OA19258A - Triazolopyrazine - Google Patents

Triazolopyrazine Download PDF

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Publication number
OA19258A
OA19258A OA1201500152 OA19258A OA 19258 A OA19258 A OA 19258A OA 1201500152 OA1201500152 OA 1201500152 OA 19258 A OA19258 A OA 19258A
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alkyl
substituted
groups
iii
anyone
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OA1201500152
Inventor
Harald Engelhardt
Christian Smethurst
Davide Gianni
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Boehringer Ingelheim International Gmbh
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Abstract

The present invention encompasses compounds of general formula (I) wherein the groups R1 to R3 have the meanings given in the claims and in fee specification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell proliferation pharmaceutical preparations containing such compounds and their uses as a medicament.

Description

This invention relates to compounds of the general formula (I)
R\
wherein the groups R1 to R3 hâve the meanings given in the daims and in the spécification. The compounds of the invention are suitable for the treatment of diseases characterized by excessive or abnormal cell prolifération, pharmaceutical préparations containing such compounds and their uses as a médicament. The compounds of the invention are BRD4 inhibitors.
Background of the invention
Histone acétylation is most usually associated with the activation of gene transcription, as the modification loosens the interaction of the DNA and the histone octomer by changing the electrostatics. In addition to this physical change, spécifie proteins bind to acetylated lysine residues within histones to read the epigenetic code. Bromodomains are small (about 110 amino acid) distinct domains within proteins that bind to acetylated lysine résides commonly but not exclusively in the context of histones. There is a family of around 50 proteins known to contain bromodomains, and they hâve a range of fimetions within the cell.
The BET family of bromodomain containing proteins comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-T) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction. Recent research has established a compelling rationale for targeting BRD4 in cancer. BRD4 remains bound to transcriptional start sites of genes expressed during the entry into the G1 phase of the cell cycle, and is functioning to recruit the positive transcription élongation factor complex (P-TEFb), resulting in increased expression of growth promoting genes (Yang and Zhou, Mol. Cell. Biol. 28, 967, 2008). Importantly, BRD4 has been identified as a component of a récurrent t(l5; 19) chromosomal translocation in an aggressive form of human squamous carcinoma (French et al., Cancer Res. 63, 304, 2003). Such translocations express the tandem N-terminal bromodomains of BRD4 as an in-frame chimera with the NUT (nuclear protein in testis) protein, genetically defining the so-called NUT midline carcinoma (NMC). Functional studies in patient-derived NMC cell lines hâve validated the essential rôle of the BRD4-NUT oncoprotein in maintaining the prolifération and the différentiation block of these malignant cells. In addition, BRD4 has been identified as a critical sensitivity déterminant in a genetically defined AML mouse model (Zuber et al., Nature 2011 478(7370):524-8). Suppression of BRD4 led to robust anti-leukemic effects in vitro and in vivo, accompanied by terminal myeloid différentiation. Interestingly, BRD4 inhibition triggered MYC down-regulation in a broad array of mouse and human leukemia cell lines examined, indicating that small molécule BRD4 inhibitors may provide a means to suppress the MYC pathway in a range of AML subtypes.
Finally, the other family members of the BET family hâve also been reported to hâve some function in controlling or executing aspects of the cell cycle, and hâve been shown to remain in complex with chromosomes during cell division suggesting a rôle in the maintenance of epigenetic memory (Leroy et ai, Mol. Cell. 2008 30(1 ):51-60).
Examples of bromodomain inhibitors are benzodiazépine dérivatives, disclosed in WO2011/054553, and imidazo [4,5] quinoline dérivatives, disclosed in WO2011/054846.
Thus, there is the need to provide BRD4 inhibitors useful for the prévention and/or treatment of diseases characterized by excessive or abnormal cell prolifération, such as cancer.
Detailed description of the invention
The présent invention relates to compounds of formula (I)
R\
wherein,
R1 is -Ci^alkyl or -Ci-shaloalkyl;
R2 is selected from -NHR4, -Ci-salkyl, -Ci.shaloalkyl, halogen and -S-Ci-3alkyl;
β
R is a 5-12 membered heteroaryl, which group is substituted with -X-R10 and 10 optionally further substituted with one ore more groups independently selected from R9;
R4 is selected from -Cj.salkyl and 5-12 memebered heterocycloalkyl, which heterocycloalkyl can be optionally substituted with one or more groups independently selected from R5;
R5 is selected from -Ci-salkyl, -Ci^haloalkyl and -Ci.3alkylene-O-Ci.3alkyl;
R9is selected from-Ci.5alkyl, -O-Ci.5alkyl, -N(Ci.5alkyl)2, halogen, -Ci. 3alkylene-O-Ci.3alkyl, -Ci.5alkylene-N(-Ci.5alkyl, -Ci.5alkyl), 5-12 memebered heterocycloalkyl,wherein the heterocycloalkyl group can be optionally substituted with one or more groups independently selected from =O, -Ci.3alkyl, or
R9 is selected from -Cô-waryl and 5-12 memebered heteroaryl, wherein the aryl and heteroaryl groups can be optionally and independently substituted with one ore more groups selected from halogen, -Ci^alkyl, -O-Ci.jalkyl, -Ci^haloalkyl, -O-Ci^haloalkyl, -N(Ci-5alkyl, Ci^alkyl) and -NH-Ci-salkyl;
X is -Ci.jalkylene- or -O-;
R10 is-Cé-ioaryl or 5-12 membered heteroaryl, each of which groups can be optionally substituted with one or more groups selected from halogen, -Ci-3alkyl, -O-Ci-3alkyl, -Ci^haloalkyl, -O-Ci^haloalkyl;
wherein the compounds of formula (I) may be optionally be présent in the form of salts.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R1 is -CH3.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R2 is -NHR4 and R4 is a 5-6 membered heterocycloalkyl, optionally substituted as defined herein in the description and daims.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R2 is -NHR4 and R4 is tetrahydrofuran or piperidine, wherein the piperidine is substituted with one group selected from -CH3, -CH2CH3, CH2CH2CH3 and -(CH2)2-O-CH3.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R2 is -NHR4 and R4 is -Ci^alkyl.
In a preferred embodiment, the invention relates to comopunds of formula (I), wherein R2 is -NHR4 and R4 is -CH3 or -CH(CH3)2.
In a preferred embodiment, the invention relates to compounds of formula (I), A wherein R is -Ci-3alkyl.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R3 is a 5-9 membered heteroaryl substituted with -X-R10 and optionally further substituted with one or more groups independently selected from R9, wherein R9, R10 and X are as defined herein in the description and the claims.
Preferably, R3 is optionally further substituted with one or two R9.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein -X-R10 is selected from -CH2-phenyl, -CH(CH3)-phenyl, -CH2-pyridyl, -CH(CH3)-pyridyl, -O-phenyl, each of which phenyl or pyridyl groups is optionally substituted with -F or -CH3.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein -X-R10 is selected from -CH2-phenyl, -CH2-pyridyl, -CH(CH3)-phenyl, 10 -CH(CH3)-pyridyl, each of which pyridyl or phenyl group is optionally substituted with -F or -CH3.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R3 is selected from pyrazolyl imidazol, benzimidazolyl, imidazopyridine and imidazopyrimidine and R3 is substituted with -X-R10 and R3 is optionally 15 further substituted with one or more groups independently selected from R9, wherein R9, R10 and X are as defined herein in the description and the claims.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R9 is independently selected from -C].3alkyl, -O-Ci.3alkyl, -N(C].3alkyl)2, phenyl and 6 membered heterocycloalkyl, which heterocycloalklyl can be 20 optionally substituted with one or more groups independently selected =0 and
-C].3alkyl.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein R3 is imidazopyridine or benzimidazol substituted with -CH2-phenyl or -CH2-pyridyl, -CH(CH3)-pyridyl and optionally further substituted with -Ci.3alkyl 25 or 5-12 memebered heterocycloalkyl wherein the heterocycloalkyl group can be optionally substituted with one or more groups independently selected from -Ci.3alkyl.
In a preferred embodiment, the invention relates to compounds of formula (I), •5 wherein R is imidazopyridine or benzimidazol substituted with -CH2-phenyl, -CH(CH3)-pyridyl or -CH2-pyridyl and substituted with -CH(CH3 )2 or morpholinyl or piperazinyl, wherein the morpholinyl or piperazinyl groups is optionally substituted with one or more groups selected from -Ci-3alkyl.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein the 5-9 membered heteroaryl in R position is attached to the core of the structure via a carbon atom.
In a preferred embodiment, the invention relates to compounds of formula (I), wherein the pyridyl moiety in R10 position is bound to -X- in 2-position.
In a further embodiment, the invention relates to compounds of formula (I) for use in the treatment of cancer.
In a further embodiment, the invention relates to compound of general formula (I) according to anyone of the embodiments described herein in the description and the claims - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of cancer.
In a further embodiment, the invention relates to pharmaceutical préparation comprising as active substance one or more compounds of general formula (I) according to anyone of the embodiments described herein in the description and the claims optionally in combination with conventional excipients and/or carriers.
In a further embodiment, the invention relates to pharmaceutical préparation comprising a compound of general formula (I) according to anyone of the embodiments described herein in the description and the claims - or one of the pharmaceutically acceptable salts thereof - and at least one other cytostatic or cytotoxic active substance, different from formula (I).
The présent invention further relates to hydrates, solvatés, polymorphs, métabolites, dérivatives and prodrugs of compounds of general formula (I).
The présent invention further relates to a pharmaceutically acceptable sait of a compound of general formula (I) with anorganic or organic acids or bases.
In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof- as médicaments.
In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - for use in a method for treatment of the human or animal body.
In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of cancer, infections, inflammations and autoimmune diseases.
In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - for use in a method for treatment and/or prévention of cancer, infections, inflammations and autoimmune diseases in the human and animal body.
In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of cancer.
In another aspect the invention relates to the use of the compounds of general formula (I) - or the pharmaceutically acceptable salts thereof-in the treatment and/or prévention of cancer.
In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - for use in a method for treatment and/or prévention of cancer in the human or animal body.
In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or prévention of hematopoietic malignancies, preferably AML, MM.
In another aspect the invention relates to compounds of general formula (I) - or the pharmaceutically acceptable salts thereof- for use in the treatment and/or prévention of solid tumors, preferably to lung, liver, colon, brain, thyroid, pancréas, breast, ovary and prostate cancer.
In another aspect the invention relates to a process for the treatment and/or prévention of cancer comprising administering a therapeutically effective amount of a compound of general formula (I) - or one of the pharmaceutically acceptable salts thereof — to a human being.
In another aspect the invention relates to a pharmaceutical préparation containing as active substance one or more compounds of general formula (I) - or the pharmaceutically acceptable salts thereof - optionally in combination with conventional excipients and/or carriers.
In another aspect the invention relates to a pharmaceutical préparation comprising a compound of general formula (I) - or one of the pharmaceutically acceptable salts thereof- and at least one other cytostatic or cytotoxic active substance, different from formula (I).
Définitions
Ternis that are not specifically defined here hâve the meanings that are apparent to the skilled man in the light of the overall disclosure and the context as a whole.
As used herein, the following définitions apply, unless stated otherwise.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, -Ci.5alkyl means an alkyl group or radical having 1 to 5 carbon atoms. In general, for groups comprising two or more subgroups, the first named sub-group is the radical attachment point, for example the substitutent -Ci-salkyl-Cs-iocylcoalkyl, means a CAiocylcoalkyl group which is bound to a Cj.salkyl, the latter of which is bound to the core structure or to the group to which the substitutent is attached.
The indication of the number of members in groups that contain one or more heteroatom(s) (heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total atomic number of ail the ring members or chain members or the total of ail the ring and chain members.
The person skilled in the art will appreciate that substituent groups containing a nitrogen atom can also be indicated as amine or amino. Similarly, groups containing oxygen atom can also be indicated with -oxy, like for example alkoxy. Groups containing-C(O)- can also be indicated as carboxy; groups containing -NC(O)- can also be indicated as amide; groups containing -NC(O)N- can also be indicated as urea; groups containing -NS(O)2- can also be indicated as sulfonamide.
Alkyl dénotés monovalent, saturated hydrocarbon chains, which may be présent in both linear and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono- or polysubstitution in each case, on ail the hydrogen-carrying carbon atoms.
The term Ci^alkyl includes for example methyl (Me; -CH3), ethyl (Et; -CH2CH3), 1-propyl (π-propyl; π-Pr; -CH2CH2CH3), 2-propyl (z-Pr; wo-propyl; -CH(CH3)2), 1-butyl (π-butyl; n-Bu; -CH2CH2CH2CH3), 2-methyl- 1-propyl (fso-butyl; z-Bu; -CH2CH(CH3)2), 2-butyl (sec-butyl; sec-Bu; -CH(CH3)CH2CH3), 2-methyl-2-propyl (terZ-butyl; Z-Bu; -€(043)3), 1-pentyl (n-pentyl;
-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 3-methyl- 1-butyl (rio-pentyl; -CH2CH2CH(CH3)2), 2-methyl-2butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 2,2-dimethyl-lpropyl (zzeo-pentyl; -CH2C(CH3)3), 2-methyl- 1-butyl (-CH2CH(CH3)CH2CH3).
By the terms propyl, butyl, pentyl, etc. without any further définition are meant saturated hydrocarbon.groups with the corresponding number of carbon atoms, wherein ail isomeric forms are included.
The above définition for alkyl also applies if alkyl is a part of another group such as for example Cx.y-alkylamino or Cx.y-alkyloxy or Cx.y-alkoxy, wherein Cx.y-alkyloxy and Cx.y-alkoxy indicate the same group.
The term alkylene can also be derived from alkyl. Alkylene is bivalent, unlike alkyl, and reqùires two biriding partners. Formally, the second vàléncy is produced by removing a hydrogen atom in an alkyl. Corresponding groups are for example -CH3 and -CH2, -CH2CH3 and -CH2CH2 or >CHCH3 etc.
The term CM-alkylene includes for example -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, -(CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2-CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C (CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))-, -(CHCH(CH3) 2)- and -C(CH3)(CH2CH3)-.
Other examples of alkylene are methylene, ethylene, propylene, 1 -methylethylene, butylène, 1-methylpropylene, 1.1-dimethyl ethylene, 1,2-dimethyl ethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, etc.
By the generic tenus propylene, butylène, pentylene, hexylene etc. without any further définition are meant ail the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propylene includes 1-methylethylene and butylène includes 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.
The above définition for alkylene also applies if alkylene is part of another group such as for example in HO-Cx.y-aIkylenamino or H2N-Cx.y-alkyIenoxy.
Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C double bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl is formed.
Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methyl-prop-2-enyl, 2-methylprop-l-enyl, l-methyl-prop-2-enyl, 1-methyl-prop-l-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methylbut-2-enyl, 3-methyl-but-l-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl, 2-methylidene-3methylbutyl, 2,3-dimethyl-but-l-enyl, hexa-l,3-dienyl, hexa-l,4-dienyl, penta-1,4dienyl, penta-l,3-dienyl, buta-l,3-dienyl, 2,3-dimethylbuta-l,3-diene etc.
By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, 5 hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. without any further définition are meant ail the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenyl includes prop-1-enyl and prop-2-enyl, butenyl includes but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-lenyl, 1 -methyl-prop-2-enyl etc.
Alkenyl may optionally be présent in the cis or trans or E or Z orientation with regard to the double bond(s).
The above définition for alkenyl also applies when alkenyl is part of another group such as for example in Cx.y-alkenylamino or Cxy-alkenyloxy.
Unlike alkylene, alkenylene consists of at least two carbon atoms, wherein at least 15 two adjacent carbon atoms are joined together by a C-C double bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms at adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenylene is formed.
Examples of alkenylene are ethenylene, propenylene, 1 -methylethenylene, 20 butenyl ene, 1-methylpropenylene, 1,1-dimethyl ethenylene,
1,2-dimethyl ethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene etc.
By the generic terms propenylene, butenylene, pentenylene, hexenylene etc.
without any further définition are meant ail the conceivable isomeric forms with the corresponding number of carbon atoms, i.e. propenylene includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and 1,2-dimethylethenylene.
Alkenylene may optionally be présent in the cis or trans or E or Z orientation with 30 regard to the double bond(s).
The above définition for alkenylene also applies when alkenylene is a part of another group as in for example HO-Cx.y-alkenylenamino or H2N-Cx.yalkenylenoxy.
Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein at least two 5 adjacent carbon atoms are joined together by a C-C triple bond. If in an alkyl as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free valencies are saturated to form two further bonds, the corresponding alkynyl is formed.
Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, 10 but-3-ynyl, l-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, 3-methyl-but-l-ynyl.
By the generic terms propynyl, butynyl, pentynyl, etc. without any further définition are meant ail the conceivable isomeric fonns with the corresponding number of carbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl, 15 butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-l-ynyl, 1 -methyl-prop-2-ynyl.
If a hydrocarbon chain carries both at least one double bond and also at least one triple bond, by définition it belongs to the alkynyl subgroup.
The above définition for alkynyl also applies if alkynyl is part of another group, as 20 in Cx.y-alkynylamino or Cx.y-alkynyloxy, for example.
Unlike alkylene, alkynylene consists of at least two carbon atoms, wherein at least two adjacent carbon atoms are joined together by a C-C triple bond. If in an alkylene as hereinbefore defined having at least two carbon atoms, two hydrogen atoms in each case at adjacent carbon atoms are formally removed and the free 25 valencies are saturated to form two further bonds, the corresponding alkynylene is formed.
Examples of alkynylene are ethynylene, propynylene, 1-methyl ethynyl ene, butynyl ene, 1-methylpropynylene, 1,1-dimethyl ethynyl ene, 1,2-dimethyl12 ethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene etc.
By the generic tenus propynylene, butynylene, pentynylene, etc. without any further définition are meant ail the conceivable isomeric forms with the con’esponding number of carbon atoms, i.e. propynylene includes 1-methylethynylene and butynylene includes 1 -methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and 1,2-dimethylethynylene.
The above définition for alkynylene also applies if alkynylene is part of another group, as in HO-Cx.y-alkynyleneamino or H2N-Cx.y-aIkynyIeneoxy, for example.
By heteroatoms are meant oxygen, nitrogen and sulphur atoms.
Haloalkyl (haloalkenyl, haloalkynyI) is derived from the previously defined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. If a .haloalkyl (haloalkenyl, haloalkynyI) is to be further substituted, the 15 substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms.
Examples of haloalkyl (haloalkenyl, haloalkynyI) are -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -cf2cf2cf3, -cf2ch2ch3, -CF=CF2, -CC1=CH2, -CBr=CH2, -CI=CH2, -CC-CF3, -CHFCH2CH3,
-CHFCH2CF3 etc.
From the previously defined haloalkyl (haloalkenyl, haloalkynyI) are also derived the terms haloalkylene (haloalkenylene, haloalkynylene). Haloalkylene (haloalkenyl, haloalkynyI), unlike haloalkyl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom 25 from a haloalkyl.
Corresponding groups are for exàmplé -CH2F and -CHF-, -CHFCH2F and -CHFCHF- or >CFCH2F etc.
The above définitions also apply if the corresponding halogen groups are part of another group.
Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The Systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they hâve at least two carbon atoms together. In spiro-hydrocarbon rings a carbon atom (spiroatom) belongs to two rings together. If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms.
Cycloalkyl itself may be linked as a substituent to the molécule via every suitable position of the ring System.
Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl (octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthalene), bicyclo[2.2.1]heptyl (norbomyl), bicyclo[4.1.0]heptyl (norcaranyl), bicyclo-[3.1 ,l]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.
The above définition for cycloalkyl also applies if cycloalkyl is part of another group as in Cx.y-cycloalkylamino or Cx.y-cycloalkyloxy, for example.
If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained.
The term cycloalkylene can thus be derived from the previously defined cycloalkyl. Cycloalkylene, unlike cycloalkyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a cycloalkyl. Corresponding groups are for example cyclohexyl and or or (cyclohexylene).
The above définition for cycloalkylene also applies if cycloalkylene is part of another group as in HO-Cx.y-cycloaIkyleneamino or H2N-Cx.y-cycIoalkyleneoxy, for example.
Cvcloalkenyl is also made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. However, the Systems are unsaturated, i.e. there is at least one C-C double bond but no aromatic System. If in a cycloalkyl as hereinbefore defined two hydrogen atoms at adjacent cyclic carbon atoms are fonnally removed and the free valencies are. saturated to form a second bond, the corresponding cycloalkenyl is obtained. If a cycloalkenyl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms. Cycloalkenyl itself may be linked as a substituent to the molécule via every suitable position of the ring System.
Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohept-1-enyl, cyclohept-2enyl, cyclohept-3-enyl, cyclohept-4-enyl, cyclobuta-l,3-dienyl, cyclopenta-1,4dienyl,. cycto^ cyclopenta-2,4-dienyE:cycl&hexa-lç3^ cyclohexa-l,5-dienyl, cyclohexa-2,4-dienyl, cyclohexa-l,4-dienyl, cyclohexa-2,5dienyl, bicyclo[2.2.1]hepta-2,5-dienyl (norboma-2,5-dienyl), bicyclo[2.2.1]hept-2enyl (norbomenyl), spiro[4.5]dec-2-ene etc.
The above définition for cycloalkenyl also applies when cycloalkenyl is part of another group as in Cx.y-cycloalkenylamino or Cx.y-cycloalkenyloxy, for example. If the free valency of a cycloalkenyl is saturated, then an unsaturated alicyclic group is obtained.
The term cycloalkenylene can thus be derived from the previously defined cycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent and requires two binding partners. Formally the second valency is obtained by removing a hydrogen atom from a cycloalkenyl. Corresponding groups are for example
The above définition for cycloalkenylene also applies when cycloalkenylene is part of another group as in HO-Cx.y-cycloalkenyleneamino or H2N-Cx.ycycloalkenyleneoxy, for example.
Aryl dénotés a mono-, bi- or tricyclic group with at least one aromatic carbocycle. Preferably it dénotés a a monocyclic group with six carbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms (two six-membered rings or one sixmembered ring with a five-membered ring), wherein the second ring may also be aromatic or, however, may also be saturated or partially saturated. If an aryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon atoms. Aryl itself may be linked as a substituent to the molécule via every suitable position of the ring System.
Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl), indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl (1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl (1,2- dihydronaphthyl), fluorenyl etc.
The above définition of aryl also applies when aryl is part of another group as in arylamino or aryloxy, for example.
If the free valency of an aryl is saturated, then an aromatic group is obtained. The term arylene can also be derived from the previously defined aryl. Arylene, unlike aryl, is bivalent and requires two binding partners. Formally, the second valency is formed by removing a hydrogen atom from an aryl. Corresponding groups are e.g.
The above définition for arylene also applies when arylene is part of another group as in HO-aryleneamino or H2N-aryleneoxy for example.
Heterocyclyl dénotés ring Systems, which are derived from the previously defined cycloalkyl, cycloalkenyl and aryl by replacing one or more of the groups -CH2independently of one another in the hydrocarbon rings by the groups -O-, -S- or -NH- or by replacing one or more of the groups =CH- by the group =N-, wherein a total of not more than five heteroatoms may be présent, at least one carbon atom may be présent between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the ring as a whole must hâve Chemical stability. Heteroatoms may optionally be présent in ail the possible oxidation stages (sulphur -à sulphoxide -SO, sulphone -SO2-; nitrogen -> N-oxide).
A direct resuit of the dérivation from cycloalkyl, cycloalkenyl and aryl is that heterocyclyl is made up of the subgroups monocyclic heterorings, bicyclic heterorings, tricyclic heterorings and spiro-heterorings, which may be présent in saturated or unsaturated form. Saturated and unsaturated, non aromatic, heterocyclyl are also defined as heterocycloalkyl. By unsaturated is meant that there is at least one double bond in the ring System in question, but no heteroaromatic System is formed. In bicyclic heterorings two rings are linked together so that they hâve at least two (hetero)atoms in common. In spiroheterorings a carbon atom (spiroatom) belongs to two rings together. If a heterocyclyl is substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon and/or nitrogen atoms. Heterocyclyl itself may be linked as a substituent to the molécule via every suitable position of the ring system. When the heterocyclyl has a nitrogen atom, the preferred position to bind the heterocyclyl substituent to the molécule is the nitrogen atom.
Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazohdinyl, thiazohdinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl, 1,4-dioxanyl, azepanyl, diazepanyl, morphohnyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-5,5-dioxide, 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [ 1,4]-oxazepanyl, tetrahydrothienyl, homothiomorpholinylXS-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-5-oxide, tetrahydrothienyl-X5-dioxide, homothiomorpholinyl-Soxide, 2,3-dihydroazet, 2//-pyrrolyl, 4H-pyranyl, 1,4-dihydropyridinyl,
8-azabicyclo[3.2.l]octyl, 8-azabicyçlo[5.1,0]octyl, 2-oxa-5-azabicyclo[2.2.1 ]heptyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl, 2,5-diazabicyclo-[2.2.1 ]heptyl, 1 -aza-bicyclo[2.2.2]octyl, 3,8-diaza-bicyclo[3.2.1 ]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl, 2,6-diaza-bicyclo[3.2.2]nonyl, l,4-dioxa-spiro[4.5]decyl, l-oxa-3.8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl, 2,7-diaza20 spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl, 3,9-diaza-spiro[5.5]undecyl, 2.8-diazaspiro[4.5]decyl etc.
Further examples are the structures illustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):
U Ο
H
Ο
The above définition of heterocyclyl also applies if heterocyclyl is part of another group as in heterocyclylamino or heterocyclyloxy for example.
If the free valency of a heteroyclyl is saturated, then a heterocyclic group is obtained.
The term heterocyclylene is also derived from the previously defined heterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heterocyclyl. Corresponding groups are for example
The above définition of heterocyclylene also applies if heterocyclylene is part of another group as in HO-heterocyclyleneamino or H2N-heterocyclyleneoxy for example.
Heteroaryl dénotés monocyclic heteroaromatic rings or polycyclic rings with at least one heteroaromatic ring, which compared with the corresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of one or more carbon atoms, one or more identical or different.heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, wherein the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and a heteroaromatic System. If a heteroaryl is to be substituted, the substitutions may take place independently of one another, in the form of mono- or polysubstitutions in each case, on ail the hydrogen-carrying carbon and/or nitrogen atoms. Heteroaryl itself may be Med as a substüuent to the molécule via every suitable position of the ring System, both carbon and nitrogen.
Examples of heteroaryl are füryl, thienyl, pyIrolyl. oxazolyl> thiazolyI> isothiazolyl, pyrazolyl, imidazolyl, tnazolyI. tetrazolyl, oxadlazolyI> ’ pyndyl, pyrimidyl, pyridazinyl, pyrazinyl, «azmy!, p>Tidylw.0XÎdej pyn.oly|.^ ox.de, pynmidmyl-Moxide, pyridazinyl^-oxide, pyrazinylW-oxide, imidazolyl’ isoxazolyW-oxide, oxazolylW-oxide, thiazolylyV-ox.de, oxadiazoIyl-TVoxide, thiadiazolyl-,V-oxide, triazolyl-rV-oxide, tetrazolyl-JV-oxide, indolyl isoindolyl, benzoftryl, benzothienyl, benzoxazolyl, benzothiazoiyl, benzisoxazolyl benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinohnyl quinoxalinyl, cinnolinyl, phthalazinyl, quinazolmyl, benzotriaziny!, indolizmyl oxazolopyndyl, imidazopyridyl, naphthyridinyl, benzoxazolyl, pyridopyridy! punnyl, ptendinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolmyWoxide, mdoW-^xide, isoqumo!^^ qui^i,,^^ quinoxaliny,_ 15 TV-oxide, phthalazinylW-oxide, indolizinyl-AT-oxide, indazolyl-W-oxide, benzothiazolyl-A-oxide, benzimidazolylW-oxide etc.
Further examples are the structures ülustrated below, which may be attached via each hydrogen-carrying atom (exchanged for hydrogen):
The above définition of heteroaryl also applies when heteroaryl is part of another group as in heteroarylamino or heteroaryloxy, for example.
If the free valency of a heteroaryl is saturated, a heteroaromatic group is obtained.
The term heteroarylene can therefore be derived from the previously defmed heteroaryl. Heteroarylene, uhlike heteroaryl, is bivalent and requires two binding partners. Formally, the second valency is obtained by removing a hydrogen atom from a heteroaryl. Corresponding groups are for example
The above définition of heteroarylene also applies when heteroarylene is part of another group as in HO-heteroaryleneamino or H2N-heteroaryleneoxy, for example.
The bivalent groups mentioned above (alkylene, alkenylene, alkynylene etc.) may also be part of composite groups (e.g. H2N-C1 ^alkylene- or HO-Ci.4alkylene-). In this case one of the valencies is saturated by the attached group (here: -NH2, -OH), so that a composite group of this kind written in this way is only a monovalent substituent over ail.
By substituted is meant that a hydrogen atom which is bound directly to the atom under considération, is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place on one atom. Substitution with a particular substituent is only possible if the permitted valencies of the substituent and of the atom that is to be substituted correspond to one another and the substitution leads to a stable compound (i.e. to a compound which is not converted spontaneously, e.g. by rearrangement, cyclisation or élimination).
Bivalent substituents such as =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2 or the like, may only be substituted at carbon atoms, wherein the bivalent substituent =O may also be a substituent at sulphur. Generally, substitution may be carried out by a bivalent substituent only at ring Systems and requires replacement by two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom that is saturated prior to the substitution. Substitution by a bivalent substituent is therefore only possible at the group -CH2- or sulphur atoms of a ring system.
Stereochemistry/Solvates/HydratesrilMess^tatedOtherwise a structural formula given in the description or in the daims or a Chemical name refers to the corresponding compound itself, but also encompasses the tautomers, stereoisomers, optical and géométrie isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.), racemates, mixtures of separate enantiomers in any desired combinations, mixtures of diastereomers, mixtures of the forms mentioned hereinbefore (if such forms exist) as well as salts, particularly pharmaceutically acceptable salts thereof. The compounds and salts according to the invention may be présent in solvated form (e.g. with pharmaceutically acceptable solvents such as e.g. water, éthanol etc.) or in unsolvated form. Generally, for the purposes of the présent invention the solvated forms, e.g. hydrates, are to be regarded as of equal value to the unsolvated 5 forms.
Salts: The term pharmaceutically acceptable is used herein to dénoté compounds, materials, compositions and/or formulations which are suitable, according to generally recognised medical opinion, for use in conjunction with human and/or animal tissue and do not hâve or give rise to any excessive toxicity, 10 irritation or immune response or lead to other problems or complications, i.e. correspond overall to an acceptable risk/benefit ratio.
The term pharmaceutically acceptable salts relates to dérivatives of the Chemical compounds disclosed in which the parent compound is modified by the addition of acid or base. Examples of pharmaceutically acceptable salts include 15 (without being restricted thereto) salts of minerai or organic acids in relation to basic functional groups such as for example amines, alkali métal or organic salts of acid functional groups such as for example carboxylic acids, etc. These salts include in particular acetate, ascorbate, benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate, camsylate, 20 carbonate, chloride/hydrochloride, citrate, edisylate, ethane disulphonate, estolate, esylate, fiimarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenyl acetate, phosphate/diphosphate, polygalacturonate, propïonate, salicylate, stéarate, subacetate, succinate, sulphamide, sulphate, tannate, tartrate, teoclate, toluenesulphonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumin and procaine. Other pharmaceutically acceptable salts may be formed 30 with cations of metals such as aluminium, calcium, lithium, magnésium, potassium, sodium, zinc, etc. (cf. also Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977),66, 1-19).
The pharmaceutically acceptable salts of the présent invention may be prepared starting from the parent compound which carries a basic or acidic functionality, by conventional Chemical methods. Generally, such salts may be synthesised by reacting the free acid or base form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent such as for example ether, ethyl acetate, éthanol, isopropanol, acetonitrile (or mixtures thereof).
Salts of acids other than those mentioned above, which are usefiil for example for purifying or isolating the compounds from the reaction mixtures (e.g. trifluoroacetates), are also to be regarded as part of the invention.
In a représentation such as for example
the letter A has the function of a ring désignation in order to make it easier, for example, to indicate the attachment of the ring in question to other rings.
For bivalent groups in which it is crucial to détermine which adjacent groups they bind and with which valency, the corresponding binding partners are indicated in brackets, where necessary for clarification purposes, as in the following représentations:
(R2)-C(O)NHor (R2)-NHC(O)-;
Groups or substituents are frequently selected from among a number of alternative groups/ substituents with a corresponding group désignation (e.g. Ra, Rb etc). If such a group is used repeatedly to define a compound according to the invention in different molecular parts, it must always be borne in mind that the varions uses are to be regarded as totally independent of one another.
By a therapeutically effective amount for the purposes of this invention is meant a quantity of substance that is capable of obviating symptoms of illness or of preventing or alleviating these symptoms, or which prolong the survival of a treated patient.
List of abbreviations
ACN, CH3CN acetonitrile
Boc /er/.butoxy carbonyl
DCM dichloromethane
DIPEA diisopropylethyl amine
DMAP dimethyl-pyridin-4-yl-amine
DMF A.M-dimethylformamidc
DMSO dimethylsulphoxide
EDTA ethylenediaminetetraacetic acid
EtOAc or EA ethyl acetate
FCS Fêtai calf sérum
h hour(s)
HATU N-[(dimethylammo)-(17/-l,2,3-triazolo[4,5-h]pyridin-l-yl)methylenej-A-methylmethan-aminium hexafluorophosphate TV-oxide
HPLC high performance liquid chromatography
KOAc potassium acetate
LiHMDS lithium hcxamcthyl disilazide
M Molar
Min minute(s)
mL Millilitre
MS mass spectrometry
N Normal
NMR nuclear résonance spectroscopy
PE petrol ether
PPh3 triphenylphosphine
DIBAL diisobutylaluminium hydride
RP reversed phase
Rpm rounds per minute
RT or rt room température
STAB Sodium triacetoxy borohydride
TBME ZerZ.butyl methyl ether
TEA triethylamine
tert tertiary
TFA trifluoroacetic acid
THF tetrahydrofuran
tR rétention time [min]
TRIS tris(hydroxymethyl)aminomethane
wt% weight percent
sat. Saturated
Ar aromatic
Other features and advantages of the présent invention will become apparent from the following more detailed Examples which exemplarily illustrate the principles of the invention without restricting its scope.
General
Unless stated otherwise, ail the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in Chemical laboratoires. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon).
The compounds are named according to the Beilstein rules using the Autonom software (Beilstein). If a compound is to be represented both by a structural formula and by its nomenclature, in the event of a conflict the structural formula is décisive.
Chromatography
Thtn layer chromatography is carried out on ready-made TLC plates of silica gel 60 on glass (with fluorescence indicator F-254) made by Merck.
The préparative high pressure chromatography (HPLC) of the example compounds according to the invention is carried out with columns made by Waters (names: Sunfîre C18 OBD, 10 pm, 30 x 100 mm Part. No. 186003971; X-Bridge C18 OBD, 10 pm, 30 x 100 mm Part. No. 186003930). The compounds are eluted usmg different gradients of H2O/ACN wherein 0.2 % HCOOH is added to the water (acid conditions). For chromatography under basic conditions the water is made basic according to the following recipe: 5 mL of ammonium hydrogen carbonate solution (158 g to 1 L H2O) and 2 ml 32 % ammonia (aq) are made uP to 15 lLwithH2O.
The analytical HPLC (reaction monitoring) of intermediate compounds is carried out with columns made by Waters and Phenomenex. The analytical equipment is also provided with a mass detector in each case.
HPLC mass spectroscopy/UV spectrometry
The rétention times/MS-ESC for charaeterising the example compounds accordtng to the invention are produced using an HPLC-MS apparatus (high performance liquid chromatography with mass detector) made by Agilent. Compounds that elute at the injection peak are given the rétention time tRet = 0.
-5 HPLC-Methods preperative prep. HPLC1
HPLC: 333 and 334 Pumps
Column: Waters X-Bridge Cl8 OBD, 10 pm, 30 x 100 mm,
Part.No. 186003930
Solvent. A. 10 mM NH4HCO3 in H2O; B: Acetonitril (HPLC grade)
Détection: Flow: Gradient: UV/Vis-155 50 ml/min
0.00 - 1.50 min: 1.50-7.50 min: 1.5% B varying
5 prep. HP LC2 HPLC: 7.50-9.00 min: 333 and 334 Pumps 100 % B z
10 Column: Solvent: Waters Sunfire Cl 8 OBD, 10 pm, 30 x 100 mm, Part.No. 186003971 A: H2O + 0.2 % HCOOH; B: Acetonitril (HPLC grade) +
15 Détection: Flow: Gradient: 0.2 % HCOOH UV/Vis-155 50 ml/min 0.00 - 1.50 min: 1.50 - 7.50 min: 7.50 - 9.00 min: 1.5% B varying 100% B
HPLC-Methods analytic LCMSBAS1
20 HPLC: Agilent 1100 Sériés
MS: Agilent LC/MSD SL
Column: Phcnbmenex Mercury Gemini Cl8, 3 pm, 2 x 20 mm,
Part.No. 00M-4439-B0-CE
Solvent: A: 5 mM NH4HCO3/20 mM NH3 in H2O; B: Acetonitril
25 (HPLC grade)
Détection: MS:Positive and négative mode
Mass range: 120-900m/z
Flow: 1.00 ml/min
Column température: 40 °C
30 Gradient: 0.00 - 2.50 min: 5 % -> 95 % B
2.50 - 2.80 min: 95 % B
2.81-3.10 min: 95 % 5 % B
FECB5
HPLC: Agilent 1100/1200 Sériés
MS: Agilent LC/MSD SL
Column: Waters X-Bridge Cl8 OBD, 5 pm, 2.1 x 50 mm
Solvent: A: 5 mM NH4HCO3/19 mM NH3 in H2O; B: Acetonitril (HPLC grade)
Détection: MS:Positive and négative mode
Mass range: 105- 1200 m/z
Flow: 1.20 ml/min
Column température: 35 °C
Gradient: 0.00 - 1.25 min: 5 % -» 95 % B 1.25 - 2.00 min: 95 % B 2.00-2.01 min: 95 %-> 5 % B
FECBM3ESI
HPLC: Agilent 1100/1200 Sériés
MS: Agilent LC/MSD SL
Column: Waters X-Bridge Cl 8 OBD, 5 pm, 2.1 x 50 mm
Solvent: A: 5 mM NH4HCO3/19 mM NH3 in H2O; B: Acetonitril (HPLC grade)
Détection: MS:Multimode ESI Positive and négative mode
Mass range: 105 — 1200 m/z
Flow: 1.20 ml/min
Column température: 35 °C
Gradient: 0.00-1.25 min: 5 % 100 % B 1.25-2.00 min: 100% B 2.00 - 2.01 min: 100 % -> 5 % B
VAB
HPLC: Agilent 1100/1200 Sériés
MS: Agilent LC/MSD SL
Column: Waters X-Bridge BEH Cl8, 2.5 pm, 2.1 x 30 mm XP
Solvent: A: 5 mM NH4HCO3/19 mM NH3 in H2O; B: Acetonitril (HPLC grade)
Détection: MS:Positive and négative mode
Mass range: 100- 1200 m/z < .
Flow: 1.40 ml/min
Column température: 45 °C
Gradient: FA-8 0.00 - 1.00 min: 5 % -> 100 % B 1.00- 1.37 min: 100% B 1.37 - 1.40 min: 100 % -> 5 % B
HPLC-MS: Waters - Alliance 2996
Column: Symmetryshield Cl8, 5 pm, 4.6 x 250 mm
Solvent: A: H2O + 0.1% TFA; B: Acetonitril (HPLC grade)
Détection: MS:Positive-and négative mode
Mass range: 100- 1200 m/z
Flow: 1.00 ml/min
Column température: 25 °C
Gradient: 2.00- 8.00 min: 20 % 80 % B
8.00- 19.00 min: 80 % B
19.00-20.00 min: 80% 20 % B
FSUN2
HPLC: Agilent 1100/1200 Sériés
MS: Agilent LC/MSD SL
Column: Waters Sunfire Cl 8, 5 pm, 2.1 x 50 mm
Solvent: A: H2O + 0.2% formic acid; B: Acetonitril (HPLC grade)
Détection: MS:Positive and négative mode
Mass range: 105- 1200 m/z
Flow: 1.20 ml/min
Column température: 35 °C
Gradient: 0.0 min: 5 % B
0.0 - 1.50 min: 5 % 95 % B
1.50-2.00 min: 95 % B
2.00 - 2.01 min: 95 % 5 % B
Préparation of the compounds according to the invention
The compounds according to the invention are prepared by the methods of synthesis described hereinafter, in which the substituents of the general formula hâve the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the préparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.
Unless otherwise specified, the substituents RI through R3 of the following reaction schemes are as defined in the description and daims.
The synthesis of key intermediate J from startingmaterial A is illustrated in Scheme 1.
Scheme 1 *
H
G
Starting from A, a nucleophilic aromatic substitution reaction can be used to introduce hydrazine B, which leads to C. Compound G can be synthesized applying an amidation reaction with D followed by a bromation with F. After cleavage of the 5 amide and ring closer with an orthoester dérivative I the central intermediate J can be obtained.
The synthesis of compounds of formula I - III from key intermediate J is illustrated in Scheme 2.
Scheme 2
Residue R2 can be introduced via a nucleophilic aromatic substitution reaction using the corresponding amine, alcohol, thiol or a carbo nucleophile (e.g.
diethylmalonate) to produce intermediate K.
Final compounds I were synthesized starting from intermediate K and applying a Suzuki reaction with boronic acids L.
Intermediate M, which is synthesized from K using a palladium catalyzed carbonylation reaction, is the central intermediate for final compounds II and III.
Intermediate M was condensed with aromatic/heteroaromatic diamines Q resulting in final compounds III.
Réduction of the acid of M and re oxidation of the corresponding alcohol lead to intermediated N, which is condensed with oxime O and amine P to final compounds II.
Préparation of intermediate J-l
6-bromo-8-chloro-3-methyl-[I,2,4]triazol<i|4,3-a]pyrazine J-l
Reaction scheme:
^NH, H?N 2
B-1
EtOH, 25 °C (yield: 75 %)
(yield: 100 %)
Br F-1
E-1 (yield: 13 %)
DCM; -40 °C
2-chIoro-3-hydrazinylpyrazine C-l
H ; |p NH2 TT^CI
2,3-DichIoropyrazine A-l (15 g; 100.68 mmol) and hydrazine hydrate 65 % (15.509 ml; 201.37 mmol) are dissolved in 45 ml éthanol and stirred for 1 h at 80 °C. While cooling down, a precipitate is formed. It is slurred up with a small amount of water and filtered off. It is washed with water and then dried to afford the product.
Yield: 93% (13.6 g; 94.07mmol)
HPLC-MS: (M+H) = 145/147; tRet = 0.34 min; method FECB5
N'-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide E-l
2-Chloro-3-hydrazinylpyrazine C-l (15.6 g; 108 mmol) is slurried up in (300 ml) THF and cooled down in an ice bath to -5 °C. Trifluoroacetic anhydride (17 ml; 118 mmol) is also dissolved in 300 ml THF and dropped slowly to the First solution. After 1 h most of the THF is evaporated, than a small amount of water is added and the mixture is extracted with DCM. The organic phase is dried over MgSO4 and evaporated to dryness.
Yield: 100 %
HPLC-MS: (M+H)+ = 241/243; tRet =1.31 min; method FSUN2
N'-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifIuoroacetohydrazide G-l
O
N'-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide E-l (19,5 g; 81.1 mmol) is dissolved in 300 ml anhydrous DCM and cooled down to - 40 °C. Afterwards NBS (18.8 g; 105 mmol) is added and stirred for .l hour. The solution is diluted with water and extracted with DCM. The organic phase is then purified with flash chromatography: cHex/(EtOAc/CH3COOH= 9/1) = 80% / 20% to 70% / 30% within 10 column volumes.
Yield: 11% (2.83 g; 8.859 mmol)
HPLC-MS: (M-H)’ = 317/319/321; tRet = 1.79 min; method FSUN2
3S
5-bromo-3-chloro-2-hydrazmyIpyrazine H-l
H if Y NH2
N'-(5-bromo-3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide G-l (1.59 g;
4.97 mmol) is dissolved in 30 ml EtOH and treated with 3 ml conc. HCl. It is stirred for 2 hours at 100 °C. The reaction mixture is cooled down, diluted with water and then the pH adjusted to 8 with saturated NaHCO3 solution. The water phase is extracted with EtOAc, the organic layer dried over MgSO4 and evaporated to dryness.
Yield:71 % (945 mg; 3.51 mmol)
HPLC-MS: (M-H)‘ = 221/223/225; tRet = 1.32 min; method FECB5
6-bromo-8-chIoro-3-methyl-[l,2,4]triazolo[4,3-a]pyrazine J-l
5-bromo-3-chloro-2-hydrazinylpyrazine H-l (945 mg; 3.51 mmol) is dissolved in 12 ml trimethyl orthoacetate and heated up to 130 °C for 1 hour. The solution is diluted with water and extracted with EtOAc. The organic phase is then purified with flash chromatography: cHex/EtOAc = 70% / 30% to 55% / 45% within 10 column volumes.
Yield: 71% (824 mg; 3.33 mmol)
HPLC-MS: (M+H)+ = 247/249/251; tRet = 1.23 min; method FECB5
Préparation of intermediate K-l tert-butyl 4-({6-bromo-3-methyl-[l,2,4]triazolo[4,3-a]pyrazin-8yl}amino)piperidine-l-carboxylat
6-bromo-8-chloro-3-methyl-[l,2,4]triazolo[4,3-a]pyrazine J-l (3.24 g; 13.1 mmol), 4-amino-l-boc-piperidine (5.24 g; 26.2 mmol) and hünigbase (2.44 ml; 14.4 mmol) are dissolved in 30 ml THF and are stirred for 16 hours at 25 °C. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is separated and dried over MgSC>4 and evaporated to dryness.
Yield: 98 % (6.60 g; 12.8 mmol)
HPLC-MS: (M+H) = 411/413; tRet = 0.88 min; method VAB
Préparation of intermediate K-3
6-bromo-3,8-dimethyI-[l,2,4]triazolo[4,3-a]pyrazine K-3
Caesiumcarbonate (7ώ5 g; 22.3 mmol) is suspended in 5 ml NMP. To this suspension di-tert-butyl malonate (4.80 g; 22.3 mmol) is added and the resulting 15 mixture is.stirred for 30 min at 25 °C. Finally ô-bromo-S-chloro-j-methyl[l,2,4]triazolo[4,3-a]pyrazine J-l (1.00 g; 4.04 mmol) is added and the reaction mixture is stirred for 18 h at 25 °C. The reaction mixture is treated with aqueous 1 N HCl until the pH value is below 5 and then extracted with DCM. The organic layer is separated and dried over MgSÛ4 and is evaporated to dryness.
The crude intermediate is purified using reverse phase chromatography (method prep. HPLC2). The intermediate is dissolved in 5 ml DCM and 5 ml TFA and stirred for 16 h at 40 °C. The reaction mixture is evaporated and the crude product is purified using reverse phase chromatography (method prep. HPLC2).
Yield: 15 % (138 mg; 0.61 mmol)
HPLC-MS: (M+H)+ = 227/229; tRet = 0.47 min; method VAB
According to the procedures of K-l and K-3 the intermediates K-2 are synthesized.
MS (M+H)+; HPLCtRet. HPLC [min]Method
Y=N / \
K-2 M+H=242/244;
Λ X Βγ^Ή^ΉΗ tRet.= 0.59 V ÆO
K-3 M+H=227/229; VAB
X X Br^N^- ÎRet.= 0.47
\=N / \
K-4 N ZzN Xl Br N NH M+H=256/258; tRet = 0.64 VAB
K-5 Îi 1 M+H=270/272; VAB
II J Br N NH ÎRet = θ·69
\=N / \
K-6 N ZzN il ΒΓΉ NH M+H=298/300; VAB
ό
Préparation of intermediate M-l
8-({l-[(tert-butoxy)carbonyl]piperidin-4-yl}amino)-3-methyI[l,2,4]triazoIo[4,3-a]pyrazine-6-carboxy!ic acid M-l
tert-butyl4-({6-bromo-3-methyl-[l,2,4]triazolo[4,3-a]pyrazin-8yl}amino)piperidine-l-carboxylat K-l (1.85 g; 3.59 mmol), dichloro[l,l’bis(diphenylphosphino)ferrocene] palladium (II) dichlormethane adduct (310 mg, 0.38 mmol) and triethylamine (910 mg; 8.99 mmol) are dissolved in 10 ml methanol and 10 ml NMP. The reaction mixture is stirred for 3 h at 70°C and 2 bar CO pressure. The reaction mixture is diluted with water and extracted with EtOAc. The organic layer is separated and dried over MgSO4 and evaporated to dryness. The crude product is purified using method prep. HPLC1. This intermediate is dissolved in 20 ml THF and is treated with 10 ml of a 1 N aqueous LiOH solution. After 1 h the reaction mixture is diluted with water and extracted with DCM. The organic layer is separated and dried over MgSO4 and evaporated to dryness. Yield: 72 % (976 mg; 2.59 mmol) HPLC-MS: (M-H)’ = 375; tRet = 0.88 min; method FECB5
According to the procedures of M-l the intermediates M-2 and M-3 are synthesized.
MS (M+H)+; HPLCtRet, HPLC [min] Method
M+H=208; WA1,
0.0 VAB
Structure
MS (M+H)+; tRet. HPLC [min]
HPLCMethod
M-3
M+H=193; tRet = 0.0
M-4
M+H=222;
tRet= 0.0
VAB
M-5
M-6
M+H=236; tRet = 0.0
M+H=264; tRet = 0.0
VAB
VAB
Préparation of intermediate L-l (l-methyl-5-phenoxy-lH-pyrazol-4-yl)boronic acid
l-Methyl-5-phenoxy-lH-pyrazole-4-carboxylic acid ethyl ester
Phénol (30.3 g; 322 mmol) is dissolved in DMA and K2CO3 (88.9 g; 643 mmol) is added portion wise. It is stirred for 10 minutes, then 5-Bromo-l-methyl-lHpyrazole-4-carboxylic acid ethyl ester (50.0 g; 215 mmol) is dropped to the reaction mixture and heated up to 140 °C for 16 hours. A 10 % ci trie acid solution is added and extracted with DCM. The organic layer is washed with sodium bicarbonate and brine, then dried and purified through column chromatography.
Yield: 43 % (22.5 g; 91.37 mmol)
HPLC-MS: (M+H)+ = 247; tRet = 3.50 min; method LCMS FA-8 l-Methyl-5-phenoxy-lH-pyrazoIe-4-carboxylic acid o
l-Methyl-5-phenoxy-lH-pyrazole-4-carboxylic acid ethyl ester (22.6 g;
91.4 mmol) is dissolved in THF/MeOH (1/1) and LiOH in water (7.67 g;
183 mmol) is added. After 16 hours at ambient température the reaction mixture is washed with EtOAc. The aqueous layer is acidified with 1 N HCl and extracted with EtOAc. The organic layer is dried and evaporated.
Yield: 80 % (16.0 g; 73.3 mmol)
HPLC-MS: (M+H)+ = 219; tRet = 2.88 min; method LCMS FA-8 l-Methyl-5-phenoxy-lH-pyrazol-4-ylamine
To a stirred mixture of l-Methyl-5-phenoxy-lH-pyrazole-4-carboxylic acid (16.0 g; 73.3 mmol), t- BuOH (51.2 g; 691 mmol) in 1,4-dioxane under argon are added DIPEA (37.4 g ; 290 mmol) and diphenylphosphoryl azide (41.6 g;
151 mmol). After 10 minutes at ambient température it is heated up to 110 °C and stirred for 3 hours. The solvent is evaporated and the crude material purified by column chromatography. This compound is dissolved in DCM and treated with
M HCl in 1,4-dioxane. It is stirred for 2 days at ambient température. The solvent is evaporated and the residue dissolved in water and washed with EtOAc. The aqueous layer is basified with aqueous NaHCO3 solution and is extracted with EtOAc. The organic layer is dried and concentrated to dryness.
Yield: 32 % (16.0 g; 73.3 mmol)
HPLC-MS: (M+H)+ = 190; tRet = 2.32 min; method LCMS FA-8
4-Iodo-l-methyl-5-phenoxy-lH-pyrazole
l-Methyl-5-phenoxy-lH-pyrazol-4-ylamine (4.50 g; 23.8 mmol) is dissolved in H2SO4 and cooled to 0 °C. NaNO2 (1.64 g; 23.8 mmol) is dissolved in water and is added to the reaction mixture. It is stirred for 1 hour at 0 °C then Kl (15.8 g;
95.1 mmol) is added whilst vigorous stirring and warming up to ambient température within 30 minutes. It is treated with water and neutralized with saturated NaHCO3 solution. The water layer is extracted with DCM, dried and purified by column chromatography.
Yield: 38 % (2.70 g; 8.99 mmol)
HPLC-MS: (M+H)+ = 301; tRet = 3.74 min; method LCMS FA-8 (l-methyl-5-phenoxy-lH-pyrazol-4-yl)boronic acid
HO^ /OH B
4-Iodo-l-methyl-5-phenoxy-lH-pyrazole (862 mg; 2.75 mmol) is dissolved in ml THF extra dry and cooled down to -78 °C. Afterwards n-BuLi (1.80 ml;
2.88 mmol; 1.6 mol/1 in Hexane) and Triisopropyl borate (982.28 mg; 5.22 mmol) are added. It is stirred for 1 hour. The reaction mixture is quenched with 1 ml water and purified with reversed phase chromatography under basic conditions.
Yield: 67 % (400 mg; 1.84 mmol)
HPLC-MS: (M+H)+ = 219; tRet = 1.34 min; method FECB5
Préparation of intermediate L-2 (5-benzyl-l-methyl-lH-pyrazol-4-yl)boronic acid
OH
I
(4-Bromo-2-methyl-2H-pyrazol-3-yl)-phenyl-methanol
N-N
4-Bromo-2-methyl-2H-pyrazole-3-carbaldehyde (1.00 g; 5.29 mmol) is dissolved in 5.0 ml of anhydrous THF and cooled down to - 78 °C. Phenylmagnesium chloride 2 mol/1 (6.61 ml; 13.2 mmol) is added and the reaction mixture is stirred for 1 hour. It is warmed up to 0 °C and is quenched carefully with water, then extracted with DCM. The organic layers are pooled, dried over MgSO4 and purified by using reversed phase chromatography under basic conditions.
Yield: 82 % (1.16 g; 4.35 mmol)
HPLC-MS: (M+H)+ = 267; tRet = 1.59 min; method FECBM3ESI
5-Benzyl-4-bromo-l -methyl-1 H-pyrazole
N-N (4-Bromo-2-methyl-2H-pyrazol-3-yl)-phenyl-methanol (0.50 g; 1.87 mmol) is treated with 3.0 ml TFA and Triethylsilane (1.49 ml; 9.36 mmol) and is heated to 50 C for 16 hours. The product is purified via reversed phase chromatography under acid conditions.
Yield: 56 % (0.26 g; 1.06 mmol)
HPLC-MS: (M+H)+ = 251/253; tRet = 1.71 min; method FECBM3ESI (5-benzyl-l-methyl-lH-pyrazol-4-yl)boronic acid
OH
I
5-Benzyl-4-bromo-l -methyl-1 H-pyrazole (0.27 g; 1.06 mmol) is dissolved in
5.0 ml anhydrous THF and cooled down to — 78 °C. Afterwards triisopropyl borate (0.46 ml; 2.01 mmol) and n-BuLi; 1,6 mol/1 in Hexane; (0.69 ml; 1.11 mmol) are added. It is stirred for 1 hour within the desired product is formed. It is warmed to 25 °C and quenched with water. It is purified with reverse phase chromatography by using basic conditions.
Yield: 39 % (0.08 g; 0.41 mmol)
HPLC-MS: (M+H)+ = 217; tRet = 1.41 min; method FECBM3ESI
Préparation of intermediate L-5 (5-benzyl-l-methyl-lH-pyrazol-4-yl)boronic acid - L-5
Reaction Scheme:
L-5-1
L-5-2 L-5-3
L-5 L-5-4
Intermediate L-5-4 is synthesized according to the procedures described in Bioorganic & Med. Chem. Letters 18(2) 509-512 2008. For the synthesis of the boronic acid L-5 the procedures described for L-l and L-2 are used.
HPLC-MS: (M+H)+ = 233; tRet = 0.73 min; method VAB
According to the procedures of L-l and L-2 the intermediates L-3 and L-4 are synthesized.
MS (M+H)1
Structure tRet. HPLC HPLC-Method
L-4
M+H=231; tRet = 0-76
VAB
General method for préparation of compounds of formula I
6-(3-benzyl-l-methyl-lH-pyrazol-4-yl)-N,3-dimethyl-[l,2,4]triazolo[4,3a]pyrazin-8-amine 1-1
Intermediate G-2 (32 mg; 0.13 mmol), boronic acid L-3 (30 mg; 0.13 mmol), Cs2CO3 70 % solution in water (0.05 ml; 0.25 mmol) and Pd[P(t-Bu)3]2 (5 mg; 0.01 mmol) are suspended with THF/NMP = 2/1 (0.3 ml) and flushed with argon. It * 'X is stirred at 90 °C for 1 hour. The crude reaction mixture is purified by using reversed phase chromatography under acid conditions (Method: prep. HPLC2). Yield: 33 % (0.02 g; 0.04 mmol)
HPLC-MS: (M+H)+ = 417; tRet = 1.05 min; method LCMSBAS1
According to 1-1 the following examples are synthesized.
M+H= 347; tRet.= 1.11
LCMSBAS1
MS (M+H)+; tRet. HPLC [min]
M+H= 34.9;. tRet = 1.12
HPLC-Method
LCMSBASl
General method for préparation of compounds of formula II
6-(l-benzyl-5-methyl-4-phenyl-lH-imidazoI-2-yl)-N,3-dimethyl[1,2,4] triazolo [4,3-a] pyrazin-8-amine II-1
3-methyl-8-(methylamino)-[l,2,4]triazolo[4,3-a]pyrazine-6-carbaldehyde
3-methyl-8-(methylamino)-[l,2,4]triazolo[4,3-a]pyrazine-6-carboxylic acid M-2 (300 mg; 1.45 mmol) is dissolved in 2 ml THF and is treated with 1 M borane-THF complex (4 ml; 4.00 mmol). The reaction mixture is stirred for 16 h at 50 °C.
Afterwards the reaction mixture is cool down to 0°C and 1 N aqueous HCl is added until the pH values is less than 7.
It is diluted with DCM, the organic lays is separated and dried over MgSO4. The crude product is purified by using reversed phase chromatography (Method: prep. HPLC1). This intermediate is suspended in 20 ml Chloroform and treated with manganèse dioxide (350 mg; 4.07 mmol). The reaction mixture is stirred for 4 days at 50 °C. Afterwards the solid material is filtered oif and.the solvent is evaporated. Yield: 16 % (44 mg; 0.23 mmol)
HPLC-MS: (M+H)+ = 192; tRet = 0.52 min; method FECB5
6-(l-benzyI-5-methyI-4-pheïiyl-lH-imidazol-2-yl)-N,3-dimethyl[l,2,4]triazolo[4,3-a]pyrazin-8-amine II-l
3-Methyl-8-methylamino-[l,2,4]triazolo[4,3-a]pyrazine-6-carbaldehyde (34 mg; 0.18 mmol), benzylamine (20 μΐ; 0.18 mmol) and 1-hydroxyimino-l-phenyl propan-2-one (32 mg; 0.18 mmol) are dissolved in 0.6 ml acetic acid stirred for 2 h at 120°C. The reaction mixture is treated with water and extracted with DCM. The organic layer is dried over MgSO4 and evaporated to dryness. The crude intermediate is dissolved in 20 ml of THF and treated with Ra-Ni. The reaction mixture is stirred for 2 days at 25°C and 4 bar hydrogen atmosphère. The solid materials are filtered off and the crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Yield: 33 % (25 mg; 0.06 mmol)
HPLC-MS: (M+H)+ = 410; tRet =1.17 min; method LCMSBAS1
According to II-1 the following examples are synthesized.
# Structure M® ! HPLC-Method tRet. HPLC [min]
II-2
II-3
M+H= 348; tRet = 1.09
M+H= 333; tRet = LU
LCMSBAS1
LCMSBAS1
Préparation of intermediate Q-6
N-4-Benzyl-6-(4-methyl-piperazin-l-yl)-pyridme-3,4-diamine Q-6
2,4-Dichloro-5-nitro-pyridine (250 mg; 1.29 mmol), benzylamine (153 μΐ;
1.42 mmol) and DIPEA (314 μΐ; 1.94 mmol) are suspended in 1 ml NMP and stirred for 1 h at 25 °C. To this suspension 1-methylpiperazine (159 μΐ; 1.43 mmol) is added and the resulting mixture is stirred for 16 h at 50 °C. The crude intermediate is purified using reversed phase chromatography (prep. HPLC). This intermediate is dissolved in 30 ml THF and palladium on carbon is added. The reaction mixture is stirred for 3 h at 25 °C and 4 bar hydrogen pressure. The solid material is filtered off and the solvent is evaporated.
Yield: 48 % (184 mg; 0.62 mmol)
HPLC-MS: (M+H)+ = 298; tRet = 0.68 min; method VAB
Préparation of intermediate Q-29
6-(propan-2-yl)-4-N-(pyridin-2-yimethyl)pyridine-3,4-diamine
2,4-Dichloro-5-nitro-pyridine (500 mg; 2.46 mmol), pyridine-2-yl-methylamine (260 μΐ; 2.49 mmol) and triethylamine (400 μΐ; 2.82 mmol) are suspended in 1 ml NMP and stirred for 1 h at 25 °C. The reaction mixture is diluted with water and the precipitate is filltered off, washed with water and methanol and dried.
Yield: 87 % (566 mg; 2.14 mmol)
This intermediate (125 mg, 0.47 mmol), 2-Isopropenyl-4,4,5,5-tetramethyl[l,3,2]dioxaborolane (200 μΐ; 1.06 mmol), Cs2CO3 (300 mg; 0.90 mmol) and Pd DPPF (30 mg; 0.04 mmol) are suspended with l,2dimethoxyethane/water = 3/1 (10 ml) and flushed with argon. It is stirred at 95 °C for 1 hour. The crude reaction 5 mixture is purified by using reversed phase chromatography under basic conditions (Method: prep. HPLC1).
Yield: 43 % (55 mg; 0.20 mmol)
This intermediate (40 mg, 0.15 mmol) is dissolved in 10 ml methanol and palladium on carbon is added. The reaction mixture is stirred for 3 h at 25 °C and 4 bar hydrogen pressure. The solid material is filtered off and the solvent is evaporated.
Yield: 95 % (35 mg; 0.14 mmol)
HPLC-MS: (M+H)+ = 242; tRet = 0.68 min; method VAB
According to the procedures of Q-6 and Q-29 the intermediates Q-l - Q-39 are synthesized.
Q-i
Q-2
Q-3
MS (M+H)+; HPLCtRet, HPLC [min]_____Method commercial available
M+H=213; tRet = 1-96
M+H=213; tRet.= 1.96
FECB5
FECB5
Q-5
F
M+H=217; tRet.= 0-87 VAB
M+H=235; \7 Λ TD
tRet = 0.89 V Ad
M+H=298; tRet = 0.68 VAB
M+H=200; VAD
tRet = 0.69 V Aid
M+H=299; \7 Λ T5
tRet =0.71 V Ajd
M+H=284; tRet= 0.76 VAB
M+H=297; tRet = 1-54 FECB5
Structure
MS (M+H)+; tRet. HPLC [min]
HPLCMethod
Q-ll
Q-12
Q-13
Q-14
Q-15
Q-16
M+H=309; tRet = 1 -63
M+H=313; tRet- 0.80
M+H=299; tRet= 1-30
M+H=286;
tRet.= 0.56
M+H=285; tRet= 0.78
M+H=284; tRet.= 0.72
MS (M+H)+;
ÎRet. HPLC [min]
M+H=304;
ÎRet = θ·63
M+H=300; tRet = 0.66
M+H=300; tRet= 0-66
M+H=244; tRet= 0.59
M+H=243; tRet = 0.77
M+H=200; tRet.= 0.70
M+H=230;
tRet = 1-44
HPLCMethod
VAB
VAB
VAB
FECB5
MS (M+H)+; tRet. HPLC [min]
M+H=214; tRet.^ 0.76
M+H=215; tRet = 0.20
M+H=201; tRet = 0.52
M+H=300; tRet= 0.63
M+H=231;
tRet = 0.62
M+H=243; tRet = 0.68
M+H=3l4; tRet= 1.40
HPLCMethod
VAB
VAB
VAB
VAB
VAB
VAB
FECB5
MS (M+H)+;
tRet. HPLC [min]
M+H=257;
ÎRet = 0-72
M+H=285; tRet= 0-54
M+H=284; tRet = 0-73
M+H=298; tRet = 0-76
M+H=256; tRet = θ·89
M+H=299; tRet~ 1-26
M+H=298; tRet= 0-57
HPLCMethod
VAB
VAB
VAB
VAB
VAB
FECB5
VAB
MS (M+Hf; tRet. HPLC [min]
M+H=286; tRet = 0-54
M+H=285; tRet = 0-59
M+H=215;
ÎRet = 1 -24
M+H=299; tRet.= 0.55
HPLCMethod
VAB
VAB
General method for préparation of compounds of formula III
N-[6-(l-benzyl-lH-l,3-benzodiazol-2-yl)-3-methyl-[l,2,4]triazolo[4,3a] pyr azin-8-yl] -1 -methylpiperidin-4-amine III-1
N-[6-(l-benzyl-lH-l,3-benzodiazol-2-yl)-3-methyl-[l,2,4]triazolo[4,3a] pyrazin-8-yl] piperidin-4-amine
8-( {1 -[(tert-butoxy)carbonyl]piperidin-4-yl} amino)-3-methyl-[1,2,4]triazolo[4,3a]pyrazine-6-carboxylic acid M-l (238 mg; 0.63 mmol), Hünigbase (306 μΐ;
1.89 mmol) and HATU ( 264 mg; 0.69 mmol) are dissolved in 2 ml DMF. The reaction mixture is stirred for 10 min, then N-benzyl-l,2-diaminobenzene Q-l (138 mg; 0.69 mmol) is added and the resulting mixture is stirred for an additional
1 h at 25 °C. The reaction mixture is diluted with water and DCM. The organic layer is separated and dried over MgSO4 and the solvent is evaporated. The crude intermediate is dissolved in 4 ml acetic acid and stirred at 100 °C for 3 h.
Afterwards the reaction mixture is neutralized with aqueous NaHCO3 solution and extracted with DCM. The crude intermediate is dissolved in 10 ml DCM and 10 ml 15 TFA and stirred for 1 h at 25 °C. Afterwards the reaction mixture is neutralized with aqueous NaHCO3 solution and extracted with DCM. The organic layer is separated and dried over MgSO4 and the solvent is evaporated. The crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Yield: 33 % (93 mg; 0.21 mmol)
HPLC-MS: (M+H)+ = 439; tRet = 0.77 min; method VAB
N-[6-(l-benzyl-lH-l,3-benzodiazoI-2-yl)-3-methyl-[l,2,4]triazolo[4,3a]pyrazin-8-yl]-l-methylpiperidin-4-amine
N-[6-(l-benzyl-lH-l,3-benzodiazol-2-yl)-3-methyl-[l,2,4]triazolo[4,3-a]pyrazin-8yl]piperidin-4-amine (93 mg; 0.21 mmol) is dissolved in 300 μΐ THF, treated with
DIPEA (62 μΐ; 0.29 mmol) and formaldéhyde (62 μΐ; 0.83 mmol). To this reaction mixture ST AB (62 mg; 0.29 mmol) is added and the reaction mixture is stirred for 2 hours. The crude reaction mixture is purified by reversed phase chromatograph (Method: prep. HPLC1).
Yield: 60 % (58 mg; 0.13 mmol)
HPLC-MS: (M+H)+ = 453; tRet = 1.19 min; method LCMSBAS1
According to III-1 the following examples are synthesized.
MS (M+H)+; HPLCtRet. HPLC [min] Method
SR*
LCMSBAS1
M+H= 511; tRet = 1.23
LCMSBAS1
MS (M+H)+;
HPLCtRCt. HPLC [min] Method
M+H=511;
tRet = 1.23
M+H= 497; tRet = 1-19
M+H= 515;
tRet.= 1-2
M+H= 533; tRet .= 1-22
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
Structure
MS (Μ+Η)+; tRet. HPLC [min]
HPLCMethod
ΙΠ-7
ΠΙ-8
ΙΠ-9
ΙΠ-10
ΠΙ-11
M+H= 370;
tRet.= 1-14
M+H= 469; tRet= 1.01
LCMSBAS1
LCMSBAS1
M+H= 454; tRet.= 1-03 LCMSBAS1
M+H=371; tRet = 1.03 LCMSBAS1
M+H= 470; tRet.= 1-08 LCMSBAS1
MS (M+H)+; tRet. HPLC [min] HPLCMethod
M+H= 582; LCMSBAS1
ÎRet.= 1-1
M+H= 468; tRet.= 1-06 LCMSBAS1
M+H= 455; tRet.= 1-07 LCMSBAS1
M+H= 607; tRet.= 1.04 LCMSBAS1
M+H= 480;
tRet.= 1.01
LCMSBAS1
Structure
MS (Μ+Η)+; tRet. HPLC [min]
HPLCMethod
IH-17
ΙΠ-18
ΙΠ-19
ΗΙ-20
ΙΗ-21
M+H= 483;
tRet = 0.77
M+H= 497; tRet = 0.82
M+H= 512; tRet.= 1-23
M+H= 470; tRet = 0.84
M+H= 469; tRet.= 0-88
VAB
VAB
LCMSBASl
LCMSBASl
LCMSBASl # Structure
MS (M+H) ; HPLCtRet. HPLC [min] Method
III-22
III-23
ΙΠ-24
III-25
À
III-26
M+H=457;
ΐκΛ-0.84
M+H= 456; tRet - 0.88
M+H= 513;
ÎRet = 0.86
M+H= 455; tRet = 0.99
M+H= 484; tRet = 0.99
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
ΠΙ-27
III-28
ΠΙ-29
ΠΙ-30
ΠΙ-31
Structure
MS (Μ+Η)+; tRet. HPLC [min]
HPLCMethod
M+H= 485; tRet = 0.95
M+H= 503; tRet = 1-02
M+H= 499; tRet.” 1-01
M+H= 499; tRet - 1.01
M+H= 443; tRet= 1.02
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
Structure
MS (M+H)+; tRet. HPLC [min]
HPLCMethod
III-32
III-33
III-34
III-35
III-36
M+H= 442; tRet .= 1.10
M+H= 399; tRet = 1-06
M+H= 429; tRet = 1-06
M+H= 413; tRet.= 1.13
M+H= 414;
tRet.= 0.92
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
Structure
MS (Μ+Η)+;
HPLCÎRet. HPLC [min] Method
ΙΠ-37
ΙΠ-38
ΙΙΙ-39
ΙΠ-40
ΙΠ-41
Μ+Η= 400; tRet = 0.87
M+H= 499; tRet = 1-02
M+H= 430; tRet = 0.99
M+H= 442;
tRet.= 1.08
M+H= 513; tRet = 1-09
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
HI-42
ΠΙ-43
ΙΙΙ-44
ΗΙ-45
ΗΙ-46
Structure
MS (Μ+Η)+; HPLCtRet HPLC [min] Method
LCMSBAS1
LCMSBAS1
LCMSBAS1
M+H= 497;
ÎRet. 1-16
M+H= 455;
tRet.= 1.35
LCMSBAS1
LCMSBAS1
ΙΠ-47
ΙΠ-48
ΙΙΙ-49
ΙΙΙ-50
ΠΙ-51
Structure
MS (M+H)+; ÎRet. HPLC [min] HPLCMethod
M+H= 470; tRet .= 0.81 LCMSBAS1
Μ+Η=469;
ÎRet = 0.85
M+H- 457; tRet = 0.81
M+H-456;
ÏRet.= 0.86
M+H-513;
tRet.= 0.82
LCMSBAS1
LCMSBAS1
LCMSBAS1
LCMSBAS1
MS (M+H)+;
HPLCtRet. HPLC [min] Method
LCMSBASl
M+H= 470; tRet = 0.81
LCMSBASl
Biological Methods
BRD4-H4 tetraacetylated peptide inhibition AlphaScreen
This assay is used to détermine whether the compounds inhibit the interaction between the first (BRD4-BD1) or the second (BRD4-BD2) bromodomain of BRD4 and the tetraacetylated histone H4 peptide.
Compounds are diluted in serial dilution 1:5 in assay buffer from lOmM stock in
DMSO (100 μΜ start concentration) in white OptiPlate-384 (PerkinElmer). A mix consisting of 15nM GST-BRD4-BD1 protein (aa 44-168) or 150nM GST-BRD4BD2 (aa 333-460) and 15 nM biotinylated Acetyl-Histone H4 (Lys5, 8, 12, 16) peptide is prepared in assay buffer (50mM HEPES pH=7.4; 25mM NaCl; 0,05% Tween 20; 0.1% bovine sérum albumin (BSA); 10 mM dithiothreitol (DTT)). 6 μΐ of the mix is added to the compound dilutions. Subsequently, 6 μΐ of premixed
AlphaLISA Glutathione Acceptor Beads and AlphaScreen Streptavidin Donor Beads from PerkinElmer (in assay buffer at a concentration of 10 pg/ml each) are added and the samples are incubated for 30 min at RT in the dark (shaking
300 rpm). Afterwards, the signal is measured in a PerkinElmer Envision HTS Multilabel Reader using the AlphaScreen protocol from PerkinElmer.
Each plate contains négative Controls where biotinylated Acetyl-Histone H4 peptide and GST-BRD4-BD1 or GST-BRD4-BD2 are left out and replaced by assay buffer. Négative control values are entered as low basis value when using the software GraphPad Prism for calculations. Furthermore, a positive control (probe molécule JQ1 + with protein/ peptide mix) is pipetted. Détermination of IC50 values are carried out using GraphPad Prism 3.03 software (or updates thereof).
Table summarizing the IC50 of the compounds of the invention exemplified above
Ex# BRD4-BD1 IC50 [nM] Ex# BRD4-BD1 IC50 [nM] Ex# BRD4-BD1 IC50 [nM]
1-1 61 ΙΠ-1 7 ΙΠ-28 1
1-2 41 III-2 41 ΠΙ-29 9
1-3 41 III-3 49 III-30 9
1-4 18 III-4 8 ΠΙ-31 13
1-5 8 III-5 9 III-32 7
II-l 4 III-6 9 ΠΙ-33 20
II-2 15 III-7 22 III-34 45
II-3 31 ΙΠ-8 9 III-35 15
III-9 14 III-36 28
III-10 18 III-37 14
in-n 9 III-38 17
III-12 7 ΙΠ-39 126
III-13 9 III-40 18
m-14 10 III-41 74
III-15 3 III-42 66
III-16 5 III-43 34
ΠΙ-17 17 III-44 32
ΠΙ-18 26 ΙΠ-45 69
ΠΙ-19 - 38 ΠΙ-46 243
III-20 13 III-47 12
III-21 8 ΙΠ-48 8
III-22 3 ΙΠ-49 4
III-23 3 ΙΠ-50 5
III-24 20 ΠΙ-51 13
III-25 11 III-52 31
ΠΙ-26 5 ΠΙ-53 12
ΠΙ-27 10
On the basis of their biological properties the compounds of general formula (1) according to the invention, their tautomers, racemates, enantiomers, diastereomers, 5 mixtures thereof and the salts of ail the above-mentioned forms are suitable for treating diseases characterised by virus infection, inflammatory diseases and abnormal cell prolifération, such as cancer.
For example, the following cancers may be treated with compounds according to 10 the invention, without being restricted thereto: brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain métastasés, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour 15 and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the végétative nervous System such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffmoma) and glomus-caroticum tumour, tumours on 20 the peripheral nervous System such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon carcinoma, colorectal carcinoma, anal carcinoma, carcinoma of the large bowel, tumours of the 25 small intestine and duodénum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancréas, bladder cancer or carcinoma of the bladder; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas (NSCLC) such as plate épithélial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low-malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endométrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endométrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma (MM)), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, éosinophilie granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvénile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo-maligna and acral-lentiginous melanoma; rénal cancer such as for example kidney cell carcinoma or hypemephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer; throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma such as for example vaginal cancer or vaginal carcinoma; plate épithélial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate épithélial carcinoma of the skin; thymomas, cancer of the urethra and cancer of the vulva.
Preferred cancers, which may be treated with compounds according to the invention, are hematopoietic malignancies (including but not limited to AML, MM), as well as solid tumors including but not limited to lung, liver, colon, brain, thyroid, pancréas, breast, ovary and prostate cancer.
The new compounds may be used for the prévention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other state-of-the-art compounds, such as e.g. cytostatic or cytotoxic substances, cell prolifération inhibitors, anti-angiogenic substances, steroids or antibodies.
The compounds of general formula (I) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.
Chemotherapeutic agents which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutéthimide, cyproterone acetate, fmasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example platelet derived growth factor and hépatocyte growth factor, inhibitors are for example growth factor antibodies, growth factor receptor antibodies and tyrosine kinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum dérivatives (e.g. cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and varions chemotherapeutic agents such as amifostin, anagrelid, clodronat, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfimer.
Other possible combination partners are 2-chlorodesoxyadenosine, 2-fluorodesoxycytidine, 2-methoxyoestradiol, 2C4, 3-alethine, 131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A 105972, A 204197, aldesleukin, alitretinoin, altretamine, alvocidib, amonafide, anthrapyrazole, AG-2037, AP-5280, apaziquone, apomine, aranose, arglabin, arzoxifene, atamestane, atrasentan, auristatin PE, AVLB, AZ10992, ABX-EGF, ARRY-300, ARRY-142886/AZD-6244, ARRY-704/AZD-8330, AS-703026, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BBR-3464, BBR-3576, bevacizumab, biricodar dicitrate, BCX-1777, bleocin, BLP-25, BMS-184476, BMS-247550, BMS-188797, BMS-275291, BNP-1350, BNP-7787, BIBW 2992(afatinib), BIBF 1120 (Vargatef™), bleomycinic acid, bleomycin A, bleomycin B, bryostatin-1, bortezomib, brostallicin, busulphan, CA-4 prodrug, CA-4, CapCell, calcitriol, canertinib, canfosfamide, capecitabine, carboxyphthalatoplatin, CCI-779, CEP-701, CEP-751, CBT-1 cefixime, ceflatonin, ceftriaxone, celecoxib, celmoleukin, cemadotin, CH4987655/RO-4987655, chlorotrianisene, cilengitide, ciclosporin, CDA-II, CDC-394, CKD-602, clofarabin, colchicin, combretastatin A4, CHS-828, CLL-Thera, CMT-3 cryptophycin 52, CTP-37, CP-461, CV-247, cyanomorpholinodoxorubicin, cytarabine, D 24851, decitabine, deoxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, desoxyepothilone B, dexamethasone, dexrazoxanet, diethylstilbestrol, diflomotecan, didox, DMDC, dolastatin 10, doranidazole, E7010, E-6201, edatrexat, edotreotide, efaproxiral, eflomithine, EKB-569, EKB-509, elsamitrucin, epothilone B, epratuzumab, ER-86526, erlotinib, ET-18-OCH3, ethynylcytidine, ethynyloestradiol, exatecan, exatecan mesylate, exemestane, exisulind, fenretinide, floxuridine, folie acid, FOLFOX, FOLFIRI, formestane, galarubicin, gallium maltolate, gefinitib, gemtuzumab, gimatecan, glufosfamide, GCS-IOO, G17DT immunogen, GMK, GPX-100, GSK-5126766, GSK-1120212, GW2016, granisetron, hexamethylmelamine, histamine, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab, idatrexate, idenestrol, IDN-5109, IMC-1C11, immunol, indisulam, interferon alpha-2a, interferon alfa-2b, interleukin-2, ionafamib, iproplatin, irofiilven, isohomohalichondrin-B, isoflavone, isotretinoin, ixabepilone, JRX-2, JSF-154, J-107088, conjugated oestrogens, kahalid F, kétoconazole, KW-2170, lobaplatin, leflunomide, lenograstim, leuprolide, leuporelin, lexidronam, LGD-1550, linezolid, lutetium texaphyrin, lometrexol, losoxaritrone, LU 223651, lurtotecan, mafosfamide, marimastat, mechloroethamine, methyltestosteron, méthylprednisolone, MEN-10755, MDX-H210, MDX-447, MGV, midostaurin, minodronic acid, mitomycin, mivobulin, MK-2206, MLN518, motexafin gadolinium, MS-209, MS-275, MX6, neridronate, neovastat, nimesulide, nitroglycerin, nolatrexed, norelin, N-acetylcysteine, 06-benzylguanine, omeprazole, oncophage, ormiplatin, ortataxel, oxantrazole, oestrogen, patupilone, pegfilgrastim, PCK-3145, pegfilgrastim, PBI-1402, PEG-paclitaxel, PEP-005, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed, pentrix, perifosine, perillylalcohol, PG-TXL, PG2, PLX-4032/RO-5185426, PT-100, picoplatin, pivaloyloxymethylbutyrate, pixantrone, phenoxodiol O, PKI 166, plevitrexed, plicamycin, polyprenic acid, porfïromycin, prednisone, prednisolone, quinamed, quinupristin, RAF-265, ramosetron, ranpimase, RDEA-119/BAY 869766, rebeccamycin analogues, revimid, RG-7167, rhizoxin, rhu-MAb, risedronate, rituximab, rofecoxib, Ro-317453, RO-5126766, RPR 109881A, rubidazon, rubitecan, R-flurbiprofen, S-9788, sabarubicin, SAHA, sargramostim, satraplatin, SB 408075, SU5416, SU6668, SDX-101, semustin, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SRL-172, sorafenib, spiroplatin, squalamine, suberanilohydroxamic acid, sutent, T 900607, T 138067, TAS-103, tacedinaline, talaporfin, tariquitar, taxotere, taxoprexin, tazarotene, tegafur, temozolamide, tesmilifene, testosterone, testosterone propionate, tesmilifene, tetraplatin, tetrodotoxin, tezacitabine, thalidomide, theralux, therarubicin, thymectacin, tiazofurin, tipifarnib, tirapazamine, tocladesine, tomudex, toremofin, trabectedin, TransMID-107, transretinic acid, traszutumab, tretinoin, triacetyluridine, triapine, trimetrexate, TLK-286TXD 258, urocidin, valrubicin, vatalanib, vincristine, vinflunine, virolizin, WX-UK1, vectibix, Volasertib (or other polo-like kinae inhibitors), xeloda, XELOX, XL-281, XL-518/R-7420, YM-511, YM-598, ZD-4190, ZD-6474, ZD-4054, ZD-0473, ZD-6126, ZD-9331, ZDI839, zoledronat and zosuquidar.
Suitable préparations include for example tablets, capsules, suppositories, solutions - particularly solutions for injection (s.c., i.v., i.m.) and infusion - élixirs, émulsions or dispcrsible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.
Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as com starch or alginic acid, binders such as starch or gélatine, lubricants such as magnésium stéarate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups or élixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonie agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali métal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gélatine capsules.
Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the dérivatives thereof.
Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffine (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. éthanol or glycerol), carriers such as e.g. natural minerai powders (e.g. kaolins, clays, talc, chalk), synthetic minerai powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnésium stéarate, talc, stearic acid and sodium lauryl sulphate).
The préparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gélatine and the like. Moreover, lubricants such as magnésium stéarate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
For parentéral use, solutions of the active substances with suitable liquid carriers may be used.
However, it may sometimes be necessary to départ from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered. Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may hâve to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.
The formulation examples which follow illustrate the présent invention without restricting its scope:
Examples of pharmaceutical formulations
A) Tablets___ _______per tablet
active substance according to formula (I) lactose 100 mg 140 mg
corn starch polyvinylpyrrolidone magnésium stéarate 240 mg 15 mg 5 mg 500 mg
The fmely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnésium stéarate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.
B) Tablets_________________________________________ _______per tablet
active substance according to formula (I) lactose 80 mg 55 mg
corn starch microcrystalline cellulose polyvinylpyrrolidone sodium-carboxymethyl starch magnésium stéarate 190 mg 35 mg 15 mg 23 mg 2mg
400 mg
The fïnely ground active substance, some of the com starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining com starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnésium stéarate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
C) Ampoule solution active substance according to formula (I) sodium chloride water for inj.
mg mg mL
The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonie. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptie conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims (22)

1. A compound of formula (I)
(I) wherein,
R1 is -Ci.3alkyl or -Ci.3haloalkyl;
R2 is selected from -NHR4, -Ci-salkyl, -Ci.5haloalkyl, halogen and -S-Ci.3alkyl;
R is a 5-12 membered heteroaryl, which group is substituted with -X-R and optionally further substituted with one or more groups independently selected from R9;
R4 is selected from -Ci-salkyl and 5-12 memebered heterocycloalkyl, which heterocycloalkyl can be optionally substituted with one or more groups independently selected from R5;
R5 is selected from -Cj.5alkyl, -Ci.5haloalkyl and -Ci.3alkylene-O-Ci.3alkyl;
R9is selected from -Ci.5alkyl, -O-Ci.5alkyl, -N(Ci.5alkyl)2, halogen, -Ci.3alkylene-O-Ci.3alkyl, -Ci.5alkylene-N(-Ci-5alkyl, -Ci.5alkyl), 5-12 memebered heterocycloalkyl,wherein the heterocycloalkyl group can be optionally substituted with one or more groups independently selected from =O, -Ci.3alkyl, or
R9 is selected from -Cô-ioaryl and 5-12 memebered heteroaryl, wherein the aryl and heteroaryl groups can be optionally and independently substituted with one ore more groups selected from halogen, -Ci.3alkyl, -O-Cisalkyl, -C].3haloalkyl, -O-Ci.3haloalkyl, -N(Ci-5alkyl, Ci-salkyl) and -NH-C^alkyl;
X is -Ci-3alkylene- or -O-;
R10 is-Cô-ioaryl or 5-12 membered heteroaryl, each of which groups can be optionally substituted with one or more groups selected from halogen, -Ci^alkyl, -O-Ci-3alkyl, -Ci^haloalkyl, -O-Ci.3haloalkyl;
wherein the compounds of formula (I) may be optionally be présent in the form of salts.
2. A compound according to claim 1, wherein R1 is -CH3.
3. A compound according to claim 1 or 2, wherein R2 is -NHR4 5 6 7 8 * and R4 is a 5-6 membered heterocycloalkyl, optionally substituted as defined in claim 1.
4. A compound according to claim 3, wherein R4 is tetrahydrofuran or piperidine, wherein the piperidine is substituted with one group selected from -CH3, -CH2CH3,-CH2CH2CH3 and -(CH2)2-O-CH3.
5. A compound according to anyone of claims 1 or 2, wherein R2 is -NHR4 and R4 is -Ci-3alkyl.
6. A compound according to claim 5, wherein R2 is -NHR4 and R4 is -CH3 or -CH(CH3)2.
7. A compound according to anyone of claims 1 or 2, wherein R2 is -Ci-3alkyl.
8. A compound according to anyone of claims 1 to 7, wherein R is a 5-9 membered heteroaryl substituted with -X-R10 and optionally further substituted with one or more groups independently selected from R9, wherein R9, X and R10 are defined as in claim 1.
9. A compound according to anyone of daims 1 to 8, wherein -X-R10 is selected from -CH2-phenyl, -CH(CH3)-phenyl, -CH2-pyridyl, -CH(CH3)-pyridyl, -O-phenyl, each of which phenyl or pyridyl groups is optionally substituted with -F or -CH3.
10. A compound according to claim 9, wherein -X-R10 is selected from -CH2phenyl, -CH2-pyridyl, -CH(CH3)-phenyl, -CH(CH3)-pyridyl, each of which pyridyl or phenyl group is optionally substituted with —F or —CH3.
11. A compound according to claim 8, wherein R3 is selected from pyrazolyl, imidazol, benzimidazolyl, imidazopyridine and imidazopyrimidine and R is substituted with -X-R10 and R3 is optionally further substituted with one or more groups independently selected from R9 wherein R9, X and R10 are defined as in claim 1.
12. A compound according to anyone of claims 1 to 11, wherein R9 is independently selected from -Ci.3alkyl, -O-Ci_3alkyl, -N(Ci-3alkyl)2, phenyl and 6 membered heterocycloalkyl, which heterocycloalklyl can be optionally substituted with one or more groups independently selected =O and -Ci^alkyl.
13. A compound according to claim 11, wherein R3 is imidazopyridine or benzimidazol substituted with -CH2-phenyl or -CH2-pyridyl, -CH(CH3)pyridyl and optionally further substituted with -C|.3alkyl or 5-12 memebered heterocycloalkyl wherein the heterocycloalkyl group can be optionally substituted with one or more groups independently selected from -Ci-3alkyl.
14. A compound according to claim 13, wherein R3 is imidazopyridine or benzimidazol substituted with -CH2-phenyl, -CH(CH3)-pyridyl or -CH2pyridyl and with -CH(CH3 )2 or morpholinyl or piperazinyl, wherein the morpholinyl or piperazinyl groups is optionally substituted with one or more groups selected from -Ci-3alkyl.
15. A compound according to claim 1 selected from
EX# Structure Ex # Structure
EX# Structure III-ll \=N An vd / III-13 \=N ΓγΝ ^/N;y^rr''NH / \—-N । / ΙΠ-15 \=N An H-n A ΠΙ-17 \=N n?n ΝγΑΑΗ y}y O O / III-19 Z Ex# Structure III-12 \:=N zNY^N^NH °\ ΠΙ-14 \=N nAn /nY^n^nh À ΠΙ-16 \=N N^'N N-N DV^AnH 0 AyA III-18 \=N\ nAN ^/N;Y^n^nh y# N\ OO / III-20 EX# Structure ΙΠ-31 : 1 ΙΠ-33 'y=N , *ΧΧ φ - ΠΙ-35 \=Ν ν^ν φ A ΙΠ-37 \=Ν Μ >>Ν ^/Ν^γ^Ν^ΝΗ dA A w ΠΙ-39 À vW Ex# Structure ΠΙ-32 \=N it Λ W ΠΙ-34 uX. -φ A w III-36 \=N N-^N /N<Af n^nh Φ A w III-38 \=N it _/^γ^Ν^ΝΗ y>X a< OQ ΙΠ-40 \=N it i'i o
wherein the compound may be optionally be présent in the form of salts.
16. A compound of general formula (I) according to anyone of daims 1 to 15 - or the pharmaceutically acceptable salts thereof - for use in the treatment and/or 5 prévention of cancer.
17. Pharmaceutical préparation comprising as active substance one or more compounds of general formula (I) according to anyone of daims 1 to 15 optionally in combination with conventional excipients and/or carriers.
18. Pharmaceutical préparation comprising a compound of general formula (I) 10 according to anyone of daims 1 to 15 - or one of the pharmaceutically acceptable salts thereof - and at least one other cytostatic or cytotoxic active substance, different from formula (I).
19. A compound of general formula (I) according to anyone of daims 1 to 15 or the pharmaceutically acceptable salts thereof - for use as médicaments.
20. A compound of general formula (I) according to anyone of claims 1 to 15 - or the pharmaceutically acceptable salts thereof - for use in the treatment of hematopoietic malignancies.
21. A compound of general formula (I) according to anyone of claims 1 to 15
5 - or the pharmaceutically acceptable salts thereof - for use in the treatment of
AML or MM.
22. A compound of general formula (I) according to anyone of claims 1 to 15 - or the pharmaceutically acceptable salts thereof - for use in the treatment of lung, liver, colon, brain, thyroid, pancréas, breast, ovary and prostate cancer.
OA1201500152 2012-11-16 2013-11-15 Triazolopyrazine OA19258A (en)

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Application Number Priority Date Filing Date Title
EP12192987.1 2012-11-16

Publications (1)

Publication Number Publication Date
OA19258A true OA19258A (en) 2020-06-05

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