WO2003064428A1 - Furano- and thienopyrimidines as neurokinase inhibitors - Google Patents

Abstract

The invention provides in one embodiment the use of a compound represented by the general formula I wherein the variable groups are as defined in the claims or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of Parkinson's Disease, dementia such as age related dementia, HIV-1 associated dementia, AIDS dementia complex, HIV encephalopathy and senile dementia of the Alzheimer's type and memory disorders, cerebral ischemias and spinal cord ischemias, ischemias following stroke or traumatic injuries of the brain or the spinal cord, Huntington Chorea, multiple sclerosis, glaucoma, promotion of survival of transplanted cells, ALS/Motor neuron Disease, neuronal trauma or age related macular degeneration. The patent provides in another embodiment for novel compounds of general formula I. The patent provides in yet another embodiment for a pharmaceutical composition comprising a compound of general formula I. The compounds of the invention are neurokinase inhibitors.

Description

Furano- and thienopyrimidines as neurokinase inhibitors

The invention provides novel compounds useful as neurokinase inliibitors. As such, neurokinases are involved in cell death and the compounds of the invention are consequently useful in several diseases and disorders involving neurodegeneration and cell death in the central nervous system.

Background of the invention

The stress activated protein kinase (SAPK) pathways are divided into two pathways, the SAPK/c-jun NH2-terminal kinase (SAPK/JNK) and the SAPK/p38 pathway. The SAPK/JNK pathway mediates cellular responses to a wide variety of conditions that are stressful to cells, for example UN light, inflammatory cytokines, oxidative stress, deprivation of growth factors, toxins (MPTP/MPP⁺ and Aβ peptides) and heat shock (Mielke K, Herdegen T Prog. Neurobiol. 2000, 61 : 45-60).

The cellular response to the activation of the pathway is processes such as inflammation and/or apoptotic cell death.

Mixed Lineage Kinases (MLKs) are part ofthe SAPK/JΝK pathway and belong to the family of Mitogen Activated Protein Kinase Kinase Kinases (MAPKKKs). At present the MLK family of kinases consists of 6 members, MLK1, MLK2, MLK3, Dual Leucine zipper Kinase (DLK), Leucine Zipper Kinase (LZK) and Mitogen Activated Protein Like Triple Kinase (MLTK).

The activation of MLKs is mediated by small GTPases (Racl and Cdc42) (Teramoto et al. J. Biol. Chem. 1996, 271: 27225-27228.). Upon activation, the MLKs phosphorylate and activate Mitogen Activated Protein Kinase Kinase (MKK4) and/or MKK7 (Davis et al. Cell 2000, 103: 239-252.) Upon phosphorylation and activation, these kinases phosphorylate and activate the JΝK family of kinases, which then activate a panel of transcription factors, with c-jun and ATF-2 (Activating Transcription Factor-2) being the best characterized (Herdegen et al. Neuroscientist 1999, 5: 147-154). Inhibitors of MLKs (e.g. CEP- 1347) are known to be able to prevent cell death in a variety of in vitro and in vivo models for neuronal degeneration (Maroney, et al. J. Neurosci. 1998, 18: 104-111; Saporito et al. J. Neurochem. 2000, 75: 1200-1208; Pirvola et al. J. Neurosci. 2000, 20: 43-50.; Bozyczko-Coyne et al. J. Neurochem. 2001, 77: 849-863.). Diseases and conditions wherein neurodegeneration and inflammation are thought to play a primary role in disease development may benefit from treatment with inhibitors of MLKs. Such diseases include neurodegenerative diseases such as Parkinson's Disease, dementia such as age related dementia, HJN-1 associated dementia, ALDS dementia complex, HIN encephalopathy, vascular dementia and senile dementia of the Alzheimer's type and memory disorders; ALS Motor neuron Disease, neuronal trauma, age related macular degeneration, cerebral ischemias and spinal cord ischemias, ischemias following stroke or traumatic brain injuries or spinal cord injuries, Huntington Chorea, multiple sclerosis, glaucoma, acute damages of the CΝS such as stroke and traumatic injury of the brain or spinal cord and in the promotion of survival of transplanted cells.

WO 0075145 discloses thienopyrimidines useful in the treatment of inflammation.

WO 9924440 discloses thienopyrimidines different from the compounds of the present invention. The compounds of WO9924440 are described as useful in the treatment of cancer.

WO 2002051849 discloses thienopyrimidines. The compounds of WO9924440 are described as cyclin-dependent kinase 4 (Cdk4) inhibitors useful in the treatment of cancer.

Summary of the invention

The invention provides the use of a compound ofthe general formula I

wherein

A represents O or S;

W represents O, NH, NR¹;

R⁴ and R⁵ are independently selected from the group represented by hydrogen, halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy, Cι_₆-alk(en yn)yloxy- C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en yn)yl, halo- C_1-6-aUt(en/yn)yl, halo-C_1-6-alk(en yn)yloxy, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl- Cι_-6-alk(en/yn)yl, acyl, C_1-6-alk(en yn)yloxycarbonyl, C_1-6-alk(en/yn)ylsulfonyl, -NR⁷R⁸ and R N- -e-alk en/yntyl-;

R³ represents hydrogen, halogen, Ci_₆-alk(en yn)yl, C_3-8-cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy, hydroxy- C₁_₆-alk(en/yn)yl, Cι_₆-alk(en/yn)yloxy, C^- alk(en/yn)yloxy-C_1-6-alk(en yn)yl, C_3-8-cycloalk(en/yn)oxy, C₁_₆-alk(en yn)yl sulfanyl, acyl, R⁷R⁸N-C_!_₆-alk(en/yn)yl or -NR⁷R⁸ ;

or R³ represents a group ofthe formula

-R⁹-Ar² wherein R⁹ represents O, NH, NR^1', S, -CONR^1'-, - CO- or C_1-6-alkyl, C_2-6-alkenyl, which may optionally be substituted by OH, halogen, C_1-6-alkoxy or C_3-8-cycloalkyl;

R⁶ represents C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, C_3-8-cycloalk(en)yl- C_1-6-alk(en/yn)yl or Ar¹;

Ar¹ and Ar² are independently selected from the group represented by aryl, a heterocycle or a carbocycle all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en yn)yl, C₁_₆-alk(en/yn)yloxy, C_1-6-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy-C₁_₆-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl aryloxy-,

halo-C₁_₆-alk(en/yn)yloxy, C_1-6-alk(en yn)yl- sulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano- C_1-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, C₁_₆-alk(en/yn)yl-CONR¹ -C_1-6-alk(en/yn)yl,

C_1-6-alk(en/yn)yl-CONR^r-, -CONR⁷R⁸ or R⁷R⁸NCO-C₁.₆-alk(en yn)yl;

R⁷ and R⁸ are independently selected from the group represented by hydrogen and C_1-6-alk(en/yn)yl which may be further substituted by hydroxy, halogen, C_1-6-alkoxy, cyano, nitro, C_3-8-cycloalk(en)yl, C _-8-cycloalk(en)yl-C_1-6-alk(en yn)yl, aryl or a heterocycle; or R⁷ and R⁸ together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one or more further heteroatoms and may optionally be substituted by halogen, C_1-6-alk(en/yn)yl, hydroxy, hydroxy- Cι_-6-alk(en/yn)yl or acyl;

the aryls may be further substituted by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, Cι_-6-alk(en/yn)yloxy, Cι_-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-Cι_-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yloxy, C_3-8-cycloalk(en)yl,

C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, C_1-6-all (en/yn)ylsulfonyl, or -NR^7'R^8' wherein -NR R^8' is as defined for -NR⁷R⁸ above provided that any aryl substituent on -NR R is not further substituted; and R¹ and R¹ are independently selected from the group represented by C_1-6-alk(en/yn)yl, C _-8-cycloalk(en)yl, aryl, hydroxy-C_1-6-alk(en/yn)yl,

C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl and acyl;

or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of Parkinson's Disease, dementia such as age related dementia, HIN-1 associated dementia, AIDS dementia complex, HIN encephalopathy and senile dementia of the Alzheimer's type and memory disorders, cerebral ischemias and spinal cord ischemias, ischemias following stroke or traumatic injuries of the brain or the spinal cord, Huntington Chorea, multiple sclerosis, glaucoma, promotion of survival of transplanted cells, ALS/Motor neuron Disease, neuronal trauma or age related macular degeneration.

The invention provides a method for the treatment of diseases and disorders such as Parkinson's Disease, dementia such as age related dementia, HIN-1 associated dementia, AIDS dementia complex, HIN encephalopathy and senile dementia of the Alzheimer's type and memory disorders, cerebral ischemias and spinal cord ischemias, ischemias following stroke or traumatic injuries of the brain or the spinal cord, Huntington Chorea, multiple sclerosis, glaucoma, promotion of survival of transplanted cells, ALS/Motor neuron Disease, neuronal trauma or age related macular degeneration, comprising the administration of an effective amount of a compound of Formula I as above.

In another embodiment, the invention provides a compound represented by the general formula I

wherein

A represents O or S;

W represents O, NH, NR¹ ;

R⁴ and R⁵ are independently selected from the group represented by hydrogen, halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy, C₁_₆-alk(en yn)yloxy- C_1-6-alk(en yn)yl, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo- C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yloxy, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl- Cι_-6-alk(en/yn)yl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, C_1-6-alk(en yn)ylsulfonyl, -NR⁷R⁸ and R⁷R⁸N-C₁_₆-alk(en yn)yl-;

and

i) R represents a group ofthe formula

-R⁹-Ar²

wherein R⁹ represents O, NH, NR^1', S, -CONR^1'-, -CO-, C_1-6-alkyl or

C_2-6-alkenyl, wherein said C_1-6-alkyl or C_2-6-alkenyl optionally is substituted by OH, halogen, C_1-6-alkoxy or C_3-8-cycloalkyl;

and R⁶ represents Cι_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, C _-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl or Ar¹;

or

ii) R³ represents halogen, C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy,

C₁-₆-alk(en/yn)yloxy,

C i _-6-alk(en/yn)yloxy-C ι _-6-alk(en/yn)yl, C_3-8-cycloalk(en/yn)oxy ,

C_1-6-alk(enyn)ylsulfanyl, acyl,

or -NR⁷R⁸ ; and R⁶ represents indolyl, hydroxy-C_1-6-alk(en/yn)yl-thiophenyl, C i _-6-alk(en/yn)yloxy-C i _-6-alk(en/yn)yl-thiophenyl, benzo [1,3] dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, C_1-6-alk(en yn)yloxy-C_1-6-alk(en/yn)yl,

C_1-6-alk(en/yn)yloxy-C_1-6-alk(en yn)yloxy-C_1-6-alk(en/yn)yl, aryloxy-, aryl- C i _-6-alk(en/yn)yloxy, halo-C ₁_₆-alk(en/yn)yloxy , C i _-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano- Cι_-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-Cι_-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl,

C i _-6-alk(en/yn)yloxycarbonyl, C ι .e-all n/yn l-CONR¹ -C i _-6-alk(en/yn)yl,

-CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en yn)yl;

Ar¹ and Ar² are independently selected from the group represented by aryl, a heterocycle or a carbocycle all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C₁_₆-alk(en yn)yloxy, C_1-6-alk(en/yn)yloxy- C i _-6-alk(en yn)yl,

aryloxy-, a yl- -e-alk en yhJyloxy, halo- -e-all n/ynJyloxy, C_1-6-alk(en/yn)yl- sulfanyl, hydroxy, hyα^oxy-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano- Cι_-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, C₁-₆-alk(en/yn)yl-CONR^1'-C_1-6-alk(en/yn)yl,

Ci_-6-alk(en yn)yl-CONR^1'-, -CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en/yn)yl;

R⁷ and R⁸ are independently selected from the group represented by hydrogen and C_1-6-alk(en/yn)yl which may be further substituted by hydroxy, halogen, C_1-6-alkoxy, cyano, nitro, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, aryl or a heterocycle; or R⁷ and R⁸ together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one or more further heteroatoms and may optionally be substituted by halogen, C_1-6-alk(en/yn)yl, hydroxy, hydroxy- C_1-6-alk(en/yn)yl or acyl; the aryls may be further substituted by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, Cι_-6-alk(en/yn)yloxy, C_1-6-alk(en yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en yn)yloxy, C_3-8-cycloalk(en)yl,

C_3-8-cycloalk(en)yl-C_1-6-alk(en yn)yl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, C_1-6-alk(en yn)ylsulfonyl, or -NR⁷ R^8' wherein -NR⁷ R^8' is as defined for -NR⁷R⁸ above provided that any aryl substituent on -NR⁷ R⁸ is not further substituted;

and R¹ and R¹ are independently selected from the group represented by C_1-6- alk(en/yn)yl, C_3-8-cycloalk(en)yl, aryl, hydroxy- C_1-6-alk(en yn)yl, C_3-8- cycloalk(en)yl-C_1-6-alk(en yn)yl and acyl;

or a pharmaceutically acceptable acid addition salt thereof;

provided that if A is S, W is NH, R⁴ and R⁵ are both hydrogen, and R³ is t-butyl, then R⁶ is not an optionally substituted hydroxyphenyl; and

provided that the compound is not N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yι)- N'-(thiophen-2-ylmethylene)-hydrazine.

The invention provides, in yet another embodiment, a compound as above as a medicament.

The invention provides a pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceutically acceptable acid addition salt thereof or prodrug thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.

Detailed description of the invention

In a preferred embodiment ofthe invention, A is S. In a preferred embodiment ofthe invention, W is NH. In a preferred embodiment ofthe invention, R⁴ and R⁵ are both hydrogen. In a preferred embodiment ofthe invention, R³ is C₁_₆-alk(en yn)yl, or R⁹-Ar². hi a more preferred embodiment of the above, R⁹ is C_1-6-alkyl optionally substituted by OH.

In another more preferred embodiment of the above, R³ is methyl, ethyl, isopropyl or an optionally substituted benzyl, 1-phenethyl or pyridylmethyl.

In an even more preferred embodiment of the above, R³ is an optionally substituted benzyl, 1-phenethyl or pyridylmethyl.

In a yet even more preferred embodiment of the above, benzyl, 1-phenethyl or pyridylmethyl are unsubstituted or substituted by -CONR⁷R⁸. In another more preferred embodiment ofthe above, R³ is C_1-6-alkyl.

In an even more preferred embodiment of the above, R³ is Cι_-6-alkyl wherein the carbon adjacent to the heterocyclic ring is a primary, secondary or tertiary carbon.

In a yet even more preferred embodiment of the above, R³ is methyl, ethyl or isopropyl.

In a preferred embodiment of the invention, R⁶ represents C_1--6-alk(en/yn)yl or Ar¹ wherein Ar¹ is an optionally substituted thiophenyl, indolyl, phenyl, pyrrolyl, quinolinyl, benzo[l,3]dioxolyl or thiazolyl.

In a more preferred embodiment ofthe above, Ar¹ is an optionally substituted indolyl, hydroxy-C ι _-6-alk(en/yn)yl-thiophenyl, C _{\ -6}-alk(en/yn)yloxy-C _{\ -6}-alk(en yn)yl- thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en yn)ylphenyl or hydroxyphenyl.

In an even more preferred embodiment of the above, Ar¹ is an optionally substituted indolyl, hydroxy-C ι _-6-alk(en/yn)yl-thiophenyl, C _1-6-alk(en/yn)yloxy-C _{\ -6}-alk(en/yn)yl- thiophenyl.

In particular embodiments of the invention, indolyl is indol-3-yl and/or thiophenyl is thiophen-2-yl.

In another more preferred embodiment of the above, Ar¹ is unsubstituted or substituted one or more times by C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, hydroxy, nitro, halogen, R⁷R⁸NCO-C_1-6-alk(en/yn)yl; -NR⁷R⁸, C_1-6-alk(en/yn)yl-CON-, cyano, C_3-8-cycloalk(en)yl, C_1-6-alk(en/yn)yloxycarbonyl or aryl. In a preferred embodiment of the invention, A is S, W is NH, and R⁴ and R⁵ are both hydrogen, and R³ is an optionally substituted benzyl, 1-phenethyl, pyridylmethyl, methyl, ethyl or isopropyl, and R⁶ is C_1-6-alk(en yn)yl, or Ar¹ wherein Ar¹ is optionally substituted thiophenyl, phenyl, indolyl, pyrrolyl, quinolinyl, thiazolyl or benzo[l,3]dioxolyl.

In a preferred embodiment of the above, R³ is an optionally substituted benzyl, 1-phenethyl or pyridylmethyl.

In more preferred embodiment ofthe above, Ar¹ is unsubstituted or substituted one or more times by C_1-6-alk(en yn)yl, C_1-6-alk(en/yn)yloxy, hydroxy, nitro, halogen, R⁷R⁸NCO-C_1-6-alk(en/yn)yl; -NR⁷R⁸, Cι_-6-alk(en/yn)yl-CON-, cyano,

C _-8-cycloalk(en)yl, C_1-6-alk(en/yn)yloxycarbonyl or aryl and R³ is methyl, ethyl or isopropyl, 1-phenethyl or benzyl, which may be substituted by -CONR⁷R⁸.

In a particular embodiment, the invention is related to a compound of formula I wherein

i) R³ represents a group ofthe formula

-R⁹-Ar²

wherein R⁹ represents O, NH, NR^1', S, -CONR^1'-, -CO-, C_1-6-alkyl or C_2-6-alkenyl, wherein said C_1-6-alkyl or C _-6-alkenyl optionally is substituted by OH, halogen, C_1-6-alkoxy or C_3-8-cycloalkyl;

and R⁶ represents C₁-₆-alk(en/yn)yl, C_3-8-cycloalk(en yn)yl, C_3-8-cycloalk(en)yl- C_1-6-alk(en/yn)yl or Ar¹;

or

ii) R³ represents halogen, C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy,

C ό-aU n/ynJyloxy, C_1-6-alk(en yn)yloxy-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en/yn)oxy, C_1-6-alk(en yn)yl sulfanyl, acyl, R⁷R⁸N-Cι_₆-alk(en/yn)yl or -NR⁷R⁸ ;

and R⁶ represents indolyl, hydroxy-C₁.₆-alk(en/yn)yl-thiophenyl, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl-thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C_1-6-alk(en yn)yloxy, C i _-6-alk(en/yn)yloxy-C _{\ -6}-alk(en/yn)yl, C ₁_₆-alk(en/yn)yloxy-C _{\ -6}-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, aryloxy-, aryl-C_1-6-alk(en yn)yloxy, halo-C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano-Cι_-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(eιVyn)yl, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl, C i _-6-alk(en/yn)yloxycarbonyl, C _\ -e-alk^n/yn l-CONR¹ -C ι _-6-alk(en/yn)yl,

C_1-6-alk(en/yn)yl-CONR^1'-, -CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en/yn)yl;

provided that if A is S, W is NH, R⁴ and R⁵ are both hydrogen, and R³ is t-butyl, then R⁶ is not optionally substituted hydroxyphenyl; and

provided that the compound is not N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)- N'-(thiophen-2-ylmethylene)-hydrazine.

In a more particular embodiment ofthe above, R³ represents a group ofthe formula

-R⁹-Ar²

wherein R⁹ represents O, NH, NR^1', S, -CONR^1'-, -CO-, C_1-6-alkyl or C_2-6-alkenyl, wherein said C_1-6-alkyl or C_2-6-alkenyl optionally is substituted by OH, halogen, C_1-6-alkoxy or C_3-8-cycloalkyl;

and R⁶ represents C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en yn)yl, C_3-8-cycloalk(en)yl- Cι_-6-alk(en/yn)yl or Ar¹. In another more particular embodiment of the above, R³ represents halogen, C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en yn)yl, aryl, a heterocycle, hydroxy, hydroxy- C_1-6-alk(en yn)yl, C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en yn)yl, C_3-8-cycloalk(en yn)oxy, C_1-6-alk(en yn)yl sulfanyl, acyl,

or -NR⁷R⁸ ;

and R⁶ represents indolyl, hydroxy-C_1-6-alk(en/yn)yl-thiophenyl,

Ci.β-alk^n/yn loxy-Cμe-alk^n/yn l-miophenyl, benzo[l ,3]dioxolyl, pyrrolyl, C_1-6-alk(en yn)ylphenyl or hydroxyphenyl all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy-C_1-6-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, aryloxy-, aryl-C_1-6-alk(en/yn)yloxy, halo-C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C _1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano-C_1-6-alk(en yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, C_1-6-alk(en/yn)yl-CONR^1'-C_1-6-alk(en/yn)yl,

or R⁷R⁸NCO-C_1-6-alk(en/yn)yl.

In an even more particular embodiment ofthe above, A is S, W is NH and R⁴ and R⁵ are both hydrogen, and R³ is an optionally substituted benzyl, 1-phenethyl, pyridylmethyl, methyl, ethyl or isopropyl, and R⁶ is optionally substituted indolyl, hydroxy-C_1-6-alk(en yn)yl-thiophenyl, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl- thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl.

In a yet even more particular embodiment of the above, R is methyl, ethyl or isopropyl, and R⁶ is an optionally substituted. In a more preferred embodiment of the above, Ar¹ is an optionally substituted indolyl, hydroxy-C _1-6-alk(en/yn)yl-thiophenyl, C i _-6-alk(en yn)yloxy-C _{\ -6}-alk(en/yn)yl-thiophenyl.

In another even more particular embodiment, indolyl, hydroxy-Cι_-6-alk(en/yn)yl- thiophenyl, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl-thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en yn)ylphenyl or hydroxyphenyl is unsubstituted or substituted one or more times by C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)yloxy- C_1-6-alk(en yn)yl, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en yn)yloxy-C_1-6-alk(en/yn)yl, hydroxy, nitro, halogen, R⁷R⁸NCO-C_1-6-alk(en/yn)yl; -NR⁷R⁸, C_1-6-alk(en/yn)yl- CONR¹-, cyano, C_3-8-cycloalk(en)yl, C_1-6-alk(en yn)yloxycarbonyl or aryl and R³ is methyl, ethyl or isopropyl, 1-phenethyl, benzyl or pyridylmethyl, which may be substituted by -CONR⁷R⁸.

Particular compounds ofthe invention are compounds la-69a ofthe examples.

Definition of substituents

Halogen means fluoro, chloro, bromo or iodo.

The expression C_1-6-alk(en yn)yl means a C_1-6-alkyl, C_2-6-alkenyl or a C_2-6-alkynyl group. The expression C_3-8-cycloalk(en)yl means a C_3-8-cycloalkyl- or cycloalkenyl group.

The term C_1-6-alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including but not limited to methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-mefhyl-2-propyl and 2-methyl-l -propyl.

Similarly, C_2-6 alkenyl and C_2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, including one double bond and one triple bond respectively, including but not limited to ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.

The term C_3-8-cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, etc.

The term C_3-8-cycloalkenyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms and including one double bond. In the term C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl and C_1-6-alk(en/yn)yl are as defined above.

The terms C_1-6-alk(en yn)yloxy, C₁_₆-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, Cι_-6-alk(en/yn)ylsulfanyl, hydroxy-C_1-6-alk(en/yn)yl,

halo- C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)ylsulfonyl, cyano-C_1-6-alk(en/yn)yl, hydroxy- C_1-6-alk(en/yn)yl, NR^xR^y- C_1-6-alk(en/yn)yl, NR^rCO- Cι^-al (en/yn)yl etc. designate such groups in which the C_1-6-alk(en/yn)yl is as defined above. The terms halo-, hydroxy-, cyano- etc. are to be understood as the C₁_₆-alk(en/yn)yl- part can be substituted one or more times with such substituent. The term halo- designates halogen as defined above

As used herein, the term C_1-6-alk(en/yn)yloxycarbonyl refers to groups ofthe formula -COO-Cι_-6-alk(en/yn)yl, wherein C_1-6-alk(en yn)yl are as defined above.

As used herein, the term acyl refers to formyl, C_1-6-alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C_1-6-alk(en/yn)ylcarbonyl, C_3-8-cycloalk(en)ylcarbonyl or a C _-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl-carbonyl group.

The term heterocycle designates rings such as 5-membered monocyclic rings such as 3H-l,2,3-oxathiazole, 1,3,2-oxathiazole, 1,3,2-dioxazole, 3H-l,2,3-dithiazole, 1,3,2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, lH-l,2,3-triazole, isoxazole, oxazole, isothiazole, thiazole, lH-imidazole, lH-pyrazole, lH-pyrrole, furan or thiophene and 6-membered monocyclic rings such as 1,2,3-oxathiazine, 1,2,4-oxathiazine, 1,2,5-oxathiazine, 1,4,2-oxathiazine, 1,4,3-oxafhiazine, 1,2,3-dioxazine, 1,2,4-dioxazine, 4H-l,3,2-dioxazine, 1,4,2-dioxazine,

2H-l,5,2-dioxazine, 1,2,3-dithiazine, 1,2,4-dithiazine, 4H-l,3,2-dithiazine, 1,4,2-dithiazine, 2H-l,5,2-dithiazine, 2H-l,2,3-oxadiazine, 2H-l,2,4-oxadiazine, 2H-l,2,5-oxadiazine, 2H-l,2,6-oxadiazine, 2H-l,3,4-oxadiazine, 2H- 1,2,3 -thia- diazine, 2H-l,2,4-thiadiazine, 2H-l,2,5-thiadiazine, 2H-l,2,6-thiadiazine, 2H-l,3,4-thiadiazine, 1,2,3-triazine, 1,2,4-triazine, 2H-l,2-oxazine, 2H-l,3-oxazine, 2H-l,4-oxazine, 2H-l,2-thiazine, 2H-l,3-thiazine, 2H-l,4-thiazine, pyrazine, pyridazine, pyrimidine, 4H-l,3-oxathiin, 1,4-oxathiin, 4H-l,3-dioxin, 1,4-dioxin, 4H-l,3-dithiin, 1,4-dithiin, pyridine, 2H-pyran or 2H-thiin,

bicyclic compounds wherein the above rings are fused to a benzene ring, such as indole, benzofuran, isobenzofuran, benzothiophen, benzimidazol, quinoline, isoquinoline, dihydroquinoline,

or completely saturated rings such as morpholin, piperidin, azepin, piperazin, homopiperazin, and ring systems fused to a benzene ring, such as benzodioxan, benzodithiodioxan, benzo[l,3]dioxol, dihydroindol, dihydrobenzofuran or dihydrobenzothiophen.

The term aryl refers to carbocyclic, aromatic systems such as phenyl, naphtyl, anthracene and phenantrene.

The terms aryloxy and

refer to aryl as defined and C_1-6-alk(en/yn)yloxy as defined above.

The term carbocyclic refers to partly or completely saturated systems such as cyclohexen, indan or flurene.

The term heteroatom refers to atoms different from carbon and hydrogen, such as nitrogen, oxygen and sulphur.

Exemplary of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The acid addition salts ofthe invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like, hi general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

Some of the compounds of the present invention contain chiral centres and such compounds exist in the fonn of isomers (e.g. enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.

Racemic forms can be resolved into the optical antipodes by known methods, for example, by chromatography on an optically active matrix. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.

Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981).

Optically active compounds can also be prepared from optically active starting materials.

Pharmaceutical composition

The pharmaceutical compositions of this invention, or those which are manufactured in accordance with this invention, may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients, or other additives normally used in the art may be used. Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of 0.01 to 100 mg.

The total daily dose is usually in the range of 0.05 - 500 mg, and most preferably in the range of 0.1 to 50 mg ofthe active compound ofthe invention.

General methods of preparation

The compounds ofthe invention are prepared by the following general methods: a) Condensation of a compound with formula II

II wherein A, W, R⁴, R⁵ and R³ are as described above, with an aldehyde A^-CHO wherein Ar¹ is as defined above.

b) Condensation of a compound with formula III.

III

wherein W, A, R⁴, R⁵, R⁷ and R⁸ are as defined above with aldehydes ofthe formula Ar^CHO. The condensation of starting materials of formula II or III with aldehydes A^-CHO is performed by standard procedures known to chemists skilled in the art. This includes condensation at temperatures between 50-100 °C in a suitable protic or aprotic solvent such as DMSO or MeOH and in the presence of a catalytic amount of an acid such as HC1 (cone, aq.).

Starting materials of formula II are prepared according to standard procedures known to chemists skilled in the art as outlined below. Ethyl cyanoacetate is reacted with aldehydes or ketones and elemental sulphur in the presence of a suitable base, such as triethylamine or diethylamine, in the presence of a suitable solvent, such as ethanol, followed by condensation with either formamide at temperatures of 150 to 200 °C, or with a nitrile derivative such as acetonitrile or benzonitrile, in the absence or presence of an appropriate solvent, such as dioxane, in the presence of acid, such as HC1 (gaseous). The resulting thienopyrimidinones are converted to the corresponding 4-chloro-thienopyrimidines by standard procedures known to chemists skilled in the art, such as reaction with POCl₃ in DMF, with or without an aprotic solvent such as 1,2-dichloroethane at a suitable temperature.

Alternatively, for the variation of R³, compounds of the general formula II, wherein R³ is hydrogen, are deprotonated ort/7.0 to sulfur by the application of strong bases like butyllithium or lithium diisopropylamide (LDA), in aprotic solvents, such as THF or ether, at a suitable temperature. These lithiated species can directly be reacted with suitable electrophiles, including aldehydes, ketones, acid halides, chloro formates, isocyanates, and alkyl halides, reactions well known to the chemist skilled in the art.

The obtained 4-chloro-thienopyrimidines are converted to a properly substituted hydrazine compound by reaction at a suitable temperature with a suitable hydrazine derivative in the absence or presence of a (non-nucleophilic) solvent such as THF.

Starting materials with the general formula III are prepared according to general methods known to the chemists skilled in the art by applying the compounds N and NI as intermediates, as outlined below,

wherein A, R⁴, R⁵, R⁷ and R⁸ are as defined above, and R' is a suitable alkyl such as methyl or ethyl.

Compounds of the general formula V, where R' is e.g. methyl or ethyl, are prepared according to the methods described above for the synthesis of compounds of the general formula II by selection of appropriate starting materials for the synthesis described.

The esters ofthe general structure N are then saponified to the corresponding acids by methods known to chemists skilled in the art, this includes reaction with aqueous KOH. The resulting acids are then chlorinated by standard procedures known to chemists skilled in the art, such as reaction with POCl₃ in DMF, with or without an aprotic solvent such as 1,2-dichloroethane at a suitable temperature. The resulting acid-chloride substituted 4-chloro-thienopyrimidines are hydrolysed partially or fully under aqueous workup conditions and are re-converted into the acid chloride substituted 4-chloro-thienopyrimidines by the treatment with chlorinating agent, such as thionyl chloride, which then can be converted into amides of the general structure NI by standard methods known to the chemists skilled in the art, such as reaction with primary or secondary amines with or without base with or without a suitable non- nucleophilic solvent, such as e.g. THF or DMF, at a suitable temperature.

Alternatively, after the first chlorination reaction, the resulting acid-chloride substituted 4-chloro-tliienopyrimidines can directly be converted to compounds of the general formula N by in-situ reaction with with primary or secondary amines. Chlorides of the general structure NI are then converted to hydrazine compounds of the general formula III by the reaction with a properly substituted hydrazine derivative in the absence or presence of a non-nucleophilic solvent, such as THF, at a suitable temperature.

Examples

Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with an IonSpray source and a Shimadzu LC-8A/SLC-10A LC system. Column: 30 X 4.6 mm Waters Symmmetry C18 column with 3.5 μm particle size; solventsystem: A = water/trifluoroacetic acid (100:0.05) and B = water/acetonitrile/trifluoroacetic acid (5:95:0.03); method: Linear gradient elution with 90% A to 100% B in 4 min and with a flow rate of 2 mL/min. Purity was determined by integration of the UN (254 nm) and ELSD trace. The retention times (RT) are expressed in minutes.

1H ΝMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument. Deuterated dimethyl sulfoxide (99.8%D) was used as solvent. TMS was used as internal reference standard. Chemical shift values are expressed in ppm. The following abbreviations are used for multiplicity of ΝMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet, br s = broad singlet and br = broad signal. For column chromatography silica gel of the type Kieselgel 60, 40-60 mesh ASTM was used.

Preparation of intermediates

Ethyl-4-(3-oxopropyl)-benzoate, ethyl-3-(3-oxopropyl)-benzoate and mβthyl- 2-(3-oxopropyl)-benzoate were prepared by Sonogashira reaction and subsequent reduction and oxidation reactions according to the procedure described for ethyl- 3-(3-oxopropyl)-benzoate by C.-P. Chuang et al. J. Org. Chem. 1988, 53, 3210.

2-Amino-3-ethoxycarbonyl thiophene was prepared according to the method as described by M. Guetschow et al. J. Med. Chem. 1999, 42, 5437, and subsequently reacted to 4-chloro-thieno[2,3rf]pyrimidine by ring closure with formamide (M. Robba et al. Bull. Chim. Soc Chim. Fr. 1975, 587) and chlorination with phosphorous oxychloride (M. Robba et al. Bull. Chim. Soc. Chim. Fr. 1975, 592).

2-Ethylindole-3-carbaldehyde, 2-isopropylindole-3-carbaldehyde and 2-cyclopropyl- indole-3-carbaldehyde were prepared by the Madelung-syathesis according to W. J. Houlihan et al. J. Org. Chem. 1981, 46, 4511, and subsequent Vilsmeyer-Haack- formylation according to C. J. Moody and J. G. Ward J. Chem. Soc. PT1, 1984, 12, 2895.

3-Methoxythiophene-2-carbaldehyde and 3-isopropoxythiophene-2-carbaldehyde were prepared from 3-bromothiophene by nucleophillic substitution with methanol and isopropanol, respectively, according to the procedure of M. A. Keegstra et al. Tetrahedron 1992, 48, 3633, followed by the reaction with n-butyllithium and subsequently N,N-dimethylformamide in analogy to the procedure of A. K. Mohanakrishnan et al. Tetrahedron 1999, 55, 11745.

3-Hydroxymethyltlιiophene-2-carbaldehyde was prepared from 3-hydroxy- methylthiophene by the reaction with two equivalents of n-butyllithium and subsequent reaction with N,N-dimethylformamide in analogy to the procedure of A. K. Mohanakrishnan et al. Tetrahedron 1999, 55, 11745.

5-Hydroxymethyl-3-methylthiophene-2-carbaldehyde was prepared by initial protection of 3-methylthiophene-2-carbaldehyde as the dioxolan in analogy to the procedure by A. J. Carpenter et al. Tetrahedron 1985, 41, 3803, followed by the reaction with n-butyllithium and subsequently N,N-dimethylformamide in analogy to the procedure of Y. Lee et al. Tetrahedron 2001, 57, 5339, and reduction of the resulting aldehyde by sodium borohydride as described in the same reference. The dioxolan moiety was cleaved to the aldehyde function by treatment with hydrochloric acid as described by J. G. Laquindanum et al. J. Am. Chem. Soc. 1998, 120, 664.

5-(l-Hydroxypropyl)-3-methylthiophene-2-carbaldehyde, 5-methoxymethyl-

3-methylthiophene-2-carbaldehyde, 5-(2-methoxyethoxymethyl)-3-methylthiophene- 2-carb aldehyde, and 5-formyl-4-methyl-thiophene-2-carboxylic acid methylamide were prepared analogously using propion aldehyde, methoxymethyl chloride, l-chloromethoxy-2-methoxyethane, and methyl isocyanate, respectively, as electrophiles after the lithiation with n-butyllithium.

5-(2,2-Dimethylpropionyl)-3-methylthiophene-2-carbaldehyde was prepared analogously using 2,2-dimethylpropionaldehyde after the lithiation with n-butyllithium, followed by the oxidation of the resulting alcohol function to the ketone with N-methylmorpholine N-oxide and tetrapropyl ammonium perruthenate as described by S. V. Ley et al. Synthesis 1994, 639.

Other aldehydes useful as starting materials are commercial available or may be made by methods analogous to those desribed above or by other methods known to the skilled chemist.

A. Thieno[2,3-<t pyrimidin-4-yl-hydrazines ofthe general formula II

Tlιieno[2,3-rf]pyrimidin-4-yl-hydrazines of the general formula II were prepared by a general procedure as described below for the preparation of (6-methyl- thieno[2,3- |pyrimidin-4-yl)hydrazine.

2-Amino-5-methyl-thiophene-3-carboxylic acid ethyl ester:

Ethyl cyanoacetate (45.7 g), propion aldehyde (23.9 g) and S₈ (12.8 g) were dissolved in EtOH (96%, 220 mL) with magnetic stirring. Diethyl amine (56 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 65 °C overnight. The reaction mixture was filtered to remove solids and the liquid phase concentrated in vacuo to yield a dark oil. The crude product was purified by column chromatography using 10% EtOAc/hept. with 1% triethyl amine as eluent to yield 59.6 g (80%). 1H NMR (D₆-DMSO): 1.23 (t, 3H); 2.18 (d, 3H); 4.13 (q, 2H); 6.48 (dt, 1H); 7.06 (br s, 2H). 6-Methyl-4a, 7a-dihydro-3H-thieno[2,3-d]pyrimidin-4-one:

Formamide (400 mL) was heated at 170 °C and 2-amino-5-methyl-thiophene- 3-carboxylic acid ethyl ester (45.5 g) was added. The mixture was heated at 190 °C with stirring for 6h. The crude product was filtered from the reaction mixture and washed with H₂O and ice-cold EtO Ac, and dried in vacuo to yield 35 g ofthe product as a brown solid (86%). 1H NMR (D₆-DMSO): 3.29 (d, 3H); 7.08 (dt, IH); 8.04 (s, IH); 12.38 (br, IH).

4-Chloro-6-methyl-thieno[2,3-d]pyrimidine: DMF (29 mL) was placed in a round bottom flask under an argon atmosphere and cooled to 0 °C. POCl₃ (57.5 g) was added slowly. The mixture was stirred at 0 °C for 10 min, then heated to RT. After 25 min the mixture had solidified, and the solid was broken up with a spatula. 6-Methyl-4α,7α-dihydro-3H-thieno[2,3- ]pyrimidin-4-one (25 g) was added under an argon atmosphere along with 1,2-dichloroethane (180 mL). The mixture was heated at 65 °C over night. The reaction mixture was poured onto ice (800 mL) and transferred to a separation funnel with NaΗCO₃ (sat.) (800 mL) and EtOAc (2 L). The phases were separated, and the aqueous layer was extracted with EtO Ac (2 L). The organics were combined, washed with H O (2 x 1 L) and brine (1 L), dried over Na₂SO₄, filtered and evaporated in vacuo. The crude product was purified on silica using a gradient from 5% EtO Ac/heptane to 10% EtO Ac/heptane as eluent.

Yield: 19.2 g, (69%). 1H NMR (D₆-DMSO): 2.67 (d, 3H); 7.30 (dt, IH); 8.86 (s, IH).

4-Chloro-6-[(2, 6-difluorophenyl)-hydroxymethyl]-thieno[2, 3-dJpyrimidine:

Diisopropylamine (1.2 mL) was dissolved in THF (dry, 30 mL) under an argon atmosphere. n-Butyllithium (4.8 mL, 1.6 M in hexane) was added dropwise at 0 °C and the resulting mixture was stirred 15 minutes at 0 °C. The mixture was cooled to -75 °C, and a solution of 4-chloro-thieno[2,3rf]pyrimidine (1.0 g in 10 mL THF) was added dropwise. After stirring for lh at -75 °C, 2,6-difluorobenzaldehyde (830 μL) was added dropwise. After 45 minutes at -75 °C, the reaction mixture was allowed to warm to ambient temperature. Saturated aqueous ammonium chloride (50 mL) followed by water (20 mL) were added under vigorous stirring. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic phases were washed with water (2 x 150mL) and brine (150 mL), dried over sodium sulphate, and evaporated in-vacuo to dryness. The crude brown product was recrystallized from ethyl acetate / heptane to furnish 1.28 g title compound as brownish crystalline solid (70%).

1H-NMR (D₆-DMSO): 6.44 (d, IH), 7.04 (d, 2H), 7.10 - 7.18 (m, 3H), 7.43 - 7.55 (m, IH), 8.90 (s, IH).

(6-Methyl-thieno [2, 3 -d]pyrimidin-4-yl) -hydrazine: 4-Chloro-6-methyl-thieno[2,3- ]pyrimidine (5 g) was weighed into a flask and hydrazine hydrate (55 mL) was added. The reaction mixture was heated at 70 °C with stirring for 3h, then cooled to 0 °C and H₂O (140 mL) was added. Stirred for lh, then the product was filtered from the mixture and washed with cold H₂O and ice-cold EtOAc. Yield: 4.6 g (95%) 1H NMR (D₆-DMSO): 2.51 (s, 3H); 4.55 (br s, 2H); 7.28 (br s, IH); 8.29 (s, IH); 8.99 (br s, IH).

The following hydrazines were prepared analogously:

(6-Ethyl-thieno[2, 3-d]pyrimidin-4-yl)-hydrazine: Yield: 1.52 g (91%, from chloro derivative)

1H NMR (D₆-DMSO): 1.28 (t, 3H); 2.86 (dq, 2H); 4.48 (br, 2H); 7.33 (br s, IH); 8.29 (s, IH); 8.97 (br s, IH).

(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine: Yield: 2 g (80%, from chloro derivative)

1H NMR (D₆-DMSO): 1.32 (d, 6H); 3.20 (h, IH); 4.57 (br s, 2H); 7.37 (br s, IH); 8.31 (s, IH); 8.99 (br s, IH).

(6-Benzyl-thieno[2, 3-d]pyrimidin-4-yl)-hydrazine: Yield: 2.6 g (89%, from chloro derivative)

1H NMR (D₆-DMSO): 4.21 (s, 2H); 4.57 (br s, 2H); 7.23-7.43 (6H); 8.30 (s, IH); 9.04 (br s, IH). [6-(l-Phenylethyl)-thieno[2,3-d]pyrimidin-4-yl]-hydrazine: Yield: 2.89 g (95%, from chloro derivative)

1H NMR (D₆-DMSO): 1.65 (d, 3H); 4.41 (q, 1H); 4.46 (br, IH); 7.19-7.40 (5H); 7.45 (br s, IH); 8.28 (s, IH); 9.02 (br s, IH).

[6-(2-Fluorobenzyl)~thieno[2,3-d]pyrimidin-4-yl] -hydrazine:

Yield: 593 mg (55%, from chloro derivative)

1H-NMR (De-DMSO): 4.22 (s, 2H), 4.55 (s, 2H), 7.16 - 7.25 (m, 2H), 7.30 - 7.43 (m,

3H), 8.29 (s, IH), 9.07 (br s, IH).

[6-(4-Fluorobenzyl)-thieno[2,3-dJpyrimidin-4-ylJ-hydrazine:

Yield: 710 mg (89%, from chloro derivative)

1H-NMR (De-DMSO): 4.19 (s, 2H), 4.55 (br s, 2H), 7.13 - 7.20 (m, 2H), 7.30 - 7.36

(m, 3H), 8.29 (s, IH), 9.05 (br s, IH).

[6-(2-Methoxybenzyl)-thieno[2,3-d]pyrimidin-4-yl]-hydrazine:

Yield: 719 mg (50%, from chloro derivative)

1H-NMR (D₆-DMSO): 3.81 (s, 3H), 4.10 (s, 2H), 4.54 (br s, 2H), 6.88 - 6.94 (m, IH),

7.01 (d, IH), 7.20 - 7.31 (m, 3H), 8.27 (s, IH), 9.02 (br s, IH).

(6-Pyridin-2-ylmethyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine:

Yield: 820 mg (83%, from chloro derivative)

1H-NMR (D₆-DMSO): 4.33 (s, 2H), 4.55 (br s, 2H), 7.25 - 7.30 (m, IH), 7.37 - 7.40

(m, 2H), 7.77 (dt, IH), 8.29 (s, IH), 8.52 - 8.55 (m, IH), 9.05 (br s, IH).

(6-Pyridin-3-ylmethyl-thieno[2,3-d]pyrimidin-4~yl)-hydrazine:

Yield: 828 mg (84%, from chloro derivative)

1H-NMR (De-DMSO): 4.25 (s, 2H), 4.55 (br s, 2H), 7.35 - 7.40 (m, 2H), 7.68 - 7.73

(m, IH), 8.29 (s, IH), 8.48 (dd, IH), 8.55 (m, IH), 9.06 (br s, IH).

{6-[(2,6-Difluorophenyl)-hydroxymethyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine: Yield: 1.16 g (92%, from chloro derivative) 1H-NMR (D₆-DMSO): 4.53 (br s, 2H), 6.29 (d, IH), 6.69 (d, IH), 7.13 (t, 2H), 7.29 (br s, IH), 7.44 - 7.47 (m, IH), 8.31 (s, IH), 9.02 (br s, IH).

B. Thieno[2,3-<t]pyrimidin-4-yl-hydrazines of formula III

(Thieno[2,3-J]pyrimidin-4-yl)-hydrazines ofthe general formula III were prepared by a general procedure as described below for the preparation of {6-[4-(2-hydroxy- ethylcarbamoyl)-benzyl]-thieno[2₅3-d]pyrimidin-4-yl}-hydrazine.

6-[(4-Ethyloxycarbonyl)-benzyl]-4a, 7a-dihydro-3H-thieno[2,3-d]pyrimidin-4-one:

This compound was prepared after the method described for 6-Methyl-4a,7a-dihydro-

3H-thieno[2,3-d]pyrimidin-4-one.

LC/MS (m/z) 315 (MH⁺); RT = 2.40; purity (UN, ELSD): 98%, 96%.

1H ΝMR (D₆-DMSO): 1.31 (t, 3H); 4.29 (s, 2H); 4.31 (q, 2H); 7.18 (s, IH); 7.46 (d, 2H); 7.93 (d, 2H); 8.05 (s, IH); 12.42 (b, IH).

4-(4-Oxo-3, 4-dihydro-thieno[2, 3 -d]pyrimidin-6-ylmethyl) -benzoic acid: 6-[(4-Ethyloxycarbonyl)-benzyl]-4a,7a-dihydro-3H-thieno[2,3-d]pyrimidin-4-one (11.4 g) was dispensed in a mixture of THF (110 mL) and methanol (38 mL). Aqueous sodium hydroxide solution (1 M, 113 mL) was added and the resulting mixture was stirred 3 hours at 70 °C. After cooling to room temperature, aqueous hydrochloric acid (0.1 M, 1210 mL) and water (1140 mL) were added. The precipitate was filtered, washed with water and ice-cold ethyl acetate, and dried in vacuo. Yield: 10.1g (97%). 1H ΝMR (D₆-DMSO): 4.29 (s, 2H); 7.19 (s, IH); 7.43 (d, 2H); 7.91 (d, 2H); 8.06 (s, IH); 12.46 (br, IH); 12.90 (br, IH).

4-(4-Chloro-thieno[2,3-d]pyrimidin-6-ylmethyl)-benzoic acid:

DMF (3.9 mL) was placed in a round bottom flask under an argon atmosphere and cooled to 0 °C. POCl₃ (4.6 mL) was added slowly. The mixture was stirred at 0 °C for 10 min, then allowed to warm to room temperature. After 15 min, the solidified mixture was broken up with a spatula. 4-(4-Oxo-3,4-dihydro-thieno[2,3-d]pyrimidin- 6-ylmethyl)-benzoic acid (3.6 g) was added under an argon atmosphere along with 1,2-dichloroethane (15 mL). The mixture was heated four hours at 65 °C. The reaction mixture cooled to room temperature and poured onto ice (150 mL) and transferred to a separation funnel with aqueous NaHCO₃ (sat.) (150 mL) and ethyl acetate (350 mL). The phases were separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The organics were combined, washed with water (2 x 150 mL) and brine (150 mL), dried over Na₂SO₄ , filtered and evaporated in vacuo. Yield: 3.8 g, (100%).

LC/MS (m/z) 305 (MH⁺); RT = 2.52; purity (UN, ELSD): 88%, 98%. 1H ΝMR (D₆-DMSO): 7.45 (s, IH); 7.49 (d, 2H); 7.93 (d, 2H); 8.88 (s, IH). The acid proton was not visible under the conditions used.

{6-[4-(2-hydroxy-ethylcarbamoyl)-benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine: 4-(4-Chloro-thieno[2,3-d]pyrimidin-6-ylmethyl)-benzoic acid (1.29 g) was dissolved in thionyl chloride (5 mL) and heated 1.5 h at 80 °C. The excess of thionyl chloride was evaporated and the residue was dissolved in dry THF (8.4 mL, resulting compound concentration 0.5 M). This solution was used for split synthesis. One aliquot (700 μL) was added to a mixture of triethylamine (73 μL) and a solution of 2-hydroxyethylamine (700 μL, 0.5M in dry THF) at 0 °C. The resulting mixture was stirred 0.5 hours at 0 °C and then warmed to room temperature. Hydrazine hydrate was added, and the mixture was heated 1.5 hours at 70 °C. After cooling to room temperature, water (6 mL) was added. The precipitate was filtered and washed with water and ice-cold ethyl acetate. Yield: 91 mg (75%). LC/MS (m/z) 344 (MH⁺); RT = 1.04; purity (UN, ELSD): 91%, 99%.

The following hydrazines were prepared analogously:

{6-[3~(2-hydroxy-ethylcarbamoyl)-benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine: LC/MS (m/z) 344 (MH⁺); RT = 1.11; purity (UV, ELSD): 94%, 100%.

{6-[2-(2-hydroxy-ethylcarbamoyl)-benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine: LC/MS (m/z) 344 (MH⁺); RT = 1.08; purity (UN, ELSD): 97%, 100%. {6-[3-(2-methoxy-ethylcarbamoyl)-benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine: LC/MS (m/z) 358 (MH⁺); RT = 1.26; purity (UN, ELSD): 90%, 100%.

{6-[3-(pyridin-3-ylmethylcarbamoyl)-benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine: LC/MS (m/z) 391 (MH⁺); RT = 1.03; purity (UN, ELSD): 93%, 100%.

Compounds o the invention:

Examples

1 a N-(6-Benzyl-thieno[2, 3-d]pyrimidin-4-yl)-N'-(3-methyl-thiophen-2-ylmethylene)- hydrazine

200 μL of a 20 mM stock solution of (6-Benzyl-thieno[2,3-< |pyrimidin-4-yl)- hydrazine in DMSO containing 10 mol% HCl (cone, aq.) was mixed with 200 μL of a 20 mM stock solution of 3-methyl-tlιiophene-2-carbaldehyde in DMSO under an argon atmosphere. The resulting mixture was incubated for 3h at 85 °C, then cooled to room temperature and diluted with DMSO to a 2 mM solution. The crude product was of a sufficient purity for in vitro testing without further purification. 1H ΝMR (D₆-DMSO): 2.29 (s, 3H); 4.25 (br s, 2H); 6.95 (d, IH); 7.25-7.41 (5H); 7.52 (d, IH); 7.65 (br s, IH); 8.38 (s, IH); 8.40 (s, IH); 11.62 (br s, IH). LC/MS (m/z) 365 (Mt ); RT = 2.80; purity (UN, ELSD): 87%, 98%.

The following methylenehydrazines were prepared analogously:

2a N-(6-Ethyl-thieno[2, 3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-ylmethylene)- hydrazine: LC/MS (m/z) 336 (MH⁺); RT = 2.03; purity (UN, ELSD): 85%, 98%.

3a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-methoxy-benzylidene)- hydrazine:

LC/MS (m/z) 391 (MH⁺); RT = 2.10; purity (UN, ELSD): 84%, 100%. 4a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-methyl-lH-indol-3-ylmethylene)- hydrazine:

LC/MS (m/z) 399 (MH⁺); RT = 2.40; purity (UN, ELSD): 92%, 100%.

5a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2,5-dimethyl-l-phenyl-lH-pyrrol- 3 -ylmethylene) -hydrazine: LC/MS (m/z) 439 (MH⁺); RT = 2.69; purity (UN, ELSD): 86%, 99%.

6a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-methyl-5-nitro-lH-indol- 3 -ylmethylene) -hydrazine:

LC/MS (m/z) 395 (MH⁺); RT = 2.30; purity (UN, ELSD): 83%, 100%.

7a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-acetamido-benzylidene)- hydrazine: LC/MS (m/z) 402 (MH⁺); RT = 2.07; purity (UN, ELSD): 82%, 99%.

8a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-quinolin-4-ylmethylene-hydrazine: LC/MS (m/z) 396 (MH⁺); RT = 2.02; purity (UN, ELSD): 88%, 100%.

9a N-(6-Isopropyl-thieno[2, 3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-yl- methylene) -hydrazine: LC/MS (m/z) 350 (MH⁺); RT = 2.19; purity (UN, ELSD): 82%, 100%.

10a N-(6-Benzyl-thieno[2, 3-d]pyrimidin-4-yl)-N'-(2, 3-dimethyl-benzylidene)- hydrazine:

LC/MS (m/z) 373 (MH⁺); RT = 2.84; purity (UN, ELSD): 82%, 98%.

11a N-(lH~Indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2, 3-d]pyrimidin-4-yl)- hydrazine: LC/MS (m/z) 336 (MH⁺); RT = 2.13; purity (UN, ELSD): 81%, 100%. 12a N-(2-Chloro-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin- 4-yl) -hydrazine: LC/MS (m/z) 371 (MH⁺); RT = 2.38; purity (UN, ELSD): 94%, 100%.

13a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-[bis-(2-cyano-ethyl)-amino]- benzylidene) -hydrazine: LC/MS (m/z) 467 (MH⁺); RT = 2.32; purity (UN, ELSD): 91%, 100%.

14a N-(6-Ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(lH-indol-3-ylmethylene)-hydrazine: LC/MS (m/z) 322 (MH⁺); RT = 1.95; purity (UN, ELSD): 94%, 100%.

15a N-{6-(l-Phenyl-ethyl)-thieno[2,3-d]pyrimidin-4-yl}-N'-(2-chloro-4-hydroxy- benzylidene) -hydrazine:

LC/MS (m/z) 410 (MH⁺); RT = 2.57; purity (UN, ELSD): 73%, 99%.

16a N-(6-Benzyl-thieno[2, 3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-ylmethylene) - hydrazine:

LC/MS (m/z) 399 (MH⁺); RT = 2.33; purity (UN, ELSD): 81%, 100%.

17a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3,5-dibromo-4-hydroxy- benzylidene) -hydrazine: LC/MS (m/z) 519 (MH⁺); RT = 2.61; purity (UN, ELSD): 84%, 100%.

18a N-(2-Isopropyl-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin- 4-yl) -hydrazine:

LC/MS (m/z) 379 (MH⁺); RT = 2.41; purity (UN, ELSD): 87%, 100%.

19a N-(2-Methyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine: LC/MS (m/z) 322 (MH⁺); RT = 1.82; purity (UN, ELSD): 86%, 97%.

20a N-(2-Isopropyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2,3-d]pyrimidin- 4-yl)-hydrazine: LC/MS (m/z) 350 (MH^"); RT = 2.14; purity (UN, ELSD): 89%, 100%.

21 a N-(2-Ethyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2, 3-dJpyrimidin-4-yl)- hydrazine: LC/MS (m/z) 336 (MH⁺); RT = 1.97; purity (UN, ELSD): 88%, 100%.

22a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(-(3-bromo-4-hydroxy-

5-methoxy-benzylidene)-hydrazine:

LC/MS (m/z) 422 (MH⁺); RT = 2.20; purity (UN, ELSD): 83 %, 100 %.

23a N-Benzo[l,3]dioxol-4-ylmethylene-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine:

LC/MS (m/z) 341 (MH⁺); RT = 2.52; purity (UN, ELSD): 90%, 96%.

24a N-(6-Ethyl-thieno[2, 3-d]pyrimidin-4-yl)-N'-(5-cyano~lH-indol-3-ylmethylene)- hydrazine: LC/MS (m/z) 347 (MH"); RT = 1.93; purity (UN, ELSD): 96%, 100%.

25a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-hydroxy-4-methoxy- benzylidene) -hydrazine:

LC/MS (m/z) 343 (MH⁺); RT = 1.88; purity (UN, ELSD): 96%, 100%.

26a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-iodo-5-methoxy- benzylidene) -hydrazine: LC/MS (m/z) 469 (MH⁺); RT = 2.28; purity (UN, ELSD): 93%, 100%.

27a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-methyl-but-2-enylidene)- hydrazine:

LC/MS (m/z) 323 (MH⁺); RT = 2.32; purity (UN, ELSD): 70%, 95%.

28a N-(2-Cyclopropyl-lH-indol-3-ylmethylene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-

4-yl) -hydrazine:

LC/MS (m/z) 362 (MH⁺); RT = 2.18; purity (UN, ELSD): 87%, 100%. 29a N-(2-Chloro-lH-indol-3-ylmethylene)-N'-(6-ethyl~thieno[2, 3-dJpyrimidin-4-yl)- ^' hydrazine: LC/MS (m/z) 357 (MH⁺); RT = 2.19; purity (UN, ELSD): 93%, 100%.

30a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(7-methyl-lH-indol-3-ylmethylene)- hydrazine: LC/MS (m/z) 399 (MH⁺); RT = 2.40; purity (UN, ELSD): 91%, 100%.

31a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-fluoro-benzylidene)-hydrazine: LC/MS (m/z) 363 (MH⁺); RT = 2.88; purity (UN, ELSD): 70%, 95%.

32a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-bromo-4-hydroxy-5-methoxy- benzylidene) -hydrazine:

LC/MS (m/z) 470 (MH⁺); RT = 2.38; purity (UN, ELSD): 83%, 100%.

33a N-(6-Isopropyl-thieno[2, 3-d]pyrimidin-4-yl)-N'-(3, 5-dϊbromo-4-hydroxy- benzylidene)-hydrazine:

LC/MS (m/z) 471 (MH⁺); RT = 2.47; purity (UN, ELSD): 84%, 100%.

34a N-(2-Cyclopropyl-lH-indol-3-ylmethylene)-N'-[6-(l-phenyl-ethyl)-thieno-

[2, 3-d] pyrimidin-4-yl] -hydrazine: LC/MS (m/z) 439 (MH⁺); RT = 2.61; purity (UN, ELSD): 82%, 100%.

35a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-methoxy- benzylidene)-hydrazine:

LC/MS (m/z) 343 (MH⁺); RT = 1.88; purity (UN, ELSD): 84%, 100%.

36a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2,6-dimethoxy-4-hydroxy- benzylidene) -hydrazine: LC/MS (m/z) 373 (MH⁺); RT = 2.02; purity (UN, ELSD): 90%, 100%.

31aN-(2,6-Difluoro-benzylidene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine: LC/MS (m/z) 319 (MH*); RT - 2.72; purity (UN, ELSD): 86%, 100%. 38a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-thiophen-2-ylmethylene- hydrazine: LC/MS (m/z) 303 (MH⁴); RT = 2.34; purity (UN, ELSD): 83%, 100%.

39a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(5-methyl-thiophen-2-ylmethylene)- hydrazine: LC/MS (m/z) 365 (MH⁺); RT = 2.73; purity (UN, ELSD): 83%, 100%.

40a N-(5-Fluoro-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin- 4-yl)-hydrazine:

LC/MS (m/z) 354 (MH⁺); RT = 2.22; purity (UN, ELSD): 92%, 100%.

41a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-[(2-cyano-ethyl)-methyl-amino]- benzylidene) -hydrazine: LC/MS (m/z) 428 (MH⁺); RT = 2.37; purity (UN, ELSD): 92%, 100%.

42a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(6-[methyloxycarbonyl]- lH-indol-3-ylmethylene)-hydrazine:

LC/MS (m/z) 394 (MH⁴); RT = 2.11; purity (UN, ELSD): 93%, 100%.

43a N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-thiazol-2-ylmethylene-hydrazine: LC/MS (m/z) 352 (MH⁺); RT = 2.46; purity (UN, ELSD): 83%, 97%.

44a N-(6-Isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(l-[2-cyanophenyl]-lH-indol- 3 -ylmethylene) -hydrazine:

LC/MS (m/z) 438 (MH⁺); RT = 2.57; purity (UN, ELSD): 94%, 100%.

45a N-(2, 5-Dimethyl-benzylidene)-N'-(6-ethyl-thieno[2, 3-d]pyrimidin-4-yl)- hydrazine: LC/MS (m/z) 311 (MH⁺); RT = 2.60; purity (UN, ELSD) : 96%, 100%.

46a N-(7-Ethyl-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin- 4-yl)-hydrazine: LC/MS (m/z) 364 (MH⁺); RT = 2.36; purity (UN, ELSD): 87%, 99%.

47a N-(6-Ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(l-methyl-2-[methyloxycarbonyl]- lH-pyrrol-3-ylmethylene)-hydrazine: LC/MS (m/z) 344 (MH^4"); RT = 1.89; purity (UN, ELSD): 90%, 100%.

48a N-(2-Isopropyl-lH-indol-3-ylmethylene)-N'-{6-[2-(2-hydroxy-ethylcarbamoyl)- benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine: LC/MS (m/z) 513 (MH⁺); RT = 1.92; purity (UN, ELSD): 87%, 100%.

49a N-(2-Methyl-lH-indol-3-ylnιethylene)-N'-{6-[3-(pyridin-3-ylmethylcarbamoyl)- benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine:

LC/MS (m/z) 532 (MH⁺); RT = 1.62; purity (UN, ELSD): 71%, 96%.

50a N-(l -Methyl- lH-indol-3-ylmethylene)-N'-{6-[3-(2-hydroxy-ethylcarbamoyl)- benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine: LC/MS (m/z) 485 (MH⁺); RT = 1.82; purity (UN, ELSD): 93%, 100%.

51a N-(4-Methyl-lH-indol-3-ylmethylene)-N'-{6-[4-(2-hydroxy-ethylcarbamoyl)- benzyl] -thieno [2, 3-d]pyrimidin-4-yl}-hydrazine:

LC/MS (m/z) 485 (MH⁺); RT = 1.84; purity (UN, ELSD): 82%, 100%.

52a N-[6-(2-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(5-hydroxymethyl-

3-methylthiophen-2-ylmethylene)-hydrazine: LC/MS (m/z) 413 (MH¹); RT = 2.24; purity (UN, ELSD): 89%, 100%.

53a N-[6-(2-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methoxythiophen-

2-ylmethylene)-hydrazine:

LC/MS (m/z) 399 (MH⁺); RT = 2.52; purity (UN, ELSD): 93%, 100%.

54a N-[6-(2-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-hydroxymethyl- thioplιen-2-ylmethylene)-hydrazine:

LC/MS (m/z) 399 (MH⁺); RT = 2.30; purity (UN, ELSD): 84%, 98%. 55a N-[6-(2-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methylthiophen-

2-ylmethylen e) -hydrazine: LC/MS (m/z) 383 (MH⁴); RT = 2.75; purity (UN, ELSD): 80%, 100%.

56a N-{6-[(2, 6-Difluorophenyl)-hydroxymethyl]-thieno[2, 3-d]pyrimidin-4-yl}-

N'-(3-isopropoxythiophen-2-ylmethylene)-hydrazine: LC/MS (m/z) 461 (MH⁴); RT = 2.38; purity (UN, ELSD): 80%, 100%.

57a N-{6-[(2, 6-Difluorophenyl)-hydroxymethyl]-thieno[2, 3-d]pyrimidin-4-yl}- N'-(3-hydroxymethylthiophen-2-ylmethylene)-hydrazine:

LC/MS (m/z) 433 (MH¹); RT = 1.82; purity (UN, ELSD): 84%, 99%.

58a N-(5-hydroxymethyl-3-methylthiophen-2-ylmethylene)-N'-(6-pyridin-2-ylmethyl- thieno[2,3-d]pyrimidin-4-yl)-hydrazine: LC/MS (m/z) 396 (MH⁺); RT = 1.28; purity (UN, ELSD): 86%, 100%.

59a N-(5-Hydroxymethyl-3-methylthiophen-2-ylmethylene)-N'-[6-(2-methoxybenzyl)- thieno[2,3-d]pyrimidin-4-yl]-hydrazine:

LC/MS (m/z) 425 (MH⁺); RT = 2.20; purity (UN, ELSD): 89%, 100%.

60a N-[6-(4-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(5-hydroxymethyl-

3-methylthiophen-2-ylmethylene)-hydrazine:

LC/MS (m/z) 413 (MH⁴); RT = 2.24; purity (UN, ELSD): 88%, 100%.

61a N-[6-(2-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-[5-(l-hydroxypropyl)- 3-methylthiophen-2-ylmethylene]-hydrazine: LC/MS (m/z) 441 (MH⁺); RT = 2.50; purity (UN, ELSD): 80%, 98%.

62a N-{6-[4-(2-Methoxy-ethylcarbamoyl)-benzyl]-thieno[2,3-d]pyrimidin-4-yl}- N'-(2-Methyl-lH-indol-3-ylmethylene)-hydrazine:

LC/MS (m/z) 499 (MH⁺); RT = 1.94; purity (UN, ELSD): 84%, 99%. 63a N-(5-hydroxymethyl-3-methylthiophen-2-ylmethylene)-N'-(6-pyridin-3-ylmethyl- thieno[2,3-d]pyrimidin-4-yl)-hydrazine: LC/MS (m/z) 396 (MH⁺); RT = 1.24; purity (UN, ELSD): 97%, 100%.

64a N-[6-(2-Fluorobenzyl)-thieno[2, 3-d]pyrimidin-4-yl]-N'-(5-methoxymethyl-

3-methylthiophen-2-ylmethylene)-hydrazine: LC/MS (m/z) 427 (MH⁴); RT = 2.72; purity (UN, ELSD): 73 %, 98%.

65a N-[6-(2-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-[5-(2-methoxyethoxy- methyl)-3-methylthiophen-2-ylmethylene] -hydrazine:

LC/MS (m/z) 471 (MH⁺); RT = 2.65; purity (UN, ELSD): 79%, 99%.

66a N-[6-(2-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methyl-5-methyl- carbamoylthiophen-2-ylmethylene)-hydrazine: LC/MS (m/z) 440 (MH⁴); RT = 2.27; purity (UN, ELSD): 77%, 96%.

67a N-{6-[(2, 6-Difluorophenyl)-hydroxymethyl]-thieno[2, 3-d]pyrimidin-4-yl}-

N'-[5-(2,2-dimethylpropionyl)-3-methylthiophen-2-ylmethylene]-hydrazine: LC/MS (m/z) 501 (MH⁴); RT = 2.83; purity (UN, ELSD): 94%, 99%.

68a N-[6-(2-Fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methylbut-

2-enylidene) -hydrazine:

LC/MS (m/z) 341 (MH⁺); RT = 2.39; purity (UN, ELSD): 76%, 97%.

69a N-(6-Ethylthieno[2, 3-d]pyrimidin-4-yl)-N'-(5-hydroxymethyl-3-methyl-thiophen- 2-ylmethylene)-hydrazine: LC-MS (m/z) (M+H)⁺ 333.1 RT=1.77 (UN, ELSD) 87.4%, 100%.

Assays

The kinase domain of human mixed lineage kinase 1 (MLKIKD) was prepared with an Ν-terminal glutathione-S-transferase (GST) fusion partner by expression in baculovirus and purification via glutathione affinity chromatography. The activity assay for MLK1 was performed in 96-well Millipore Multiscreen plates. Each 50 μL assay mixture contained 50 mM HEPES (pH 7.0), 1 mM EGTA, 10 mM MgCl₂, 1 mM DTT, 25 mM β-glycerophosphate, 60 μM ATP, 1 μCi [γ-³²P]ATP, 0.1% BSA, 500 μg/mL myelin basic protein, 2% DMSO, 1 uM test compound, and 1 μg/mL of baculoviral GST-MLKI_KD- Samples were incubated for 15 min at 37 °C. The reaction was stopped by adding ice-cold 50% TCA, and the proteins were allowed to precipitate for 30 min at 4 °C. The plates were then washed four times with 200 μL of ice-cold 25% TCA. Supermix scintillation cocktail was added, and the plates were allowed to equilibrate for 1-2 hours prior to counting in the Wallac MicroBeta 1450 Plus scintillation counter.

The results of the above assay show that the compounds la-68a, exemplified above, inhibit MLK1 below 3μM (IC₅₀). Most of the compounds have activity below lμM (IC₅₀). Some ofthe compounds have activity below lOOnM (IC_SQ).

Formulation Examples

The pharmaceutical formulations of the invention may be prepared by conventional methods in the art.

For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc. Typical examples of recipes for the formulation ofthe invention are as follows:

1) Tablets containing 5.0 mg of a compound ofthe invention calculated as the free base:

Compound la 5.0 mg Lactose 60 mg

Maize starch 30 mg

Hydroxypropylcellulose 2.4 mg

Microcrystallme cellulose 19.2 mg

Croscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg

2) Tablets containing 0.5 mg of a compound ofthe invention calculated as the free base:

Compound la 0.5 mg Lactose 46.9 mg

Maize starch 23.5 mg

Povidone 1.8 mg

Microcrystallme cellulose 14.4 mg

Croscarmellose Sodium Type A 1.8 mg Magnesium stearate 0.63 mg.

Claims

Claims

1. The use of a compound represented by the general formula I

wherein

A represents O or S;

W represents O, NH, NR¹;

R⁴ and R⁵ are independently selected from the group represented by hydrogen, halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C₁-₆-alk(en/yn)yloxy, C₁_₆-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C _1-6-alk(en/yn)yl, halo- C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yloxy, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl- C_1-6-alk(en/yn)yl, acyl, C_1-e-alk(en/yn)yloxycarbonyl, -e-alk^n/ynJylsulfonyl, -NR⁷R⁸ and R⁷R⁸N-C₁_₆-alk(en/yn)yl-;

R³ represents hydrogen, halogen, C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy, hydroxy-C ₁_6-a]k(en7yn)yl, -e-aU n/ynjyloxy, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en/yn)oxy, C₁_₆-alk(en/yn)yl sulfanyl, acyl, R⁷R⁸N-Ci_₆-allc(en/yn)yl or -NR⁷R⁸ ;

or R³ represents a group ofthe formula

-R⁹-Ar² wherein R⁹ represents O, NH, NR^1', S, -CONR^1'-, - CO-, C_1-6-alkyl or C_2-6-alkenyl, wherein said C_1-6-alkyl or C_2-6-alkenyl optionally is substituted by OH, halogen, C_1-6-alkoxy or C_3-8-cycloalkyl;

R⁶ represents C₁-₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, C _-8-cycloalk(en)yl- C_1-6-alk(en/yn)yl or Ar¹;

Ar¹ and Ar² are independently selected from the group represented by aryl, a heterocycle or a carbocycle all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy, C_1-6-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, C₁_e-alk(en/yn)yloxy-C₁_₆-alk(en/yn)yloxy-C₁-₆-alk(en/yn)yl, aryloxy-, aiyl-Ci-e-aU n/yntyloxy, halo- -e-alk^n/ynJyloxy, Cι_-6-alk(en/yn)yl- sulfanyl, hydroxy, hydroxy-C_1-e-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano- C_1-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, C_3-s-cycloalk(en)yl-C_1-e-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, ^' acyl, C_1-6-alk(en/yn)yloxycarbonyl,

C_1-6-alk(en/yn)yl-CONR^r-, -CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en yn)yl;

R and R are independently selected from the group represented by hydrogen and

which may be further substituted by hydroxy, halogen, C_1-6-alkoxy, cyano, nitro, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, aryl or a heterocycle; or R⁷ and R⁸ together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one or more further hetero atoms and may optionally be substituted by halogen, C_1-6-alk(en/yn)yl, hydroxy, hydroxy- C_1-6-alk(en/yn)yl or acyl;

the aryls may be further substituted by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C _1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yloxy, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, acyl, C_1-6-alk(en/yn)yloxycarbonyl,

C_1-6-alk(en yn)ylsulfonyl, or -NR⁷ R^8' wherein -NR^7'R^8' is as defined for -NR⁷R⁸ above provided that any aryl substituent on -NR⁷ R^8' is not further substituted; and R¹ and R¹ are independently selected from the group represented by

alk(en/yn)yl, C_3-8-cycloalk(en)yl, aryl, hydroxy-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl- C_1-6-allc(en/yn)yl and acyl;

or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of Parkinson's Disease, dementia such as age related dementia, HIN-1 associated dementia, AIDS dementia complex, HIN encephalopathy and senile dementia of the Alzheimer's type and memory disorders, cerebral ischemias and spinal cord ischemias, ischemias following stroke or traumatic injuries of the brain or the spinal cord, Huntington Chorea, multiple sclerosis, glaucoma, promotion of survival of transplanted cells, ALS/Motor neuron Disease, neuronal trauma or age related macular degeneration.

2. The use according to claim 1 of a compound of formula I wherein A is S.

3. The use according to any ofthe above claims of a compound of formula I wherein W is ΝH.

4. The use according to any ofthe above claims of a compound of formula I wherein R⁴ and R⁵ are both hydrogen.

5. The use according to any ofthe above claims of a compound of formula I wherein R³ is C_1-6-alk(en/yn)yl, or R⁹-Ar².

6. The use according to claim 5 of a compound of formula I wherein R is C_1-6-alkyl optionally substituted by OH.

The use according to claim 5 of a compound of formula I wherein R is C_1-6-alkyl.

8. The use according to claim 7 of a compound of formula I wherein R³ is -6-alkyl wherein the carbon adjacent to the heterocyclic ring is a primary, secondary or tertiary carbon.

9. The use according to claim 8 of a compound of formula I wherein R³ is methyl, ethyl or isopropyl.

10. The use according to claim 5 of a compound of formula I wherein R³ is methyl, ethyl, isopropyl or an optionally substituted benzyl, 1-phenethyl or pyridylmethyl.

11. The use according to claim 10 of a compound of formula I wherein benzyl, 1-phenethyl or pyridylmethyl are unsubstituted or substituted by -CONR⁷R⁸.

12. The use according to any ofthe above claims of a compound of formula I wherein R⁶ represents Cι_-6-alk(en/yn)yl or Ar¹ wherein Ar¹ is an optionally substituted thiophenyl, indolyl, phenyl, pyrrolyl, quinolinyl, benzo[l,3]dioxolyl or thiazolyl.

13. The use according to claim 12 of a compound of formula I wherein R⁶ represents Ar¹ wherein Ar¹ is an optionally substituted indolyl, hydroxy-C_1-6-alk(en/yn)yl- thiophenyl, C _{1 -6}-alk(en/yn)yloxy-C _{1 -6}-alk(en/yn)yl-thiophenyl, .

14. The use according to claim 13 of a compound of formula I wherein Ar¹ is unsubstituted or substituted one or more times by Cι_-6-alk(en/yn)yl, -e-al en/yn loxy, C_1-e-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy- C_1-6-alk(en/yn)yloxy-C_1-e-alk(en/yn)yl, hydroxy, nitro, halogen, R⁷R⁸NCO- Cι_-6-alk(en/yn)yl; -NR⁷R⁸, C_1-6-alk(en/yn)yl-CON-, cyano, C_3-8-cycloalk(en)yl, C_1-6-alk(en/yn)yloxycarbonyl or aryl.

15. The use according to any ofthe claims above of a compound of formula I wherein A is S, W is NH, and R⁴ and R⁵ are both hydrogen, and R³ is optionally substituted benzyl, 1-phenethyl, methyl, ethyl or isopropyl, and R⁶ is

or Ar¹ wherein Ar¹ is an optionally substituted thiophenyl, phenyl, indolyl, pyrrolyl, quinolinyl, thiazolyl or benzo[l,3]dioxolyl.

16. The use according to claim 15 of a compound of formula I wherein Ar¹ is unsubstituted or substituted one or more times by C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)yloxy-C₁.₆-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy- C_1-6-alk(en/yn)yloxy-C_1-e-alk(en/yn)yl, hydroxy, nitro, halogen, R⁷R⁸NCO-

C_1-6-alk(en/yn)yl; -NR⁷R⁸, -e-alk en/yn l-CONR¹-, cyano, C_3-8-cycloalk(en)yl, C_1-6-alk(en/yn)yloxycarbonyl or aryl and R³ is methyl, ethyl or isopropyl, 1-phenethyl, benzyl or pyridylmethyl, which may be substituted by -CONR⁷R⁸.

17. The use according to any of claims 15 or 16 of a compound of formula I wherein R³ is an optionally substituted benzyl, 1-phenethyl, pyridylmethyl, and R⁶ is C_1-6-alk(en/yn)yl, or Ar¹ wherein Ar¹ is substituted thiophenyl or optionally substituted phenyl, indolyl, pyrrolyl, quinolinyl, thiazolyl or benzo[l,3]dioxolyl.

18. The use according to any ofthe claims above of a compound of formula I wherein

i) R³ represents a group ofthe formula

-R^y-Ar²

wherein R⁹ represents O, NH, NR^1', S, -CONR^1'-, -CO-, C_1-6-alkyl or C_2-6-alkenyl, wherein said C_1-6-alkyl or C_2-6-alkenyl optionally is substituted by OH, halogen, C_1-6-alkoxy or C_3-8-cycloalkyl;

and R represents C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, C _-8-cycloalk(en)yl- C_1-6-alk(en/yn)yl or Ar¹;

or

ii) R³ represents halogen, Ci-_θ-alk^n/yhjyl, C_3-8-cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy,

C_1-6-alk(en/yn)yloxy-C_1-6-alk(en yn)yl, C_3-8-cycloalk(en/yn)oxy, C_1-6-alk(en/yn)yl sulfanyl, acyl, R⁷R⁸N-C₁_₆-allc(en/yn)yl or -NR⁷R⁸ ;

and R⁶ represents indolyl, hydroxy-Ci-e-al^en/^yl-thiophenyl,

C i _-6-alk(en/yn)yloxy-C ι _-6-alk(en/yn)yl-thiophenyl, benzo [1,3] dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, C_1-e-alk(en/yn)yloxy-C_1-e-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy-C_1-e-alk(en/yn)yloxy- Ci-e-all n/ynjyl, aryloxy-, aryl-C_1-6-alk(en/yn)yloxy, halo-C_1-6-alk(en/yn)yloxy, C_1-e-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C _1-6-alk(en/yn)yl, halo-C_1-6-alk(en yn)yl, cyano-C_1-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, -e-alk^n/yhJylsulfonyl, aryl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, C_1-e-alk(en/yn)yl-CONR^1'-C_1-6-alk(en yn)yl,

C_1-6-alk(en/yn)yl-CONR^r-, -CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en/yn)yl;

provided that if A is S, W is NH, R⁴ and R⁵ are both hydrogen, and R³ is t-butyl, then R⁶ is not optionally substituted hydroxyphenyl; and

provided that the compound is not N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)- N'-(thiophen-2-ylmethylene)-hydrazine.

19. The use according to claim 18 of a compound of formula I wherein R³ represents a group ofthe formula

-R⁹-Ar²

wherein R⁹ represents O, NH, NR^{1 '}, S, -CONR^1'-, -CO-, C_1-6-alkyl or C_2-6-alkenyl, wherein said Cι_-6-alkyl or C_2-6-alkenyl optionally is substituted by OH, halogen, C_1-6-alkoxy or C_3-8-cycloalkyl;

and R⁶ represents C₁-₆-alk(en yn)yl, C_3-8-cycloalk(en/yn)yl, C_3-8-cycloalk(en)yl- C_1-6-alk(en/yn)yl or Ar¹.

20. The use according to claim 18 of a compound of formula I wherein R³ represents halogen, -e-alk^n/yhJyl, C_3-8-cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, C_1-e-alk(en/yn)yloxy, C_1-6-alk(en/yn)yloxy-

C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en yn)oxy, C_1-e-alk(en/yn)yl sulfanyl, acyl, R⁷R⁸N- -e-alkten/yn l or -NR⁷R⁸ ; and R^δ represents indolyl, hydroxy-C_1-6-alk(en/yn)yl-thiophenyl,

Cμe-al^en/^yloxy-C e-al^en/^yl-thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, C i _-6-alk(en/yn)yloxy-C \ _₆-alk(en/yn)yl, C ₁_₆-alk(en/yn)yloxy-C ι _-6-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, aryloxy-, aιyl-C_1-6-alk(en yn)yloxy, halo-C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano- C_1-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸- C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl, C_1-6-alk(en/yn)yloxycarbonyl,

C_1-6-alk(en/yn)yl-CONR^r-, -CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en/yn)yl.

21. The use according to claim 20 of a compound of formula I wherein A is S, W is NH and R⁴ and R⁵ are both hydrogen, and R³ is an optionally substituted benzyl,

1-phenethyl, pyridylmethyl, methyl, ethyl or isopropyl, and R^δ is optionally substituted indolyl, hydroxy-C_1-6-alk(en/yn)yl-thiophenyl,

C_1-6-alk(en/yn)yl-thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl.

22. The use according to claim 21 of a compound of formula I wherein R³ is methyl, ethyl or isopropyl, and R⁶ is an optionally substituted indolyl, hydroxy- C_1-6-alk(en/yn)yl-thiophenyl, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl-thiophenyl,.

23. The use according to any of claims 21-22 of a compound of formula I wherein indolyl, hydroxy-C ι -e-alk^n/yn l-thiophenyl, C ι _-6-alk(en/yn)yloxy-C _-6-alk(en yn)yl- thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl is unsubstituted or substituted one or more times by Cι-₆-alk(en/yn)yl, C i _-6-alk(en/yn)yloxy, C i _-6-alk(en/yn)yloxy-C ι _-6-alk(en/yn)yl, C ι _-6-alk(en/yn)yloxy- C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, hydroxy, nitro, halogen, R⁷R⁸NCO- Cι_-6-alk(en/yn)yl; -NR⁷R⁸, C e-aU n yn l-CONR¹-, cyano, C_3-8-cycloalk(en)yl, C₁-₆-alk(en/yn)yloxycarbonyl or aryl and R³ is methyl, ethyl or isopropyl, 1-phenethyl or benzyl, which may be substituted by -CONR R .

24. The use according to any of the above claims of a compound of formula I said compound being:

N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N^,-(3-methyl-thiophen-2-yhnethylene)- hydrazine, N-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-ylmethylene)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-methoxy-benzylidene)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-methyl-lH-indol-3-ylmethylene)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2,5-dimethyl-l-phenyl-lH-pyrrol-

3 -ylmethylene)-hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-methyl-5-nitro-lH-indol-

3-ylmethylene)-hydrazine, N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-acetamido-benzylidene)-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-quinolin-4-ylmethylene-hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-ylmethylene)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2,3-dimethyl-benzylidene)-hydrazine, N-(lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine,

N-(2-chloro-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-[bis-(2-cyano-ethyl)-amino]- benzylidene)-hydrazine, N-(6-ethyl-tlιieno[2,3-d]pyrimidin-4-yl)-N'-(lH-indol-3-ylmethylene)-hydrazine,

N-{6-(l-phenyl-ethyl)-thieno[2,3-d]pyrimidin-4-yl}-N'-(2-chloro-4-hydroxy- benzylidene)-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-yhnethylene)- hydrazine, N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3,5-dibromo-4-hydroxy-benzylidene)- hydrazine,

N-(2-isopropyl-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-

4-yl)-hydrazine, N-(2-methyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(2-isopropyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine, N-(2-ethyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(-(3-bromo-4-hydroxy-5-methoxy- benzylidene)-hydrazine,

N-benzo[l,3]dioxol-4-ylmethylene-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(5-cyano-lH-indol-3-ylmethylene)- hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-hydroxy-4-methoxy-benzylidene)- hydrazine, N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-iodo-5-methoxy- benzylidene)-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-methyl-but-2-enylidene)-hydrazine,

N-(2-cyclopropyl-lH-indol-3-ylmethylene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine, N-(2-chloro-lH-indol-3-ylmethylene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(7-methyl-lH-indol-3-ylmethylene)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-fluoro-benzylidene)-hydrazine, N-(6-benzyl-thieno [2,3 -d]pyrimidin-4-yl)-N' -(3 -bromo-4-hydroxy-5-methoxy- benzylidene)-hydrazine,

N-(6-isopropyl-tlτieno[2,3-d]pyrimidin-4-yl)-N'-(3,5-dibromo-4-hydroxy- benzylidene)-hydrazine, N-(2-cyclopropyl-lH-indol-3-ylmethylene)-N'-[6-(l-phenyl-ethyl)-thieno-

[2,3 -d]pyrimidin-4-yl] -hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-methoxy-benzylidene)- hydrazine, N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2,6-dimethoxy-4-hydroxy- benzylidene)-hydrazine,

N-(2,6-difluoro-benzylidene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-thiophen-2-ylmethylene-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(5-methyl-thiophen-2-ylmethylene)- hydrazine,

N-(5-fluoro-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-[(2-cyano-ethyl)-methyl-amino]- benzylidene)-hydrazine, N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(6-[methyloxycarbonyl]-lH-indol-

3 -ylmethylene)-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-thiazol-2-ylmethylene-hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(l-[2-cyanophenyl]-lH-indol-

3 -ylmethylene)-hydrazine, N-(2,5-dimethyl-benzylidene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine,

N-(7-ethyl-lH-mdol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(l-methyl-2-[methyloxycarbonyl]-

1 H-pyrrol-3 -ylmethylene)-hydrazine, N-(2-isopropyl-lH-indol-3-ylmethylene)-N'-{6-[2-(2-hydroxy-ethylcarbamoyl)- benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine,

N-(2-methyl-lH-indol-3-ylmethylene)-N'-{6-[3-(pyridin-3-ylmethylcarbamoyl)- benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine,

N-(l-methyl-lH-indol-3-ylmethylene)-N'-{6-[3-(2-hydroxy-ethylcarbamoyl)-benzyl]- thieno[2,3-d]pyrimidin-4-yl}-hydrazine,

N-(4-methyl-lH-indol-3-ylmethylene)-N'-{6-[4-(2-hydroxy-ethylcarbamoyl)-benzyl]- thieno[2,3-d]pyrimidin-4-yl}-hydrazine, N- [6-(2-fluorob enzyl)-thieno [2,3 -d]pyrimidin-4-yl] -N'-(5 -hydroxymethyl-

3-methylthiophen-2-ylmethylene)-hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N^,-(3-methoxythiophen-

2-ylmethylene)-hydrazine, N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-hydroxymethylthiophen-

2-ylmethylene)-hydrazine,

N- [6-(2-fluorob enzyl)-thieno [2,3 -d]pyrimidin-4-yl] -N'-(3 -methylthiophen-

2-yhnethylene)-hydrazine,

N-{6-[(2,6-difluorophenyl)-hydroxymethyl]-thieno[2,3-d]pyrimidin-4-yl}- N'-(3-isopropoxythiophen-2-ylmethylene)-hydrazine,

N-{6-[(2,6-difluorophenyl)-hydroxymethyl]-thieno[2,3-d]pyrimidin-4-yl}-

N'-(3-hydroxymethylthiophen-2-ylmethylene)-hydrazine,

N-(5-hydiOxymethyl-3-methylthiophen-2-ylmethylene)-N'-(6-pyridin-2-ylmethyl- thieno[2,3-d]pyrimidin-4-yl)-hydrazine, N-(5-hydiOxymethyl-3-methylthiophen-2-ylmethylene)-N'-[6-(2-methoxybenzyl)- thieno[2,3-d]pyrimidin-4-yl]-hydrazine,

N-[6-(4-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(5-hydroxymethyl-

3-methylthiophen-2-ylmethylene)-hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-[5-(l-hydroxypropyl)- 3-methylthiophen-2-ylmethylene]-hydrazine,

N-{6-[4-(2-methoxy-ethylcarbamoyl)-benzyl]-thieno[2,3-d]pyrimidin-4-yl}-

N'-(2-methyl-lH-indol-3-ylmethylene)-hydrazine,

N-(5-hydroxymethyl-3-methylthiophen-2-ylmethylene)-N'-(6-pyridin-3-ylmethyl- thieno[2,3-d]pyrimidin-4-yl)-hydrazine, N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(5-methoxymethyl-

3-methylthiophen-2-ylmethylene)-hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-[5-(2-methoxyethoxymethyl)-

3 -methylthiophen-2-ylmethylene] -hydrazine,

N- [6-(2-fluorobenzyl)-thieno [2, 3 -d]pyrimidin-4-yl] -N'-(3 -methyl-5 -methyl- carbamoylthiophen-2-ylmethylene)-hydrazine,

N-{6-[(2,6-difluorophenyl)-hydroxymethyl]-thieno[2,3-d]pyrimidin-4-yl}-

N'-[5-(2,2-dimethylpropionyl)-3-methylthiophen-2-ylmethylene]-hydrazine, N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methylbut-2-enylidene)- hydrazine, or

N-(6-ethylthieno[2,3-d]pyrimidin-4-yl)-N'-(5-hydroxymethyl-3-methyl-thiophen-2- ylmethylene)-hydrazine;

or a pharmaceutically acceptable salt thereof.

25. A method for the treatment of Parkinson's Disease, dementia such as age related dementia, HIN-1 associated dementia, AIDS dementia complex, HIN encephalopathy and senile dementia of the Alzheimer's type and memory disorders, cerebral ischemias and spinal cord ischemias, ischemias following stroke or traumatic injuries of the brain or the spinal cord, Huntington Chorea, multiple sclerosis, glaucoma, promotion of survival of transplanted cells, ALS/Motor neuron Disease, neuronal trauma or age related macular degeneration, in a living animal body, including a human, comprising administering a therapeutically effective amount of a compound of formula I according to claims 1 to 24 or a pharmaceutically acceptable acid addition salt thereof.

26. A compound represented by the general formula I

wherein

A represents O or S;

W represents O, ΝH, ΝR¹; R⁴ and R⁵ are independently selected from the group represented by hydrogen, halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C₁_e-alk(en/yn)yloxy, C₁_₆-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo- C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yloxy, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl- C_1-6-alk(en/yn)yl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, C_1-6-alk(en/yn)ylsulfonyl, -NR⁷R⁸ and R⁷R⁸N-C₁_₆-allc(en/yn)yl-;

and

i) R³ represents a group ofthe formula

-R⁹-Ar²

wherein R⁹ represents O, NH, NR^1', S, -CONR^1'-, -CO-, C_1-6-alkyl or C_2-6-alkenyl, wherein said C_1-6-alkyl or C_2-6-alkenyl optionally is substituted by OH, halogen, C_1-6-alkoxy or C_3-8-cycloalkyl;

and R⁶ represents C^e-alk^n/yn l, C_3-8-cycloalk(en/yn)yl,

C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl or Ar¹;

or

ii) R³ represents halogen, C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy, hydroxy-C₁_e-alk(en/yn)yl, Ci_₆-alk(en/yn)yloxy, Cι_-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en/yn)oxy,

C_1-6-alk(en yn)ylsulfanyl, acyl, R⁷R⁸N-C₁_₆-alk(en/yn)yl or -NR⁷R⁸ ;

and R⁶ represents indolyl, hydroxy-C_1-e-alk(en/yn)yl-thiophenyl, C i _-6-alk(en/yn)yloxy-C _1-6-alk(en/yn)yl-thiophenyl, benzo [1,3] dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl,

C_1-e-alk(en/yn)yloxy-C_1-e-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, aryloxy-, aryl- C_1-6-alk(en/yn)yloxy, halo-C₁_e-alk(en/yn)yloxy, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano- C_1-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(en yn)yl, C_3-8-cycloalk(en)yl, Cs-s-cycloalk en l-Ci-e-alk^n/ynJyl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl, C_1-6-alk(en/yn)yloxycarbonyl, -θ-aik en/yn l-CONR^{1 '}-C_1-6-alk(en/yn)yl,

C_1-e-alk(en/yn)yl-CONR^1'-, -CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en/yn)yl;

Ar and Ar are independently selected from the group represented by aryl, a heterocycle or a carbocycle all of which may be substituted one or more times by halogen, cyano, nitro, C_1-6-alk(en/yn)yl,

C_1-6-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, C₁_e-alk(en/yn)yloxy-C₁_e-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, aryloxy-, aryl- -e-all n/yntyloxy, halo-C₁_₆-alk(en/yn)yloxy, C_1-6-alk(en/yn)yl- sulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, cyano- C_1-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, C _-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl, Cι_-6-alk(en/yn)yloxycarbonyl, Ci-e-alk en ynJyl-CONR¹ -C_1-6-alk(en/yn)yl,

Cι_-6-alk(en/yn)yl-CONR^r-, -CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en/yn)yl;

R⁷ and R⁸ are independently selected from the group represented by hydrogen and C_1-6-alk(en/yn)yl which may be further substituted by hydroxy, halogen, Cι_-6-alkoxy, cyano, nitro, C_3-8-cycloalk(en)yl, C _-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, aryl or a heterocycle; or R⁷ and R⁸ together with the nitrogen to which they are attached form a 3-7-membered ring which optionally contains one or more further heteroatoms and may optionally be substituted by halogen, C_1-6-alk(en/yn)yl, hydroxy, hydroxy- C_1-6-alk(en/yn)yl or acyl;

the aryls may be further substituted by halogen, cyano, nitro, C_1-6-alk(en/yn)yl, C_1-6-aUt(en/yn)yloxy, C_1-6-alk(en/yn)ylsulfanyl, hydroxy, hydroxy-C _1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yl, halo-C_1-6-alk(en/yn)yloxy, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, acyl, C_1-6-alk(en/yn)yloxycarbonyl,

C_1-6-alk(en/yn)ylsulfonyl, or -NR⁷ R^8' wherein -NR⁷ R^8' is as defined for -NR⁷R⁸ above provided that any aryl substituent on -NR⁷ R⁸ is not further substituted; and R¹ and R¹ are independently selected from the group represented by C_1-6-alk(en/yn)yl, C_3-8-cycloalk(en)yl, aryl, hydroxy-C _1-6-alk(en/yn)yl,

C_3-8-cycloalk(en)yl-C_1-e-alk(en/yn)yl and acyl;

or a pharmaceutically acceptable acid addition salt thereof;

provided that if A is S, W is NH, R⁴ and R⁵ are both hydrogen, and R³ is t-butyl, then R is not optionally substituted hydroxyphenyl; and

provided that the compound is not N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)- N'-(thiophen-2-ylmethylene)-hydrazine.

27. The compound according to claim 26 wherein A is S.

28. The compound according to any of claims 26-27 wherein W is NH.

29. The compound according to any of claims 26-28 wherein R⁴ and R⁵ are both hydrogen.

30. The compound according to any of claims 26-29 wherein R³ represents a group of the formula

-R⁹-Ar²

wherein R⁹ represents O, NH, NR^1', S, -CONR^1'-, -CO-, C_1-6-alkyl or C_2-e-alkenyl, wherein said C_1-6-alkyl or C_2-6-alkenyl optionally is substituted by OH, halogen, Cμe-alkoxy or C_3-8-cycloalkyl;

and R⁶ represents C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, C_3-8-cycloalk(en)yl- C_1-6-alk(en/yn)yl or Ar¹.

31. The compound according to claim 30 wherein R⁹ is C_1-6-alkyl optionally substituted by OH.

32. The compound according to any of claims 30-31 wherein R³ is an optionally substituted benzyl, 1-phenethyl or pyridylmethyl.

33. The compound according to claim 32 wherein benzyl, 1-phenethyl or pyridylmethyl are unsubstituted or substituted by -CONR⁷R⁸.

34. The compound according to any of claims 30-33 wherein R⁶ represents C_1-6-alk(en/yn)yl or Ar¹ wherein Ar¹ is an optionally substituted thiophenyl, indolyl, phenyl, pyrrolyl, quinolinyl, benzo[l,3]dioxolyl or thiazolyl.

35. The compound according to claim 34 wherein R⁶ represents Ar¹ wherein Ar¹ is an optionally substituted indolyl, hydroxy-C _1-6-alk(en/yn)yl-thiophenyl,

Cι_-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl-thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl.

36. The compound according to claims 34 or 35 wherein Ar¹ is unsubstituted or substituted one or more times by C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)yloxy, Cι_-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, C₁_₆-alk(en/yn)yloxy-C₁_₆-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, hydroxy, nitro, halogen, R⁷R⁸NCO-C_1-6-alk(en/yn)yl; -NR⁷R⁸, Cι_-6-alk(en/yn)yl-CONR¹-, cyano, C_3-8-cycloalk(en)yl, C_1-6-alk(en yn)yloxycarbonyl or aryl.

37. The compound according to any of the claims 30-36 wherein A is S, W is N and R⁴ and R⁵ are both hydrogen, and R³ is an optionally substituted benzyl, 1-phenethyl, pyridylmethyl, and R⁶ is C_1-6-alk(en/yn)yl or Ar¹ wherein Ar¹ is optionally substituted thiophenyl, phenyl, indolyl, pyrrolyl, quinolinyl, thiazolyl or benzo[l,3]dioxolyl.

38. The compound according to any of claims 26-37 wherein R³ represents halogen,

C₁_₆-alk(en/yn)yl, C_3-8-cycloalk(en/yn)yl, aryl, a heterocycle, hydroxy, hydroxy- C_1-6-alk(en/yn)yl, -e-alk en/ynJyloxy, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl,

C_3-8-cycloalk(en/yn)oxy, C_1-e-alk(en/yn)ylsulfanyl, acyl,

or -NR⁷R⁸ ; and R⁶ represents indolyl, hydroxy-C_1-6-alk(en/yn)yl-thiophenyl, C_1-6-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl-thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl all of which may be substituted one or more times by hydrogen, halogen, cyano, nitro, C_1-6-alk(en/yn)yl,

C_1-6-alk(en/yn)yloxy- C_1-6-alk(en/yn)yl, C₁_e-alk(en yn)yloxy-C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl, aryloxy-, aryl-C₁_₆-alk(en/yn)yloxy, halo-C₁_₆-alk(en/yn)yloxy, C_1-6-alk(en/yn)yl- sulfanyl, hydroxy, hydroxy-C_1-6-alk(en/yn)yl, halo-C_1-e-alk(en/yn)yl, cyano- C_1-6-alk(en/yn)yl, NR⁷R⁸, NR⁷R⁸-C_1-6-alk(eιVyn)yl, C_3-8-cycloalk(en)yl, C_3-8-cycloalk(en)yl-C_1-6-alk(en/yn)yl, C_1-6-alk(en/yn)ylsulfonyl, aryl, acyl, C_1-6-alk(en yn)yloxycarbonyl, -e-alk^n/yn l-CONR¹ -C_1-6-alk(en/yn)yl,

Cι_-6-alk(en yn)yl-CONR^1'-, -CONR⁷R⁸ or R⁷R⁸NCO-C_1-6-alk(en/yn)yl.

39. The compound according to claim 38 wherein R³ is C_1-6-alkyl.

40. The compound according to claim 39 wherein R³ is C_1-6-alkyl wherein the carbon adjacent to the heterocyclic ring is a primary, secondary or tertiary carbon.

41. The compound according to claim 40 wherein R³ is methyl, ethyl, isopropyl.

42. The compound according to any of claims 39-41 wherein A is S, W is N and R 4 and R⁵ are both hydrogen, and R³ is an optionally substituted benzyl, 1-phenethyl, pyridylmethyl, methyl, ethyl or isopropyl, and R⁶ is optionally substituted indolyl, hydroxy-C _{1 -6}-alk(en/yn)yl-thiophenyl, C \ _-6-alk(en/yn)yloxy-C_{1 -6}-alk(en/yn)yl- thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl.

43. The compound according to claim 42 wherein R³ is methyl, ethyl or isopropyl, and R⁶ is optionally substituted indolyl, hydroxy-C_1-6-alk(en/yn)yl-thiophenyl, C_1-6- alk(en/yn)yloxy-C ι _-6- alk(en/yn)y 1-thiophenyl, .

44. The compoxmd according to any of claims 42-43 wherein indolyl, hydroxy-C_1-6- alk(en/yn)yl-thiophenyl, C_1-6-alk(en/yn)yloxy-C_1-6-alk(en/yn)yl-thiophenyl, benzo[l,3]dioxolyl, pyrrolyl, C_1-6-alk(en/yn)ylphenyl or hydroxyphenyl is unsubstituted or substituted one or more times by C_1-6-alk(en/yn)yl, C_1-6-alk(en yn)yloxy, hydroxy, nitro, halogen, R⁷R⁸NCO-C_1-6-alk(en/yn)yl; -NR⁷R⁸,

C^-alk^n/yh l-CONR¹-, cyano, C_3-8-cycloalk(en)yl, C_1-6-alk(en/yn)yloxycarbonyl or aryl and R³ is methyl, ethyl or isopropyl, 1-phenethyl or benzyl, which may be substituted by -CONR⁷R⁸.

45. The compound according to any of claims 26-44 said compound being:

N-(6-Benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-methyl-thiophen-2-ylmethylene)- hydrazine,

N-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-ylmethylene)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-methoxy-benzylidene)- hydrazine,

N-(6-b enzyl-thieno [2,3 -d]pyrimidin-4-yl)-N'-(4-methyl- 1 H-indol-3 -ylmethylene)- hydrazine, N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2,5-dimethyl-l-phenyl-lH-pyrrol-

3 -ylmethylene)-hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N^,-(2-methyl-5-nitro-lH-indol-

3-ylmethylene)-hydrazine,

N-(6-benzyl-thieno [2,3 -d]pyrimidin-4-yl)-N' -(4-acetamido-benzylidene)-hydrazine, N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-quinolin-4-ylmethylene-hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-ylmethylene)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2,3-dimethyl-benzylidene)-hydrazine,

N-(lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine, N-(2-chloro-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-[bis-(2-cyano-ethyl)-amino]- benzylidene)-hydrazine,

N-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(lH-indol-3-ylmethylene)-hydrazine, N-{6-(l-phenyl-ethyl)-thieno[2,3-d]pyrimidin-4-yl}-N'-(2-chloro-4-hydroxy- benzylidene)-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-methyl-lH-indol-3-ylmethylene)- hydrazine, N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3,5-dibromo-4-hydroxy-benzylidene)- hydrazine,

N-(2-isopropyl-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-

4-yl)-hydrazine, N-(2-methyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(2-isopropyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(2-ethyl-lH-indol-3-ylmethylene)-N'-(6-methyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-isopropyl-thieno [2,3 -d]pyrimidin-4-yl)-N' -(-(3 -bromo-4-hydroxy-5-methoxy- benzylidene)-hydrazine,

N-benzo[l,3]dioxol-4-ylmethylene-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine, N-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(5-cyano-lH-indol-3-ylmethylene)- hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-hydroxy-4-methoxy-benzylidene)- hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-iodo-5-methoxy- benzylidene)-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-methyl-but-2-enylidene)-hydrazine,

N-(2-cyclopropyl-lH-indol-3-ylmethylene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(2-chloro-lH-indol-3-ylmethylene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(7-methyl-lH-indol-3-ylmethylene)- hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2-fluoro-benzylidene)-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3-bromo-4-hydroxy-5-methoxy- benzylidene)-hydrazine, N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(3,5-dibromo-4-hydroxy- benzylidene)-hydrazine,

N-(2-cyclopropyl-lH-indol-3-ylmethylene)-N'-[6-(l-phenyl-ethyl)-thieno-

[2,3-d]pyrimidin-4-yl]-hydrazine, N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-hydroxy-3-methoxy-benzylidene)- hydrazine,

N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(2,6-dimethoxy-4-hydroxy- benzylidene)-hydrazine,

N-(2,6-difluoro-benzylidene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine, N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-thiophen-2-ylmethylene-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(5-methyl-thiophen-2-ylmethylene)- hydrazine,

N-(5-fluoro-lH-indol-3-ylmethylene)-N'-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)- hydrazine, N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(4-[(2-cyano-ethyl)-methyl-amino]- benzylidene)-hydrazine,

N-(6-isopiOpyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(6-[methyloxycarbonyl]-lH-indol-

3 -ylmethylene)-hydrazine,

N-(6-benzyl-thieno[2,3-d]pyrimidin-4-yl)-N'-thiazol-2-ylmethylene-hydrazine, N-(6-isopropyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(l-[2-cyanophenyl]-lH-indol-

3-ylmethylene)-hydrazine,

N-(2,5-dimethyl-benzylidene)-N'-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-hydrazine,

N-(7-ethyl- lH-indol-3 -ylmethylene)-N'-(6-isopropyl-thieno [2,3 -d]pyrimidin-4-yi)- hydrazine, N-(6-ethyl-thieno[2,3-d]pyrimidin-4-yl)-N'-(l-methyl-2-[methyloxycarbonyl]-

1 H-pyrrol-3 -ylmethylene)-hydrazine,

N-(2-isopropyl-lH-indol-3-ylmethylene)-N'-{6-[2-(2-hydroxy-ethylcarbamoyl)- benzylj-thieno [2,3 -d]pyrimidin-4-yl} -hydrazine,

N-(2-methyl-lH-indol-3-ylmethylene)-N'-{6-[3-(pyridin-3-ylmethylcarbamoyl)- benzyl]-thieno[2,3-d]pyrimidin-4-yl}-hydrazine,

N-(l-methyl-lH-indol-3-ylmethylene)-N'-{6-[3-(2-hydroxy-ethylcarbamoyl)-benzyl]- thieno [2,3 -d]pyrimidin-4-yl} -hydrazine, N-(4-methyl-lH-indol-3-ylmethylene)-N'-{6-[4-(2-hydroxy-ethylcarbamoyl)-benzyl]- thieno [2,3 -d]pyrimidin-4-yl} -hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(5-hydroxymethyl-

3-methylthiophen-2-ylmethylene)-hydrazine, N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methoxythiophen-

2-ylmethylene)-hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-hydroxymethylthiophen-

2-ylmethylene)-hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methylthiophen- 2-ylmethylene)-hydrazine,

N-{6-[(2,6-difluorophenyl)-hydroxymethyl]-thieno[2,3-d]pyrimidin-4-yl}-

N'-(3-isopropoxythiophen-2-ylmethylene)-hydrazine,

N-{6-[(2,6-difluorophenyl)-hydroxymethyl]-thieno[2,3-d]pyrimidin-4-yl}-

N'-(3-hydroxymethylthiophen-2-yhnethylene)-hydrazine, N-(5-hydroxymethyl-3-methylthiophen-2-ylmethylene)-N'-(6-pyridin-2-ylmethyl- thieno [2,3 -d]pyrimidin-4-yl)-hydrazine,

N-(5-hydroxymethyl-3-methylthiophen-2-ylmethylene)-N'-[6-(2-methoxybenzyl)- thieno[2,3-d]pyrimidin-4-yl]-hydrazine,

N-[6-(4-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(5-hydroxymethyl- 3-methylthiophen-2-ylmethylene)-hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-[5-(l-hydroxypropyl)-

3-methylthiophen-2-ylmethylene]-hydrazine,

N-{6-[4-(2-methoxy-ethylcarbamoyl)-benzyl]-thieno[2,3-d]pyrimidin-4-yl}-

N' -(2-methyl- 1 H-indol-3 -ylmethylene)-hydrazine, N-(5-hydroxymethyl-3-methylthiophen-2-ylmethylene)-N'-(6-pyridin-3-ylmethyl- thieno[2,3-d]pyrimidin-4-yl)-hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(5-methoxymethyl-

3-methylthiophen-2-ylmethylene)-hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-[5-(2-methoxyethoxymethyl)- 3 -methylthiophen-2-yhnethylene] -hydrazine,

N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methyl-5-methyl- carbamoylthiophen-2-ylmethylene)-hydrazine, N-{6-[(2,6-difluorophenyl)-hydroxymethyl]-thieno[2,3-d]pyrimidin-4-yl}-N'-[5-(2,2- dimethylpropionyl)-3 -methylthiophen-2-ylmethylene] -hydrazine, N-[6-(2-fluorobenzyl)-thieno[2,3-d]pyrimidin-4-yl]-N'-(3-methylbut-2-enylidene)- hydrazine, or N-(6-ethylthieno[2,3-d]pyrimidin-4-yl)-N'-(5-hydroxymethyl-3-methyl-thiophen-2- ylmethylene)-hydrazine;

or a pharmaceutically acceptable salt thereof.

46. The compound according to any ofthe claims 26-45 as a medicament.

47. A pharmaceutical composition comprising a compound according to any of claims 26-45 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.