, 1.5 equiv.). The resulting mixture was stirred for about 5-20 min (preferably about 15 min) followed by dropwise addition of AcOH (1-3 equiv.; preferably, 1.5 equiv.). If obtained, the reaction mixture becomes too viscous that it is easy to mix, additional organic solvent such as DCE, MeCN, MeOH, or a mixture of MeCN/MeOH; preferably, DCE) optionally added to facilitate stirring. The obtained reaction mixture was stirred at room temperature for about 1-48 hours, preferably, about 20 hours). The obtained reaction mixture was slowly poured into an aqueous solution of a base (such as saturated aqueous solution of NaHCO3) followed by optional addition of solid NaHCO3,andstirred for about 0.5-3 hours (preferably about 2 h). The layers were separated, and the organic solution is dried over anhydrous Na2SO4orMgSO4, filtered and concentrated to dryness under reduced pressure. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Fig�exposure to General procedure EE

Example No. EE.1: Ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl

In a round bottom flask was placed ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95,9 g, 521 mmol, example No. DD.1) and DCE (1.8 l). The resulting solution was cooled to about 0°C. and dropwise added AcOH (45 ml, 780 mmol) and dibenzylamine (120 ml, 625 mmol), resulting in the formation of a thick slurry. The obtained reaction mixture is heated to about 10°C and add additional DCE (500 ml). Portions add triacetoxyborohydride sodium (166 g, 781 mmol) and the resulting reaction mixture was stirred at room temperature for about 20 hours. The obtained reaction mixture was slowly poured into a stirred saturated aqueous solution of NaHCO3(1.5 l), followed by portion addition of solid sodium bicarbonate (175 g). The resulting mixture was stirred for about 2 hours and the organic layer is isolated, dried over anhydrous Na2SO4and concentrated to dryness under reduced pressure. The crude yellow oil is purified by column chromatography with silica gel using EtOAc/heptane as eluent (0-20% EtOAc in heptane). The solvent was removed under reduced pressure, resulting in the ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl (136,6 g, 72%) in the form of white solids: LC/MS (Table2, Method (a) Rt=3,26 min; MS m/z: 366 (M+H)+.

General procedure FF: Dibenzylamine Amin

To a suspension of palladium catalyst (for example Pd(OH)2-C or Pd/C; preferably, Pd(OH)2-C) (of 0.01-0.1 equiv., preferably, from 0.02 equiv.) in an organic solvent (preferably EtOH) was added a compound of dibenzylamine (preferably 1 equiv.). The resulting mixture is shaken or stirred at a temperature of about 25-60°C (preferably about 50°C) for about 1-96 h (preferably about 1.5 hour) at a pressure of about 30-414 kPa N2(preferably, about 207 kPa N2). After removal of the source of N2the obtained mixture was filtered through a layer of celite may®, and the filtrate obtained is concentrated under reduced pressure, yielding the desired product. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure FF

Example No. FF.1: Ethyl 4-amino-2-ethylcyclopentadienyl

Into the reactor containing the suspension of 20% Pd(OH)2-C (12.9 g, 92,0 mmol) in EtOH (1.0 l) was added ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl (129 g, 352 mmol, example No. EE.1). The reaction mixture was shaken�himout for about 90 minutes at a temperature of about 50°C at a pressure of H 2about 207 kPa. After removal of the source of N2the obtained mixture was filtered through a layer of celite may®, and the filtrate obtained is concentrated under reduced pressure, yielding ethyl 4-amino-2-ethylcyclopentadienyl (64,5 g, 99%) as a yellow syrup:1H NMR (CDCl3) δ 4,03-3,88 (m, 2H), 3,17 (m, 1H), 2,68 (m, 1H), 2,09-2,02 (m, 2H), 2,02-to 1.94 (m, 2H), only 1.84 (m, 1H), 1,58-of 1.48 (m, 1H), 1,32-of 1.18 (m, 1H), 1,09 (m, 3H), of 1.03 (m, 2H), 0,78 to 0.69 (m, 3H).

General procedure GG: Hydrolysis of the ester to the carboxylic acid

In a flask containing an ester (preferably 1 equiv.) or in pure form or in an organic solvent (such as 1,4-dioxane, MeOH, or THF/MeOH, preferably 1,4-dioxane) was added an aqueous solution of a base (such as aqueous NaOH or LiOH, 1-10 equiv., preferably, 2-6 equiv.). The resulting mixture was stirred at a temperature of about 0-100°C (preferably at room temperature) for about 1-12 hours (preferably about 4-8 hours). The obtained reaction mixture was then acidified by adding a suitable aqueous acid (such as aqueous HCl solution). The layers were separated, and the aqueous layer extracted with optional additional organic solvent (such as EtOAc or DCM, preferably DCM). The organic layer or layers are not necessarily dried over anhydrous Na2SO4or MgSO4, filtered and concentrated to dryness under reduced pressure�and, getting crude target compound. Alternatively, the reaction mixture obtained was concentrated under reduced pressure, yielding the crude target compound in the form of a carboxylate salt. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure GG

Example No. GG.1: (1S,2R,4S)-4-(cyclopropanesulfonyl)-2-ethylcyclopentadienyl acid

Into a flask containing (1S,2R,4S)-ethyl 4-(cyclopropanesulfonyl)-2-ethylcyclopentadienyl (11,1 g, 38.4 mmol, example No. 15, step F) was added aqueous NaOH (1 n, 210 ml, 210 mmol). After stirring at room temperature for about 8 h, the reaction mixture was acidified to about pH 1 using 6 n HCl aqueous solution, and extracted with DCM (3×150 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding (1S,2R,4S)-4-(cyclopropanesulfonyl)-2-ethylcyclopentadienyl acid with 25 mol.% DCM as excipient (10.7 g, 99%): LC/MS (table 2, Method a) Rt=1,71 min; MS m/z: 260 (M-H)-.

General procedure HH: Dehydration of amide to nitrile

Speciesarea (preferably, 1 equiv.) and a dehydrating agent (preferably, POCl3) (10-30 equiv.; preferably, 20 equiv.) heated at a temperature of about 30-80°C (preferably about 60°C) with stirring for about 1-3 hours (preferably about 1 hour). The obtained reaction mixture is then concentrated to dryness under reduced pressure. The resulting crude product is separated between an organic solvent (such as EtOAc and a saturated aqueous solution of NaHCO3. The layers were separated, and the organic solution was washed with brine and dried over anhydrous Na2SO4or MgSO4, filtered and concentrated to dryness under reduced pressure. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure HH

Example No. HH.1: 6-chloro-4-(trifluoromethyl)nicotinamide

A mixture of 6-chloro-4-(trifluoromethyl)nicotinamide (0,847 g, 3.77 mmol, example No. 27) and POCl3(of 7.03 ml, 75,0 mmol) is heated at a temperature of about 60°C with stirring for about 1 hour. The obtained reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure and the resulting material p�sdelat between the cooled saturated aqueous solution of NaHCO 3(30 ml) and EtOAc (30 ml). The layers were separated, and the organic solution was washed with a saturated aqueous solution of NaHCO3(30 ml) and brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure, yielding 6-chloro-4-(trifluoromethyl)nicotinamide (0,67 g, 86%) as a brown liquid: LC/MS (table 2, Method a) Rt=2,31 min;1NNMR (CDCl3) δ 8,87 (s, 1H), the 7.75 (s, 1H).

General procedure II: the Process of purification using preparative chiral HPLC

Chiral purification is carried out using a Varian 218 LC pumps, Varian CVM 500 with switchable valves and heaters for automatic control of the solvent, column and temperature and the collector fractions Varian 701. Methods of detection include a detector with variable wavelength Varian 210, inline polarimeter (PDR-chiral advanced laser polarimeter, model ALP2002), which is used for the quantitative determination of optical rotation (+/-) and evaporative light scattering detector (NT) (PS-ELS 2100 (Polymer Laboratories)), using a 100:1 split flow. Use the following NT parameters: evaporator: 46°C, nebulizer: 24°C and the gas flow: 1,1 SLM.

Table II.1
Examples of the preparation using General procedure II from Ruzimatov
The racemateProductExample No.Rtmin(Table 2,
Method)
m/z ESI+
(M+N)+
Example # N. 1.55N-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl [table 3, Method 4, Rt22 min, opt.BP=positive]II.1.11,77(a)375
Example # N. 1.56N-((1S,3S,4R)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-methylcyclopentene)cyclopropanesulfonyl [table 3, Method 4, Rt31 min, opt.BP=negative]II.1.21,81(a)360
Example # N. 1.56N-((1R,3R,4S)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-methylcyclopentene)cyclopropanesulfonyl [table 3, Method 4, Rt34 min, opt.BP=positive]II.1.3of 1.82(a)360

Example # N. 1.53N-((1R,4S)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]Piras�n-1-yl)cyclopentyl)cyclopropanesulfonyl [table 3, Method 7, Rt13,5 min, opt.BP=negative]II.1.41,77(a)375
Example # N. 1.53N-((1S,4R)-3,3-dimethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl [table 3, Method 7, Rt15,5 min, opt.BP=negative]II.1.51,77(a)375
Example # N. 1.57N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl [table 3, Method 8, Rt16,5 min, opt.BP=negative]II.1.61,94(a)374
Example # N. 1.57N-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl [table 3, Method 8, Rtof 23.5 min, opt.BP=positive]II.1.71,95(a)374
Example # N. 1.19
N-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclobutanemethanamine [table 3, Method 6, Rt14,0 min, opt.BP=positive]II.1.8 1,75(a)389
Example # N. 1.19N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclobutanemethanamine [table 3, Method 6, Rt17,0 min, opt.BP=negative]II.1.91,75(a)389
Example # N. 1.20N-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopentanemethanol [table 3, Method 6, Rt14,0 min, opt.BP=positive]II.1.101,83(a)403
Example # N. 1.20N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopentanemethanol [table 3, Method 6, Rt17,0 min, opt.BP=negative]II.1.111,83(a)403
Example # N. 1.61N-((1S,3R,4S)-3-ethyl-4-(3-methyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl [table 3, Method 1, Rt20,0 min, opt.BP=negative]II.1.121,93(a)388

Example # N. 1.61N-((1R,3S,4R)-3-ethyl-4-(3-methyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl [table 3, Method 1, Rt19,0 min, opt.BP=positive]II.1.131,93(a)388
Example # N. 1.52N-((1R,3S,4R)-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl [table 3, Method 3, Rt= 12,0 min, opt.BP=positive]II.1.141,62(a)361
Example No. 3.103-((3S,4S)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-demerol-1-yl)-3-oxopropanenitrile [table 3, Method 9, Rt=7,8 min, opt.BP=negative]II.1.151,05(a)256

Table II.2
Examples of the preparation using General procedure II for the separation skalemic mixtures
Skalemic mixtureProductExample No.Rtmin (Method) m/z ESI+
(M+N)+
4-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)benzosulfimide (obtained using A from (1S,3R)-3-atsetamido-2,2-dimethylcyclobutane acid [obtained as described in Tetrahedron: Asymmetry 2008, 19, 302-308] and the example of receiving No. 9, EDC, C cDIEA, JJ, N with 4-cyanobenzoyl-1-sulphonylchloride [Maybridge], DIEA, N)4-cyano-N-((1R,3S)-2,2-dimethyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)benzosulfimide (table 3, Method 5, Rt=16,0 min, opt.BP=negative)II.2.11,88(a)422

4-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)benzosulfimide (obtained using A from (1S,3R)-3-atsetamido-2,2-dimethylcyclobutane acid [obtained as described in Tetrahedron: Asymmetry 2008, 19, 302-308] and the example of getting No. 9, EDC, with DIEA, JJ, N with 4-cyanobenzoyl-1-sulphonylchloride, [Maybridge], DIEA, H)4-cyano-N-((1S,3R)-2,2-dimethyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)-benzosulfimide (table 3, Method 5, Rt=11,0 min, opt.BP=positive)II.2.21,88(A)6-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutylamine)nicotinamide (obtained using A from (1S,3R)-3-atsetamido-2,2-dimethylcyclobutane acid [obtained as described in Tetrahedron: Asymmetry 2008, 19, 302-308] and the example of getting No. 9, EDC, C with DIEA, JJ, O with 6-fornicationem [Matrix], N)6-((1S,3R)-2,2-dimethyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutylamine)-nicotinamide (table 3, Method 2, Rt=6,4 min, opt.BP=positive)II.2.31,87(a)359
6-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutylamine)nicotinamide (obtained using A from (1R,3S)-3-atsetamido-2,2-dimethylcyclobutane acid [obtained as described in Tetrahedron: Asymmetry 2008, 19, 302-308] and the example of getting No. 9, EDC, C with DIEA, JJ, O with 6-fornicationem [Matrix], N)6-((1R,3S)-2,2-dimethyl-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutylamine)-nicotinamide (table 3, Method 2, Rt=8,8 min, opt.BP=negative)II.2.41,87(a)359

General procedure JJ: Acid hydrolysis of acetyl-substituted amine

To a solution of N-acetam�Yes (preferably, 1 equiv.) in an organic solvent (such as 1,4-dioxane) was added acid, such as 6 n HCl aqueous solution (3-100 equiv., preferably, 40 equiv.). The obtained reaction mixture is heated at a temperature of about 60-100°C (preferably about 100°C) for about 1-24 h (preferably about 16 h). The obtained reaction mixture is allowed to cool to room temperature before it is divided between an organic solvent (such as EtOAc or DCM) and an aqueous solution of a base (such as NaHCO3, NaCO3orNaOH, preferably, NaHCO3) and the aqueous layer extracted with optional additional organic solvent (such as EtOAc or DCM). The organic layer is dried over anhydrous MgSO4orNa2SO4, filtered and concentrated under reduced pressure. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure JJ

Example No. JJ.1: (1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutanone

To a solution of N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutyl)acetamide (2.20 g, with 4.86 �mol, obtained using A from example receipt No. 9, and (1S,3R)-3-atsetamido-2,2-dimethylcyclobutane acid [obtained as described inTetrahedron: Asymmetry2008, 19, 302-308] with EDC, C DIEA) in 1,4-dioxane (30 ml), was added 6 n aqueous solution of HCl (32.4 per ml, 194 mmol). The reaction mixture is heated at a temperature of about 100°C for about 16 hours. The reaction mixture was allowed to cool to room temperature and it is shared between EtOAc (500 ml) and an aqueous solution of NaHCO3(500 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding (1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclobutanone (1,56 g, 78%) as a solid yellow-brown: LC/MS (table 2, Method a) Rt=1,60 min; MS m/z: 411 (M+H)+.

General procedure KK: Cyclopropylamine using chloroiodomethane

To an alkene, cycloalkene or α,β-unsaturated ketone (preferably 1 equiv.) in an organic solvent (for example, in Et2O, toluene or DCM, preferably DCM) is added dropwise to diethylzinc (preferably, 1.1 M in toluene, 1-10 equiv., preferably, 5 equiv.). The obtained reaction mixture was stirred at room temperature for about 10-40 minutes (preferably about 10 min). The obtained reaction mixture was cooled to about 0°C., followed by the addition of� solution dropwise chloroiodomethane (1-10 equiv., preferably, 5 equiv.) in an organic solvent (for example, in Et2O, toluene or DCM, preferably DCM). The obtained reaction mixture was heated to room temperature and stirred for about 1-20 hours (preferably about 18 hours). To the resulting reaction mixture was then added saturated aqueous solution of NH4Cl and stirred for about 10-60 minutes (preferably about 20 min). The resulting mixture is extracted with an organic solvent (preferably DCM). The organic layer is optionally washed with a saturated aqueous solution of NaHCO3and/or salt solution. In all cases, the resulting solution was dried over anhydrous Na2SO4orMgSO4then decanted or filtered prior to concentrating under reduced pressure. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure KK

Example No. KK.1: (1R,2S,4R,5S)-methyl 4-(ethoxycarbonyl)bicyclo[3.1.0]hexane-2-carboxylate

To (1S,4R)-4-(tert-butoxycarbonylamino)cyclopent-2-inkarbaeva acid (2.70 g, of 11.8 mmol, example No. 17) in DCM (170 ml) slowly add diethylzinc (1.1 M in toluene, 54,0 ml of 59.4 mmol). The resulting mixture was stirred for about 10 min at room temperature, cooled to about 0°C., and treated dropwise with a solution chloroiodomethane (4,30 ml of 59.4 mmol) in DCM (24 ml). The obtained reaction mixture is allowed to warm to room temperature and stirred for about 18 hours. Add a saturated aqueous solution of NH4Cl (10 ml), and the resulting mixture was stirred for about 20 min the Layers were separated, and the aqueous layer was then extracted with DCM (20 ml). The combined organic layers washed with brine (20 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography with silica gel performing a gradient elution 0-100% EtOAc/heptane to obtain (1R,2S,4R,5S)-methyl 4-(ethoxycarbonyl)bicyclo[3.1.0]hexane-2-carboxylate (0.95 g, 35%): LC/MS (table 2, Method a) Rt=1,88 min; MS m/z: 228 (M+H)+.

General procedure LL.1: Receive promotility from chloride, using 1-methyl-3-nitro-1-nitrosoguanidine

To a mixture of aqueous base (such as 45% KOH) (100-200 equiv., preferably, 125 equiv.) and an organic solvent (such as Et2O) at a temperature of about-20-20°C (preferably about 0°C) was added 1-methyl-3-nitro-1-nitrosoguanidine [TCI] (5-20 equiv., preferably, 12 equiv.) portions DL� obtain CH 2N2in situ. After about 0.5-2.0 hours (preferably about 0.5 hour), the layers were separated, and the organic layer is slowly added to a solution of appropriately substituted acid chloride (preferably 1 equiv.) in an organic solvent (such as THF, 1,4-dioxane or Et2O, preferably THF) at a temperature of about-20-20°C (preferably about 0°C). The obtained reaction mixture was stirred for about 0.5-2.0 hours (preferably about 0.5 hour at a temperature of about-20-20°C (preferably about 0°C. before dropwise added 48% aqueous HBr solution (10-40 equiv., preferably, 14 equiv.). After about 15-30 minutes, preferably, about 15 min) the reaction mixture obtained was washed with saline solution after the optional addition of an organic solvent (such as EtOAc). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure LL.1

Example No. LL.1.1: (R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate

To a mixture of 45% water�th KOH solution (30 ml, 2,70 mmol) and Et2O (100 ml) at a temperature of about 0°C. portionwise added 1-methyl-3-nitro-1-nitrosoguanidine (5.0 g, 34 mmol, TCI). After about 30 min the layers were separated, and the organic layer is slowly added to a solution of (R)-(9H-fluoren-9-yl)methyl 3-(chlorocarbonyl)piperidine-1-carboxylate (1.0 g, 2.7 mmol) obtained using W from (R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-3-carboxylic acid (Fluka) in THF (10 ml). The obtained reaction mixture was slowly stirred for about 30 minutes at a temperature of about 0°C. before dropwise added 48% aqueous HBr solution (2.0 ml, 37 mmol). After about 15 minutes, the reaction mixture obtained was washed with brine (2×100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding (R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate (1.10 g, 95%) as a clear oil: LC/MS (table 2, Method a) Rt=2,59 min; MS m/z: 428/430 (M+H)+.

General procedure LL.2: Getting promotility of chloride using trimethylsilyldiazomethane

A solution of appropriately substituted acid chloride (preferably 1 equiv.) in an organic solvent (such as THF, MeCN, Et2O or THF/MeCN, preferably, THF/MeCN) was added to a solution of 2.0 M trimethylsilyldiazomethane (2 M in Et2O) (2-10 equiv., �predpochtitelno, 4 equiv.) at a temperature of about-20-20°C (preferably about 0°C) in a suitable organic solvent, such as THF, MeCN, Et2O or THF/MeCN, preferably, THF/MeCN). The obtained reaction mixture was stirred for about 0.5-5 hours (preferably about 4 hours) at a temperature of about-20-20°C (preferably about 0°C. before dropwise added 48% aqueous HBr solution (5-40 equiv., preferably, 10 equiv.). Approximately 0-30 min (preferably about 0 min) the reaction mixture obtained was concentrated to dryness, yielding the desired product, or optionally washed with saline solution after the optional addition of an organic solvent (such as EtOAc). In cases where the obtained reaction mixture is treated with water, the organic layer dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The raw material is not necessarily clear, using precipitation, crystallization, and/or grind thoroughly with a suitable solvent (or solvents) and/or using chromatography, obtaining the target compound.

Illustration of General procedure LL.2

Example No. LL.2.1 (R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate

(R)-(9H-fluoren-9-yl)methyl 3-(chlorocarbonyl)piperidine-1-carboxylate (4,21 �, of 11.4 mmol, obtained using W from (R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)piperidine-3-carboxylic acid [Fluka]) was dissolved in a mixture of THF and MeCN (1:1, 16 ml) and added to a solution trimethylsilyldiazomethane (2 M in Et2O, 22,8 ml, 45.5 mmol) and THF/MeCN (1:1, 16 ml) at a temperature of about 0°C. the resulting mixture was stirred at a temperature of about 0°C for about 4 hours followed by dropwise addition of HBr (48% aqueous solution of 6.2 ml, 114 mmol). The organic solvents were removed, and the resulting precipitate was collected by filtration and air dried, yielding (R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate (4,46 g, 92%): LC/MS (table 2, Method a) Rt=2,59 min; MS m/z: 428/430 (M+H)+.

General procedure MM: Recovery of α,β-unsaturated ketone to allyl alcohol

In a round bottom flask was placed the α,β-unsaturated ketone (preferably 1 equiv.), organic solvent (such as MeOH or EtOH, preferably MeOH) and heptahydrate of cerium chloride(III) (1-2 equiv., preferably, 1.25 equiv.) followed by the addition of portions of a reducing agent such as sodium borohydride (1-2 equiv., preferably, 1.25 equiv.). The resulting mixture was stirred at room temperature for about 5-24 hours (preferably about 16 h). The obtained reaction mixture was quenched with an aqueous solution of acid (such as saturated aqueous solution� NH 4Cl). The resulting mixture was stirred for about 5-30 min (preferably about 10 min), followed by the addition of organic solvent (such as Et2O). The layers were separated, and the aqueous layer extracted with an organic solvent (such as Et2O). The combined organic layers washed with a saturated aqueous solution of NaHCO3, dried over anhydrous Na2SO4orMgSO4, filtered and concentrated to dryness under reduced pressure. Raw material optionally further purified using precipitation, crystallization, or grind thoroughly with a suitable solvent (or solvents) or using chromatography, obtaining the target compound.

Illustration of General procedure MM

Example No. MM.1: CIS - and TRANS-ethyl-4-hydroxy-2-Methylcyclopentane-2-enecarboxylate

In a round bottom flask was placed ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (2,04 g, 12.1 mmol, example No. CC.1), MeOH (30 ml), and heptahydrate of cerium chloride(III) (5,65 g, 15.2 mmol) followed by the addition in portions sodium borohydride (0,574 g, 15.2 mmol). The resulting suspension was stirred at room temperature for about 16 hours. Add a saturated aqueous solution of NH4Cl (50 ml). The resulting mixture was stirred for about 10 min and add Et2O (60 ml). Slo� share, and the aqueous layer was extracted with Et2O (3×30 ml). The combined organic layers washed with a saturated aqueous solution of NaHCO3, dried over anhydrous MgSO4, filtered and concentrated to dryness under reduced pressure. The obtained residue was purified using chromatography on silica gel processing, elwira mixture 20-60% EtOAc/pentane, resulting in CIS-ethyl 4-hydroxy-2-Methylcyclopentane-2-enecarboxylate (0.96 g, 46%):1H NMR (400 MHz, CDCl3) δ 5,77-5,71 (m, 1H), 4,63 (m, 1H), 4,28-4,11 (m, 2H), 3,27-3,20 (m, 1H), 2,59 (ush.s, 1H), 2,41-of 2.30 (m, 1H), 2,00 (l,J=14.2 Hz, 1H), 1,79 (d, J=1.2 Hz, 3H), 1,30 (t,J=7,1 Hz, 3H) and TRANS-ethyl 4-hydroxy-2-Methylcyclopentane-2-enecarboxylate (0,69 g, 33%):1H NMR (400 MHz, CDCl3) δ 5,63 (DD,J=a 1.8, and 3.4 Hz, 1H), 4,98 (m, 1H), 4,20-4,11 (m, 2H), 3,60-of 3.53 (m, 1H), 2,57 (DDD,J=4,4, 7,1, 13.9 Hz, 1H), 1.98 m (DDD,J=3,5, 8,4, 13.9 Hz, 1H), 1,80 (l,J=1,4, 3H), 1.46 in (ush.s, 1H), 1,27 (t,J=7,1 Hz, 3H).

Example No. 1: 1-(2-methylcyclohexyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of 5-(4-tert-butylphenylmethyl)-2-hydrazine-5H-imidazo[2,3-b]pyrazine (0.40 g, 1.2 mmol, example No. 3) and DIEA (0.20 ml, 1.2 mmol) in 1,4-dioxane (12 ml) at a temperature of about 0°C was added 2-methylcyclohexanecarboxylic (0.19 g, 1.2 mmol, example No. 4). After completion of the addition, the bath with ice is removed, and the reaction mixture is allowed to warm to room temperature. About� after 1 hour, add SOCl2(0.42 ml, 5.8 mmol) and the reaction mixture is heated at a temperature of about 90°C for about 1 hour. The reaction mixture is allowed to cool to room temperature and then added an aqueous solution of Na2CO3(2 M, with 11.6 ml of 23.2 mmol) and MeOH (12 ml). The reaction mixture is heated at a temperature of about 90°C for about 3 days. The reaction mixture was concentrated under reduced pressure to remove MeOH, and then separated between EtOAc (50 ml) and a saturated aqueous solution of NaHCO3(40 ml). The organic layer was isolated and dried over anhydrous Na2SO4and the solvent concentrated under reduced pressure. The obtained residue is purified on silica gel (12 g) using EtOAc as eluent, and then purified using HPLC with reversed phase (table 2, Method b). The combined product containing fractions concentrated under reduced pressure to remove MeCN and the resulting precipitate collected by vacuum filtration to obtain 1-(2-methylcyclohexyl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine in the form of white solids (0.10 g, 35%): LC/MS (table 2, Method a) Rt=a 1.84 min; MS m/z: 256 (M+H)+.

Example No. 2: 1-(piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Stage A: Benzyl 4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate

Benzyl 4-(chlorocarbonyl)piperidine-1-carboxylate (0.41 grams of 1.4 mmol, example No. 5) was added to a solution of 5-(4-tert-butylphenylmethyl)-2-hydrazine-5H-imidazo[2,3-b]pyrazine (0.50 g, 1.4 mmol, example No. 3) and DIEA (0.25 ml, 1.4 mmol) in 1,4-dioxane (15 ml) at a temperature of about 0°C. After completion of the addition, the bath with ice is removed, and the reaction mixture is allowed to warm to room temperature. After about 1 hour add SOCl2(0.53 ml, 7.2 mmol) and the reaction mixture is heated at a temperature of about 90°C for about 1 hour. The reaction mixture is allowed to cool to room temperature, then added an aqueous solution of Na2CO3(2 M, with 14.5 ml, 29,0 mmol) and the reaction mixture is heated at a temperature of about 90°C for about 3 days. The reaction mixture is separated using EtOAc (50 ml) and saturated aqueous solution of NaHCO3(40 ml). The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The obtained residue is purified on silica gel (12 g), elwira 50-100% EtOAc in heptane to obtain benzyl 4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate in the form of a solid yellow (0,34 g, 61%): LC/MS (table 2, Method a) Rt=1,89 min; MS m/z: 377 (M+H)+.

Stage B: 1-(piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

Benzo�l 4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-carboxylate (0,34 g, of 0.90 mmol) and 10% Pd-on-charcoal (0.10 g, 0.09 mmol) in MeOH (30 ml) is shaken in a hydrogen atmosphere at a pressure of about 414 kPa for about 5 hours. The source of N2removed, and the reaction mixture was filtered through celite may® and concentrated under reduced pressure, yielding 1-(piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine in a solid yellow color (0.18 g, 77%): LC/MS (table 2, Method a) Rt=0,70 min; MS m/z: 243 (M+H)+.

Example 3: 3-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)-3-oxopropanenitrile

To a suspension of 1-(piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0,090 g of 0.37 mmol, example 2) and pyridine (of 0.12 ml, 1.5 mmol) in DMF (5 ml) was added perftoralkil 2-cyanoacetate (0,14 g, 0,56 mmol, example No. 6). After about 3 hours at room temperature, the obtained reaction mixture was quenched using MeOH (0.5 ml) and then purified using HPLC with reversed phase (table 2, Method b). The appropriate fractions and concentrate lyophilizer to obtain 3-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)piperidine-1-yl)-3-oxopropanenitrile in the form of white solids (0.005 g, 4%): LC/MS (table 2, Method a) Rt=1,24 min; MS m/z: 310 (M+H)+.

Example No. 4: 1-(1-(cyclopropylmethyl)piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

� suspension of 1-(piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0,090 g, of 0.37 mmol, example 2) and pyridine (of 0.12 ml, 1.5 mmol) in DMF (5 ml) was added cyclopropanesulfonyl (0,060 g, 0.41 mmol). After about 3 hours at room temperature, the obtained reaction mixture was quenched using MeOH (0.5 ml), and then purified using HPLC with reversed phase (table 2, Method b). The appropriate fractions and concentrate lyophilizer to obtain 1-(1-(cyclopropylmethyl)piperidine-4-yl)-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine in the form of white solids (0.008 g, 6%): LC/MS (table 2, Method a) Rt=1,52 min; MS m/z: 347 (M+H)+.

Example No. 5: 1-cyclohexyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine

To a solution of 5-(4-tert-butylphenylmethyl)-2-hydrazine-5H-imidazo[2,3-b]pyrazine is 0.39 g, 1.1 mmol; example No. 3) and DIEA (0.20 ml, 1.1 mmol) in 1,4-dioxane (12 ml) at a temperature of about 0°C was added cyclohexanecarbonitrile (0.17 g, 1.1 mmol). The reaction mixture is then heated at room temperature for about 1 hour. Add SOCl2(of 0.41 ml, 5.6 mmol) and the reaction mixture heated at about 90°C for about 1 hour. The reaction mixture was cooled to room temperature and slowly added an aqueous solution of Na2CO3(2 M, 12 ml, 24 mmol) followed by the addition of 1,4-dioxane (5 ml). The reaction mixture is heated at a temperature of about 60°C for about 72 h. R�promotional mixture was cooled to room temperature and concentrated under reduced pressure. The crude product is diluted with EtOAc (40 ml) and washed with a saturated aqueous solution of NaHCO3(40 ml) and brine (40 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography with silica gel performing a gradient elution 0-100% heptane/EtOAc (12 g column), and dried in a vacuum thermostat at a temperature of about 55°C for about 18 h, yielding 1-cyclohexyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0,109 g, 40%): LC/MS (table 2, Method a) Rt=of 1.66 min; MS m/z: 242 (M+H)+.

Example No. 6: N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

Stage A: Tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentanecarbonyl

To a mixture of 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (2,50 g, 8,24 mmol, example No. 9) and (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g, 9,07 mmol, Peptech) in DCM (30 ml) was added EDC.HCl (1.90 g, of 9.89 mmol). After about 4.5 hours adding water (30 ml) and the layers were separated. The aqueous layer was then extracted with EtOAc (15 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved� in DCM (15 ml) and purified by column chromatography with silica gel, performing a gradient elution 40-100% EtOAc in heptane, yielding tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentylamine (4.20 g, 97%): LC/MS (table 2, Method a) Rt=2,27 min; MS m/z: 515 (M+H)+.

Step B: Tert-butyl (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine

To a solution of tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentylamine (4,73 g, 9,19 mmol) in 1,4-dioxane (50 ml) was added TEA (5,10 ml, 36.8 mmol) and SOCl2(1.34 ml, 18.4 mmol). The obtained reaction mixture is heated at a temperature of about 80°C. after About 1.5 hours, add a saturated aqueous solution of Na2CO3(100 ml) and heating was resumed at a temperature of about 80°C for about 6 hours. The obtained reaction mixture was cooled to room temperature for about 3 days and then heated at a temperature of about 80°C for about 16 hours. Add water and EtOAc (100 ml each) and the layers were separated. The aqueous layer was then extracted with additional EtOAc (2×100 ml). The combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude solid material triturated with petroleum ether (boiling point 30-60°C; 30 ml), and collec�t vacuum filtration, washing with additional petroleum ether (boiling point 30-60°C; 20 ml) to give tert-butyl (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine in a solid light brown color (2,86 g, 86%): LC/MS (table 2, Method a) Rt=1,75 min; MS m/z: 343 (M+H)+.

Step C: Hydrochloride (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine

To a mixture of tert-butyl (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (1,57 g, 4,59 mmol) in 1,4-dioxane (45 ml) was added HCl (4 M in 1,4-dioxane, 8.0 ml, 32,0 mmol). The obtained reaction mixture is then heated at a temperature of about 60°C. after About 2 hours the reaction mixture obtained was cooled to room temperature, filtered, rinsing with Et2O (50 ml), and the solid product was dried in a vacuum thermostat for a night out at a temperature of about 60°C, obtaining a hydrochloride (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (1,38 g, 95%): LC/MS (table 2, Method a) Rt=0,74 min; MS m/z: 243 (M+H)+.

Step D: N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

To a mixture of the hydrochloride salt of (1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (0.300 g, 0,952 mmol) in DMF (9 ml) was added TEA (0,462 ml of 3.33 mmol�) and cyclopropanesulfonyl (0,097 ml, of 0.95 mmol). After about 1.5 hours at room temperature, the reaction mixture was diluted with water (10 ml) and extracted with DCM (3×15 ml). The combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Raw material is added MeOH (~50 ml) and filtered a small amount of insoluble material (<0.01 g). To the filtrate was added a silica gel (2 g), and the resulting mixture was concentrated under reduced pressure. The mixture was purified with silica gel by column chromatography with silica gel, elwira by stages with a gradient of DCM/MeOH/NH4OH from 990:9:1 to 980:18:2, getting a solid off-white color, which is dried in a vacuum thermostat at a temperature of about 70°C. the Solid product was dissolved in hot MeOH. The resulting material was filtered while it is hot for removal of sediment. The resulting filtrate is treated with ultrasound until it cools to get thin slurry, which was then concentrated under reduced pressure and dried in a vacuum thermostat at a temperature of about 100°C, yielding N-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (of 0.21 g, 64%): LC/MS (table 2, Method a) Rt=1,51 min; MS m/z: 347 (M+H)+.

Example No. 7: N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.]Octan-1-yl)cyclopropanesulfonyl

Stage A: Tert-butyl 4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)bicyclo[2.2.2]octane-1-ylcarbamate

In a round bottom flask was placed 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (3,75 g, 11.1 mmol, example No. 9), 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (3.0 g, 11 mmol, Prime Organics), HATU (to 4.23 g, 11.1 mmol), TEA (6.2 ml, 44 mmol), and DCM (65 ml). The obtained reaction mixture was stirred at room temperature for about 16 hours. The obtained reaction mixture was diluted with water (30 ml) and the layers were separated. The obtained reaction mixture was filtered through celite may® and washed with DCM (60 ml). The organic layer was washed with water (3×50 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography with silica gel performing a gradient elution 0-100% EtOAc in DCM to obtain tert-butyl 4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)bicyclo[2.2.2]octane-1-ylcarbamate in the form of a solid amorphous brown (of 5.38 g, 87%): LC/MS (table 2, Method a) Rt=2,40 min; MS m/z 555 (M+H)+.

Stage B: 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-amine

In a round bottom flask was placed tert-butyl 4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)guide�asynchrony)bicyclo[2.2.2]octane-1-ylcarbamate (to 5.38 g, of 9.40 mmol), SOCl2(0,69 ml of 9.40 mmol), TEA (of 1.57 ml, 11.3 mmol) and 1,4-dioxane (72 ml). The obtained reaction mixture is heated at a temperature of about 80°C for about 2 hours. The obtained reaction mixture was cooled to room temperature, was added EtOAc (100 ml) and the layers were separated. The organic layer was washed with water (3×30 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding the crude mixture of tert-butyl 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]octane-1-ylcarbamate and 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-amine in the form of a solid brown color (8.5 g). To this crude mixture is added HCl (4 n in 1,4-dioxane, 12 ml, 48,0 mmol), and 1,4-dioxane (56 ml). The obtained reaction mixture was stirred at a temperature of about 60°C for about 4 hours. Further added HCl (4 M in 1,4-dioxane, 12 ml, 48,0 mmol) and stirring was continued at a temperature of about 60°C for about 3 hours. The obtained reaction mixture was cooled to room temperature. The resulting precipitate was filtered and washed with Et2O (50 ml). The solid product was stirred with NaHCO3(5% in water, 15 ml) for about 2 hours. The solid product was filtered, washed with water, and dried in a vacuum incubator at a temperature of about 60°C for about 15 hours, yielding 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triaz�lo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-amine in the form of a solid yellow-brown color (2,95 g, 72% over 2 stages): LC/MS (table 2, Method a) Rt=1,57 min; MS m/z 437 (M+H)+.

Step C: N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl

In a round bottom flask was placed 4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-amine (0.40 g, at 0.92 mmol), TEA (of 0.51 ml, 3.7 mmol) in DCM (3 ml) and DMF (6 ml). Added dropwise cyclopropanesulfonyl (0.16 g, 1.1 mmol) and the resulting suspension was stirred at room temperature for about 18 hours. The solvent was removed under reduced pressure and added DCM (10 ml). The crude material is purified by column chromatography with silica gel performing a gradient elution 0-10% MeOH/DCM, yielding N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl (0.27 g, 55%): LC/MS (table 2, Method a) Rt=2,14 min; MS m/z 541 (M+H)+.

Step D: N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl

In a round bottom flask was placed N-(4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl (0.27 g, 0.50 mmol), aqueous NaOH (1 n, 1.0 ml, 1.0 mmol) and 1,4-dioxane (8 ml). The obtained reaction mixture was stirred at a temperature of about 60°C for about�ARD 2 hours. Add NH4OAc (50 mm aqueous buffer, 2 ml) and DMF (7 ml), and insoluble material is removed using filtration. The filtrate obtained is purified using HPLC with reversed phase (table 2, Method c). The appropriate fractions were combined, the organic solvent was concentrated under reduced pressure, the resulting solid material is collected by filtration, washed with water (20 ml) and lyophilizers, yielding N-(4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl in the form of a solid (0.11 g, 56%): LC/MS (table 2, Method a) Rt=of 1.53 min; MS m/z 387 (M+H)+.

Example No. 8: 7-cyclohexyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine

Stage A: Tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate

The flask is placed Pd2(dba)3(1.3 g, of 1.42 mmol), di-tert-butyl-(2',4',6'-triisopropylsilyl-2-yl)Foshan (1.21 g, of 2.84 mmol) and 1,4-dioxane (75 ml). A mixture of the catalyst-ligand Tegaserod using the cycle vacuum/purge with nitrogen (3 times) and heated at a temperature of about 80°C for about 10 min Then added 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (5.0 g, 14.2 mmol, example No. 7), tert-BUTYLCARBAMATE (2.5 g, 21,29 mmol) and NaOt-Bu (2.05 g, 21,29 mmol). After an additional cycle vacuum/nitrogen purge, the reaction mixture was heated at EVAP�re about 80°C for about 16 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (70 ml). The reaction mixture was filtered, and the filtrate obtained was washed with water (3×20 ml). The organic layer is dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure, obtaining a solid reddish-brown color. The crude material is purified using chromatography on silica gel processing, performing a gradient elution with 10-50% EtOAc in heptane, resulting in tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate in the form of an amorphous yellow substance (1.0 g, 18%): LC/MS (table 2, Method a) Rt=2,63 min; MS m/z: 389 (M+H)+.

Step B: Hydrochloride 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-amine

Tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate (1.00 g, 2.57 mmol) was treated according to General procedure I to obtain the hydrochloride of 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-amine (0.40 g, 54%): LC/MS (table 2, Method a) Rt=to 1.94 min; MS m/z: 289 (M+H)+.

Step C: 7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine

To a suspension of the hydrochloride of 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-amine (0.10 g, 0.35 mmol) and 2-bromo-1-cyclohexylethane (0,078 g, 0.38 mmol, 3B Pharmachem) in n-BuOH (1.5 ml) was added DIEA (0,067 g, 0.52 mmol) and the resulting solution is heated at a temperature of about 17°C in a CEM™ for about 30 min. The solvent was removed under reduced pressure to obtain 7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine in the form of a crude solid which is used in stage D without further purification: LC/MS (table 2, Method a) Rt=2,71 min; MS m/z: 395 (M+H)+.

Step D: 7-cyclohexyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine

7-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine (0.13 g, 0.33 mmol) was dissolved in 1,4-dioxane (5 ml) and added aqueous NaOH (2 n, 0.5 ml). The resulting mixture was heated at boiling to reflux for about 30 min the Organic solvent was removed under reduced pressure. The aqueous phase is neutralized using 1 n HCl aqueous solution and extracted with EtOAc (2×25 ml). The combined organic extracts were washed with brine (15 ml), dried over anhydrous MgSO4, and concentrated under reduced pressure. The obtained residue was purified using HPLC with reversed phase (table 2, Method h), resulting in 7-cyclohexyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine in a solid off-white color (0,011 g, 14%): LC/MS (table 2, Method a) Rt=2,06 min; MS m/z: 241 (M+H)+.

Example # 9: 8-cyclohexyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine

Stage A: Tert-butyl 2-cyclohexyl-2-oxoethyl-(5-tosyl-5H-pyrrol�[2,3-b]pyrazine-2-yl)carbamate

NaH (60% in mineral oil, 0,020 g, 0.49 mmol) was added to dry DMF (3 ml). The resulting suspension was cooled to about 0°C. and dropwise added a solution of tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate (0.19 g, 0,489 mmol, example # 8, step A) in dry DMF (2 ml). The reaction mixture was allowed to warm to room temperature and was added 2-bromo-1-cyclohexylethane (0.10 g, 0.49 mmol, 3B PharmaChem). The obtained reaction mixture was stirred for about 2 hours, and then concentrated under reduced pressure. As a result of purification using flash chromatography on silica gel with the elution 100% heptane for 10 min, then with a gradient of 10-20% EtOAc in heptane over 20 min receive tert-butyl 2-cyclohexyl-2-oxoethyl(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)carbamate in the form of an amorphous yellow substance (0,080 g, 32%): LC/MS (table 2, Method a) Rt=3,13 min; MS m/z: 513 (M+H)+.

Step B: 8-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine

Concentrated H2SO4(4 ml) was added to tert-butyl 2-cyclohexyl-2-oxoethyl-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)carbamate (0.07 g, 0.14 mmol) and the reaction mixture was stirred for about 30 min at room temperature. The reaction mixture was poured into ice water (75 ml) and extracted with EtOAc (2×50 ml). United about�egy for organic extracts washed with brine, dried over anhydrous MgSO4and concentrated, resulting in 8-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine in the form of a yellow oil, which was used in example No. 9, in step C without further purification (0,051 g, 95%): LC/MS (table 2, Method a) Rt=2,79 min; MS m/z: 395 (M+H)+.

Step C: 8-cyclohexyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine

Aqueous NaOH (2 n, 0.3 ml) was added to 8-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine (0,051 g, 0.13 mmol) in 1,4-dioxane (3 ml), and the resulting mixture heated at the boiling to reflux for about 1 hour. The organic solvent was removed under reduced pressure, and the aqueous phase is neutralized with an aqueous solution of 1 n HCl and extracted with EtOAc (2×15 ml). The combined organic extracts were washed with brine (1×10 ml), dried over anhydrous MgSO4and concentrated in vacuo. The residue was again suspended in MeCN (2 ml) and the resulting precipitate was collected by filtration and dried, resulting in 8-cyclohexyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine in a solid yellow-brown color (0.006 g, 19%): LC/MS (table 2, Method a) Rt=2,12 min; MS m/z: 241 (M+H)+.

Example # 10: 1-cyclohexyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

Stage A: (E)-2-styryl-5-tosyl-5H-imidazo[2,3-b]pyrazine

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To a solution of 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (3.1 g, 8.8 mmol, example No. 7), PdCl2(dppf).DCM (0,719 g, 0,880 mmol) and (E)-styrylboronic acid (2,60 g, a 17.6 mmol) in THF (3 ml) and water (2 ml) was added Na2CO3(2.33 g, 22,0 mmol). The obtained reaction mixture Tegaserod argon for about 5 min the reaction mixture Obtained is heated to about 50°C. after Approximately 24 hours, the obtained reaction mixture is added additionally PdCl2(dppf).DCM (0,719 g, 0,880 mmol), (E)-styrylboronic acid (2,60 g, a 17.6 mmol) and Na2CO3(2.33 g, 22,0 mmol). After heating at a temperature of about 50°C for about 48 h, the reaction mixture obtained was cooled to room temperature and diluted with DCM (200 ml) and water (200 ml). The organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purify by column chromatography with silica gel performing a gradient elution of 20-60% EtOAc in heptane containing 5% DCM, yielding (E)-2-styryl-5-tosyl-5H-imidazo[2,3-b]pyrazine in a solid yellow (1.2 g, 36%). LC/MS (table 2, Method a) Rt=2,99 min; MS m/z: 376 (M+H)+.

Stage B: 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde

To a solution of (E)-2-styryl-5-tosyl-5H-imidazo[2,3-b]pyrazine (1.2 g, 3.2 mmol) in 1,4-dioxane (20 ml) � water (2.0 ml) is added sodium periodate (2,73 g, of 12.8 mmol) followed by the addition of osmium tetroxide (2.5% in t-BuOH, 4,01 ml, 0,320 mmol). After about 1 day at room temperature, add a further quantity of sodium periodate (2,73 g of 12.78 mmol) and osmium tetroxide (2.5% in t-BuOH, 4,01 ml, 0,320 mmol). After about 2 days, add a water solution of Na2S2O3(100 ml) and EtOAc (100 ml). The organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting solid material is triturated with heptane to remove benzaldehyde. The resulting solid material was dried under vacuum to give 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde in a solid brown color (0.77 g, 80%): LC/MS (table 2, Method a) Rt=2,01 min; MS m/z: 334 (M+H)+.

Step C: N-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)cyclohexanecarboxylic

To a solution of 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde (0,150 g, 0,498 mmol) in MeOH (10 ml) was added hydroxylamine (50% solution in water, 0,061 ml, 1.0 mmol). The obtained reaction mixture is heated to about 45°C. after About 2 hours the reaction mixture obtained was cooled to room temperature and concentrated under reduced pressure, yielding crude 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde in a solid yellow-brown color. LC/MS(table 2, Method (a) Rt=2,15 min; MS m/z: 317 (M+H)+. To a solution of the crude oxime in THF (20 ml) was added AcOH (0,285 ml, 4,98 mmol) followed by the addition of zinc dust (<10 micron, 0,130 g, 1.99 mmol). After another 2 hours to the resulting reaction mixture is added an additional amount of AcOH (0,285 ml, to 4.98 mmol) and zinc dust (<10 micron, 0,130 g, 1.99 mmol). After another 2 hours to the resulting reaction mixture is added an additional amount of AcOH (0,285 ml, to 4.98 mmol) and zinc dust (<10 micron, 0,130 g, 1.99 mmol). After about 15 hours, the obtained reaction mixture is diluted with DCM (5 ml) and filtered. The filtrate obtained was washed with a saturated aqueous solution of NaHCO3and saline. The organic layer was dried over anhydrous Na2SO4, filtered, treated with HCl (4 M in 1,4-dioxane, 1 ml) and concentrated under reduced pressure, obtaining a hydrochloride (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine: LC/MS (table 2, Method a) Rt=of 1.64 min; MS m/z: 303 (M+H)+. To a suspension of crude americanled in DCM (10 ml) was added TEA (0,208 ml, 1.49 mmol) followed by the addition of cyclohexanecarbonitrile (0,101 ml, 0,747 mmol). After about 30 minutes, the obtained reaction mixture is diluted with DCM and washed with a saturated aqueous solution of NaHCO3(25 ml) and brine (25 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under�igenom pressure. The crude amide is purified by column chromatography with silica gel performing a gradient elution 40-80% EtOAc in DCM, yielding N-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)cyclohexanecarboxylic in a solid yellow-brown color (0,081 g, 39% over 2 stages). LC/MS (table 2, Method a) Rt=2,40 min; MS m/z: 413 (M+H)+.

Stage D: 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

To a solution of N-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)cyclohexanecarboxylate (0,081 g, 0,196 mmol) in THF (1 ml) at room temperature is added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (0,104 g, 0,196 mmol, TCI). After about 15 h, the reaction mixture obtained was concentrated under reduced pressure. The resulting residue suspended in EtOAc/DCM (1:1) and filtered through a cake of silica gel (5 g), elwira EtOAc/DCM (1:1, approximately 100 ml). As a result of concentrating the obtained filtrate get crude N-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)cyclohexanecarboxylic. Raw tioned dissolved in THF (1 ml) and added diacetoacetate (0,0626 g, 0,196 mmol). After about 30 min at room temperature, add additional diacetoacetate (0,0626 g, 0,196 mmol). After about 4 hours the reaction mixture obtained is diluted with EtOAc, filtered, concentrated under reduced pressure and purified on �hromatograficheskaja a column of silica gel, performing a gradient elution 50-95% EtOAc in heptane, yielding 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine in the form of a yellow oil (0,020 g, 25%): LC/MS (table 2, Method a) Rt=2,77 min; MS m/z: 395 (M+H)+.

Step E: 1-cyclohexyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

To a solution of 1-cyclohexyl-6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (0,020 g, 0,051 mmol) in 1,4-dioxane (3 ml) was added aqueous NaOH (2 n, 0,380 ml, 0,760 mmol). The obtained reaction mixture is heated at about 90°C. after 5 hours the reaction mixture obtained was cooled to room temperature, diluted with EtOAc (10 ml) and a saturated aqueous solution of NH4Cl (10 ml). The organic layer was isolated and washed with water (10 ml), then brine (10 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding 1-cyclohexyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine in a solid yellow-brown color (0,011 g, 90%): LC/MS (table 2, Method a) Rt=1,92 min; MS m/z: 241 (M+H)+.

Example No. 11: 8-cyclohexyl-3H-dipyrrole[1,2-a:2',3'-e]pyrazine

Stage A: (E)-1-cyclohexyl-3-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)prop-2-EN-1-he

To a solution of diethyl 2-cyclohexyl-2-oxoethylidene (0,609 g, 2,32 mmol) in THF (10 ml) �dobavlaut NaH (60% dispersion in mineral oil, 0,0664 g of 1.66 mmol). After about 30 minutes, add a solution of 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde (0.20 g, 0.64 mmol, example No. 10, step B) in THF (10 ml). After about 2 hours, the obtained reaction mixture was added EtOAc (50 ml) and a saturated aqueous solution of NH4Cl (50 ml). The organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was triturated with IPA (20 ml) to give (E)-1-cyclohexyl-3-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)prop-2-EN-1-he's in a solid yellow-brown color (0.20 g, 73%): LC/MS (table 2, Method a) Rt=3,06 min; MS m/z: 410 (M+H)+.

Stage B: 1-cyclohexyl-3-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)propane-1-he

To a solution of (E)-1-cyclohexyl-3-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)prop-2-EN-1-one (0.050 g, 0.12 mmol) in EtOAc (5 ml) was added palladium (10% on carbon, 0,0065 g, 0,0061 mmol). The obtained reaction mixture was purged with hydrogen, and the hydrogen atmosphere support, using a balloon. After about 1 hour at room temperature, the obtained reaction mixture was filtered and concentrated under reduced pressure, yielding 1-cyclohexyl-3-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)propane-1-it is in the form of oil (0.050 g, 100%): LC/MS (table 2, Method a) Rt=2,94 min; MS m/z: 412 (M+H)+.

Step C: 8-cyclohexyl-3-tosyl-3H-dipyrrole�[1,2-a:2',3'-e]pyrazine

To a solution of 1-cyclohexyl-3-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)propane-1-one (0.050 g, 0.12 mmol) in THF (2 ml) was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (0,071 g, 0.13 mmol, TCI). After about 6 hours at room temperature, the obtained reaction mixture is diluted with EtOAc (50 ml) and NaHCO3(50 ml). The organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography with silica gel performing a gradient elution from 40 to 90% EtOAc in heptane, getting 8-cyclohexyl-3-tosyl-3H-dipyrrole[1,2-a:2',3'-e]pyrazine in a solid yellow-brown color (0,020 g, 42%). LC/MS (table 2, Method a) Rt=3,39 min; MS m/z: 394 (M+H)+.

Step D: 8-cyclohexyl-3H-dipyrrole[1,2-a:2',3'-e]pyrazine

To a solution of 8-cyclohexyl-3-tosyl-3H-dipyrrole[1,2-a:2',3'-e]pyrazine (0.015 g, 0,038 mmol) in 1,4-dioxane (3 ml) was added aqueous NaOH (2 n, and 0.29 ml of 0.57 mmol). The obtained reaction mixture is heated at about 90° C. after About 15 hours the reaction mixture obtained was cooled to room temperature and diluted with EtOAc (5 ml) and a saturated aqueous solution of NH4Cl (5 ml). The organic layer is isolated, washed with water (5 ml) then brine (5 ml), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The obtained residue was triturated with a mixture of EtOAc/heptane (1:1, 1 ml). The resulting solid material is collected by filtration and dried under vacuum to yield 8-cyclohexyl-3H-dipyrrole[1,2-a:2',3'-e]pyrazine in a solid yellow-brown color (0.005 g, 55%). LC/MS (table 2, Method a) Rt=2,78 min; MS m/z: 240 (M+H)+.

Example No. 12 N-(4-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl

Stage A: Tert-butyl 4-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methylcarbamoyl)bicyclo[2.2.2]octane-1-ylcarbamate

To a solution of 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde (0.49 g, 1.6 mmol, example No. 10, step B) in MeOH (10 ml) was added hydroxylamine (50% in water, 0,199 ml, 3.25 mmol). The obtained reaction mixture is heated to about 40°C. after About 2 hours the reaction mixture obtained was cooled to room temperature and concentrated under reduced pressure. To a solution of the crude oxime in THF (10 ml) and AcOH (with 0.93 ml, 16 mmol) was added zinc dust (<10 micron, 0,425 g, 6.50 mmol). After about 4 hours at room temperature, the obtained reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3andfiltered through celite may®. The layers were separated, and the organic layer dried over baie�water Na 2SO4, filtered, treated with HCl (4 n in 1,4-dioxane, 1 ml) and concentrated under reduced pressure. To a solution of crude amine in DCM (10 ml) was added 4-(tert-butoxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylic acid (of 0.48 g, 1.8 mmol, Prime Organics), TEA (of 0.23 ml, 1.6 mmol) and HATU (of 0.618 g, 1,63 mmol). After about 4 hours at room temperature, the obtained reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3andfiltered through celite may®. The layers were separated, and the organic layer dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude amide is purified by column chromatography with silica gel performing a gradient elution 20-80% EtOAc in DCM, yielding tert-butyl-4-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methylcarbamoyl)bicyclo[2.2.2]octane-1-ylcarbamate in a solid yellow-brown color (0,205 g, 23%). LC/MS (table 2, Method a) Rt=2,52 min; MS m/z: 554 (M+H)+.

Step B: Tert-butyl 4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]octane-1-ylcarbamate

To a solution of tert-butyl 4-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methylcarbamoyl)bicyclo[2.2.2]octane-1-ylcarbamate (0,205 g, 0,370 mmol) in THF (5 ml) was added 2,4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (0,215 g, 0,407 mmol, TCI America). After about 15 h at room Tempe�the atur to the resulting reaction mixture was added diacetoacetate (0,295 g, 0,926 mmol). After about 2 hours, the obtained reaction mixture is diluted with EtOAc (30 ml) and filtered through celite may®. The filtrate obtained is concentrated under reduced pressure, and the crude mixture purified by column chromatography with silica gel performing a gradient elution 20-80% EtOAc in DCM, yielding tert-butyl 4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]octane-1-ylcarbamate in a solid yellow-brown color (0.175 g, 84%). LC/MS (table 2, Method a) Rt=2,84 min; MS m/z: 536 (M+H)+.

Step C: N-(4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl

Into a flask containing tert-butyl 4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]octane-1-ylcarbamate (0.175 g, 0,327 mmol) was added a solution of HCl (4 n in 1,4-dioxane, 5 ml). After about 2 hours at room temperature the reaction mixture obtained was concentrated under reduced pressure. Crude amidohydrolase dissolved in DCM (10 ml) and to the resulting reaction mixture was added TEA (of 0.36 ml, 2.6 mmol) followed by the addition of cyclopropanemethylamine (0.18 g, 1.3 mmol). After about 2 hours at room temperature is added DMF (3 ml) and the resulting reaction mixture was concentrated under reduced pressure to remove DCM. Then after about 4 hours at room temperature, � obtained reaction mixture was added EtOAc (20 ml) and saturated aqueous solution of NaHCO 3(20 ml). The organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography with silica gel, using 20-80% EtOAc in DCM, yielding N-(4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl in a solid yellow-brown color (0.025 g, 14%). LC/MS (table 2, Method a) Rt=2,34 min; MS m/z: 540 (M+H)+.

Step D: N-(4-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl

To a solution of N-(4-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanecarboxamide (0.025 g, 0.046 mmol) in 1,4-dioxane (3 ml) was added aqueous NaOH (2 n, 0.35 ml, of 0.70 mmol). The obtained reaction mixture is heated to about 90°C. after About 6 hours, the reaction mixture obtained was cooled to room temperature and add EtOAc (3 ml) and a saturated aqueous solution of NH4Cl (1.5 ml). The layers were separated, and the organic layer was washed with water (1.5 ml), then brine (1.5 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding N-(4-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)bicyclo[2.2.2]Octan-1-yl)cyclopropanesulfonyl in a solid yellow-brown color (0,012 �, 67%). LC/MS (table 2, Method a) Rt=1.65 V min; MS m/z: 386 (M+H)+.

Example No. 13: 3-((3R,4R)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-demerol-1-yl)-3-oxopropanenitrile

Stage A: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

A solution of 2-bromo-5H-imidazo[2,3-b]pyrazine (78,0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 ml) was added, dropwise, over about 60 min to a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g, 532 mmol) in anhydrous DMF (543 ml) at a temperature of about 0-5°C. the Reaction brown solution was stirred for about 30 min at a temperature of about 0-5°C. and Then added dropwise a solution of p-toluensulfonate (94,0 g, 492 mmol) in anhydrous DMF (272 ml) for about 60 minutes at a temperature of about 0-5°C. the reaction mixture Obtained is stirred at a temperature of about 0-5°C for about 1 hour, then allowed to warm to room temperature and stirred for about 18 hours at room temperature. The obtained reaction mixture was slowly poured into ice water (6 l), followed by the addition of aqueous NaOH (2.5 M, 50,0 ml, 125 mmol). The resulting precipitate was collected by filtration and stirred with cold water (3×200 ml). The solid product is collected by filtration and dried to constant weight in a vacuum incubator at a temperature of �Colo at 55°C, resulting in 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine: (134,6 g, 97%) as a solid beige color: LC/MS (table 2, Method d) Rt=to 1.58 min; MS m/z: 352/354 (M+H)+.

Step B: (E)-2-styryl-5-tosyl-5H-imidazo[2,3-b]pyrazine

To a solution of 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (75 g, 213 mmol), adduct PdCl2(dppf)-CH2Cl2(8,69 g, 10.6 mmol) and (E)-styrylboronic acid (39,4 g, 266 mmol) in THF (600 ml) was added Na2CO3(of 27.1 g, 256 mmol) and water (300 ml). The obtained reaction mixture Tegaserod nitrogen for about 45 min the reaction mixture Obtained is heated at about 65°C for about 16 hours, then add adduct PdCl2(dppf)-CH2Cl2(3.50 g, 4,29 mmol). After about 18 hours, the reaction mixture was cooled to room temperature. The layers were separated, and the organic layer was concentrated under reduced pressure. The obtained residue was triturated with EtOH (300 ml)/DCM (100 ml) and filtered. The resulting precipitate was triturated with hot EtOH (400 ml) and filtered, then washed with EtOH (200 ml) and Et2O (400 ml). The resulting filtrates were combined, concentrated under reduced pressure, and the obtained residue was triturated with EtOH (300 ml)/DCM (100 ml) and stirred over night, providing the opportunity to slowly evaporate DCM. The resulting mixture was filtered and washed with EtOH (100 ml) and Et2 O (100 ml), receiving a second batch. The combined filter cakes are dried in vacuum to give (E)-2-styryl-5-tosyl-5H-imidazo[2,3-b]pyrazine (72,7 g, 91%) as a solid yellow-brown: LC/MS (table 2, Method a) Rt=2,66 min; MS m/z: 376 (M+H)+.

Stage C: 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde

To a solution of (E)-2-styryl-5-tosyl-5H-imidazo[2,3-b]pyrazine (72,3 g, 193 mmol) in 1,4-dioxane (1500 ml) and water (300 ml) was added NaIO4(165 g, 770 mmol), was then added OsO4(5.00 g, 19.7 mmol). The reaction mixture was stirred at a temperature of about 25°C for about 16 hours. The reaction mixture was concentrated under reduced pressure, and then separated using 10% aqueous solution of Na2S2O3(1000 ml) and DCM (1000 ml). The organic layer was washed with water (2×500 ml), filtered and the layers to remove nerastvorimogo sediment, and share. The organic layer was dried over anhydrous Na2SO4, filtered through celite may®, and concentrated. The obtained residue was purified by filtration through a layer of silica gel (1000 g), elwira 0-5% EtOAc in DCM. The obtained fraction was concentrated, and the solid product triturated with heptane. The resulting mixture was filtered, and the filter cake was washed with heptane. The specified procedure is repeated in order to collect nerastvorim sediment. The solid material is collected,then dissolved in 2% EtOAc in DCM and passed through a layer of silica gel (100 g), elwira 2% EtOAc in DCM. The filtrate obtained is concentrated under reduced pressure. Two batches were pooled, yielding 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde (39,1 g, 67%) as a solid substance is not white: LC/MS (table 2, Method a) Rt=2,17 min; MS m/z: 302 (M+H)+.

Step D: (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methanol

To a solution of 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carbaldehyde (37,6 g, 125 mmol) in EtOH (500 ml) and 1,4-dioxane (500 ml) was added NaBH4(4.72 in g, 125 mmol) in one portion. After about 3 hours to the resulting reaction mixture was slowly added an aqueous solution of HCl (1 n, 400 ml). The resulting mixture was concentrated to half the original volume under reduced pressure, and to this mixture was added EtOAc (1000 ml) and water (500 ml). The layers were separated, and the aqueous layer was extracted with EtOAc (500 ml). The combined organic layers dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure, yielding (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methanol (35,9 g, 95% yield) as a solid yellow-brown: LC/MS (table 2, Method a) Rt=1,97 min; MS m/z: 304 (M+H)+.

Step E: 2-(azidomethyl)-5-tosyl-5H-imidazo[2,3-b]pyrazine

To a solution of (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methanol (35,8 g, 118 mmol) in DCM (600 ml) was added SOCl2(21.5 ml, 295 mmol. After about 4 hours at room temperature add additional SOCl2(at 8.60 ml, 118 mmol). After about 16 hours the reaction mixture was concentrated under reduced pressure and washed with a saturated aqueous solution of NaHCO3(1000 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was dissolved in DCM (600 ml) and treated again SOCl2(of 21.51 ml, 295 mmol). After about 16 hours at room temperature, the reaction mixture is concentrated under reduced pressure, then added DCM (500 ml) and saturated aqueous solution of NaHCO3(500 ml). The layers were separated, and the organic layer dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. To the resulting residue was added DMF (500 ml) was then added NaN3(38,3 g, 589 mmol). After about 16 hours at room temperature, add EtOAc (500 ml) and the organic solution was washed with a mixture of water:brine (1:1, 2000 ml). The layers were separated, and the aqueous layer was then extracted with EtOAc (500 ml). The combined organic layers washed with brine (3×1000 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding 2-(azidomethyl)-5-tosyl-5H-imidazo[2,3-b]pyrazine (32,65 g, 82% yield) as a solid yellow-brown: LC/MS (table , Method (a) Rt=2,31 min; MS m/z: 329 (M+H)+.

Stage F: Hydrochloride (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine

To a solution of 2-(azidomethyl)-5-tosyl-5H-imidazo[2,3-b]pyrazine (32,6 g, 99,0 mmol) in THF (100 ml) and water (50 ml) was added Ph3P (31,3 g, 119 mmol). The obtained reaction mixture was heated at about 45°C for about 16 hours. The resulting mixture is allowed to cool to room temperature followed by removal of THF under reduced pressure. The obtained mixture was separated between EtOAc (500 ml) and brine (250 ml), dried over anhydrous Na2SO4and filtered. The resulting filtrate is diluted with EtOAc to 1 l total volume. To the rapidly stirred solution was added, dropwise, 4 n HCl (4 n in dioxane, 30,0 ml, 120 mmol), leading to the formation of a precipitate of yellow-brown color. Add MeOH (10 ml), and the resulting mixture was filtered through about 15 minutes the resulting precipitate was triturated with Et2O (1000 ml) for about 10 min, filtered and washed with Et2O (500 ml), obtaining hydrochloride (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine (32.0 g, 90%) as a solid yellow-brown: LC/MS (table 2, Method a) Rt=1,44 min; MS m/z: 303 (M+H)+.

Stage G: 1-(tert-butoxycarbonyl)-4-demerol-3-carboxylic acid

Hydrochloride 4-meth�nicotinebuy acid (5.00 g, of 36.5 mmol, ASDI) and platinum oxide(IV) (0.35 g, 1.54 mmol) is shaken in AcOH (100 ml) under hydrogen pressure of about 414 kPa for about 72 hours. The obtained reaction mixture was filtered through celite may® and concentrated under reduced pressure, yielding the hydrochloride of 4-demerol-3-carboxylic acid (7.4 g, containing residual AcOH), which is used further without further purification. To a solution of acid (7,40 g, 36.4 mmol) and NaHCO3(15,3 g, 182 mmol) in MeCN (75 ml) and water (125 ml) was added Boc2O (11,0 ml of 47.3 mmol). The reaction mixture was stirred at a temperature of about 25°C for about 16 hours. The obtained reaction mixture is diluted with Et2O (100 ml) and acidified to pH 1 using 4 n HCl aqueous solution. The layers were separated, and the organic solution was washed with brine (2×100 ml), dried over anhydrous Na2SO4, filtered and concentrated. Formed a white solid, which was triturated with heptane and collected by vacuum filtration, yielding 1-(tert-butoxycarbonyl)-4-demerol-3-carboxylic acid (5.2 g, 58% over 2 stages): LC/MS (table 2, Method a) Rt=2,01 min; MS m/z: 242 (M-H)-.

Stage H: Tert-butyl 4-methyl-3-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methylcarbamoyl)piperidine-1-carboxylate

To a suspension of the hydrochloride (5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine (29,6 g, 87,0 mmol, stud�I (F), 1-(tert-butoxycarbonyl)-4-demerol-3-carboxylic acid (21,2 g, 87,0 mmol, step G) and HATU (33.2 g, 87,0 mmol) in DCM (400 ml) was added DIEA (46,0 ml, 263 mmol). After stirring for about 18 hours at room temperature, the reaction mixture obtained was washed with a saturated aqueous solution of NaHCO3(400 ml). The organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography with silica gel (330 g column), performing a gradient elution with 50-100% EtOAc in heptane, yielding tert-butyl 4-methyl-3-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 95%) as a foam yellow-brown: LC/MS (table 2, Method a) Rt=2,38 min; MS m/z: 528 (M+H)+.

Step I: Tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-methyl-3-((5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)methylcarbamoyl)piperidine-1-carboxylate (44 g, 83 mmol) in 1,4-dioxane (500 ml) was added a Reagent Lawson (20.2 g, a 50.0 mmol). The reaction mixture is heated at a temperature of about 80°C for about 1 hour. The reaction mixture is allowed to cool to room temperature, then add diacetoacetate (26,6 g, 83,0 mmol). After about 1 hour, add additional�Uo diacetoacetate patients (13.3 g, 42.0 mmol). After about 15 minutes, the reaction mixture was poured into a stirred EtOAc (2 l). After 15 min, the reaction mixture was filtered through celite may®, and the filtrate obtained is concentrated under reduced pressure. The obtained residue was triturated with EtOAc (500 ml) and filtered. The filtrate obtained is concentrated under reduced pressure and purified by column chromatography with silica gel (330 g column), performing a gradient elution with 10-50% EtOAc in heptane, yielding tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)piperidine-1-carboxylate (19 g, 44%) in the form of white solids: LC/MS (table 2, Method a) Rt=2,57 min; MS m/z: 510 (M+H)+.

Stage J: Tert-butyl 3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-demerol-1-carboxylate

To a solution of tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)piperidine-1-carboxylate (19.0 g, of 37.3 mmol) in 1,4-dioxane (100 ml) was added aqueous NaOH (1 n, 74,6 ml, 74,6 mmol). The reaction mixture is heated at a temperature of about 60°C for about 30 min and left to cool to room temperature followed by the addition of 10% aqueous solution of AcOH (250 ml). The resulting mixture was extracted with EtOAc (2×250 ml) and the combined organic layers washed with brine (200 ml), dried over anhydrous Na2SO4and filtered. Get�nny filtrate is concentrated under reduced pressure and purified by column chromatography with silica gel (330 g), performing a gradient elution 10-70% EtOAc in heptane, yielding tert-butyl 3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-demerol-1-carboxylate (12.3 g, 93%) as a white foam: LC/MS (table 2, Method a) Rt=1,96 min; MS m/z: 356 (M+H)+.

Stage K: Hydrochloride of 1-(4-demerol-3-yl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

To a solution of tert-butyl 3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-demerol-1-carboxylate (12,2 g, at 34.3 mmol) in 1,4-dioxane (100 ml) was added 4 n HCl (4 n in 1,4-dioxane, of 25.7 ml, 103 mmol). The obtained reaction mixture is heated at a temperature of about 60°C for about 2 hours. The resulting mixture is allowed to cool to room temperature and diluted with Et2O (100 ml). The resulting mixture was triturated and filtered and the resulting precipitate was washed with Et2O (100 ml) to obtain hydrochloride of 1-(4-demerol-3-yl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (10 g, 98% yield) as a solid yellow-brown: LC/MS (table 2, Method a) Rt=the 1.05 min; MS m/z: 256 (M+H)+.

Stage L: 3-((3R,4R)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-demerol-1-yl)-3-oxopropanenitrile

To a solution of hydrochloride of 1-((3)-4-demerol-3-yl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (10.0 g, at 34.3 mmol), DIEA (23,9 ml, 137 mmol) and 2-tsianuksusnogo acid (4,37 g, to 51.4 mmol) vdmp (100 ml) was added EDC (of 7.88 g, of 41.1 mmol). The obtained reaction mixture was stirred at a temperature of about 25°C for about 16 hours. Add additional EDC (of 7.88 g, 41.1 mmol) and after 5 hours the reaction mixture was quenched with water (30 ml) and concentrated under reduced pressure. The obtained residue was separated between DCM (2×500 ml) and brine (500 ml). The combined organic layers dried over anhydrous Na2SO4andfiltered. The filtrate obtained is concentrated under reduced pressure and purified by column chromatography with silica gel (120 g column), performing a gradient elution 0-10% MeOH in DCM followed by chiral chromatography, yielding 3-((3R,4R)-3-(6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine-1-yl)-4-demerol-1-yl)-3-oxopropanenitrile [table 3, Method 9, Rt14,5 min, opt.BP=positive] (2.1 g, 24%) as a solid substance is not white: LC/MS (table 2, Method a) Rt=the 1.05 min; MS m/z: 256 (M+H)+.

Example # 14: N-((1S,3R,4S)-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

Stage A: Sodium 4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-Methylcyclopentane-1,3-Dienst

In a round bottom flask was placed THF (1 l) followed added in portions sodium hydride (60% dispersion in mineral oil, to 30.7 g, 0,77 mo�ü). The resulting mixture was cooled to about -10°C and added dropwise ethyl 3-oxobutanoate (97 ml, 0.77 mol) over about 1 hour in order to maintain its internal temperature is lower than about 10°C. the resulting mixture was stirred at room temperature for about 1 hour, yielding a clear yellow solution, and added dropwise methyl 4-chloroacetoacetate (44,3 ml, 0,384 mol) for about 5 min the resulting mixture was heated at about 50°C for about 19 hours, yielding a suspension of yellow-orange color. The obtained reaction mixture was then concentrated under reduced pressure, and the resulting solid material is transferred to a beaker and diluted with water (350 ml). The solid product is collected by vacuum filtration, and the filter cake was washed with water (150 ml) and dried in vacuum for about 1 hour. Solid product suspended in Et2O (500 ml), filtered, washed with Et2O (500 ml), and dried under vacuum to give sodium 4-(ethoxycarbonyl)-2-(methoxycarbonyl)-3-Methylcyclopentane-1,3-Dienst (77,4 g, 81%) as a solid beige color:1H NMR (DMSO-d6) δ 3,96 (kV,J=7,1 Hz, 2H), were 3.33 (s, 3H), 2,72 (l,J=2,2 Hz, 2H), 2,47 (t,J=2.1 Hz, 3H), 1,15 (t,J=7,1 Hz, 3H).

Step B: Ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate

In a round bottom flask was placed a sodium 4-(ethoxycarbonyl)-2-(methods�dicarbonyl)-3-Methylcyclopentane-1,3-Dienst (105 g, 0,420 mol) and digim (1 l) to give a yellow suspension. To this mixture was added AcOH (100 ml, 1.7 mol), and portions add sodium iodide (280 g, 1.9 mol) for about 5-10 minutes the reaction mixture Obtained is then heated at reflux for about 3 h, cooled to room temperature, and poured into ice water (800 ml). The resulting material was extracted with Et2O (3×500 ml). The combined organic extracts were washed with brine (2×500 ml), dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure, yielding a brown liquid, which was purified using vacuum distillation (80-85°C, 40 PA) to give ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (40,6 g, 57%) as a yellow oil:1H NMR (CDCl3) δ 6,06 is 5.98 (m, 1H), 4,30-4,11 (m, 2H), 3,72-in 3.65 (m, 1H), 2,77-of 2.66 (m, 1H), 2,66-of 2.57 (m, 1H), 2,17 (s, 3H), 1,30 (t,J=7,1 Hz, 3H).

Step C: Ethyl 2-methyl-4-oxocyclopentanecarboxylate

In a round bottom flask was placed 10% palladium-on-charcoal (7.6 g, 7.1 mmol). The flask was cooled to about 0°C. and add EtOAc (580 ml) in a nitrogen atmosphere. A cooling bath is removed, and added ethyl 2-methyl-4-oxocyclopent-2-enecarboxylate (60,0 g, 357 mmol). Hydrogen gas was bubbled through the resulting mixture for about 5 min, and the resulting mixture was then stirred in an atmosphere in�Dorada (1 ATM.) within about 48 hours. The source of hydrogen is removed, and the resulting mixture was bubbled with nitrogen for about 5 min and filtered through a layer of celite may®. The filter cake was washed with EtOAc (500 ml). The filtrate obtained is concentrated under reduced pressure, yielding ethyl 2-methyl-4-oxocyclopentanecarboxylate (59,9 g, 99%) as a yellow liquid:1H NMR (CDCl3) δ 4,23-4,14 (m, 2H), 3,18 (DDD,J=5,6, 6,8, 8,1 Hz, 1H), 2,73-to 2.65 (m, 1H), 2,60 (DDD,J=1,7, 5,5, is 18.7 Hz, 1H), 2,42-to 2.29 (m, 2H), 2.15 per day (DDD,J=1,7, 7,9, with 18.3 Hz, 1H), 1,29 (t,J=7,1 Hz, 3H), 1.07 to (l,J=7,0 Hz, 3H).

Step D: Ethyl 4-(dibenzylamino)-2-methylcyclohexanecarboxylic

In a round bottom flask was placed ethyl 2-methyl-4-oxocyclopentanecarboxylate (10.0 g, to 58.8 mmol) and DCE (180 ml). The resulting solution was cooled to about 0°C. and dropwise added AcOH (5,7 ml, 100 mmol) and dibenzylamine (11.3 ml, at 58.8 mmol), resulting in the formation of a thick slurry. The obtained reaction mixture is heated to about 10°C and portions add triacetoxyborohydride sodium (to 21.2 g, 100 mmol) and the resulting reaction mixture was stirred at room temperature for about 20 hours. The obtained reaction mixture was slowly poured into a stirred saturated aqueous solution of NaHCO3(300 ml) for about 20 min the Layers were separated, and the aqueous phase extracted with DCM (3×100 ml). The combined organic extracts were washed with brine�m (2×100 ml), dried over anhydrous Na2SO4and concentrated to dryness under reduced pressure. The crude yellow oil is purified using flash column-chromatography, performing a gradient elution of 0-30% EtOAc in heptane. The solvent was removed under reduced pressure, yielding ethyl 4-(dibenzylamino)-2-methylcyclohexanecarboxylic (15.5 g, 75%) as a colorless oil:1H NMR (pyridine-d5) δ 7,53 (DD,J=0,9, 7,9 Hz, 4H), 7,43-7,35 (m, 4H), to 7.33-7,25 (m, 2H), 4,22-4,06 (m, 2H), 3,79 (l,J=14.2 Hz, 2H), 3,70 (l,J=14.2 Hz, 2H), 3,34-to 3.22 (m, 1H), 2,76 (DD,J=7,9, of 16.6 Hz, 1H), 2,25 was 2.13 (m, 1H), 2,09-to 1.94 (m, 2H), 1,88-to 1.79 (m, 1H), 1,52 (DD,J=10,5, to 22.5 Hz, 1H), 1,16 (t,J=7,1 Hz, 3H), 0.98 m (l,J=7,0 Hz, 3H).

Step E: Ethyl 4-amino-2-methylcyclohexanecarboxylic

Into the reactor containing the suspension of 20% moisture Pd(OH)2-C (5,00 g and 35.6 mmol) in EtOH (355 ml), was added ethyl 4-(dibenzylamino)-2-methylcyclohexanecarboxylic (50.0 g, 142 mmol). The reaction mixture was shaken for about 60 minutes at a temperature of about 50°C at a pressure of H2about 207 kPa. The resulting mixture was filtered through a layer of celite may®, and the filtrate obtained is concentrated under reduced pressure, yielding ethyl 4-amino-2-methylcyclohexanecarboxylic (23,5 g, 96%) as a yellow oil:1H NMR (CDCl3) δ a 4.24 of 4.02 (m, 2H), 3,41-3,27 (m, 1H), with 2.81 (DD,J=7,6 and 15.4 Hz, 1H), 2,36-of 2.20 (m, 1H), 2,21-2,02 (m, 4H), 1,81-to 1.69 (m, 1H), 1,33 was 1.15 (m, 4H), 0.98 m (l,J7,0 Hz, 3H).

Stage F: Ethyl 4-(cyclopropanesulfonyl)-2-methylcyclohexanecarboxylic

A solution of ethyl 4-amino-2-methylcyclohexanecarboxylic (15.0 g, 88,0 mmol) in DMF (210 ml) was cooled to about 0°C in an ice bath. Add TEA (30,5 ml, 219 mmol), and stirring was continued at a temperature of about 0°C for about 15 min and then added dropwise to cyclopropanesulfonyl (12.3 g, 88,0 mmol, Matrix). The resulting solution was stirred at a temperature of about 0°C for about 2 hours. Bath ice is removed, and stirring the obtained reaction mixture is continued at room temperature for about 3 hours. The reaction mixture was concentrated under reduced pressure and added EtOAc (200 ml) and water (100 ml). The layers were separated, and the organic layer was washed with a saturated aqueous solution of NaHCO3(60 ml) and brine (60 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding an oil red-brown color. The crude material is purified by column chromatography with silica gel performing a gradient elution with 10-30% EtOAc in heptane, yielding ethyl 4-(cyclopropanesulfonyl)-2-methylcyclohexanecarboxylic (21,3 g, 88%) as a yellow oil:1H NMR (CDCl3) δ 5.25 in (l,J=9.9 Hz, 1H), 4,23-4,06 (m, 2H), 4.03 us to 3.90 (m, 1H), 2,80 (TD,J=3,1, 7.5 Hz, 1H), 2,46-of 2.30 (m, 2H), 2.29 goals-for 2.14 (m, 2H), 1,97 (DDD,J =3,2, 4,2, 14.2 Hz, 1H), 1,42 (DDD,J=7,5, 11,5, to 13.1 Hz, 1H), 1,29 (t,J=7,1 Hz, 3H), 1,20-to 1.14 (m, 2H), and 1.02 (d,J=6,9 Hz, 3H), 1.00 to 0,96 (m, 2H).

Stage G: 4-(cyclopropanesulfonyl)-2-methylcyclopentanone acid

Into a flask containing ethyl 4-(cyclopropanesulfonyl)-2-methylcyclohexanecarboxylic (7.5 g, 27.3 mmol) was added aqueous NaOH (1 n, 150 ml, 150 mmol). After stirring at room temperature for about 5 hours, the reaction mixture was acidified to pH of about 1 with an aqueous solution of 6 n HCl and extracted with DCM (3×100 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding crude 4-(cyclopropanesulfonyl)-2-methylcyclopentanone acid containing about 5 mol % DCM (6.6 g, 97%), in the form of white solids:1H NMR (DMSO-d6) δ 12,09 (s, 1H), 7,11 (l,J=8,1 Hz, 1H), 3,66-of 3.53 (m, 1H), 2,78-of 2.68 (m, 1H), 2,50 (tkv,J=5,1, to 7.7 Hz, 1H), 2,29-of 2.17 (m, 1H), 2,17-of 2.01 (m, 2H), equal to 1.82 (dt,J=9,9, a 12.7 Hz, 1H), 1,24 (dt,J=8,9, and 12.4 Hz, 1H), 0.98 to 0.85 in (m, 7H).

Stage H: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

A solution of 2-bromo-5H-imidazo[2,3-b]pyrazine (78,0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 ml) was dropwise added over about 60 min to a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g, 532 mmol) in anhydrous� DMF (543 ml) at a temperature of about 0-5°C. The reaction brown solution was stirred for about 30 min at a temperature of about 0-5°C. and Then added dropwise a solution of p-toluensulfonate (94,0 g, 492 mmol) in anhydrous DMF (272 ml) for about 60 minutes at a temperature of about 0-5°C. the reaction mixture Obtained is stirred at a temperature of about 0-5°C for about 1 hour, then allowed to warm to room temperature and stirred for about 18 hours at room temperature. The obtained reaction mixture was slowly poured into ice water (6 l), followed by the addition of aqueous NaOH (2.5 M, 50,0 ml, 125 mmol). The resulting precipitate was collected by filtration and stirred with cold water (3×200 ml). The solid product is collected by filtration and dried to constant weight in a vacuum thermostat at a temperature of about 55°C, resulting in 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (134,6 g, 97%) as a solid pale beige: LC/MS (table 2, Method d) Rt=to 1.58 min; MS m/z: 352/354 (M+H)+.

Step I: Tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide

The flask was added Pd2(dba)3(3,90 g of 4.26 mmol), di-tert-butyl-(2',4',6'-triisopropylsilyl-2-yl)Foshan (3,62 g, 8,52 mmol) and anhydrous 1,4-dioxane (453 ml). Societalization-ligand Tegaserod, using the cycle vacuum/purge with nitrogen (3 times) and heated at a temperature of about 80°C for about 10 min, then was added 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (30,0 g, 85 mmol), tert-butyl, hydrazinecarboxamide (16,9 g, 128 mmol) and NaOt-Bu (12.3 g, 128 mmol). After an additional cycle vacuum/nitrogen purge, the reaction mixture is heated at a temperature of about 80°C. after About 50 min, the reaction mixture obtained was cooled to room temperature and filtered through a layer of silica gel, over which is a layer of celite may®, washing with EtOAc (3×150 ml). To the filtrate is added water (300 ml) and the organic layer isolated. The aqueous layer was extracted with additional EtOAc (3×200 ml). The combined organic extracts were washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaHCO3and brine (400 ml each), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding a dark brown oil (45 g). The brown oil was dissolved in DCM (250 ml), was added silica gel (200 g), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was purified with silica gel column chromatography on silica gel performing a gradient elution from 25 to 65% EtOAc in heptane, yielding a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide�the [main regioisomer] and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [secondary regioisomer] (18,8 g, 50%): LC/MS (table 2, Method d) Rt=1,47 min; MS m/z: 404 (M+H)+.

Stage J: 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine

To a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide (18,8 g of 46.6 mmol) in 1,4-dioxane (239 ml) was added HCl (4 M in 1,4-dioxane, 86 ml, 345 mmol). The reaction mixture is heated at a temperature of about 60°C for about 1 hour and then cooled to 15-20°C. the Solid product is collected by vacuum filtration, washed with cold 1,4-dioxane (2×20 ml), and then stirred with a saturated aqueous solution of NaHCO3andwater (1:1, 150 ml). After about 1 hour rapid foaming ceases, and the solid product collected by vacuum filtration, washed with ice water (3×20 ml) and dried in a vacuum thermostat to constant weight, yielding 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine in a solid bright yellow brown (8,01 g, 50%): LC/MS (table 2, Method d) Rt=1,28 min; MS m/z: 304 (M+H)+.

Stage K: N-(3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

To a solution of 4-(cyclopropanesulfonyl)-2-methylcyclopentanone acid (15.3 g, the 61.8 mmol, step G) in DCM (300 ml) was added 2-Hydra�inil-5-tosyl-5H-imidazo[2,3-b]pyrazine (18.3 g, of 57.2 mmol, step (J), HATU (22,9 g, 60,1 mmol) and TEA (32.0 ml, 229 mmol). After stirring at room temperature for about 1 hour, the reaction mixture was diluted with water (250 ml). The layers were separated, and the aqueous layer was extracted with DCM (2×200 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material is diluted with DCM, resulting in a dense suspension. To the resulting suspension is added heptane, the mixture was filtered, yielding solid substance is not white. To the filtrate was added a silica gel (25 g), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was purified with silica gel column chromatography on silica gel performing a gradient elution of 60 to 100% EtOAc in heptane. Contains the product fractions were pooled and concentrated under reduced pressure. The resulting solid material is a yellow-brown colour add previously collected sediment, and dried using a vacuum pump, for about 14 hours, getting impure N-(3-methyl-4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentyl)cyclopropanesulfonyl of 25.2 g), contaminated about 50 mol % of tetramethylrhodamine. To a solution of impure N-(3-methyl-4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentyl)cycloprop�of sulfonamide of 25.2 g, for 47.4 mmol) in 1,4-dioxane (395 ml) was added TEA (of 26.5 ml, 189 mmol) and thionylchloride (3.5 ml, 48 mmol). The reaction mixture is heated at a temperature of about 80°C for about 1.5 hours, and by this time, the reaction mixture is cured. The reaction mixture was cooled to room temperature, and the solid product was dissolved in DCM (1 l). The organic portion was washed with water (2×500 ml) and brine (2×500 ml), dried over MgSO4, filtered and concentrated to half volume under reduced pressure. Add silica gel (75 g), and the remaining solvent removed under reduced pressure. The resulting mixture was purified by column chromatography with silica gel performing a gradient elution 0-50% acetone in DCM. Contains the product fractions were pooled and concentrated under reduced pressure, and by this time formed a thick gel, which is then cured, to thereby produce N-(3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (18,1 g, 62%) as a solid light brown color: LC/MS (table 2, Method a) Rt=2,16 min; MS m/z: 515 (M+H)+.

Stage L: N-((1S,3R,4S)-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

A mixture of N-(3-methyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclops�Teal)cyclopropanecarboxamide (7.1 g, a 13.9 mmol), 1,4-dioxane (139 ml) and aqueous 1 n NaOH (about 30.0 ml, 30.0 mmol) was heated at a temperature of about 60°C for about 2 hours. The reaction mixture was cooled to room temperature, diluted with water (150 ml) and extracted with EtOAc (3×150 ml). The combined organic layers washed with brine (200 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was triturated with EtOAc (50 ml) and filtered, yielding the solid material is a yellow-brown color, which is purified using preparative chiral HPLC (table 3, Method 3, Rt=18 min, opt.BP.=the negative). Contains the product fractions were pooled and concentrated, yielding solid pale yellow color. The solid product was dissolved in a mixture of 1:1 DCM:MeOH (100 ml), add 10 g of silica gel, and the resulting mixture was concentrated. The resulting mixture was purified by column chromatography with silica gel, using a gradient elution 0-100% DCM/MeOH/Et2NH from (990:9:1) to DCM/MeOH/Et2NH (970:27:3). Contains the product fractions were pooled and concentrated, yielding a white solid. The solid product is dissolved in boiling EtOH (150 ml), and treated with ultrasound for about 1 hour. The solvent was removed under reduced pressure, and the solid product was dried in a vacuum thermostat at a temperature of about 70°C for okolo hour. Add water (12 ml) and EtOH (3 ml) and the resulting suspension is brought to reflux for 2 hours. The suspension was cooled to room temperature, and then cooled to a temperature of about 0°C in an ice bath. Solids filtered off, washing with chilled ice water (about 3 ml) and dried in a vacuum thermostat, yielding N-((1S,3R,4S)-3-methyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (0.5 g, 10.4 per cent) in the form of white solids containing 0.5% EtOH: LC/MS (table 2, Method a) Rt=to 1.61 min; MS m/z: 361 (M+H)+.

Example # 15: N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

Stage A: Sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-Dienst

In a round bottom flask was placed THF (1.5 l), followed added in portions sodium hydride (60% dispersion in mineral oil, 70,0 g, 1.75 mol). Add an additional amount of THF (500 ml), and the resulting mixture was cooled to about -10°C and added dropwise to ethylbromoacetate (250 ml, 1.8 mol) over about 1 hour in order to maintain its internal temperature is lower than about 10°C. the resulting mixture was stirred at room temperature for about 0.5 hour, getting transparent�tion yellow solution, and added dropwise methyl 4-chloroacetoacetate (100 ml, 0.88 mol) for about 5 min the resulting mixture was heated at about 50°C for about 19 hours, getting the suspension reddish-orange color. The obtained reaction mixture was then concentrated under reduced pressure and the resulting liquid is transferred to a beaker and diluted with water (350 ml). The resulting mixture was stirred bath and placed on ice for about 2 hours. The solid product is collected by vacuum filtration and the filter cake was washed with water (150 ml) and dried in vacuum. Solid product suspended in Et2O (1.5 l), filtered, washed with Et2O (1.5 l) and dried in vacuum. The resulting solid material azeotropic distillation with toluene (1 l) to obtain a solid product, which is again suspended in Et2O (1 l) and collected by vacuum filtration. The filter cake was washed with Et2O (500 ml) and dried under vacuum to give sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-Dienst (204,2 g, 89%) as a solid beige color:1H NMR (DMSO-d6) δ 3,94 (kV,J=7,1 Hz, 2H), and 3.46 (s, 3H), of 3.04 (q,J=7,2 Hz, 2H), 2,66 (s, 2H), and 1.13 (t,J=7,1 Hz, 3H), 0.99 (no t,J=7.3 Hz, 3H).

Step B: Ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

In a round bottom flask was placed a sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methox�carbonyl)cyclopenta-1,3-Dienst (250 g, 0.94 mole) and digim (1.1 l), obtaining a suspension of green, then added AcOH (140 ml, 2.4 mol). To this mixture was portionwise added sodium iodide (490 g, 3.3 mole) for about 5-10 min After the addition the temperature rises to about 16°C to about 36°C. the Obtained reaction mixture was heated at reflux for about 3 h, cooled to room temperature, and was poured onto a mixture of ice (2 l) and saturated aqueous NaHCO3(4 l). The resulting material was extracted with Et2O (4×1.2 l), and combined organic layers dried over anhydrous MgSO4and filtered. The solvent was removed under reduced pressure, yielding a brown liquid (250 ml) which was purified using vacuum distillation (80-92°C, 40 PA) to give ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (95,7 g, 56%) as a yellow syrup:1H NMR (CDCl3) δ of 6.04 (m, 1H), 4,26-4,15 (m, 2H), 3,76-of 3.69 (m, 1H), 2,75-of 2.57 (m, 2H), 2,56 is 2.44 (m, 2H), 1,32-of 1.26 (m, 3H), 1,23-of 1.18 (m, 3H).

Step C: Ethyl 2-ethyl-4-oxocyclopentanecarboxylate

In a round bottom flask was placed 10% palladium-on-charcoal (10 g, 9.4 mmol). The flask was cooled to about 0°C. and EtOAc (400 ml) was added in a nitrogen atmosphere. A cooling bath is removed, and added ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47,8 g, 263 mmol). Hydrogen gas was bubbled through the resulting mixture for approximately� 5 min, and the mixture then stirred under a hydrogen atmosphere for about 48 hours. The source of hydrogen is removed, the resulting mixture was bubbled with nitrogen for about 5 min and filtered through a layer of celite may®. The filter cake was washed with EtOAc (400 ml). The filtrate obtained is concentrated under reduced pressure, yielding ethyl 2-ethyl-4-oxocyclopentanecarboxylate (48,0 g, 99%) as a yellow liquid:1H NMR (CDCl3) δ 4,23-4,10 (m, 2H), up 3.22 (m, 1H), 2,59-of 2.50 (m, 1H), 2,44-to 2.28 (m, 3H), 2.26 and is 2.16 (m, 1H), 1,58-1,46 (m, 1H), 1.41 to 1,30 (m, 1H), 1,30 is 1.23 (m, 3H), 1.02 mm is 0.91 (m, 3H).

Step D: Ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl

In a round bottom flask was placed ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95,9 g, 521 mmol) and DCE (1.8 l). The resulting solution was cooled to about 0°C. and dropwise add glacial AcOH (45 ml, 780 mmol) and dibenzylamine (120 ml, 625 mmol), resulting in the formation of a thick slurry. The obtained reaction mixture is heated to about 10°C, removing the cooling bath and add a further amount of DCE (500 ml). Portions add triacetoxyborohydride sodium (166 g, 781 mmol) and the resulting reaction mixture was stirred at room temperature for about 20 hours. The obtained reaction mixture was slowly poured into a stirred saturated aqueous solution of NaHCO3(1.5 l), followed by portion addition of solid NaHCO3 (175 g, 2083 mmol). The resulting mixture was stirred for about 2 hours, and the organic layer is isolated, dried over anhydrous Na2SO4and concentrated to dryness under reduced pressure. The crude yellow oil is purified by column chromatography with silica gel performing a gradient elution 0-20% EtOAc/heptane. The solvent was removed under reduced pressure, resulting in the ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl (136,6 g, 72%) in the form of white solids: LC/MS (table 2, Method a) Rt=3,26 min; MS m/z: 366 (M+H)+.

Step E: Ethyl 4-amino-2-ethylcyclopentadienyl

Into the reactor containing the suspension of 20% wet. Pd(OH)2-C (12.9 g, 92,0 mmol) in EtOH (1.0 l), was added ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl (129 g, 352 mmol). The reaction mixture was shaken for about 90 minutes at a temperature of about 50°C at a pressure of H2about 207 kPa. The resulting mixture was filtered through a nylon membrane and the filtrate obtained is concentrated under reduced pressure, yielding ethyl 4-amino-2-ethylcyclopentadienyl (64,5 g, 99%) as a yellow syrup:1H NMR (CDCl3) δ 4,03-3,88 (m, 2H), 3,17 (m, 1H), 2,68 (m, 1H), 2,09-2,02 (m, 2H), 2,02-to 1.94 (m, 2H), only 1.84 (m, 1H), 1,58-of 1.48 (m, 1H), 1,32-of 1.18 (m, 1H), 1,09 (m, 3H), of 1.03 (m, 2H), 0,78 to 0.69 (m, 3H).

Stage F: (1S,2R,4S)-ethyl 4-(cyclopropanesulfonyl)-2-atrticle�acarboxy

A solution of ethyl 4-amino-2-ethylcyclopentadienyl (20,5 g, 111 mmol) in DMF (340 ml) was cooled to about 0°C in an ice bath. Add TEA (38.6 ml, 277 mmol), and stirring was continued at a temperature of about 0°C for about 15 min, and then added, dropwise, cyclopropanesulfonyl (15.6 g, 111 mmol, Matrix). The resulting solution was stirred at a temperature of about 0°C for about 2 hours. Bath ice is removed, and continue stirring the obtained reaction mixture at room temperature for about 3 hours. The reaction mixture was concentrated under reduced pressure and added EtOAc (200 ml) and water (60 ml). The layers were separated, and the organic layer was washed with a saturated aqueous solution of NaHCO3(60 ml) and brine (60 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding an oil reddish brown. The crude material is purified by column chromatography with silica gel, elwira by stages with a gradient of 10% EtOAc in heptane, then 15% EtOAc in heptane, followed 20% EtOAc in heptane, yielding a yellow oil (27,3 g) which was purified using preparative chiral HPLC (table 3, Method 9, Rt=9,5 min, opt.BP.=negative) to obtain (1S,2R,4S)-ethyl 4-(cyclopropanesulfonyl)-2-ethylcyclopentadienyl (11,1 g, 35%): LC/MS (table 2, Method a) Rt=2,25 min; MS m/z: 290 (M+H)+.

Stage G: (1S,2R,4S)-4-(cyclopropanesulfonyl)-2-ethylcyclopentadienyl acid

Into a flask containing (1S,2R,4S)-ethyl) 4-(cyclopropanesulfonyl)-2-ethylcyclopentadienyl (11,1 g, 38.4 mmol) was added 1N aqueous NaOH (210 ml, 210 mmol). After stirring at room temperature for about 8 h, the reaction mixture was acidified to about pH 1 using 6 n HCl aqueous solution, and extracted with DCM (3×150 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding crude (1S,2R,4S)-4-(cyclopropanesulfonyl)-2-ethylcyclopentadienyl acid containing about 25 mol % DCM (10.7 g, 99%): LC/MS (table 2, Method a) Rt=1,71 min; MS m/z: 260 (M-H)-.

Stage H: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

A solution of 2-bromo-5H-imidazo[2,3-b]pyrazine (78,0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 ml) was dropwise added over about 60 min to a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g, 532 mmol) in anhydrous DMF (543 ml) at a temperature of about 0-5°C. the Reaction brown solution was stirred for about 30 min at a temperature of about 0-5°C. and Then added dropwise a solution of p-toluensulfonate (94,0 g, 492 mmol) in beswt�ω DMF (272 ml) for about 60 minutes at a temperature of about 0-5°C. The obtained reaction mixture was stirred at a temperature of about 0-5°C for about 1 hour, then allowed to warm to room temperature and stirred for about 18 hours. The obtained reaction mixture was slowly poured into ice water (6 l) followed by the addition of aqueous NaOH (2.5 M, 50,0 ml, 125 mmol). The resulting precipitate was collected by filtration and stirred with cold water (3×200 ml). The solid product is collected by filtration and dried to constant weight in a vacuum thermostat at a temperature of about 55°C, resulting in 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (134,6 g, 97%) as a solid beige color: LC/MS (table 2, Method d) Rt=to 1.58 min; MS m/z: 352/354 (M+H)+.

Step I: Tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide

The flask is placed Pd2(dba)3(3,90 g of 4.26 mmol), di-tert-butyl-(2',4',6'-triisopropylsilyl-2-yl)Foshan (3,62 g, 8,52 mmol) and anhydrous 1,4-dioxane (453 ml). A mixture of the catalyst-ligand Tegaserod using the cycle vacuum/purge with nitrogen (3 times) and heated at a temperature of about 80°C for about 10 min, then was added 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (30,0 g, 85 mmol), tert-butyl, hydrazinecarboxamide (16,9 g, 128 mmol), and NaOt-Bu (to 12.28 g, 128 mmol). After additional�intellego cycle vacuum/nitrogen purge, the reaction mixture is heated at a temperature of about 80°C. after About 50 min, the reaction mixture obtained was cooled to room temperature and filtered through a layer of silica gel (6 cm×6 cm in diameter), over which is a layer of celite may® (1 cm×6 cm in diameter), rinsing with EtOAc (3×150 ml). To the filtrate is added water (300 ml) and the organic layer isolated. The aqueous layer was extracted with additional EtOAc (3×200 ml). The combined organic extracts were washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaHCO3, and brine (400 ml each), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding a dark brown oil (45 g). The brown oil was dissolved in DCM (250 ml), was added silica gel (200 g), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was purified with silica gel column chromatography on silica gel performing a gradient elution from 25 to 65% EtOAc in heptane, yielding a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [main regioisomer] and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [secondary regioisomer] (18,8 g, 50%): LC/MS (table 2, Method d) Rt=1,47 min; MS m/z: 404 (M+H)+.

Stage J: 2-hydrazine-5-tosyl-5H-PI�Rolo[2,3-b]pyrazine

To a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide (18,8 g of 46.6 mmol) in 1,4-dioxane (239 ml) was added HCl (4 M in 1,4-dioxane, 86 ml, 345 mmol). The reaction mixture is heated at a temperature of about 60°C for about 1 hour and then cooled to 15-20°C. the Solid product is collected by vacuum filtration, washed with cold 1,4-dioxane (2×20 ml), and then stirred with a saturated solution of NaHCO3andwater (1:1, 150 ml). After about 1 hour, the rapid evolution of gas ceases, and the solid product collected by vacuum filtration, washed with ice water (3×20 ml), and dried in a vacuum thermostat to constant weight, yielding 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine in a solid light yellowish brown (8,01 g, 50%): LC/MS (table 2, Method d) Rt=1,28 min; MS m/z: 304 (M+H)+.

Stage K: N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

To a mixture of (1S,2R,4S)-4-(cyclopropanesulfonyl)-2-ethylcyclopentadienyl acid (of 8.43 g, 30,1 mmol, step G) in DCM (160 ml) was added 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (9,20 g, 28.8 mmol, step (J), HATU (11.5 g, to 30.3 mmol) and TEA (16,0 ml, 115 mmol). After paramasivan�I at room temperature for about 1 hour, the reaction mixture was diluted with water (150 ml). The layers were separated, and the aqueous layer was extracted with DCM (2×150 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DCM and purified by column chromatography with silica gel performing a gradient elution of 60 to 100% EtOAc in heptane. Contains the product fractions were pooled, concentrated under reduced pressure, and dried using a vacuum pump, yielding N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentyl)cyclopropanesulfonyl (14.1 g) as a foam yellow-brown color, containing about 50 mole % of tetramethylrhodamine and about 35 mol % EtOAc. To a solution of impure N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentyl)cyclopropanecarboxamide (14.0 g, is 22.9 mmol) in 1,4-dioxane (125 ml) was added TEA (13 ml, 93 mmol) and thionylchloride (2.5 ml, at 34.3 mmol). The reaction mixture is heated at a temperature of about 80°C for about 2.5 hours, then the reaction mixture was cooled to room temperature and add water and EtOAc (150 ml each). The layers were separated, and the aqueous layer was extracted with additional EtOAc (2×100 ml). The combined organic layers washed with brine (100 ml), dried over anhydrous Na2SO4, filtered,�will centerour under reduced pressure, and dried in vacuum. The crude material is purified by column chromatography with silica gel performing a gradient elution of 60 to 100% EtOAc in heptane while controlling the wavelength of 330 nm. Contains the product fractions were pooled, and concentrated under reduced pressure, obtaining a solid light brown color. The solid product is treated with ultrasound with EtOAc (60 ml) for about 10 minutes, allowed to stand at room temperature for about 5 min, collected by vacuum filtration, washing with additional EtOAc (20 ml), and dried in a vacuum incubator at a temperature of about 60°C, yielding N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl, with about 40 mole % EtOAc (8,08 g, 50% over 2 stages): LC/MS (table 2, Method a) Rt=2,30 min; MS m/z: 529 (M+H)+.

Stage L: N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl

A mixture of N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanecarboxamide (8,00 g, and 13.8 mmol), 1,4-dioxane (80 ml) and 1 n aqueous NaOH solution (about 30.0 ml, 30.0 mmol) was heated at a temperature of about 60°C for about 2 hours. Then the reaction mixture was diluted with water (100 ml) and extracted with EtOAc (3×100 ml). The combined organic with�OI washed with brine (100 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography with silica gel performing a gradient elution 0-100% DCM/MeOH/Et2NH (970:27:3) in DCM then elution DCM/MeOH/Et2NH (950:45:5). Contains the product fractions were pooled, concentrated under reduced pressure, and dried in a vacuum thermostat at a temperature of about 70°C for about 12 hours, obtaining a solid product, which was triturated with Et2O, filtered, rinsing with additional amounts of Et2Oh, and dissolved in hot MeOH. The resulting solution was concentrated under reduced pressure, obtaining a solid product, which was dissolved in hot MeOH (200 ml), treated with ultrasound, while cooling to form a suspension, concentrated under reduced pressure, and dried in a vacuum thermostat at a temperature of about 50°C, obtaining a solid off-white color. To the solid product is added EtOAc (30 ml) to give a suspension, which is heated using a jet dryer, and then treated with ultrasound for about 15 minutes After standing at room temperature for about 15 min, the obtained white solid product is collected by vacuum filtration, washed with additional EtOAc (15 ml), and dried in vacuum t�rotate at a temperature of about 50°C. The solid product was dissolved in hot EtOH (~200 ml), filtered to remove insoluble secondary material (<10 mg), treated with ultrasound for about 10 min while cooling, getting a white suspension, which was concentrated under reduced pressure. The obtained white solid material was dried in a vacuum incubator at a temperature of about 60°C, yielding N-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentyl)cyclopropanesulfonyl (3,43 g, 67%): LC/MS (table 2, Method a) Rt=to 1.67 min; MS m/z: 375 (M+H)+.

Example # 16: (R)-1-(3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile

Stage A: Tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate

The flask is placed Pd2(dba)3(1.3 g, 1.4 mmol), di-tert-butyl-(2',4',6'-triisopropylsilyl-2-yl)Foshan (1.21 g, of 2.84 mmol), and 1,4-dioxane (75 ml). A mixture of the catalyst-ligand Tegaserod using the cycle vacuum/purge with nitrogen (3 times) and heated at a temperature of about 80°C for about 10 minutes Add 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (5.0 g, 14 mmol, example No. 7), tert-BUTYLCARBAMATE (2.5 g, 21 mmol) and NaOt-Bu (2.05 g, a 21.3 mmol). After an additional cycle vacuum/nitrogen purge, the reaction mixture is heated at a temperature of about 80°C for an eye�about 16 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (70 ml). The obtained reaction mixture was filtered, and the filtrate obtained was washed with water (3×20 ml). The organic layer is dried over anhydrous MgSO4, filtered, and the solvent removed under reduced pressure, obtaining a solid reddish-brown color. The crude material is purified by column chromatography with silica gel performing a gradient elution with 10-50% EtOAc in heptane, resulting in tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate in the form of an amorphous yellow substance (1.0 g, 18%): LC/MS (table 2, Method a) Rt=2,63 min; MS m/z: 389 (M+H)+.

Step B: (R)-(9H-fluoren-9-yl)methyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)amino)acetyl)piperidine-1-carboxylate

NaH (60% dispersion in mineral oil, 0,041 g, 1.0 mmol) was added to anhydrous DMF (5 ml). The resulting suspension was cooled to about 0°C. and dropwise added a solution of tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate (0.40 g, 1.0 mmol) in anhydrous DMF (5 ml). The obtained reaction mixture is allowed to warm to room temperature and added to (R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate (0,441 g, 1.03 mmol, example No. LL.1). The obtained reaction mixture was stirred for about 30 min re�, how it is divided between EtOAc (30 ml) and brine (2×100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography with silica gel (12 g column), performing a gradient elution with 10-50% EtOAc in heptane, yielding (R)-(9H-fluoren-9-yl)methyl-3-(2-(tert-butoxycarbonyl(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)amino)acetyl)piperidine-1-carboxylate as a clear oil (0,21 g, 26%): LC/MS (table 2, Method a) Rt=3,16 min; MS m/z: 736 (M+H)+.

Step C: (R)-(9H-fluoren-9-yl)methyl 3-(3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carboxylate

A mixture of (R)-(9H-fluoren-9-yl)methyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)amino)acetyl)piperidine-1-carboxylate (0.20 g, 0.27 mmol), TFA (1.0 ml, 13 mmol) and TFAA (1.0 ml, 7.1 mmol) was stirred at a temperature of about 25°C for about 16 hours. The obtained reaction mixture was separated between EtOAc (50 ml) and a saturated aqueous solution of NaHCO3(2×50 ml). The organic layer is isolated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, yielding (R)-(9H-fluoren-9-yl)methyl 3-(3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carboxylate as a clear oil (0.17 g, 99%): LC/MS (table 2, Method a) Rt=2,68 min; M� m/z 618 (M+H) +.

Step D: (R)-1-(3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile

To a solution of (R)-(9H-fluoren-9-yl)methyl 3-(3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carboxylate (0.20 g, 0,32 mmol) in 1,4-dioxane (3 ml) was added aqueous NaOH (2 N, is 0.97 ml, 1.9 mmol). The obtained reaction mixture is heated at a temperature of about 100°C for about 3 hours before it is left to cool to room temperature. The reaction mixture is neutralized using 4 n HCl in 1,4-dioxane (0.5 ml) and concentrated under reduced pressure. To the resulting residue was added MeCN (25 ml) before being concentrated under reduced pressure. This procedure is repeated before adding 1-cyano cyclopropanecarbonyl acid (0,072 g of 0.65 mmol), HATU (0,111 g, 0,291 mmol) and DMF (2 ml) followed by the addition of DIEA (0,170 ml, 0,971 mmol). After stirring at room temperature for about 3 h, the reaction mixture was separated between EtOAc (2×50 ml) and an aqueous solution of NaHCO3(50 ml). The combined organic layers dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified using HPLC with reversed phase (table 2, Method j). The combined product containing fractions concentrated under reduced pressure �La removal of MeCN and then lyophilizer, receiving (R)-1-(3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carbonyl)cyclopropanecarbonitrile in the form of white solids (0,010 g, 9%): LC/MS (table 2, Method a) Rt=to 1.67 min; MS m/z: 335 (M+H)+.

Example No. 17: 5-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile

Stage A: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

A solution of 2-bromo-5H-imidazo[2,3-b]pyrazine (78,0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 ml) was dropwise added over about 60 min to a stirred suspension of NaH (12.8 g, 532 mmol) in anhydrous DMF (543 ml) at a temperature of about 0-5°C. the Brown reaction solution was stirred for about 30 min at a temperature of about 0-5°C. and Then added dropwise a solution of p-toluensulfonate (94,0 g, 492 mmol) in anhydrous DMF (272 ml) for about 60 minutes at a temperature of about 0-5°C. the reaction mixture Obtained is stirred at a temperature of about 0-5°C for about 1 hour, then allowed to warm to room temperature and stirred for about 18 hours at room temperature. The obtained reaction mixture was slowly poured into ice water (6 l), followed by the addition of an aqueous solution of 2.5 n NaOH (50,0 ml, 125 mmol). The resulting precipitate was collected by filtration and stirred with cold water (3×200 m�). The solid product is collected by filtration and air dried for about 3 days and finally dried to constant weight in a vacuum thermostat at a temperature of about 55°C, resulting in 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (134,6 g, 97%) as a solid beige color: LC/MS (table 2, Method d) Rt=to 1.58 min; MS m/z: 352/354 (M+H)+.

Step B: Tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide

The flask was added Pd2(dba)3(3,90 g of 4.26 mmol), di-tert-butyl-(2',4',6'-triisopropylsilyl-2-yl)Foshan (3,62 g, 8,52 mmol) and anhydrous 1,4-dioxane (453 ml). A mixture of the catalyst-ligand Tegaserod using the cycle vacuum/purge with nitrogen (3 times) and heated at a temperature of about 80°C for about 10 min Sequentially added 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (30,0 g, 85 mmol example No. 7), tert-butyl, hydrazinecarboxamide (16,9 g, 128 mmol) and NaOt-Bu (to 12.28 g, 128 mmol). After an additional cycle vacuum/nitrogen purge, the reaction mixture is heated at a temperature of about 80°C. after About 50 min, the reaction mixture obtained was cooled to room temperature and filtered through a layer of silica gel (6 cm×6 cm in diameter), over which is a layer of celite may® (1 cm×6 cm in diameter), PR�of Miva with EtOAc (3×150 ml). To the filtrate is added water (300 ml) and the organic layer isolated. The aqueous layer was extracted with additional EtOAc (3×200 ml). The combined organic extracts were washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaHCO3and brine (400 ml each), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding a dark brown oil (45 g). The brown oil was dissolved in DCM (250 ml), was added silica gel (200 g), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was purified with silica gel column chromatography on silica gel performing a gradient elution from 25 to 65% EtOAc in heptane, yielding a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [main regioisomer] and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [secondary regioisomer] (18,8 g, 50%): LC/MS (table 2, Method d) Rt=1,47 min; MS m/z: 404 (M+H)+.

Step C: 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine

To a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide (18,8 g of 46.6 mmol) in 1,4-dioxane (239 ml) was added HCl (4 M in 1,4-dioxane, 86 ml, 345 mmol). The reaction mixture heating�t at a temperature of about 60°C for about 1 hour and then cooled to 15-20°C. The solid product is collected by vacuum filtration, washed with cold 1,4-dioxane (2×20 ml), and then stirred with a saturated aqueous solution of NaHCO3andwater (1:1, 150 ml). After about 1 hour, intensive gas evolution ceases and the solid product collected by vacuum filtration, washed with ice water (3×20 ml), and dried in a vacuum thermostat to obtain 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine in a solid light yellowish brown (8,01 g, 50%): LC/MS (table 2, Method d) Rt=1,28 min; MS m/z: 304 (M+H)+.

Step D: Tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentanecarbonyl

To a mixture of 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (2,50 g, 8,24 mmol) and (1R,3S)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (2.08 g, 9,07 mmol, Peptech) in DCM (30 ml) was added EDC.HCl (1.90 g, of 9.89 mmol). After stirring for about 4.5 hours at room temperature, adding water (30 ml) and the layers were separated. The aqueous layer was then extracted with EtOAc (15 ml). The combined organic layers washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in DCM (15 ml) and purified by column chromatography with silica gel performing a gradient elution 40-100% EtOAc in g�plane, getting tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentylamine (4.20 g, 97%): LC/MS (table 2, Method a) Rt=2,27 min; MS m/z: 515 (M+H)+.

Step E: Tert-butyl-(1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine

To a solution of tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentylamine (9,30 g of 18.1 mmol) in 1,4-dioxane (100 ml) was added TEA (10.0 ml, of 72.3 mmol) and SOCl2(2,11 ml of 28.9 mmol). The resulting mixture was heated at a temperature of about 80°C for about 1.5 hour. The obtained reaction mixture was cooled to room temperature, add EtOAc and water and the layers were separated. The aqueous solution was extracted with EtOAc (2×100 ml) and the combined organic layers washed with a saturated aqueous solution of NaHCO3andbrine (100 ml each). The organic extracts dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography with silica gel performing a gradient elution 25 to 100% EtOAc in DCM, yielding tert-butyl-(1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (7,65 g, 85%): LC/MS (table 2, Method a) Rt=2,37 min; MS m/z: 497 (M+H)+.

Stage F: Hydrochloride (1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[43-a]pyrazine-1-yl)cyclopentylamine

To a solution of tert-butyl (1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (8,22 g of 16.6 mmol) in 1,4-dioxane (32 ml) was added HCl (4 n in 1,4-dioxane, of 16.6 ml, up 66.2 mmol) and the resulting reaction mixture is heated at a temperature of about 60°C for about 1.5 h, then stirred at room temperature overnight. The obtained reaction mixture was filtered, washing with Et2O (100 ml). The filter cake was dried under vacuum to give solid light brown color, which is then dried in a vacuum thermostat at a temperature of about 50°C, obtaining a hydrochloride (1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (7,61 g, 93%) as a solid beige color: LC/MS (table 2, Method d) Rt=1,09 min; MS m/z: 397 (M+H)+.

Stage G: 5-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile

In a reactor were placed hydrochloride (1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (0.500 g, 1.06 mmol), n-propanol (10 ml), 5-chloropyrazine-2-carbonitrile (0,223 g, 1,60 mmol) and DIEA (0,837 ml of 4.79 mmol). The resulting mixture is heated using microwave radiation at a temperature of about 150°C for about 30 minutes Add DCM (100 ml) and obra�that solution. The organic solution was washed with water and brine solution (50 ml each), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, obtaining a solid brown color. The resulting residue is placed in DCM (30 ml) and adsorb on silica gel (5 g). The resulting material was purified by column chromatography with silica gel (80 g cartridge), elwira pure EtOAc, yielding 5-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile (0,43 g, 80%) as a solid, light yellow: LC/MS (table 2, Method d) Rt=1,40 min; MS m/z: 500 (M+H)+.

Stage H: 5-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile

A mixture of 5-((1S,3R)-3-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile (0,426 g, 0,853 mmol) and aqueous NaOH (1 n, 1,71 ml, 1,71 mmol) in 1,4-dioxane (4.4 ml) heated at a temperature of about 60°C for about 80 min the mixture was cooled to room temperature and diluted with water (40 ml). The solid precipitate is collected by vacuum filtration and washed with water to give a solid material is not white. The resulting material was dissolved in hot EtOH and allowed to cool to room temperature. The resulting precipitate was collected by filtration and �tub vacuum getting a solid off-white color, which is dried in a vacuum thermostat at a temperature of about 70°C, obtaining a solid off-white color (0,199 g). The resulting material was placed in EtOAc (10 ml) and heated at a temperature of about 70°C for about 1.5 hour. The solid product is collected by vacuum filtration, washing with EtOAc. This material was dried under vacuum to give 5-((1S,3R)-3-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile (0.19 g, 64%) as a solid substance is not white: LC/MS (table 2, Method a) Rt=1,55 min; MS m/z: 346 (M+H)+.

Example 18: 5-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile and 5-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)the pyrazine-2-carbonitrile

Stage A: Sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-Dienst

In a round bottom flask was placed THF (1.5 l) is then added in portions sodium hydride (60% dispersion in mineral oil, 70,0 g, 1.75 mol). Add an additional amount of THF (500 ml). The resulting mixture was cooled to about -10°C and added dropwise to ethylbromoacetate (250 ml, 1.8 mol) over about 1 hour in order to maintain the internal temperaturerise, than about 10°C. the resulting mixture was stirred at room temperature for about 0.5 hour, yielding a clear yellow solution, and added dropwise methyl 4-chloroacetoacetate (100 ml, 0.88 mol) for about 5 min the resulting mixture was heated at about 50°C for about 19 hours, yielding a suspension of reddish orange. The obtained reaction mixture was then concentrated under reduced pressure, and the resulting liquid was diluted with water (350 ml). The resulting mixture was stirred bath and placed on ice for about 2 hours. The solid product is collected by vacuum filtration and the filter cake was washed with water (150 ml) and dried in vacuum. Solid product suspended in Et2O (1.5 l), filtered, washed with Et2O (1.5 l) and dried in vacuum. The resulting solid material azeotropic distillation with toluene (1 l) to obtain a solid material, which is again suspended in Et2O (1 l) and collected by vacuum filtration. The filter cake was washed with Et2O (500 ml) and dried under vacuum to give sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-Dienst (204,2 g, 89%) as a solid beige color:1H NMR (DMSO-d6) δ 3,94 (kV,J=7,1 Hz, 2H), and 3.46 (s, 3H), of 3.04 (q,J=7,2 Hz, 2H), 2,66 (s, 2H), and 1.13 (t,J=7,1 Hz, 3H), 0.99 (no t,J=7.3 Hz, 3H).

Step B: Ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate

In a round bottom flask was placed a sodium 4-(ethoxycarbonyl)-3-ethyl-2-(methoxycarbonyl)cyclopenta-1,3-Dienst (250 g, 0.94 mole) and digim (1.1 l), obtaining a suspension of green, followed by the addition of AcOH (140 ml, 2.4 mol). To this mixture was portionwise added sodium iodide (490 g, 3.3 mole) for about 5-10 min After the addition the temperature rises to about 16°C to about 36°C. the Obtained reaction mixture was then heated at reflux for about 3 h, cooled to room temperature, and was poured onto a mixture of ice (2 l) and saturated aqueous NaHCO3(4 l). The resulting material was extracted with Et2O (4×1.2 l) and the combined organic layers dried over anhydrous MgSO4andfiltered. The solvent was removed under reduced pressure, yielding a brown liquid (250 ml), purified using vacuum distillation (80-92°C, 40 PA) to give ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (95,7 g, 56%) as a yellow syrup:1H NMR (CDCl3) δ of 6.04 (m, 1H), 4,26-4,15 (m, 2H), 3,76-of 3.69 (m, 1H), 2,75-of 2.57 (m, 2H), 2,56 is 2.44 (m, 2H), 1,32-of 1.26 (m, 3H), 1,23-of 1.18 (m, 3H).

Step C: Ethyl 2-ethyl-4-oxocyclopentanecarboxylate

In a round bottom flask was placed 10% palladium-on-charcoal (10 g, 9.4 mmol). The flask was cooled to about 0°C. and add EtOAc (400 ml) in a nitrogen atmosphere. A cooling bath is removed, and doba�give ethyl 2-ethyl-4-oxocyclopent-2-enecarboxylate (47,8 g, 263 mmol). Hydrogen gas was bubbled through the resulting mixture for about 5 min, and the resulting mixture was then stirred under a hydrogen atmosphere for about 48 hours at room temperature. The source of hydrogen is removed, the resulting mixture was bubbled with nitrogen for about 5 min and filtered through a layer of celite may®. The filter cake was washed with EtOAc (400 ml). The filtrate obtained is concentrated under reduced pressure, yielding ethyl 2-ethyl-4-oxocyclopentanecarboxylate (about 9:1 mixture of CIS:TRANS) (48,0 g, 99%) as a yellow liquid:1H NMR (CDCl3) δ 4,23-4,10 (m, 2H), up 3.22 (m, 1H), 2,59-of 2.50 (m, 1H), 2,44-to 2.28 (m, 3H), 2.26 and is 2.16 (m, 1H), 1,58-1,46 (m, 1H), 1.41 to 1,30 (m, 1H), 1,30 is 1.23 (m, 3H), 1.02 mm is 0.91 (m, 3H).

Step D: Ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl

In a round bottom flask was placed ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95,9 g, 521 mmol) and DCE (1.8 l). The resulting solution was cooled to about 0°C. and dropwise added AcOH (45 ml, 780 mmol) and dibenzylamine (120 ml, 625 mmol), resulting in a thick slurry. The obtained reaction mixture is heated to about 10°C, the cooling bath was removed and added an additional amount of DCE (500 ml). Triacetoxyborohydride sodium (166 g, 781 mmol) was added in portions and the resulting reaction mixture was stirred at room temperature for about 20 hours. The obtained reaction with�ect slowly poured into a saturated aqueous solution of NaHCO 3(1.5 l) under stirring, followed portioned by the addition of solid NaHCO3(175 g, 2083 mmol). The resulting mixture was stirred for about 2 hours, and the organic layer is isolated, dried over anhydrous Na2SO4and concentrated to dryness under reduced pressure. The crude yellow oil is purified using flash chromatography on silica gel using EtOAc/heptane as eluent (0-20% EtOAc) to obtain the resulting ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl (136,6 g, 72%) in the form of white solids: LC/MS (table 2, Method a) Rt=3,26 min; MS m/z: 366 (M+H)+.

Step E: Ethyl 4-amino-2-ethylcyclopentadienyl

Into the reactor containing the suspension of 20% wet. Pd(OH)2-C (12.9 g, 92,0 mmol) in EtOH (1.0 l) was added ethyl 4-(dibenzylamino)-2-ethylcyclopentadienyl (129 g, 352 mmol). The reaction mixture was shaken for about 90 minutes at a temperature of about 50°C at a pressure of H2about 207 kPa. The resulting mixture was filtered through a layer of celite may®, and the filtrate obtained is concentrated under reduced pressure, yielding ethyl 4-amino-2-ethylcyclopentadienyl (64,5 g, 99%) as a yellow syrup:1H NMR (CDCl3) δ 4,03-3,88 (m, 2H), 3,17 (m, 1H), 2,68 (m, 1H), 2,09-2,02 (m, 2H), 2,02-to 1.94 (m, 2H), only 1.84 (m, 1H), 1,58-of 1.48 (m, 1H), 1,32-of 1.18 (m, 1H), 1,09 (m, 3H), of 1.03 (m, 2H), 0,78 to 0.69 (m, 3H).

Stage F: (Ethyl 4-(tert-butoxycarbonyl�Mino)-2-ethylcyclopentadienyl

In a 250 ml round bottom flask was placed ethyl 4-amino-2-ethylcyclopentadienyl (1,96 g, 10.6 mmol) and DCM (100 ml) to give a colorless solution. The resulting solution was cooled to about 10°C and add the TEA (3,70 ml, 26.5 mmol) and di-tert-butyl of dicarbonate (2,77 g, 12.7 mmol). The resulting solution was stirred at a temperature of about 0°C for about 1 hour, then the mixture is slowly heated to room temperature and stirred for about 16 hours. Add brine (10 ml) and the layers were separated. The organic layer is dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure, yielding (ethyl 4-(tert-butoxycarbonylamino)-2-ethylcyclopentadienyl (3.3 g, 90% pure by NMR, 98%) as a turbid oil:1H NMR (CDCl3) ∆ 5,22 is 5.19 (m, 1 H), 4,18 is 4.07 (m, 3 H), 2,86-of 2.81 (m, 1 H), 2,33 and 2.26 (m, 1 H), 2,24 is 2.16 (m, 1 H), 2,03-to 1.94 (m, 1 H), 1,76 is 1.71 (m, 1 H), 1,48-of 1.41 (m, 1 H), of 1.43 (s, 9 H), of 1.27 (t, 3 H), 1,27-to 1.21 (m, 2 H), of 0.92 (t, 3 H).

Stage G: 4-(tert-butoxycarbonylamino)-2-ethylcyclopentadienyl acid

In a 250 ml round bottom flask was placed ethyl 4-(tert-butoxycarbonylamino)-2-ethylcyclopentadienyl (3.00 g, 10.5 mmol) in THF (96 ml), yielding a colorless solution. Added aqueous NaOH (1 n, 16,0 ml of 16.0 mmol) and the resulting reaction mixture was stirred for about 24 h at room�temperature. Add additional aqueous NaOH (1 n, 5.00 ml, 5.00 mmol), and stirring was continued for about 48 hours at room temperature. The obtained reaction mixture is heated at about 50°C for about 24 hours. The solvent was removed under reduced pressure. Add AcOH as long as the pH reaches the value of 5. Add EtOAc (50 ml) and the layers were separated. The aqueous layer was then extracted with EtOAc (2×30 ml). The combined organic extracts dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding a yellow oil. The resulting oil was then dried in a high vacuum, which leads to the formation of a solid which was dissolved in DCM and concentrated to dryness, again suspended in DCM and again concentrated to dryness. The remaining residue is then suspended in Et2O and concentrated to dryness and then dried under vacuum for about 3 hours, yielding 4-(tert-butoxycarbonylamino)-2-ethylcyclopentadienyl acid (2,36 g, 87%): LC/MS (table 2, Method a) Rt=of 2.09 min; MS m/z: 256 (M-H)-.

Stage H: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

A solution of 2-bromo-5H-imidazo[2,3-b]pyrazine (78,0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 ml) was dropwise added over about 60 min to a stirred suspension of NaH (12.8 g, 532 mmol) in anhydrous DMF (543 ml) at a temperature of about 0-5°C. Cor�Chevy reaction solution was stirred for about 30 min at a temperature of about 0-5°C. Then dropwise added a solution of p-toluensulfonate (94,0 g, 492 mmol) in anhydrous DMF (272 ml) for about 60 minutes at a temperature of about 0-5°C. the reaction mixture Obtained is stirred at a temperature of about 0-5°C for about 1 hour, then allowed to warm to room temperature and stirred for about 18 hours at room temperature. The obtained reaction mixture was slowly poured into ice water (6 l), followed by the addition of an aqueous solution of 2.5 n NaOH (50,0 ml, 125 mmol). The resulting precipitate was collected by filtration and stirred with cold water (3×200 ml). The solid product is collected by filtration and dried to constant weight in a vacuum thermostat at a temperature of about 55°C, resulting in 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (134,6 g, 97%) as a solid beige color: LC/MS (table 2, Method d) Rt=to 1.58 min; MS m/z: 352/354 (M+H)+.

Step I: Tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide

The flask is placed Pd2(dba)3(3,90 g of 4.26 mmol), di-tert-butyl-(2',4',6'-triisopropylsilyl-2-yl)Foshan (3,62 g, 8,52 mmol) and anhydrous 1,4-dioxane (453 ml). A mixture of the catalyst-ligand Tegaserod using the cycle vacuum/purge with nitrogen (3 times) and heated at a temperature OK�lo 80°C for about 10 min. Sequentially added 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (30,0 g, 85 mmol), tert-butyl, hydrazinecarboxamide (16,9 g, 128 mmol) and NaOt-Bu (to 12.28 g, 128 mmol). After an additional cycle vacuum/nitrogen purge, the reaction mixture is heated at a temperature of about 80°C. after About 50 min, the reaction mixture obtained was cooled to room temperature and filtered through a layer of silica gel (6 cm × 6 cm in diameter), over which is a layer of celite may® (1 cm × 6 cm in diameter), rinsing with EtOAc (3×150 ml). To the filtrate is added water (300 ml) and the organic layer isolated. The aqueous layer was extracted with additional EtOAc (3×200 ml). The combined organic extracts were washed with a saturated aqueous solution of NH4Cl, a saturated aqueous solution of NaHCO3and brine (400 ml each), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding a dark brown oil (45 g). The brown oil was dissolved in DCM (250 ml), was added silica gel (200 g), and the resulting mixture was concentrated under reduced pressure. The resulting mixture was purified with silica gel column chromatography on silica gel performing a gradient elution from 25 to 65% EtOAc in heptane, yielding a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [main regioisomer] and tert-b�Teal 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide [secondary regioisomer] (18,8 g, 50%): LC/MS (table 2, Method d) Rt=1,47 min; MS m/z: 404 (M+H)+.

Stage J: 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine

To a mixture of tert-butyl 2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide and tert-butyl 1-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)hydrazinecarboxamide (18,8 g of 46.6 mmol) in 1,4-dioxane (239 ml) was added HCl (4 M in 1,4-dioxane, 86 ml, 345 mmol). The reaction mixture is heated at a temperature of about 60°C for about 1 hour and then cooled to 15-20°C. the Solid product is collected by vacuum filtration, washed with cold 1,4-dioxane (2×20 ml), and then stirred with a saturated solution of NaHCO3and water (1:1, 150 ml). After about 1 hour, the rapid evolution of gas ends, and the solid product collected by vacuum filtration, washed with ice water (3×20 ml), and dried in a vacuum thermostat to constant weight, yielding 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine in a solid light yellowish brown (8,01 g, 50%): LC/MS (table 2, Method d) Rt=1,28 min; MS m/z: 304 (M+H)+.

Stage K: tert-butyl-3-ethyl-4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentanecarbonyl

In a round bottom flask was placed 2-hydrazine-5-tosyl-5H-imidazo[2,3-b]pyrazine (2.0 g, 6,6 mmol, step (J) and DCM (40 ml) to give a brown suspension C�ETA. To the resulting suspension is added 4-(tert-butoxycarbonylamino)-2-ethylcyclopentadienyl acid (2.0 g, 7.8 mmol, step (G), HATU (2,51 g, 6,59 mmol), and TEA (4,59 ml of 33.0 mmol) and the resulting mixture was stirred at room temperature for about 24 hours, and the dissolution occurs in approximately 2 hours. Add water (20 ml) and the layers were separated. The organic layer is washed with additional amount of water (2×15 ml), brine (2×25 ml), dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure, yielding a residue of brown. The crude material is purified by column chromatography with silica gel performing a gradient elution 0-10% MeOH/DCM. Dedicated impure material was again purified by column chromatography with silica gel performing a gradient elution 0-10% MeOH/DCM. Contains the product fractions from the two columns were pooled and concentrated, yielding tert-butyl-3-ethyl-4-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)geringerer)cyclopentylamine (2,45, 69%) as brown solids colors: LC/MS (table 2, Method d) Rt=1,47 min; MS m/z: 543 (M+H)+.

Stage L: Tert-butyl-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine

In a round bottom flask was placed tert-butyl-3-ethyl-4-(2-(5-tosyl-5H-imidazo[2,3-b]Piras�h-2-yl)geringerer)cyclopentylamine (2,45 g, 4,55 mmol) and 1,4-dioxane (24 ml), yielding a brown solution. Add TEA (2,54 ml of 18.2 mmol), was then added SOCl2(0.50 ml, 6.8 mmol). The obtained reaction mixture is heated at a temperature of about 80°C for about 5 hours. The resulting mixture was cooled to room temperature and added EtOAc (100 ml) and water (30 ml). The layers were separated, and the organic layer was washed with water (2×30 ml) and brine (2×30 ml), dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure, yielding a residue of brown. The crude material is purified by column chromatography with silica gel performing a gradient elution 0-10% MeOH/DCM. Contains the product fractions were pooled and concentrated, yielding tert-butyl (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (1.7 g, 71%): LC/MS (table 2, Method a) Rt=2,50 min; MS m/z: 525 (M+H)+.

Stage M: 3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone

In a round bottom flask was placed tert-butyl-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine (1.7 g, 3.2 mmol) and 1,4-dioxane (20 ml), yielding a brown solution. Added HCl (4 n in 1,4-dioxane, to 4.05 ml of 16.2 mmol) and the resulting mixture was stirred at a temperature of about 40°C for about 3 hours. Dissolve�RER removed under reduced pressure. Add EtOAc (50 ml) and saturated aqueous solution of NaHCO3(20 ml). The resulting solid material is collected by vacuum filtration, and dried using lyophilization, yielding a solid material is gray (0,93 g). Layers of the obtained filtrate were separated, and the aqueous layer was extracted with EtOAc (3×40 ml). The organic layer is dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure, yielding a residue of brown (0.52 g). The resulting material was pooled, yielding 3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (1.45 g, purity 80%, according to UV, 84%): LC/MS (table 2, Method a) Rt=1,76 min; MS m/z: 425 (M+H)+.

Stage N: 5-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile and 5-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)the pyrazine-2-carbonitrile

A 5 ml microwave reaction vial was placed 3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)Cyclopentanone (0.30 g, 0.71 mmol) in EtOH (2.0 ml) to give a brown suspension. Add 5-chloropyrazine-2-carbonitrile (amount of 0.118 g, 0,848 mmol, Ark Pharm) and DIEA (of 0.49 ml, 2.8 mmol). The resulting suspension is heated using microwave radiation at a temperature of about 150°C for about 1 hour. The solvent was removed by�igenom pressure and added EtOAc (50 ml) and water (20 ml). The layers were separated, and the organic layer was washed with brine (20 ml), dried over anhydrous MgSO4, filtered and the solvent removed under reduced pressure, yielding crude 5-(-3-ethyl-4-(6-tosyl-6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile (0.24 g, the purity of 40% according to UV, 0.18 mmol) was dissolved in 1,4-dioxane (10 ml), yielding a brown solution. Add a saturated aqueous solution of Na2CO3(10 ml, 27 mmol) and the resulting reaction mixture was stirred for about 96 hours at a temperature of about 50°C. the Obtained reaction mixture was cooled to room temperature, and the reaction mixture was added EtOAc (50 ml). The layers were separated, and the organic layer was washed with water (25 ml) and brine (25 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material is purified using HPLC with reversed phase (table 2, Method m) to obtain a 1:1 mixture of 5-((1S,3R,4S)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile and 5-((1R,3S,4R)-3-ethyl-4-(6H-imidazo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-1-yl)cyclopentylamine)pyrazine-2-carbonitrile (0.0025 g, 1,5%): LC/MS (table 2, Method a) Rt=of 1.81 min; MS m/z: 374 (M+H)+.

Example # 19: 3-((3R,4R)-3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)-4-demerol-1-yl)-3-oxopropanenitrile

Stage A: 1-(benzyloxycarbonyl)-4-demerol-3-carboxylic acid

Hydrochloride 4-methylnicotinic acid (5.00 g of 36.5 mmol, ASDI) and platinum oxide (IV) (0.35 g, 1.54 mmol) is shaken in AcOH (100 ml) under hydrogen pressure of about 414 kPa for about 72 hours at room temperature. The obtained reaction mixture was filtered through celite may® and concentrated under reduced pressure, yielding the hydrochloride of 4-demerol-3-carboxylic acid (7.4 g, containing the remains of AcOH), which is used further without further purification. To a portion of the acid (1.0 g, to 4.92 mmol) in 1,4-dioxane (10 ml) was added HCl (4 n in 1,4-dioxane, 4.0 ml, 16 mmol). The resulting mixture was stirred for about 10 min before adding Et2O (10 ml). The resulting precipitate was collected by vacuum filtration, washed with Et2O (5 ml), receiving the solid material (0.27 g). To the filtrate is added HCl (4 n in 1,4-dioxane, 4.0 ml, 16 mmol) and the resulting mixture was concentrated under reduced pressure to constant weight, thus adding to the resulting residue DCM (20 ml) to give a thick yellow oil (0.56 g). The two portions were combined, yielding the hydrochloride of 4-demerol-3-carboxylic acid (0,83 g, 93%). To acid (0,83 g, 4.6 mmol) was added N-(benzyloxycarbonyloxy)succinimide (1,27 g, 5.08 mmol), Na2CO3(1,71 g of 16.2 mmol) and the mixture water:1,4-dio�San (1:1, 20 ml). The resulting mixture was stirred at room temperature for about 16 hours, and the organic solvent was removed under reduced pressure. The aqueous phase is neutralized by adding 1 n HCl. The resulting solution was extracted with EtOAc (2×25 ml) and the combined organic extracts were washed with brine and dried over anhydrous MgSO4. The resulting solution was filtered and concentrated under reduced pressure, yielding 1-(benzyloxycarbonyl)-4-demerol-3-carboxylic acid (1.28 g, 100%): LC/MS (table 2, Method a) Rt=1,97 min; MS m/z: 278 (M+H)+.

Step B: Benzyl 3-(2-bromoacetyl)-4-demerol-1-carboxylate

To a solution of 1-(benzyloxycarbonyl)-4-demerol-3-carboxylic acid (1.28 g, 4,62 mmol) in DCM (40 ml) was added oxaliplatin (0,930 ml, 10.6 mmol) followed by dropwise addition of DMF (0,072 ml of 0.92 mmol). The obtained reaction mixture was stirred at room temperature overnight. The reaction mixture is concentrated, resulting in crude benzyl 3-(chlorocarbonyl)-4-demerol-1-carboxylate (1.4 g, 4.7 mmol) was dissolved in a mixture of Et2O and MeCN (1:1, 16 ml) and added to a solution trimethylsilyldiazomethane (2 M in Et2O, for 9.47 ml, 18.5 mmol) in Et2O and MeCN (1:1, 16 ml) which was cooled to about 0°C. the resulting mixture was stirred at a temperature of about 0°C for about�olo 4 hours and quenched, dropwise adding 48% aqueous HBr solution. The organic solvents were removed, and the obtained residue was purified by column chromatography with silica gel performing a gradient elution 10-40% EtOAc in heptane. Contains the product fraction is concentrated under reduced pressure, yielding benzyl 3-(2-bromoacetyl)-4-demerol-1-carboxylate (0.78 g, 47%): LC/MS (table 2, Method a) Rt=2,50 min; MS m/z: 356 (M+H)+.

Step C: 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine

A solution of 2-bromo-5H-imidazo[2,3-b]pyrazine (78,0 g, 394 mmol, Ark Pharm) in anhydrous DMF (272 ml) was dropwise added over about 60 min to a stirred suspension of NaH (60% dispersion in mineral oil, 12.8 g, 532 mmol) in anhydrous DMF (543 ml) at a temperature of about 0-5°C. the Brown reaction solution was stirred for about 30 min at a temperature of about 0-5°C, then added, dropwise, a solution of p-toluensulfonate (94,0 g, 492 mmol) in anhydrous DMF (272 ml) for about 60 minutes at a temperature of about 0-5°C. the reaction mixture Obtained is stirred at a temperature of about 0-5°C for about 1 hour, then allowed to warm to room temperature and stirred for about 18 hours at room temperature. The obtained reaction mixture was slowly poured into ice water (6 l) was then added an aqueous solution of 2.5 n NaOH (50,0 ml, 125 mmol). P�obtained precipitate is collected by filtration and stirred with cold water (3×200 ml). The solid product is collected by filtration and dried to constant weight in a vacuum thermostat at a temperature of about 55°C, resulting in 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine: (134,6 g, 97%) as a solid pale beige: LC/MS (table 2, Method d) Rt=to 1.58 min; MS m/z: 352/354 (M+H)+.

Step D: Methyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carboxylate

To a solution of 2-bromo-5-tosyl-5H-imidazo[2,3-b]pyrazine (5.00 g, 14.2 mmol) in DMF (64 ml) was added dichlorobis(triphenylphosphine)palladium (0,60 g 0,86 mmol), TEA (5,9 ml, 43 mmol) and MeOH (17 ml, 420 mmol). To a reaction flask connect the cylinder with carbon monoxide. The flask is evacuated and again fill with carbon monoxide twice, and the resulting mixture was heated at a temperature of about 65°C for about 3 hours. Add a further quantity dichlorobis(triphenylphosphine)palladium (0,60 g 0,86 mmol) and the flask was again evacuated and again fill with carbon monoxide twice. The obtained reaction mixture is heated at a temperature of about 95°C for about 16 hours in an atmosphere of carbon monoxide. The resulting mixture was cooled to room temperature and poured into ice water (350 ml). The resulting suspension was stirred for about 10 min and filtered. The filter cake was washed with water, and the solid product lyophilizer for about 48 hours, yielding methyl 5-tosyl-5H-imidazo[2,-b]pyrazine-2-carboxylate (5.0 g, the degree of purity of 90% by UV, 95%) as a solid light brown color: LC/MS (table 2, Method a) Rt=2,21 min; MS m/z: 332 (M+H)+.

Stage E: Hydrochloride 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carboxylic acid

To a solution of methyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carboxylate (2.5 g, 7.5 mmol) in 1,4-dioxane (50 ml) was added an aqueous solution of 6 n HCl (50,0 ml 1650 mmol) and the resulting reaction mixture was stirred at a temperature of about 65°C for about 5 h and at room temperature for about 72 hours. The resulting mixture was again heated at about 60°C for about 3 hours, and stirred at room temperature for about 48 hours. The resulting mixture was again heated to about 65°C for about 2 hours and then cooled to room temperature. insoluble bright yellow residue is removed by filtration, and the organic solvent was removed under reduced pressure, yielding a precipitate, which is collected and dried, yielding the hydrochloride of 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carboxylic acid (1.92 g, 72%) as a solid yellow-brown: LC/MS (table 2, Method a) Rt=of 1.48 min; MS m/z: 352 (M-H)-.

Stage F: Tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate

To a solution of hydrochloride 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carboxylic �of islote (1.92 g, 5.43 mmol) in t-BuOH (50 ml) was added TEA (1,67 ml of 11.9 mmol) and diphenylphosphoryl (1,29 ml, 5,97 mmol). The obtained reaction mixture is heated at a temperature of about 70°C for about 8 hours. The resulting mixture was cooled to room temperature, and the insoluble residue was removed by filtration. The obtained filtrate was suspended in EtOAc and filtered. The obtained filtrate was concentrated, and the crude material purified by column chromatography with silica gel performing a gradient elution 17-100% EtOAc/heptane, yielding tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate in the form of white solids (0,68 g). As a result chromatographic treatment also receive 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-carboxamide (0.39 in g, 1,23 mmol) which is subjected to the interaction with tetraacetate lead (0.55 g, 1.2 mmol) in t-BuOH (25 ml) at room temperature for about 72 hours, then kept at reflux for about 4 hours. Add a further quantity of tetraacetate lead (1,36 g of 3.07 mmol) and the resulting mixture was heated at reflux for about 2 hours. The insoluble residue was removed by filtration, and the filtrate obtained is concentrated under reduced pressure. The obtained residue was purified by column chromatography with silica gel, as disclosed above, resulting in additional comp�additional portion of the desired product (0.18 g). Both portions were pooled, yielding tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate (0.86 g, 41%): LC/MS (table 2, Method a) Rt=2,67 min; MS m/z: 389 (M+H)+.

Stage G: Benzyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)amino)acetyl)-4-demerol-1-carboxylate

To a suspension of NaH (60% dispersion in mineral oil, 0,088 g, 2.2 mmol) in DMF at a temperature of about 0°C. (10 ml) was added a solution of tert-butyl 5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylcarbamate (0.86 g, 2.2 mmol, step F) in DMF (10 ml) and the resulting mixture was stirred at a temperature of about 0°C for about 1 hour. Dropwise added a solution of benzyl 3-(2-bromoacetyl)-4-demerol-1-carboxylate (0.78 g, 2.2 mmol, step B) in DMF (5 ml), and the resulting mixture was stirred at room temperature for about 16 hours. The solvent was removed, and the obtained residue was separated between EtOAc and water (40 ml each). The organic phase was washed with brine (20 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, yielding benzyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)amino)acetyl)-4-demerol-1-carboxylate (1.45 g, 100%): LC/MS (table 2, Method a) Rt=3,14 min; MS m/z 662 (M+H)+.

Stage H: Benzyl 4-methyl-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylamino)acetyl)piperidine-1-carboxylate

Benzyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-yl)amino)acetyl)-4-demerol-1-carboxylate (1.45 g, 2.2 mmol) was stirred in HCl (4 n in 1,4-dioxane, with 0.55 ml, 2.2 mmol) at room temperature for about 90 minutes the Solvent was removed under reduced pressure and the resulting residue was neutralized using a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (2×20 ml) and the combined organic extracts were washed with saline solution (16 ml), dried over anhydrous MgSO4, filtered and concentrated, resulting in benzyl 4-methyl-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylamino)acetyl)piperidine-1-carboxylate (1,23 g, 100%) as amorphous solid substance brown: LC/MS (table 2, Method a) Rt=to 2.74 min; MS m/z: 562 (M+H)+.

Stage I: Benzyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carboxylate

To the resulting solution of benzyl 4-methyl-3-(2-(5-tosyl-5H-imidazo[2,3-b]pyrazine-2-ylamino)acetyl)piperidine-1-carboxylate (1.2 g, 2.2 mmol) in 1,4-dioxane (15 ml) was added a reagent Lawson (of 0.44 g, 1.1 mmol) and the resulting mixture was heated at a temperature of about 60°C for 90 min., the Solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography with silica gel, performing gradient elwer�tion 0-1,5% MeOH/DCM, resulting in benzyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carboxylate (0,93 g, 78%) as an amorphous yellow substance: LC/MS (table 2, Method a) Rt=2,49 min; MS m/z: 544 (M+H)+.

Stage J: Benzyl 3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)-4-demerol-1-carboxylate

To a solution of benzyl 4-methyl-3-(3-tosyl-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)piperidine-1-carboxylate (0,93 g, 1.7 mmol) in 1,4-dioxane (20 ml) was added aqueous NaOH (2 n, 1.0 ml), and the mixture was heated at a temperature of about 90°C for about 80 min the Solvents were removed under reduced pressure and the resulting residue was treated with a saturated aqueous solution of NH4Cl (26 ml) and extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (20 ml), dried over anhydrous MgSO4, filtered and concentrated, resulting in the crude product in the form of a solid amorphous material, brown color. The resulting material was purified by column chromatography with silica gel performing a gradient elution from 5% -100% MeOH/DCM, yielding benzyl 3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)-4-demerol-1-carboxylate (0.55 g, 83%) as a solid yellow: LC/MS (table 2, Method a) Rt=to 1.94 min; MS m/z: 390 (M+H)+.

Stage K: 8-(4-demerol--yl)-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine

A mixture of benzyl 3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)-4-demerol-1-carboxylate (0.55 g, 1.4 mmol) and palladium-on-charcoal (10%, of 0.38 g, 0.36 mmol) in EtOH (25 ml) is hydrogenated at room temperature under atmospheric pressure of hydrogen for about 20 hours. The catalyst was removed by filtration through a layer of celite may®, and the filtrate obtained was concentrated under vacuum to give 8-(4-demerol-3-yl)-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine (0.30 g, 83%) as an amorphous yellow substance: LC/MS (table 2, Method a) Rt=0,93 min; MS m/z: 256 (M+H)+.

Stage L: 3-((3R,4R)-3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)-4-demerol-1-yl)-3-oxopropanenitrile

To a solution of 8-(4-demerol-3-yl)-3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine (0.30 g, 1.2 mmol) in DMF (10 ml) was added DIEA (of 0.41 ml, 2.4 mmol) and EDC (of 0.68 g, 3.5 mmol). Add 2-zanoxolo acid (0.20 g, 2.4 mmol) and the resulting mixture was stirred at room temperature for about 14 hours. The solvent was removed under reduced pressure, and the obtained residue was separated between DCM and water (25 ml each). The organic phase was washed with brine (20 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material is purified by column chromatography with silica gel performing a gradient elution 0-8% MeOH in DC, getting the product in the form of white solids (0.29 g). As a result chiral separation (table 3, Method 10) substances receive the material (Rt=22,5 min, opt.BP.=positive), which is then purified by column chromatography with silica gel performing a gradient elution 0-8% MeOH in DCM, yielding 3-((3R,4R)-3-(3H-imidazo[1,2-a]imidazo[2,3-e]pyrazine-8-yl)-4-demerol-1-yl)-3-oxopropanenitrile (0.04 g, 11%): LC/MS (table 2, Method a) Rt=1,36 min; MS m/z: 323 (M+H)+.

Example # 20: 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

Stage A: 3-iodo-5-methoxy-1-methyl-1H-indole

5-methoxy-1H-indole (5.00 g, 34,0 mmol) in DMF (100 ml) was stirred with KOH (2.00 g, to 35.7 mmol) for about 15 minutes, then added iodine (g 8,80, to 34.7 mmol). The resulting mixture was stirred for about 30 min, then portions add NaH (60% dispersion in mineral oil, 1.63 g, of 40.8 mmol). After stirring for about 15 min at room temperature, add iodomethane (2,34 ml and 37.4 mmol) and the resulting mixture was stirred for about 2 hours. The solvents were removed under reduced pressure, and the resulting mixture was stirred with water (300 ml) for about 15 min, the resulting suspension is treated with DCM (100 ml) and the layers were separated. The aqueous layer was extracted with DCM (50 ml), and the United �organicheskie fractions dried over anhydrous MgSO 4, filtered and concentrated. The resulting material was purified by column chromatography with silica gel, elwira DCM, yielding 3-iodo-5-methoxy-1-methyl-1H-indole (9,48 g, 97%):1H NMR (400 MHz, DMSO-d6δ of 7.48 (s, 1H), 7,38 (d, 1H), 6,86 (DD, 1H), at 6.72 (d, 1H), 3,79 (s, 3H), to 3.76 (s, 3H); LC/MS (table 2, Method a) Rt=2,50 min.

Stage B: 5-bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl)ethinyl)pyrazine-2-amine

In a 500 ml round-bottomed flask is placed NMP (120 ml) and 3,5-dibromopyridin-2-amine (9,00 g and 35.6 mmol). The resulting mixture Tegaserod nitrogen and added Pd(Ph3P)4(3,29 g, 2.85 mmol). The flask wrapped in aluminum foil to protect from light, and added copper iodide(I) (0,678 g, to 3.56 mmol), TEA (29,8 ml, 214 mmol) and (trimethylsilyl)acetylene (3,84 g of 39.1 mmol). The resulting mixture was heated at about 55°C on an oil bath for about 1.5 hours. The resulting mixture was cooled to room temperature and added 3-iodo-5-methoxy-1-methyl-1H-indole (9,76 g, 34,0 mmol), water (0,256 ml, 14.2 mmol), NMP (1 ml) and DBU (37.5 ml, 249 mmol). The resulting mixture was stirred at room temperature for about 16 hours. The mixture is concentrated to remove volatiles, and the resulting mixture was diluted with water (800 ml) and extracted with EtOAc (4×300 ml). The combined organic layers washed with water (600 ml). The resulting emulsion was filtered through celite may® to remove insoluble material. Get�record filtrate the layers were separated, and the organic layer dried over anhydrous MgSO4, filtered, and concentrated to about 25 ml and purified by column chromatography with silica gel, elwira EtOAc. Contains the product fraction is concentrated, yielding material, which is triturated with Et2O (50 ml), filtered and washed with Et2O (2×10 ml). The resulting solid material was dried, yielding 2.94 g of the product. The filtrate obtained above was concentrated to about 6 ml and purified by column chromatography with silica gel, elwira EtOAc, receiving a second portion of the enriched material, which was triturated with Et2O (20 ml) and filtered, yielding additionally 0.42 g of product. The two portions were combined, yielding 5-bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl)ethinyl)pyrazine-2-amine (3,36 g, 26%): LC/MS (table 2, Method a) Rt=2,46 min; MS m/z: 357 (M+H)+.

Step C: 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-imidazo[2,3-b]pyrazine

5-bromo-3-((5-methoxy-1-methyl-1H-indol-3-yl)ethinyl)pyrazine-2-amine (3.25 g, 9,10 mmol) in DMF (35 ml) was treated with NaH (60% dispersion in mineral oil, 0.36 g, 9.1 mmol). After about 5 hours at room temperature, the resulting mixture was treated with another portion of NaH (60% dispersion in mineral oil, 0.036 g, 0.91 mmol), and stirred for about 16 hours. The resulting mixture was concentrated and stirred with water (50 ml) and EtOAc (40 ml). Obtained�ect filtered, and the solid products were washed until, until there remains insoluble resin. Received filtrate layers were separated, and the organic layer dried over anhydrous MgSO4, filtered and concentrated. The material was dissolved in a minimum amount of warm DMF, and purified by column chromatography with silica gel (120 g silica gel column), elwira a mixture of 95:5 DCM/MeOH. Contains the product fractions were pooled and concentrated, yielding an oil which is purified by column chromatography with silica gel (120 g silica gel column), elwira EtOAc. Contains the product fractions were pooled and concentrated, yielding oily residue which is triturated with EtOAc (20 ml), then filtered, obtaining a solid material yellow. This material was dried, yielding 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-imidazo[2,3 - b]pyrazine (1,48 g, 45%): LC/MS (table 2, Method a) Rt=2,50 min; MS m/z: 357 (M+H)+.

Stage D: 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine

2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-imidazo[2,3-b]pyrazine (0.500 g, of 1.40 mmol) in DMF (15 ml) was cooled to about 0°C, then treated with NaH (60% dispersion in mineral oil, 0,112 g, 2.80 mmol). The resulting mixture was stirred for about 15 minutes, add SEM-Cl (0,372 ml, 2.10 mmol) and the resulting mixture was heated to room�a combined temperature for about 15 min. The resulting mixture was concentrated and purified by column chromatography with silica gel (40 g silica gel column), elwira DCM, yielding 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine (0,61 g, 89%): LC/MS (table 2, Method a) Rt=3,88 min; MS m/z: 489 (M+H)+.

Stage E: (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methanol

2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine (0,815 g, 1.67 mmol), (E)-styrylboronic acid (0,272 g, 1.84 mmol, Combiblocks), Cs2CO3(1,36 g, 4,18 mmol) and PdCl2(PPh3)2(0,070 g, 0.10 mmol) in 1,4-dioxane (13 ml) and water (6.5 ml) was heated at about 70°C during the night. The resulting mixture was cooled and the solvent concentrated under reduced pressure. The resulting material was separated between water (50 ml) and EtOAc (60 ml) and the organic layer dried over anhydrous MgSO4, filtered and concentrated to a foam (1.01 g). This foam was dissolved in 1,4-dioxane (15 ml) and water (3 ml), was added 2.5 weight % osmium tetroxide in t-BuOH (0.84 ml, 0,067 mmol), and sodium periodate (1.43 g, was 6.69 mmol). The resulting mixture was stirred for about 1 hour at room temperature then added 2.5 weight % osmium tetroxide in t-BuOH (0.84 ml, 0,067 mmol) and water (3 ml). The resulting mixture was stirred in tech�of about 3 hours, then diluted with water (50 ml). The resulting mixture was extracted with EtOAc (50 ml and 25 ml volume). The combined organic solutions washed with brine (30 ml), dried over anhydrous MgSO4, filtered and concentrated, yielding an oil (0,97 g). This material was dissolved in 1,4-dioxane (10 ml) and EtOH (2 ml) then treated with NaBH4(0,063 g, 1,672 mmol) and stirred for about 30 min the Solvent was evaporated, and the material is separated between EtOAc (50 ml), water (20 ml) and a saturated aqueous solution of NaHCO3(20 ml). The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 ml). The combined organic solutions washed with brine (20 ml), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting material was purified by column chromatography with silica gel, elwira EtOAc, yielding (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methanol (0,63 g, 86%): LC/MS (table 2, Method a) Rt=2,58 min; MS m/z: 439 (M+H)+.

Stage F: 2-(azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine

(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methanol (0,63 g, 1.4 mmol) in DCM (10 ml) was treated SOCl2(0,115 ml, to 1.58 mmol) and stirred for about 15 min PR� room temperature. The solvent was evaporated, then add sodium azide (0,280 g, 4,31 mmol) and DMF (5 ml). The resulting mixture was then stirred at room temperature overnight. The solvent is evaporated, and the obtained residue was separated between water (30 ml) and EtOAc (25 ml). The aqueous layer washed with EtOAc (15 ml) then the combined organic solutions are dried over anhydrous MgSO4, filtered and concentrated, yielding 2-(azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine (0,58 g, 87%): LC/MS (table 2, Method a) Rt=3,42 min; MS m/z: 464 (M+H)+.

Stage G: (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine

2-(azidomethyl)-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine (of 0.58 g, 1.3 mmol) in THF (15 ml) was treated with triphenylphosphine (0,335 g of 1.28 mmol) and water (0,150 ml of 8.33 mmol), then heated at about 70°C for about 2 hours. The resulting mixture was cooled, then concentrated in vacuo. The resulting material was purified by column chromatography with silica gel, elwira a mixture of 9:1 DCM/MeOH containing 2.5 vol. % to 37 wt %. an aqueous solution of ammonium hydroxide, yielding (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine (0,37 g, 68%): LC/MS (table 2, Method a) Rt =2,11 min; MS m/z: 438 (M+H)+.

Stage H: N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)acetamide

(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine (0,185 g, 0,423 mmol) in THF (5 ml) was treated with pyridine (0,044 ml, 0.55 mmol) and acetic anhydride (0,044 ml, 0.47 mmol). The resulting mixture was stirred for about 5 min at room temperature and treated with AcOH (0,024 ml of 0.42 mmol). The resulting mixture was diluted with EtOAc (20 ml) and washed with water (15 ml) and brine (10 ml). The organic solution is dried over anhydrous MgSO4, filtered and concentrated, yielding N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pirollo[2,3-b]pyrazine-2-yl)methyl)acetamide (0,202 g, 100%): LC/MS (table 2, Method a) Rt=2,63 min; MS m/z: 480 (M+H)+.

Stage I: N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)acetamide

N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)acetamide (0,200 g, 0,417 mmol) in DMF (10 ml) was treated with Ethylenediamine (0.90 ml, 13 mmol) and TBAF (1 M in THF, 1.7 ml, 1.7 mmol). The resulting mixture was heated at 85°C. for about 90 min, then cooled and concentrated under reduced pressure. Paul�obtained material was stirred with water (20 ml) for about 16 hours, add Et2O (10 ml), and stirring was continued for about 15 min the Suspension was filtered, and the solid product collected and dried. The obtained filtrate was extracted with EtOAc (2×25 ml) then the combined organic solutions are dried over anhydrous MgSO4, filtered and concentrated, yielding material, which is combined with the previously collected solid material. All material is triturated with EtOAc (5 ml) and filtered, yielding solid substance. The filtrate obtained is purified by column chromatography with silica gel, elwira DCM/MeOH (9:1), obtaining the additional amount of product that is combined with the solid product obtained by thorough trituration with EtOAc, yielding N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)acetamide (0,108 g, 74%): LC/MS (table 2, Method a) Rt=of 1.91 min; MS m/z: 350.2 (M+H)+.

Stage J: 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)acetamide (0,108 g, 0,309 mmol) in 1,4-dioxane (6 ml) is treated with a reagent Lawson (0.075 g, 0,19 mmol) and heated to about 85°C for about 30 min the resulting mixture was rapidly cooled, then add another batch of reagent Lawson (0.075 g, 0,19 mmol). The resulting mixture was heated at about 85°C for about 30 min�scientists mixture was cooled to room temperature, then add mercury acetate (0.10 g, 0,31 mmol). After about 15 minutes add another batch of mercury acetate (0.10 g, 0,31 mmol). The resulting mixture was stirred for about 15 min, then diluted with EtOAc (50 ml). The resulting mixture was filtered and the filter cake washed with EtOAc (2×25 ml). The filtrate obtained is evaporated (and the resulting residue put aside), and solids, dried and triturated with DCM (20 ml). Solids are collected by filtration and washed with DCM (25 ml). The filtrate obtained is concentrated and combined with set aside the remainder obtained by filtration EtOAc. The filter cake was dissolved in DMF (1.2 ml) and purified by column chromatography with silica gel (10 g column), elwira 95:5 DCM/MeOH. Contains the product fractions are combined with the filtrate obtained in the result of careful trituration with EtOAc and DCM, concentrated, and the combined material is purified by column chromatography with silica gel (10 g column), elwira 95:5 DCM/MeOH. Contains the product fractions combined. Column of silica gel was washed with DMF (40 ml each) and all the product containing fractions are combined with the previously collected, the solvents were removed under reduced pressure. The obtained residue was triturated with MeOH (5 ml) and filtered. The filter cake triturated with water (40 ml) and 37 wt % of ammonium hydroxide (3 ml) and e�stragiht EtOAc (5×50 ml). The organic extracts were pooled and washed with brine (25 ml), dried over anhydrous MgSO4, filtered and concentrated, yielding the solid material (of 0.056 g), which was triturated with MeOH (5 ml). The solid product is collected by filtration, then dried, yielding 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine, which contains 5 wt.% MeOH (0,037 g, 36%): LC/MS (table 2, Method a) Rt=to 1.94 min; MS m/z: 332 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12,19 (s, 1H), and 8.50 (s, 1H), 7,81 (s, 1H), with 7.66 (s, 1H), USD 7.45 (DD,J=14,8, of 5.52 Hz, 2H), 7,03 (l,J=of 2.07 Hz, 1H), at 6.92 (DD,J=8,88, of 2.25 Hz, 1H), of 3.87 (s, 3H), 3,83 (s, 3H), of 2.95 (s, 3H).

Example # 21: 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

Stage A: N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)formamide

(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine (0,095 g, 0.22 mmol, example No. 20, step G) in ethylformate (4.4 ml, 54,0 mmol) is heated at a temperature of about 60°C on an oil bath for about 45 minutes the mixture was cooled and evaporated, receiving N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)formamide (0.10 g, 100%): LC/MS (table 2, Method a) Rt=2.65 m�n; MS m/z: 466 (M+H)+.

Step B: 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)formamide (0.10 g, 0.22 mmol) in 1,4-dioxane (4 ml) is treated with a reagent Lawson (0,053 g, 0.13 mmol) and heated to about 80°C in oil bath for about 15 min the mixture was cooled and added acetate mercury (0,073 g 0,23 mmol, Fluka). The resulting mixture was stirred for about 30 min at room temperature and add another batch of mercury acetate (0,073 g, 0,228 mmol, Fluka), and stirring was continued for about 2 hours at room temperature. The resulting mixture was diluted with EtOAc (20 ml) and filtered. The solvent is evaporated under reduced pressure, the material is then purified by column chromatography with silica gel, elwira DCM/MeOH (95:5). The material is then obtained after concentration of product containing fractions purified by column chromatography with silica gel, EtOAc, yielding 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (0,048 g, 49%): LC/MS (table 2, Method a) Rt=3,16 min; MS m/z: 448 (M+H)+.

Step C: 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsily)ethoxy)methyl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (0,048 g, 0.11 mmol) in DMF (4 ml) was treated with Ethylenediamine (of 0.22 ml, 3.3 mmol) and heated to about 85°C for about 5 min the resulting solution was cooled, and added TBAF (1 M in THF, of 0.11 ml, 0,11 mmol). The resulting solution was again heated at about 85°C for about 30 min the resulting mixture was cooled to room temperature and add another serving of TBAF (1 M in THF, 0,054 ml, 0,054 mmol) and heating was continued for about 1.5 hours. The resulting solution was cooled and the material purified using preparative HPLC with a reversed phase (table 2, Method I). Contains the product fractions concentrated to remove MeCN, then made basic with a saturated aqueous solution of NaHCO3and extracted with EtOAc (2×10 ml). The combined organic solutions are dried over anhydrous MgSO4, filtered and concentrated. Triturated solid product with heptane (5 ml), then collected by filtration, to thereby produce 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (0,028 g, 8%): LC/MS (table 2, Method a) Rt=of 1.91 min; MS m/z: 318,1 (M+H)+.1H NMR (400 MHz, DMSO-d6δ 12,18 (s, 1H), 8,77 (s, 1H), 8,59 (s, 1H), 7,83 (s, 1H), 7,79 (s, 1H), of 7.48 (d,J=a 2.3 Hz, 1H), 7.43 it (l,J=the 8.9 Hz, 1H), 7,20 (l,J=a 2.3 Hz, 1H), at 6.92 (DD,J=8,90, a 2.36 Hz, 1H), 3,88 (s, 3H), 3,82 (s, 3H).

Example # 22: 7-(5-m�methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

Stage A: N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)benzamide

(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methanamine (0,095 g, 0.28 mmol, example No. 20, step G) in THF (5 ml) was treated with pyridine (was 0.026 ml, 0.33 mmol) and benzoyl chloride (0,033 ml, 0.28 mmol). The resulting mixture was stirred for about 20 minutes at a temperature of about 60°C and cooled to room temperature, diluted with an aqueous solution of Na2CO3(15 ml), and extracted with EtOAc (20 ml). The organic solution is dried over anhydrous MgSO4, filtered and concentrated, yielding N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)benzamide (amount of 0.118 g, 100%): LC/MS (table 2, Method d) Rt=of 1.64 min; MS m/z: 542 (M+H)+.

Step B: 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-imidazo[2,3-b]pyrazine-2-yl)methyl)benzamide (amount of 0.118 g, 0,218 mmol) in 1,4-dioxane (3 ml) is treated with a reagent Lawson (0,070 g, 0.17 mmol) and heated to about 80°C in oil bath for about 20 min the mixture was cooled to room t�of mperature and then add a acetate mercury (0,073 g, 0,23 mmol). The resulting mixture was stirred for about 60 min at room temperature, then add another batch of mercury acetate (0,069 g, 0.22 mmol), and stirring was continued for about 20 min at room temperature. The resulting mixture was diluted with EtOAc (20 ml) and then filtered. The filtrate obtained is concentrated under reduced pressure and the material purified by column chromatography with silica gel, elwira EtOAc, yielding 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (0.055 g, 48%): LC/MS (table 2, Method d) Rt=of 1.91 min; MS m/z: 524 (M+H)+.

Step C: 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine

7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (0,054 grams, the 0.103 mmol) in DMF (3 ml) was treated with Ethylenediamine (0,207 ml of 3.09 mmol) and TBAF (1 M in THF, 0,412 ml, 0,412 mmol). The resulting solution was heated at about 90°C for 70 min, the mixture was cooled to room temperature, the mixture was diluted with EtOAc (10 ml), washed with water (6 ml), dried over anhydrous MgSO4, filtered and concentrated, yielding a residue of yellow. The obtained residue was purified by column chromatography with silica gel, elwira 1-6% MeOH/DCM getting solid yellow, ivory�ing triturated with heptane (2 ml), obtaining 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-phenyl-6H-imidazo[1,5-a]imidazo[2,3-e]pyrazine (0.004 g, 10%): LC/MS (table 2, Method a) Rt=at 2.26 min; MS m/z: 394 (M+H)+.

1. The compound of formula (I)

or its pharmaceutically acceptable salts, stereoisomers and isomers, where
T represents N, U pre�is an N, X represents CR3and Y represents N; or
T is a CR6U represents CR4, X represents CR3and Y represents N; or
T is a CR6U represents N and X represents NR3and Y is C; or
T represents O, U represents N and X represents CR3and Y represents S; or
T represents NR6U represents N and X represents CR3and Y represents S; and
R1, R2and R5each independently represents hydrogen, heteroaryl substituted with 1-2 substituents selected from (C1-C6)alkyl, (C1-C6)alkyl or (C6)aryl, optionally substituted-SO2Me;
or
T is a CR6U represents N and X represents CR3and Y represents N; or
T represents N, U represents CR4, X represents CR3and Y represents N; and
R1and R2each independently represents hydrogen, heteroaryl substituted with 1-2 substituents selected from (C1-C6)alkyl, (C1-C6)alkyl or (C6)aryl, optionally substituted-SO2Me;
R5is heteroaryl substituted with 1-2 substituents, vibrancies (C 1-C6)alkyl, -O(C1-C6)alkyl or (C6)aryl, optionally substituted-SO2Me;
R3represents hydrogen, bridging (C7-C10)cycloalkyl, which is saturated or partially unsaturated bi - or tricyclic structure; (C1-C8)alkyl, optionally substituted with one substituent selected from (C1-C6)alkyl or amino group; (C3-C10)cycloalkyl, optionally substituted with one amino group,- (C1-C6)alkyl or (C1-C6)alkyl, (C6-C8)cycloalkenyl substituted with two substituents selected from (C1-C6)alkyl, (C6)aryl, optionally substituted by one or two substituents selected from halogen,- O(C1-C6)alkyl, (C1-C6)alkyl, -OCF3or-CF3; heteroaryl, optionally substituted by one (C1-C6)alkyl; heterocyclyl, optionally substituted by one (C1-C6)alkyl or heteroaryl; or
R3is a-A-D-E-G where:
A is a bond or (C1-C6)alkylen;
D is a (C1-C2)alkylene, optionally substituted by one (C1-C6)alkyl, bridged (C6-C10)cycloalkyl, which is a rich bi - or tricyclic structure�the kill, optionally substituted by one (C1-C6)alkyl, (C3-C10)cycloalkyl, optionally substituted by one or two substituents selected from (C1-C6)alkyl or heteroaryl, (C4-C6)cycloalkenyl, optionally substituted by one (C1-C6)alkyl, (C6)Allen, heteroaryl or heterocyclyl, optionally substituted by one (C1-C6)alkyl;
E represents a bond, -Re-, -Re-C(O)-Re-, -Re-C(O)O-Re-, -Re-O-Re-, -Re-S(O)2-Re-, -Re-N(Ra)-Re-, -Re-N(Ra)C(O)-Re-, -Re-C(O)N(Ra)Re-, -Re-N(Ra)C(O)OReor Re-N(Ra)S(O)2-Re-;
where in all cases E associated with either a carbon atom or a nitrogen atom in D;
G represents hydrogen, -N(Ra)(Rb), halogen, -ORa, S(O)2Ra, -CN, -C(O)N(Ra)(Rb), -N(Ra)C(O)Rb, -C(O)Ra, -CF3N(Ra)S(O)2Rb, -(C1-C6)alkyl, optionally substituted with 1-3 substituents selected from (C1-C6) alkyl, HE or CN; -(C3-C6)cycloalkyl, optionally substituted with one CN; -heteroaryl, optionally substituted by one or two Halogens, CN, -C(O)NH2or-CF3; -heterocyclyl, optionally substituted with 1-5 Zama�by sinks, selected from oxo, (C1-C6)alkyl, halogen or-CH2HE, -(C6-C10)aryl, optionally substituted with 1-3 substituents selected from halogen,- NO2, CN, -C(O)NH2, -COCH3, -OCHF2, (C1-C6)alkyl, -N(CH3)2or-O(C1-C6)alkyl;
where in the fragment containing-N(Ra)(Rb), nitrogen, Raand Rbmay form a ring so that-N(Ra)(Rb) is an optionally substituted (C3-C6)heterocyclyl, optionally substituted with one substituent selected from halogen, -CF3or-CH2HE where specified (C3-C6)heterocyclyl linked through a nitrogen;
R4and R6each independently represents hydrogen, C1-C4)alkyl, optionally substituted with-OH, -COOH; (C3-C8)cycloalkyl, phenyl, optionally substituted-SO2CH3or-NHSO2CH3, halogen, or-J-L-M-Q;
where:
J is a (C2-C6)alkanine;
L is a bond;
M is a bond;
Q represents-C(O)ORa;
Raand Rbeach independently represents hydrogen, (C1-C4)alkyl optionally substituted with cyano, -CF3or cyclopropane; (C6)aryl, optionally substituted by halogen or-O(C1-C4)Ala�scrap; and
Rein each case, independently is a bond, (C1-C4)alkylene or (C3)cycloalkyl;
where heteroaryl, heteroaryl represent a mono - or bicyclic aromatic ring system containing 5 to 10 atoms including 1 to 3 heteroatom selected from nitrogen, oxygen, or sulfur;
heterocyclyl, heterocyclyl represent a saturated monocyclic ring system containing 5-6 atoms, including 1-2 heteroatom selected from nitrogen, oxygen or sulfur.

2. The connection of claim 1, wherein T represents N, U represents N and X represents CR3and Y represents N and forms a compound of formula (Ia)

3. The compound according to claim 1, where T is a CR6U represents N and X represents CR3and Y represents N and forms a compound of formula (Ib)

4. The connection of claim 1, wherein T represents N and U represents CR4, X represents CR3and Y represents N and forms a compound of formula (IC)

5. The compound according to claim 1, where T is a CR6U represents CR4, X represents CR3and Y represents N and forms a compound of formula (Id)

6. Connected�e according to claim 1, where T is a CR6U represents N and X represents NR3and Y is C and forms a compound of formula (Ie)

7. The connection of claim 1, wherein T represents O, U represents N and X represents CR3and Y is C and forms a compound of formula (If)

8. The compound according to claim 1, where T represents NR6U represents N and X represents CR3and Y is C and forms a compound of formula (Ig)

9. The compound according to claim 1, where R3represents hydrogen, bridging (C7-C10)cycloalkyl, which is saturated or partially unsaturated bi - or tricyclic structure; (C1-C6)alkyl, optionally substituted with one substituent selected from (C1-C6)alkyl or amino group; (C3-C10)cycloalkyl, optionally substituted by one or two amino groups, -O(C1-C6)alkyl or (C1-C6)alkyl, (C6)aryl, optionally substituted by one or two substituents selected from halogen,- O(C1-C6)alkyl, (C1-C6)alkyl, -OCF3or-CF3; heteroaryl, optionally substituted by one (C1-C6)alkyl; heterocyclyl, neoblast�flax substituted by one (C 1-C6)alkyl or heteroaryl.

10. The compound according to claim 9, wherein R3represents an optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted adamantyl, optionally substituted bicyclo[2.1.1]hexyl, optionally substituted bicyclo[2.2.1]heptyl, optionally substituted bicyclo[2.2.2]octyl, optionally substituted bicyclo[3.2.1]octyl, optionally substituted bicyclo[3.1.1]heptyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl or optionally substituted tetrahydrofuranyl.

11. The compound according to claim 1, where R3represents A-D-E-G and a is a bond or (C1-C6)alkylen.

12. The compound according to claim 11, where D represents optionally substituted bicyclo[2.2.1]heptylene, optionally substituted bicyclo[2.1.1]hexylen, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted piperidinyl or optionally substituted pyrrolidinyl.

13. The compound according to claim 12, where E is a-Re-C(O)-Re-, Re-O-Re-, -Re-S(O)2-Re-, -Re-N(Ra)-Re, -Re-(R a)C(O)-Re-, Re-C(O)N(Ra)Reor Re-N(Ra)S(O)2-Re-.

14. The compound according to claim 13, wherein G represents ORa, -CN, CF3, -N(Ra)S(O)2Rboptionally substituted (C1-C6)alkyl, optionally substituted with one CN cyclopropyl, optionally substituted by one CN cyclobutyl, optionally substituted with one CN cyclopentyl, optionally substituted phenyl, optionally substituted pyridazine, optionally substituted pyrazine, optionally substituted pyrimidine, optionally substituted pyrazole, optionally substituted pyrrolidine, optionally substituted hinzelin, optionally substituted pyridine, optionally substituted, thiazolidin or optionally substituted triazole.

15. The compound according to claim 14, where
A is a bond;
D represents optionally substituted cyclopentyl or optionally substituted piperidinyl;
E is a-Re-C(O)-Re-, -Re-N(Ra)-Re-, -Re-S(O)2-Reor Re-N(Ra)S(O)2-Re-;
where Rein each case, independently is a bond or (C1-C4)alkylene; and
G represents-CN, optionally substituted with one CN cyclopropyl, optionally substituted by one CN cyclobutyl, optional someseni� one CN cyclopentyl, optionally substituted phenyl, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted pyrazole or optionally substituted pyridine.

16. The compound according to claim 15, where R1, R2, R4, R5and R6if present, each independently represents hydrogen.

17. The compound according to claim 16 where the compound is a compound of formula (Ia)

18. The compound according to claim 16 where the compound is a compound of formula (Ib)

19. The compound according to claim 16 where the compound is a compound of formula (IC)

20. The compound according to claim 17 where the compound is a

21. The compound according to claim 17 where the compound is a

22. The compound according to claim 17 where the compound is a

23. The compound according to claim 19, where
A is a bond;
D represents optionally substituted cyclopentyl or optionally substituted piperidine;
E is a-Re-N(Ra)-Re-, -Re-C(O)-Re-, -Re-S(O)2-R