HK1159087A

HK1159087A - Antiproliferative compounds

Info

Publication number: HK1159087A
Application number: HK11113361.1A
Authority: HK
Inventors: Steffen Steurer; Peter Ettmayer; Andreas Mantoulidis
Original assignee: 贝林格尔‧英格海姆国际有限公司
Priority date: 2008-09-29
Filing date: 2009-09-28
Publication date: 2012-07-27

Description

Antiproliferative compounds

The invention relates to novel compounds of general formula (1)

Wherein the radical R¹To R³、X¹、X²、X³Q and L¹Having the definitions given in the claims and the description, as well as tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and salts of all these forms, and their use as medicaments.

Background

WO 2005/090333 and US 2006/0100204 disclose phenyl-substituted nitrogen-containing five-membered ring heteroaromatic compounds which are useful for inhibiting cytokine production and thus for treating inflammatory diseases, and WO 2008/003770 discloses that they are capable of inhibiting signal enzymes (signal enzymes) and thus for treating diseases characterized by excessive or abnormal cell proliferation. Other phenyl-and pyridyl-substituted five-membered ring heteroaromatic compounds that inhibit cytokines are disclosed in WO 2007/075896, and pyridyl-substituted triazole compounds having the same activity are disclosed in WO 2008/021388.

The aim of the present invention is to find novel active substances which can be used for the prophylaxis and/or treatment of diseases which are characterized by excessive or abnormal cell proliferation.

Detailed Description

It has now been found, surprisingly, that compounds of the general formula (1) in which the radical R is¹To R³、X¹、X²、X³Q and L¹With the definitions given below) may act as inhibitors of specific signaling enzymes involved in controlling cell proliferation. Thus, the compounds of the invention are useful, for example, in the treatment of diseases associated with the activity of these signaling enzymes and characterized by excessive or abnormal cell proliferation.

The invention therefore relates to compounds of the general formula (1)

Wherein

R¹Represents optionally substituted by one or more identical or different R^bAnd/or R^cA substituted 5-or 6-membered monocyclic or 9-or 10-membered bicyclic heteroaryl having the alkyl moiety structure (i)

Wherein the ring directly bonded to Q is a heteroaromatic ring;

R²is a taskSelected from one or more of the same or different R^bAnd/or R^cSubstituted of the following groups: c_6-10Aryl and 5-12 membered heteroaryl;

R³selected from hydrogen, -CN, -NO₂、-NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_3-5Cycloalkyl and halogen;

X¹、X²and X³Each independently of the other being selected from nitrogen and CR⁴，

Wherein the atom X on ring A¹、X²And X³At least one and not more than two of which are nitrogen atoms, and each R⁴Independently of one another, from hydrogen, -CN, -NO₂、-NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_3-5Cycloalkyl and halogen;

q is selected from

Wherein in the above five-membered ring heteroaryl, one to three ring hydrogen atoms may be independently substituted by C_1-6Alkyl substitution;

L¹is selected from (R)²) -C (O) NH-and (R)²)-NHC(O)-；

Each R^bAre suitable substituents and are selected, independently of one another, from-OR^c、-SR^c、-NR^cR^c、-ONR^cR^c、-N(OR^c)R^c、-NR^gNR^cR^cHalogen, -CN, -NO₂、-N₃、-C(O)R^c、-C(O)OR^c、-C(O)NR^cR^c、-C(O)NR^gNR^cR^c、-C(O)NR^gOR^c、-C(NR^g)R^c、-N＝CR^cR^c、-C(NR^g)OR^c、-C(NR^g)NR^cR^c、-C(NR^g)NR^gNR^cR^c、-C(NOR^g)R^c、-C(NOR^g)NR^cR^c、-C(NNR^gR^g)R^c、-OS(O)R^c、-OS(O)OR^c、-OS(O)NR^cR^c、-OS(O)₂R^c、-OS(O)₂OR^c、-OS(O)₂NR^cR^c、-OC(O)R^c、-OC(O)OR^c、-OC(O)NR^cR^c、-OC(NR^g)R^c、-OC(NR^g)NR^cR^c、-ONR^gC(O)R^c、-S(O)R^c、-S(O)OR^c、-S(O)NR^cR^c、-S(O)₂R^c、-S(O)₂OR^c、-S(O)₂NR^cR^c、-NR^gC(O)R^c、-NR^gC(O)OR^c、-NR^gC(O)NR^cR^c、-NR^gC(O)NR^gNR^cR^c、-NR^gC(NR^g)R^c、-N＝CR^cNR^cR^c、-NR^gC(NR^g)OR^c、-NR^gC(NR^g)NR^cR^c、-NR^gC(NOR^g)R^c、-NR^gS(O)R^c、-NR^gS(O)OR^c、-NR^gS(O)₂R^c、-NR^gS(O)₂OR^c、-NR^gS(O)₂NR^cR^c、-NR^gNR^gC(O)R^c、-NR^gNR^gC(O)NR^cR^c、-NR^gNR^gC(NR^g)R^cand-N (OR)^g)C(O)R^cAnd divalent substituents ═ O, ═ S, ═ NR^g、＝NOR^g、＝NNR^gR^gAnd NNR^gC(O)NR^gR^gWherein these divalent substituents may only be substituents in non-aromatic ring systems;

each R^cIndependently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^dAnd/or R^eSubstituted of the following groups: c_1-6Alkyl, 2-6 membered heteroalkyl, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl;

each R^dAre suitable substituents and are selected, independently of one another, from-OR^e、-SR^e、-NR^eR^e、-ONR^eR^e、-N(OR^e)R^e、-N(R^g)NR^eR^eHalogen, -CN, -NO₂、-N₃、-C(O)R^e、-C(O)OR^e、-C(O)NR^eR^e、-C(O)NR^gNR^eR^e、-C(O)NR^gOR^e、-C(NR^g)R^e、-N＝CR^eR^e、-C(NR^g)OR^e、-C(NR^g)NR^eR^e、-C(NR^g)NR^gNR^eR^e、-C(NOR^g)R^e、-C(NOR^g)NR^eR^e、-C(NNR^gR^g)R^e、-OS(O)R^e、-OS(O)OR^e、-OS(O)NR^eR^e、-OS(O)₂R^e、-OS(O)₂OR^e、-OS(O)₂NR^eR^e、-OC(O)R^e、-OC(O)OR^e、-OC(O)NR^eR^e、-OC(NR^g)R^e、-OC(NR^g)NR^eR^e、-ONR^gC(O)R^e、-S(O)R^e、-S(O)OR^e、-S(O)NR^eR^e、-S(O)₂R^e、-S(O)₂OR^e、-S(O)₂NR^eR^e、-NR^gC(O)R^e、-NR^gC(O)OR^e、-NR^gC(O)NR^eR^e、-NR^gC(O)NR^gNR^eR^e、-NR^gC(NR^g)R^e、-N＝CR^eNR^eR^e、-NR^gC(NR^g)OR^e、-NR^gC(NR^g)NR^eR^e、-NR^gC(NR^g)SR^e、-NR^gC(NOR^g)R^e、-NR^gS(O)R^e、-NR^gS(O)OR^e、-NR^gS(O)₂R^e、-NR^gS(O)₂OR^e、-NR^gS(O)₂NR^eR^e、-NR^gNR^gC(O)R^e、-NR^gNR^gC(O)NR^eR^e、-NR^gNR^gC(NR^g)R^eand-N (OR)^g)C(O)R^eAnd divalent substituents ═ O, ═ S, ═ NR^g、＝NOR^g、＝NNR^gR^gAnd NNR^gC(O)NR^gR^gWherein these divalent substituents may only be substituents in non-aromatic ring systems;

each R^eIndependently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^fAnd/or R^gSubstituted of the following groups: c_1-6Alkyl, 2-6 membered heteroalkyl, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl;

each R^fAre suitable substituents and are selected, independently of one another, from: OR (OR)^g、-SR^g、-NR^gR^g、-ONR^gR^g、-N(OR^g)R^g、-N(R^h)NR^gR^gHalogen, -CN, -NO₂、-N₃、-C(O)R^g、-C(O)OR^g、-C(O)NR^gR^g、-C(O)NR^hNR^gR^g、-C(O)NR^hOR^g、-C(NR^h)R^g、-N＝CR^gR^g、-C(NR^h)OR^g 、-C(NR^h)NR^gR^g 、-C(NR^h)NR^hNR^gR^g 、-C(NOR^h)R^g、-C(NOR^h)NR^gR^g、-C(NNR^hR^h)R^g、-OS(O)R^g、-OS(O)OR^g、-OS(O)NR^gR^g、-OS(O)₂R^g、-OS(O)₂OR^g、-OS(O)₂NR^gR^g、-OC(O)R^g、-OC(O)OR^g、-OC(O)NR^gR^g、-OC(NR^h)R^g、-OC(NR^h)NR^gR^g、-ONR^hC(O)R^g、-S(O)R^g、-S(O)OR^g、-S(O)NR^gR^g、-S(O)₂R^g、-S(O)₂OR^g、-S(O)₂NR^gR^g、-NR^hC(O)R^g、-NR^hC(O)OR^g、-NR^hC(O)NR^gR^g、-NR^hC(O)NR^hNR^gR^g、-NR^hC(NR^h)R^g、-N＝CR^gNR^gR^g、-NR^hC(NR^h)OR^g、-NR^hC(NR^h)NR^gR^g、-NR^hC(NOR^h)R^g、-NR^hS(O)R^g、-NR^hS(O)OR^g、-NR^hS(O)₂R^g、-NR^hS(O)₂OR^g、-NR^hS(O)₂NR^gR^g、-NR^hNR^hC(O)R^g、-NR^hNR^hC(O)NR^gR^g、-NR^hNR^hC(NR^h)R^gand-N (OR)^h)C(O)R^gAnd divalent substituents ═ O, ═ S, ═ NR^h、＝NOR^h、＝NNR^hR^hAnd NNR^hC(O)NR^hR^hWherein these divalent substituents may only be substituents in non-aromatic ring systems;

each R^gIndependently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^hSubstituted of the following groups: c_1-6Alkyl, 2-6 membered heteroalkyl, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl;

each R^hIndependently of one another, from hydrogen, C_1-6Alkyl, 2-6 membered heteroalkyl, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl;

while the compound (1) may optionally exist in the form of tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or in the form of pharmacologically acceptable salts of all of the above forms.

In one aspect (A1), the invention relates to compound (1), wherein

Q is selected from

In another aspect (A2), the invention relates to compound (1), wherein

Q represents

The invention also relates to compounds of the general formula (1),

wherein

R¹Is optionally covered byOne or more same or different R^bAnd/or R^cSubstituted 5-10 membered heteroaryl;

R²is optionally substituted by one or more identical or different R^bAnd/or R^cSubstituted of the following groups: c_6-10Aryl and 5-12 membered heteroaryl;

Wherein the atom X¹、X²And X³At least one and not more than two of which are nitrogen atoms, and each R⁴Independently of one another, from hydrogen, -CN, -NO₂、-NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_3-5Cycloalkyl and halogen;

q is optionally substituted C_1-6An alkyl-substituted five-membered heteroaromatic radical having one to three heteroatoms selected independently of one another from the group consisting of nitrogen, oxygen and sulfur,

wherein rings A and R¹Are in a1, 3 position arrangement with each other when linked to Q, and ring A and Q are connected by a carbon-carbon bond;

L¹is selected from (R)²) -C (O) NH-and (R)²)-NHC(O)-；

Each R^bAre suitable substituents and are selected, independently of one another, from-OR^c、-SR^c、-NR^cR^c、-ONR^cR^c、-N(OR^c)R^c、-NR^gNR^cR^cHalogen, -CN, -NO₂、-N₃、-C(O)R^c、-C(O)OR^c、-C(O)NR^cR^c、-C(O)NR^gNR^cR^c、-C(O)NR^gOR^c、-C(NR^g)R^c、-N＝CR^cR^c、-C(NR^g)OR^c、-C(NR^g)NR^cR^c、-C(NR^g)NR^gNR^cR^c、-C(NOR^g)R^c、-C(NOR^g)NR^cR^c、-C(NNR^gR^g)R^c、-OS(O)R^c、-OS(O)OR^c、-OS(O)NR^cR^c、-OS(O)₂R^c、-OS(O)₂OR^c、-OS(O)₂NR^cR^c、-OC(O)R^c、-OC(O)OR^c、-OC(O)NR^cR^c、-OC(NR^g)R^c、-OC(NR^g)NR^cR^c、-ONR^gC(O)R^c、-S(O)R^c、-S(O)OR^c、-S(O)NR^cR^c、-S(O)₂R^c、-S(O)₂OR^c、-S(O)₂NR^cR^c、-NR^gC(O)R^c、-NR^gC(O)OR^c、-NR^gC(O)NR^cR^c、-NR^gC(O)NR^gNR^cR^c、-NR^gC(NR^g)R^c、-N＝CR^cNR^cR^c、-NR^gC(NR^g)OR^c、-NR^gC(NR^g)NR^cR^c、-NR^gC(NOR^g)R^c、-NR^gS(O)R^c、-NR^gS(O)OR^c、-NR^gS(O)₂R^c、-NR^gS(O)₂OR^c、-NR^gS(O)₂NR^cR^c、-NR^gNR^gC(O)R^c、-NR^gNR^gC(O)NR^cR^c、-NR^gNR^gC(NR^g)R^cand-N (OR)^g)C(O)R^cAnddivalent substituent group ═ O, ═ S, ═ NR^g、＝NOR^g、＝NNR^gR^gAnd (NNR)^gC(O)NR^gR^gWherein these divalent substituents may only be substituents in non-aromatic ring systems;

each R^dAre suitable substituents and are selected, independently of one another, from-OR^e、-SR^e、-NR^eR^e、-ONR^eR^e、-N(OR^e)R^e、-N(R^g)NR^eR^eHalogen, -CN, -NO₂、-N₃、-C(O)R^e、-C(O)OR^e、-C(O)NR^eR^e、-C(O)NR^gNR^eR^e、-C(O)NR^gOR^e、-C(NR^g)R^e、-N＝CR^eR^e、-C(NR^g)OR^e、-C(NR^g)NR^eR^e、-C(NR^g)NR^gNR^eR^e、-C(NOR^g)R^e、-C(NOR^g)NR^eR^e、-C(NNR^gR^g)R^e、-OS(O)R^e、-OS(O)OR^e、-OS(O)NR^eR^e、-OS(O)₂R^e，-OS(O)₂OR^e、-OS(O)₂NR^eR^e、-OC(O)R^e、-OC(O)OR^e、-OC(O)NR^eR^e、-OC(NR^g)R^e、-OC(NR^g)NR^eR^e、-ONR^gC(O)R^e、-S(O)R^e、-S(O)OR^e、-S(O)NR^eR^e、-S(O)₂R^e、-S(O)₂OR^e、-S(O)₂NR^eR^e、-NR^gC(O)R^e、-NR^gC(O)OR^e、-NR^gC(O)NR^eR^e、-NR^gC(O)NR^gNR^eR^e、-NR^gC(NR^g)R^e、-N＝CR^eNR^eR^e、-NR^gC(NR^g)OR^e、-NR^gC(NR^g)NR^eR^e、-NR^gC(NR^g)SR^e、-NR^gC(NOR^g)R^e、-NR^gS(O)R^e、-NR^gS(O)OR^e、-NR^gS(O)₂R^e、-NR^gS(O)₂OR^e、-NR^gS(O)₂NR^eR^e、-NR^gNR^gC(O)R^e、-NR^gNR^gC(O)NR^eR^e、-NR^gNR^gC(NR^g)R^eand-N (OR)^g)C(O)R^eAnd divalent substituents ═ O, ═ S, ═ NR^g、＝NOR^g、＝NNR^gR^gAnd NNR^gC(O)NR^gR^gWherein these divalent substituents may only be substituents in non-aromatic ring systems;

each R^fAre suitable substituents and are selected, independently of one another, from-OR^g、-SR^g、-NR^gR^g、-ONR^gR^g、-N(OR^g)R^g、-N(R^h)NR^gR^gHalogen, -CN, -NO₂、-N₃、-C(O)R^g、-C(O)OR^g、-C(O)NR^gR^g、-C(O)NR^hNR^gR^g、-C(O)NR^hOR^g、-C(NR^h)R^g、-N＝CR^gR^g、-C(NR^h)OR^g、-C(NR^h)NR^gR^g、-C(NR^h)NR^hNR^gR^g、-C(NOR^h)R^g、-C(NOR^h)NR^gR^g、-C(NNR^hR^h)R^g、-OS(O)R^g、-OS(O)OR^g、-OS(O)NR^gR^g、-OS(O)₂R^g、-OS(O)₂OR^g、-OS(O)₂NR^gR^g、-OC(O)R^g、-OC(O)OR^g、-OC(O)NR^gR^g、-OC(NR^h)R^g、-OC(NR^h)NR^gR^g、-ONR^hC(O)R^g、-S(O)R^g、-S(O)OR^g、-S(O)NR^gR^g、-S(O)₂R^g、-S(O)₂OR^g、-S(O)₂NR^gR^g、-NR^hC(O)R^g、-NR^hC(O)OR^g、-NR^hC(O)NR^gR^g、-NR^hC(O)NR^hNR^gR^g、-NR^hC(NR^h)R^g、-N＝CR^gNR^gR^g、-NR^hC(NR^h)OR^g、-NR^hC(NR^h)NR^gR^g、-NR^hC(NOR^h)R^g、-NR^hS(O)R^g、-NR^hS(O)OR^g、-NR^hS(O)₂R^g、-NR^hS(O)₂OR^g、-NR^hS(O)₂NR^gR^g、-NR^hNR^hC(O)R^g、-NR^hNR^hC(O)NR^gR^g、-NR^hNR^hC(NR^h)R^gand-N (OR)^h)C(O)R^gAnd divalent substituents ═ O, ═ S, ═ NR^h、＝NOR^h、＝NNR^hR^hAnd NNR^hC(O)NR^hR^hWherein these divalent substituents may only be substituted in non-aromatic ring systemsBase:

wherein the compound (1) may also optionally exist in the form of tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or in the form of pharmacologically acceptable salts of all of the above forms.

In another aspect (A3), the invention relates to compound (1) wherein Q is optionally substituted by C_1-6An alkyl-substituted nitrogen-containing heteroaromatic group.

In another aspect (A4), the invention relates to compound (1) wherein Q is optionally substituted by C_1-6Alkyl-substituted triazoles, pyrroles, pyrazoles, imidazoles, thiazoles,Oxazole, isoAzole orDiazole.

In another aspect (A5), the invention relates to compound (1), wherein

Q is selected from

In another aspect (A6), the invention relates to compound (1), wherein

Q represents

In another aspect (B1), the invention relates to compound (1), wherein

R¹Is optionally substituted by one or more identical or different R^bAnd/or R^cA substituted 5-or 6-membered monocyclic or 9-or 10-membered bicyclic heteroaryl group, and

R^band R^cAre as defined above.

In another aspect (B2), the invention relates to compound (1), wherein

R¹Is heteroaryl selected from the group consisting of pyridyl, pyrazolyl, thiazolyl, pyrimidinyl and imidazolyl, optionally substituted with one or more R which may be the same or different^bAnd/or R^cIs substituted, and

R^band R^cAre as defined above.

In another aspect (B3), the invention relates to compound (1), wherein

R¹Is optionally substituted by one or more identical or different R^bAnd/or R^cSubstituted heteroaryl having the alkyl moiety structure (i)

Wherein the ring directly bonded to Q is a heteroaromatic ring, an

R^bAnd R^cAre as defined above.

In another aspect (B4), the invention relates to compound (1), wherein

R¹Is represented by one or more identical or different R^b2And/or R^c2Substituted heteroaryl;

each R^b2Are suitable substituents and are selected, independently of one another, from halogen, -OR^c2、-NR^c2R^c2、-SR^c2、-C(O)R^c2、-S(O)₂R^c2、-S(O)R^c2、-C(O)OR^c2、-NHC(O)R^c2、-C(O)NR^c2R^c2、-NHC(O)OR^c2、-CN、-NO₂And halogen and a divalent substituent ═ O, where the divalent substituent can only be a substituent in a non-aromatic ring system;

each R^c2Independently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^d2And/or R^e2Substituted of the following groups: c_1-6Alkyl radical, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl:

each R^d2Are suitable substituents and are selected, independently of one another, from-OR^e2、-NR^e2R^e2Halogen and-C (O) OR^e2；

Each R^e2Independently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^f2And/or R^g2Substituted of the following groups: c_1-6Alkyl radical, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl and 3-14 membered heterocycloalkyl;

each R^f2Are suitable substituents and are selected, independently of one another, from-OR^g2、-CN、-C(O)NR^g2R^g2And halogen;

each R^g2Independently of one another, from hydrogen, C_1-6Alkyl radical, C_3-10Cycloalkyl and C_6-10Aryl radicals。

In another aspect (B5), the invention relates to compound (1), wherein

R¹Is heteroaryl containing at least one substituent other than hydrogen.

In another aspect (B6), the invention relates to compound (1), wherein

R¹Is a heteroaryl group containing at least one nitrogen-containing substituent.

In another aspect (B7), the invention relates to compound (1), wherein

R¹Is composed of

Optionally substituted by one or more identical or different R^bAnd/or R^cIs substituted in which R^bAnd R^cAre as defined above.

In another aspect (B8), the invention relates to compound (1), wherein

R¹Is composed of

By one R in position 5^bOr R^cIs substituted in which R^bAnd R^cAre as defined above.

In another aspect (B9), the invention relates to compound (1), wherein

R¹To represent

R¹⁰Selected from hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl and C_3-6A cycloalkyl group,

wherein the above groups may optionally be substituted, wherever possible, by one or more of the following substituents which may be the same or different: -OH, -OC_1-6Alkyl, -C_1-6Haloalkyl, -OC_3-6Cycloalkyl radical, C_3-6Cycloalkyl, -CN, -C (O) NH₂、-C(O)NH(C_1-6Alkyl) and-C (O) N (C)_1-6Alkyl radical)₂。

In another aspect (B10), the invention relates to compound (1), wherein

R¹To represent

R¹⁰Selected from hydrogen, C_1-6Alkyl radical, C_1-6Haloalkyl, 3-6-membered heterocycloalkyl, -NH₂、-NH(C_1-6Alkyl), -N (C)_1-6Alkyl radical)₂And C_3-6A cycloalkyl group,

In another aspect (B11), the invention relates to compound (1), wherein

R¹To represent

In another aspect (B12), the invention relates to compound (1), wherein

R¹To represent

In another aspect (B13), the invention relates to compound (1), wherein

R¹To represent

In another aspect (B14), the invention relates to compound (1), wherein

R¹To represent

In another aspect (B15), the invention relates to compound (1), wherein

R¹Is selected from

In another aspect (C1), the invention relates to compound (1), wherein

R³Represents fluorine, chlorine, bromine or methyl.

In another aspect (D1), the invention relates to compound (1), wherein

X¹Denotes nitrogen, X²Represents CR^4-1And X³Represents CR^4-2And R is^4-1And R^4-2Independently of one another, from hydrogen, fluorine, chlorine and methyl, and the radicals R^4-1And R^4-2At least one of (a) and (b) represents hydrogen.

In another aspect (D2), the invention relates to compound (1), wherein

X¹Denotes nitrogen, X²Represents CH, and X³Represents CH.

In another aspect (E1), the invention relates to compound (1), wherein

R²Is optionally substituted by one or more identical or different R^bAnd/or R^cSubstituted phenyl or 5-6 membered heteroaryl,

and R is^bAnd R^cAre as defined above.

In another aspect (E2), the invention relates to compound (1), wherein

R²Is optionally substituted by one or more identical or different R^bAnd/or R^cA substituted 5-6 membered heteroaryl group,

and R is^bAnd R^cAre as defined above.

In another aspect (E3), the invention relates to compound (1), wherein

R²Is optionally substituted by one or more identical or different R^bAnd/or R^cSubstituted heteroThe group of azolyl groups,

and R is^bAnd R^cAre as defined above.

In another aspect (E4), the invention relates to compound (1), wherein

R²Is optionally substituted by one or more identical or different R^bAnd/or R^cA substituted pyridyl group,

and R is^bAnd R^cAre as defined above.

In another aspect (E5), the invention relates to compound (1), wherein

R²Is composed of

Optionally substituted by one or more identical or different R^bAnd/or R^cThe substitution is carried out by the following steps,

and R is^bAnd R^cAre as defined above.

In another aspect (E6), the invention relates to compound (1), wherein

R²Is composed of

and R is^bAnd R^cAre as defined above.

In another aspect (E7), the invention relates to compound (1), wherein

R²Is composed of

In another aspect (E8), the invention relates to compound (1), wherein

R²Is composed of

In another aspect (E9), the invention relates to compound (1), wherein

R²Is a heteroaryl selected from the group consisting of: furyl, furyl,Thienyl, pyrrolyl,Azolyl, thiazolyl, triazolyl, isoylAzolyl, isothiazolyl, pyrazolyl, imidazolyl,Oxadiazolyl, thiadiazolyl, pyridinyl and pyrimidinyl, and which are optionally substituted by one or two substituents independently selected from C_3-7Cycloalkyl, phenyl, 4-to 7-membered heterocycloalkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 1-ethylpropyl, isopentyl, neopentyl, trifluoromethyl, difluoromethyl, fluoromethyl, tert-butoxy, trifluoromethoxy,

in another aspect (E10), the invention relates to compound (1), wherein

R²Is optionally substituted by one or more identical or different R^bAnd/or R^cA substituted phenyl group, which is substituted,

and R is^bAnd R^cAre as defined above.

In another aspect (E11), the invention relates to compound (1), wherein

R²Represents a phenyl group

R⁵Selected from hydrogen, C_1-6Alkyl, -OC_1-6Alkyl radical, C_1-6Haloalkyl, -OC_1-6Haloalkyl, C_3-7Cycloalkyl and 3-7 membered heterocycloalkyl, all of which are optionally substituted by C_1-6Alkyl, -CN or-OH;

R⁶selected from hydrogen, C_1-6Alkyl, -OC_1-6Alkyl radical, C_1-6Haloalkyl, -OC_1-6Haloalkyl, -CN, -OH, halogen, -NHC_1-6Alkyl and-N (C)_1-6Alkyl radical)₂Wherein the latter two groups are optionally substituted in their alkyl moieties by-N (C)_1-6Alkyl radical)₂Substitution;

R⁷selected from: hydrogen, -OC_1-6Alkyl, halogen, -NHS (O)₂C_1-6Alkyl, -S (O)₂NH₂、-S(O)₂NHC_1-6Alkyl, -S (O)₂N(C_1-6Alkyl radical)₂，

R⁹Selected from hydrogen and C_1-6An alkyl group;

R^c1is hydrogen or optionally substituted by one or more R which may be the same or different^d1And/or R^e1Substituted C_1-6Alkyl and 3-14 membered heterocycloalkyl;

each R^d1Are suitable substituents and are selected, independently of one another, from-OR^e1、-NR^e1R^e1And halogen;

each R^e1Independently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^f1And/or R^g1Substituted of the following groups: c_1-6Alkyl radical, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl;

each R^f1Are suitable substituents and are selected, independently of one another, from-OR^g1、-NR^g1R^g1And halogen and a divalent substituent ═ O, which may be the only substituents in the non-aromatic ring system;

each R^g1Independently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^h1Substituted of the following groups: c_1-6Alkyl radical, C_3-10Cycloalkyl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl;

each R^h1Independently of one another, from C_1-6Alkyl groups and divalent substituents ═ O, which may only be substituents in non-aromatic ring systems;

or

group-NR⁹R^c1Represents a nitrogen-containing 3-to 14-membered heterocycloalkyl or 5-to 12-membered heteroaryl group, optionally substituted by one or more same or different substituents selected from R^d1And R^e1Substituted with a group of (1);

group-NR⁹R^e1Represents a nitrogen-containing 3-to 14-membered heterocycloalkyl or 5-to 12-membered heteroaryl group, optionally substituted by one or more same or different substituents selected from R^f1And R^g1Substituted with a group of (1);

group-NR⁹R^g1Represents a nitrogen-containing 3-to 14-membered heterocycloalkyl or 5-to 12-membered heteroaryl group, which is optionally substituted by one or more identical or different radicals R^h1Substitution;

R⁸selected from hydrogen, C_1-6Alkyl, -OC_1-6Alkyl, -CN, halogen, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl.

In another aspect (E12), the invention relates to a compound (1) having the structural aspect E11, wherein the group R⁵To R⁸At least one of which is not hydrogen.

In another aspect (E13), the invention relates to compound (1) having structural aspect E11, wherein

R⁵Is selected from

In another aspect (E14), the invention relates to compound (1), wherein

R²Is selected from

And R' represents and links the unit L¹The binding site of (a).

In another aspect (E15), the invention relates to compound (1), wherein

R²Is selected from

And R' represents and links the unit L¹The binding site of (a).

In another aspect (F1), the invention relates to compound (1), wherein

L¹Is represented by (R)²)-NHC(O)-。

In another aspect (F2), the invention relates to compound (1), wherein

L¹Is represented by (R)²)-C(O)NH-。

If desired, the different molecular moieties in all of the above-mentioned compounds (1) of the invention A to F can be rearranged with one another to form a combination ABCDEF, to give the preferred compounds (1). Each combination ABCDEF represents and defines an individual embodiment or a general partial quantity (genetic partial ampout) of a compound of the invention. Each individual embodiment or partial quantity defined by such a combination is expressly included in and intended for the purpose of this invention.

In another aspect, the present invention relates to a compound of general formula (1) or a pharmacologically acceptable salt thereof as a medicament.

In another aspect, the present invention relates to pharmaceutical formulations containing, as active substance, one or more compounds of general formula (1) or a pharmacologically acceptable salt thereof, optionally in combination with conventional excipients and/or carriers.

In another aspect, the present invention relates to compounds of general formula (1) for use in the treatment and/or prevention of cancer, infection, inflammation and autoimmune diseases.

In another aspect, the present invention relates to compounds of general formula (1) for use in the treatment and/or prevention of cancer.

In another aspect, the present invention relates to a pharmaceutical formulation comprising a compound of general formula (1), wherein compound (1) may optionally also be in the form of its tautomers, racemates, enantiomers, diastereomers and mixtures thereof, or in the form of a pharmaceutically acceptable salt of each of all of the aforementioned forms; and at least one other cytostatic or cytotoxic active substance different from formula (1).

Definition of

The following definitions will be used herein unless otherwise indicated.

Using a prefix C_x-y(wherein x and y each represent a natural number (x < y)) means that the chain or ring structures or the combination of chain and ring structures referred to and mentioned in the direct connection may consist of a total number of carbon atoms up to y and at a minimum of x.

Information about the number of members in a group containing one or more heteroatoms (heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl) refers to the total number of atoms in all ring members or chain members or the total number of atoms in all rings and chain members.

Alkyl groups consist of a sub-group of saturated hydrocarbon chains and unsaturated hydrocarbon chains, wherein the latter can be further subdivided into hydrocarbon chains containing double bonds (alkenyl) and hydrocarbon chains containing triple bonds (alkynyl).

Alkenyl contains at least one double bond and alkynyl contains at least one triple bond. If the hydrocarbon chain has both at least one double bond and at least one triple bond, it belongs by definition to the alkynyl subgroup. All of the above subgroups can be further subdivided into linear (unbranched) and branched. If alkyl is substituted, it may, independently of one another, be monosubstituted or polysubstituted on all hydrogen-containing carbon atoms.

Examples of individual subpopulations are listed below:

linear (unbranched) or branched saturated hydrocarbon chain:

methyl, ethyl, n-propyl, isopropyl (1-methylethyl), n-butyl, 1-methylpropyl, isobutyl (2-methylpropyl), sec-butyl (1-methylpropyl), tert-butyl (1, 1-dimethylethyl), n-pentyl, 1-methylbutyl, 1-ethylpropyl, isopentyl (3-methylbutyl), neopentyl (2, 2-dimethyl-propyl), n-hexyl, 2, 3-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, 2-ethylpropyl, n-butyl, 1-ethylpropyl, isopentyl (3-methylbutyl), neopentyl (2-methylpropyl), neopentyl (2-ethylhexyl), 2-hexyl (3-methyl-pentyl, 2, 4-dimethylpentyl group, 3-dimethylpentyl group, 2, 3-trimethylbutyl group, 3-ethylpentyl group, n-octyl group, n-nonyl group, n-decyl group, etc.

Linear (unbranched) or branched alkenyl:

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-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 1-methyl-prop-1-enyl, 1-methylenepropyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl, 3-methyl-but-1-enyl, allyl (ethenyl), allyl (prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, allyl (ethenyl), allyl (propenyl), allyl (pent-2, 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-methylene-3-methylbutyl, 2, 3-dimethyl-but-1-enyl, hex-1, 3-dienyl, hex-1, 4-dienyl, penta-1, 3-dienyl, but-1, 3-dienyl, 2, 3-dimethyl-but-1, 3-dienyl, and the like.

Straight-chain (unbranched) or branched alkynyl:

ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl and the like.

Unless otherwise indicated, the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like, refer to saturated hydrocarbon groups having the corresponding number of carbon atoms, including all isomeric forms.

Unless otherwise indicated, the terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like, refer to unsaturated hydrocarbon groups having the corresponding number of carbon atoms and one double bond, including all isomeric forms, and also including the (Z)/(E) -isomers, as appropriate and appropriate.

Unless otherwise indicated, the terms butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl and the like refer to unsaturated hydrocarbon radicals having the corresponding number of carbon atoms and two double bonds, including all isomeric forms, and also, where appropriate and in addition, the (Z)/(E) -isomers.

Unless otherwise indicated, the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like refer to unsaturated hydrocarbon radicals having the corresponding number of carbon atoms and a triple bond, including all isomeric forms.

The term alkylene may also be derived from alkyl groups as defined above and subgroups thereof. Alkylene groups, unlike alkyl groups, are divalent and require two binding ligands. Formally the second bond can be obtained by removing one hydrogen atom from the alkyl group. The corresponding group is, for example, -CH₃and-CH₂-、-CH₂CH₃and-CH₂CH₂-or > CHCH₃And the like. All subgroups of alkyl groups have a corresponding alkylene group.

Heteroatoms refer to oxygen, nitrogen and sulfur atoms.

The term heteroalkyl refers to a group derived from an alkyl group as defined by the broadest meaning above, in the following manner: with-OH, -SH or-NH in the hydrocarbon chain₂The radicals being independent of one another substituted for one or more-CH₃A group; by replacing one or more-CH groups by-O-, -S-or-NH-groups, independently of one another₂-a group; substitution of one or more > CH-groups with > N groups; -substitution of one or more ═ CH-groups with ═ N groups; by substitution of one or more CH groups by NH groups₂A group; or one or more ≡ CH groups are replaced by ≡ N groups in which no more than three heteroatoms in total may be present in a heteroalkyl group in which at least one carbon atom must be present between two oxygen atoms or between two sulfur atoms or between one oxygen atom and one sulfur atom and the entire group must be chemically stable.

As a direct result of the indirect definition/derivation of alkyl, heteroalkyl groups are composed of a sub-group of saturated hydrocarbon chains containing heteroatoms, heteroalkenyl, and heteroalkynyl groups, and may be further subdivided into straight-chain (unbranched) and branched. If substituted, the heteroalkyl groups may be monosubstituted or multisubstituted, independently of one another, on all hydrogen-containing oxygen, sulfur, nitrogen and/or carbon atoms. The heteroalkyl group itself as a substituent group may be attached to the molecule both through a carbon atom and through a heteroatom.

Examples are listed below:

dimethylaminomethyl, dimethylaminoethyl (1-dimethylaminoethyl, 2-dimethylaminoethyl), dimethylaminopropyl (1-dimethylaminopropyl, 2-dimethylaminopropyl, 3-dimethylaminopropyl), diethylaminomethyl, diethylaminoethyl (1-diethylaminoethyl, 2-diethylaminoethyl), diethylaminopropyl (1-diethylaminopropyl, 2-diethylaminopropyl, 3-diethylaminopropyl), diisopropylaminoethyl (1-diisopropylaminoethyl, 2-diisopropylaminoethyl), bis-2-methoxyethylamino, [2- (dimethylamino-ethyl) -ethyl-amino ] -methyl, diethylaminoethyl, diethylaminopropyl, diethylaminoethyl, and diethylaminoethyl, 3- [2- (dimethylamino-ethyl) -ethyl-amino ] -propyl, hydroxymethyl, 2-hydroxy-ethyl, 3-hydroxypropyl, methoxy, ethoxy, propoxy, methoxymethyl, 2-methoxyethyl, and the like.

The term heteroalkylene may also be derived from heteroalkyl groups as defined above and subgroups thereof. Heteroalkylene groups, unlike heteroalkyl groups, are divalent and require two binding ligands. Formally the second bond can be obtained by removing one hydrogen atom from the heteroalkyl group. Corresponding radicals, e.g. -CH₂NH₂and-CH₂NH-or > CHNH₂、-NHCH₃And > NCH₃or-NHCH₂-、-CH₂OCH₃and-CH₂OCH₂-or > CHOCH₃And the like. All subgroups of heteroalkyl groups have the corresponding heteroalkylene group.

Haloalkyl is derived from alkyl as defined in the broadest sense above by: one or more hydrogen atoms in the hydrocarbon chain are replaced independently of each other by the same or different halogen atoms. As a direct result of the indirect definition/derivation of alkyl groups, haloalkyl groups are composed of a subgroup of saturated halogenated hydrocarbon (hydrohalogen) chains, haloalkenyl groups, and haloalkynyl groups, and can be further subdivided into straight-chain (unbranched) and branched. If the haloalkyl group is substituted, it may, independently of one another, be monosubstituted or polysubstituted on all hydrogen-containing carbon atoms.

Typical examples are listed below:

-CF₃、-CHF₂、-CH₂F、-CF₂CF₃、-CHFCF₃、-CH₂CF₃、-CF₂CH₃、-CHFCH₃、-CF₂CF₂CF₃、-CF₂CH₂CH₃、-CF＝CF₂、-CCl＝CH₂、-CBr＝CH₂、-CI＝CH₂、-C≡C-CF₃、-CHFCH₂CH₃、-CHFCH₂CF₃and the like.

May also be defined by haloalkyl groups and subgroups thereof as defined hereinbeforeThe term haloalkylene is derived. Haloalkylene is different from haloalkyl, is divalent, and requires two binding ligands. The second bond may formally be obtained by removing one hydrogen atom from the haloalkyl group. Corresponding radicals such as-CH₂F and-CHF-, -CHFCH₂F and-CHFCHF-or > CFCH₂F, and the like. All subgroups of haloalkyl groups have corresponding haloalkylene groups.

Halogen includes fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl groups consist of subgroups of monocyclic, bicyclic and spiro hydrocarbon rings, wherein each subgroup can be further subdivided into saturated and unsaturated hydrocarbon groups (cycloalkenyl). Unsaturated means that at least one double bond is present in the ring system but that no aromatic system is formed. In a bicyclic hydrocarbon ring, the two rings are attached in such a way that they share at least two carbon atoms. In the spiro hydrocarbon ring, two rings share one carbon atom (spiro atom). If the cycloalkyl group is substituted, it can be monosubstituted or polysubstituted on all hydrogen-containing carbon atoms independently of one another. The cycloalkyl group itself as a substituent may be attached to the molecule via any suitable position of the ring system.

The following subgroups are listed by way of example:

monocyclic saturated hydrocarbon ring:

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

Monocyclic unsaturated hydrocarbon ring:

cyclopropyl-1-alkenyl, cyclopropyl-2-alkenyl, cyclobutyl-1-alkenyl, cyclobutyl-2-alkenyl, cyclopent-1-alkenyl, cyclopent-2-alkenyl, cyclopent-3-alkenyl, cyclohex-1-alkenyl, cyclohex-2-alkenyl, cyclohex-3-alkenyl, cyclohept-1-alkenyl, cyclohept-2-alkenyl, cyclohept-3-alkenyl, cyclohept-4-alkenyl, cyclobut-1, 3-dienyl, cyclopent-1, 4-dienyl, cyclopent-1, 3-dienyl, cyclopent-2, 4-dienyl, cyclohex-1, 3-dienyl, cyclohex-1, 5-dienyl, Cyclohexa-2, 4-dienyl, cyclohexa-1, 4-dienyl, cyclohexa-2, 5-dienyl, and the like.

Bicyclic hydrocarbon rings (saturated and unsaturated):

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 (norbornyl), bicyclo [2.2.1] hept-2, 5-dienyl (norbornyl-2, 5-dienyl), bicyclo [2.2.1] hept-2-enyl (norbornenyl), bicyclo [4.1.0] heptyl (norcaranyl), bicyclo [3.1.1] heptyl (pinyl) and the like.

Spiro hydrocarbon ring (saturated and unsaturated):

spiro [2.5] octyl, spiro [3.3] heptyl, spiro [4.5] dec-2-enyl and the like.

If the free valency of the cycloalkyl group is saturated, an alicyclic ring (alicyclic ring) is obtained.

The term cycloalkylene may also be derived from cycloalkyl as defined above and subgroups thereof. Cycloalkylene groups are different from cycloalkyl groups, are divalent, and require two binding ligands. The second bond may formally be obtained by removing one hydrogen atom from the cycloalkyl group.

Corresponding radicals such as cyclohexyl andcyclopentenyl andand the like.

All subgroups of cycloalkyl groups have corresponding cycloalkylene groups.

Cycloalkylalkyl refers to the combination of alkyl and cycloalkyl groups as defined above, both having their broadest meaning. Or cycloalkylalkyl may also be considered as a combination of cycloalkyl and alkylene. Formally, a cycloalkylalkyl group is obtained by first directly attaching an alkyl group as a substituent to a molecule, followed by substitution with a cycloalkyl group. Alkyl and cycloalkyl groups may be linked through carbon atoms in both groups which are suitable for this purpose. The respective subgroups of alkyl (alkylene) and cycloalkyl groups may also be included in the combination of the two groups.

Aryl represents a mono-, bi-or tricyclic carbocyclic ring having at least one aromatic ring. If an aryl group is substituted, the substitution may in each case be mono-or polysubstituted on all hydrogen-containing carbon atoms independently of one another. The aryl group itself may be attached to the molecule as a substituent via any suitable position of the ring system.

Typical examples are listed below:

phenyl, naphthyl, indanyl (2, 3-indanyl), 1, 2, 3, 4-tetrahydronaphthyl, fluorenyl, and the like.

If the free valency of the aryl group is saturated, an aromatic group is obtained.

The term arylene may also be derived from aryl groups as defined above. Arylene is different from aryl, and is divalent and requires two binding ligands. The second bond may formally be obtained by removing one hydrogen atom from the aryl group. Corresponding radicals such as phenyl andnaphthyl andand the like. All aryl subgroups have a corresponding arylene group.

Arylalkyl denotes a combination of alkyl and aryl groups as defined above, which definition has its broadest meaning in each case. Alternatively, arylalkyl groups can also be considered as combinations of aryl groups and alkylene groups. Formally, an arylalkyl group is obtained by first directly attaching an alkyl group as a substituent to a molecule and substituting it with an aryl group. The alkyl and aryl groups may be linked by any carbon atom in the two groups that is suitable for the purpose. The respective subgroups of alkyl (alkylene) and aryl groups may also be included in the combination of the two groups.

Typical examples are listed below:

benzyl, 1-phenylethyl, 2-phenylethyl, styryl, phenylallyl, and the like.

Heteroaryl denotes a monocyclic aromatic ring or a polycyclic ring having at least one aromatic ring which, in contrast to the corresponding aryl or cycloalkyl groups, does not contain one or more carbon atoms but one or more identical or different heteroatoms selected, independently of one another, from nitrogen, sulfur and oxygen, where the resulting group must be chemically stable. Heteroaryl groups are present with the proviso that they are heteroatoms and aromatic systems, but they need not necessarily be heteroaromatic systems. Thus, according to the definition, 2, 3-dihydro-1H-indol-6-yl

May be a heteroaryl group.

If the heteroaryl radical is substituted, the substitution can in each case be mono-or polysubstituted independently of one another on all hydrogen-containing carbon atoms and/or nitrogen atoms. Heteroaryl groups, which are themselves substituents, may be attached to the molecule via any suitable position in the ring system, both carbon and nitrogen.

Typical examples are listed below:

monocyclic heteroaryl group:

furyl, thienyl, pyrrolyl,Azolyl, thiazolyl, isoOxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,Oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N-Oxides, pyrazinyl-N-oxides, imidazolyl-N-oxides, isooxides(iii) an oxazolyl-N-oxide,azolyl-N-oxides, thiazolyl-N-oxides,oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-N-oxide, tetrazolyl-N-oxide, and the like.

Polycyclic heteroaryl group:

indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoAzolyl, benzothiazolyl, benzisoylOxazolyl, indoline, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolyl, quinolyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzothiazinyl, benzoxazinyl,Azolopyridinyl, imidazopyridinyl, diazanaphthyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoAzolyl, pyridopyridyl, benzotetrahydrofuryl, benzotetrahydro-thienyl, purinyl, benzodioxolyl, thiophenylOxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazolylAzinyl, benzisohAzinyl radicals, benzoOxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanone, tetrahydroquinolyl, dihydroquinolyl, dihydroquinolonyl, dihydroisoquinolonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolonyl, benzodioxinyl, benzothiophenyl, thiochromanyl, coumarinyl, chromanylOxazolone, quinolyl-N-oxide, indolyl-N-oxide, indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide, benzothiopyranyl-S-oxide and benzothiopyranyl-S, S-dioxide and the like.

If the free valency of the heteroaryl group is saturated, a heteroaromatic group is obtained.

The term heteroarylene may also be derived from heteroaryl as defined above. Heteroarylene is distinct from heteroaryl, and is divalent and requires two binding ligands. Formally the second bond can be obtained by removing one hydrogen atom from the heteroaryl group.

Corresponding radicals, e.g. pyrrolyl and2, 3-dihydro-1H-indolyl andand the like.

All subgroups of heteroaryl groups have corresponding heteroarylenes.

Heteroarylalkyl denotes a combination of said alkyl and heteroaryl as defined above, all having their broadest meaning. Alternatively, heteroarylalkyl may also be considered as a combination of heteroaryl and alkylene. Formally heteroarylalkyl is obtained by first attaching an alkyl group as a substituent directly to the molecule, followed by substitution thereof with a heteroaryl group. The attachment of the alkyl group to the heteroaryl group can be achieved on the alkyl side via any carbon atom suitable for the purpose and on the heteroaryl side via any carbon or nitrogen atom suitable for the purpose. The respective subgroups of alkyl (alkylene) and heteroaryl groups may also be included in the combination of the two groups.

The term heterocycloalkyl refers to a radical derived from a cycloalkyl group as defined above if one or more-CH's in the hydrocarbon ring₂The radicals are independently of one another replaced by an-O-, -S-or-NH-group, or one or more ═ CH-groups are replaced by an ═ N-group, and a total of not more than 5 heteroatoms may be present, at least one carbon atom must be present between two oxygen atoms and between two sulfur atoms or between one oxygen atom and one sulfur atom, and the entire radical must be chemically stable. The hetero atoms can be present in all possible oxidation stages simultaneously (S → sulfoxide-SO-, sulfone-SO)₂-; nitrogen → N-oxide) is present. It is understood that heterocycloalkyl is composed of subgroups of monocyclic, bicyclic and spiroheterocycles, each of which can be further subdivided into saturated and unsaturated (heterocycloalkenyl) groups, as defined/derived indirectly from cycloalkyl groups. The term unsaturated means that at least one double bond is present in the ring system, but no aromatic system is formed. In bicyclic heterocycles, the two rings are connected in such a way that they share at least two atoms. In spiroheterocycles, two rings share one carbon atom (the spiro atom). If it isHeterocycloalkyl is substituted, the substitution in each case being mono-or polysubstituted independently of one another on all hydrogen-containing carbon and/or nitrogen atoms. The heterocycloalkyl group itself as a substituent may be attached to the molecule via any suitable position of the ring system.

Typical examples of individual subpopulations are listed below.

Monocyclic heterocycle (saturated and unsaturated):

tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, oxacyclopropane (oxalanyl), aziridinyl (aziridinyl), azetidinyl, 1, 4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S, S-dioxide, 1, 3-dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, [1, 4] pyrrolinyl]-oxazepanyl, tetrahydrothienyl, homothiomorpholinyl-S, S-dioxide,Oxazolidone group, dihydropyrazolyl group, dihydropyrrolyl group, dihydropyrazinyl group, dihydropyridinyl group, dihydropyrimidyl group, dihydrofuranyl group, dihydropyranyl group, tetrahydrothienyl-S-oxide, tetrahydrothienyl-S, S-dioxide, homothiomorpholinyl-S-oxide, 2, 3-dihydroazetidine (dihydroazet), 2H-pyrrolyl group, 4H-pyranyl group, 1, 4-dihydropyridinyl group, and the like.

Bicyclic heterocycles (saturated and unsaturated):

8-azabicyclo [3.2.1] octyl, 8-azabicyclo [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-diaza-bicyclo- [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, and the like.

Spiroheterocycles (saturated and unsaturated):

1, 4-dioxa-spiro [4.5] decyl, 1-oxa-3.8-diaza-spiro [4.5] decyl, 2, 6-diaza-spiro [3.3] heptyl, 2, 7-diaza-spiro [4.4] nonyl, 2, 6-diaza-spiro [3.4] octyl, 3, 9-diaza-spiro [5.5] undecyl, 2, 8-diaza-spiro [4.5] decyl, and the like.

If the free valency of the heterocycloalkyl group is saturated, a heterocycle is obtained.

The term heterocycloalkylene may also be derived from heterocycloalkyl as defined above.

Heterocycloalkylene is different from heterocycloalkyl, which is divalent and requires two binding ligands. Formally the second bond can be obtained by removing one hydrogen atom from the heterocycloalkyl group. Corresponding radicals such as piperidinyl and2, 3-dihydro-1H-pyrrolyl andand the like. All subgroups of heterocycloalkyl groups have a corresponding heterocycloalkylene group.

Heterocycloalkylalkyl means a combination of the alkyl and heterocycloalkyl groups defined above, all having their broadest meaning. Alternatively, heterocycloalkylalkyl groups may also be considered a combination of heterocycloalkyl and alkylene groups. Formally, a heterocycloalkyl group is obtained by first directly attaching an alkyl group as a substituent to a molecule and then substituting it with a heterocycloalkyl group. The attachment of the alkyl group to the heterocycloalkyl group can be achieved on the alkyl side via any carbon atom suitable for the purpose, and can be achieved on the heterocycloalkyl side via any carbon or nitrogen atom suitable for the purpose. The respective subgroups of alkyl and heterocycloalkyl groups, respectively, may also be included in the combination of the two groups.

Substituted means that the hydrogen atom directly bonded to the atom is replaced by another atom or another atomic group (substituent). Depending on the starting conditions (number of hydrogen atoms) mono-or polysubstitution can take place at one atom.

Divalent substituents such as ═ S, ═ NR, ═ NOR, ═ NNRR, ═ nn (r) c (o) NRR, ═ N₂Etc. may be substituents at carbon atoms only, while divalent substituents ═ O may also be substituents of sulfur. In general, substitution by a divalent substituent can only occur in the ring system and requires exchange of two paired (geminal) hydrogen atoms, i.e. hydrogen atoms attached to the same carbon atom that is saturated before substitution. Thus substitution of divalent substituents is only possible for the-CH in the ring system₂-at a radical or at a sulphur atom.

In addition, the term "suitable substituent" means a substituent that has both a suitable valence and is capable of rendering the system chemically stable.

Certain abbreviated expressions and their corresponding structures are set forth below:

for example in the sequence a-B-C, if the member B corresponds to the structure-N ═ this is understood to be the following two cases: a-N-C and a-N-C.

For example in the sequenceIn (e), if member a corresponds to the structure > C ═ C,

then this should be understood as

For example, in the following figures,

the dotted line indicates that the ring system can be attached to the molecule via carbon 1 or 2, i.e. equivalent to the following figures:

in part of structure (i)

Wherein the ring systems are all heteroaryl according to the preceding definition, and wherein the ring which (in the case of a bicyclic group) is directly bonded to Q is a heteroaromatic ring, the atoms 1, 2 (in each case unsaturated carbon) and 3 (unsaturated nitrogen) being fixed. The ring is completed through the attachment of atoms 1 and 3 through at least two other atoms.

Examples of ring systems having alkyl moiety structure (i) are

Wherein said ring system may optionally be further substituted by one or more identical or different substituents R^bAnd/or R^cAnd (4) substitution.

In the following exemplary figures

For example, the letter a has the function of a ring indicator to more easily describe the coupling of the ring with other rings.

For divalent radicals, if the valence of the divalent radical to its adjacent group is critical, the corresponding binding partner is given in parentheses for any need to be explicitly stated, as shown in the following formula:or (R)²) -C (O) NH-or (R)²)-NHC(O)-；

The groups or substituents are typically selected from those having corresponding group names (e.g., R)^a、R^bEtc.) alternative groups/substituents. If such groups are reused in different parts of the molecule to define the compounds of the invention, it should be kept in mind that each use is considered completely independent of the other.

List of abbreviations

The features and advantages of the present invention will be understood from the following detailed examples, which are intended to illustrate the invention by way of example and not to limit the scope of the invention:

preparation of the Compounds of the invention

SUMMARY

All reactions were carried out in a commercial unit using the usual methods in a chemical laboratory unless otherwise stated. Starting materials sensitive to air and/or moisture are stored in a protective gas, and their corresponding reactions and operations are also carried out in a protective gas (nitrogen or argon).

The compounds of the invention were named according to the CAS rules using Autonom software (Beilstein).

The microwave reaction is carried out in a sealed vessel (preferably 2, 5 or 20mL) in an initiator/reactor manufactured by Biotage or an Explorer manufactured by CEM, preferably with stirring.

Chromatography method

For preparative Medium pressure chromatography (MPLC), Silica gel prepared from Millipore (name: Granula Silica Si-60A 35-70 μm, normal phase) or C-18 RP-Silica gel prepared from Macherey Nagel (RP-phase, name: Polygonrep 100-50C18) was used. Automated normal phase chromatography can also be performed on the CombiFlash company XL device manufactured by Isco and the CombiFlash Foxy 200 fraction collector. For this purpose, a commercially available RediSepRf (120g silica gel) single-pass column was used. Thin layer chromatography was performed on Ready-to-use silica gel 60TLC plates (containing fluorescent indicator F-254) made by Merck.

Preparative high performance chromatography (HPLC) of the compounds of the examples of the invention used columns made from Waters (designation: XTerra Prep. MS C18, 5 μm, 30X 100mm or XTerra Prep. MS C18, 5 μm, 50X 100mm OBD or Symmestrie C18, 5 μm, 19X 100mm or Sunfire C18 OBD, 19X 100mm, 5 μm or Sunfire Prep C10 μm OBD 50X 150mm or X-Bridge Prep C185 μm OBD 19X 50mm), Agilent (designation: Zorbax SB-C85 μm PrepHT 21.2X 50mm) and Phenomenex (designation: Gemini C185 μm AXIA 21.2X 50mm or Gemini C1810 μm 50X 150 mm). Use ofDifferent gradients of H₂O/acetonitrile or H₂O/MeOH eluted compound, with 0.1% HCOOH added to water.

Preparative normal phase high performance chromatography (HPLC) of the compounds of the examples of the present invention was performed using a chromatographic system prepared by Macherey&Nagel (name: Nucleosil, 50-7, 40X 250mm) and VDSpilab (name: Kromasil 100 NH)₂10 μm, 50 × 250 mm). The compound was eluted using different gradients of DCM/MeOH, where 0.1% NH was added₃Added to MeOH.

Analytical HPLC (reaction control) of the intermediate compounds used columns made by Agilent (name: Zorbax SB-C8, 5 μm, 21.2X 50mm or Zorbax SB-C83.5 μm 2.1X 50mm) and Phenomenex (name: Gemini C183 μm 2X 30 mm). The analytical device in each case is also equipped with a mass detector.

HPLC-Mass Spectrometry/UV-Spectroscopy

Retention time/MS-ESI characterizing compounds of the examples of the invention were obtained using an HPLC-MS apparatus (high performance liquid chromatography with mass detector)⁺. Setting retention time t of compound eluted from sample injection peak_Ret.＝0.00。

HPLC-MS method 1

HPLC：Agilent 1100Series

MS：Agilent LC/MSD SL

Column: waters, Xterra MS C18, 2.5 μm, 2.1X30mm, part number 186000592

Eluent: a: h₂O (0.1% HCOOH); b: acetonitrile (HPLC grade)

And (3) detection: MS: positive and negative modes

The mass range is as follows: 20-900m/z

Flow rate 1.10 mL/min

Column temperature: 40 deg.C

Gradient: 0.00 minute: 5% eluent B

0.00-2.50 minutes: 5% → 95% eluent B

2.50-2.80 minutes: 95% eluent B

2.81-3.10 minutes: 95% → 5% eluent B

The compounds of the invention are prepared using the synthetic methods described below, wherein the substituents of the general formula have the meanings described above. These methods are intended to illustrate the invention and do not limit the scope of the subject matter of the invention and the protected compounds to the examples. If the preparation of the starting compound is not specified, it is commercially available or can be prepared in a manner analogous to known compounds or methods described herein. The substances described in the literature are prepared according to published synthetic methods.

Reaction scheme A

Example compounds of type I:

the compounds of the present invention having an N-linked triazole ring (type I) can be prepared, for example, by one of the synthetic routes shown in reaction scheme a (synthetic methods 1-3).

Starting from the heteroaromatic, protected amino acid ester ED-1, after removal of the amino protecting group (e.g. TFA or HCl for Boc), diazotization with sodium nitrite in hydrochloric acid solution, and reaction of the resulting diazonium salt with sodium azide, the azide intermediate A-1 is obtained.

It is reacted in a copper-catalyzed 1, 3-dipolar cycloaddition reaction (synthesis method 1) with a heteroarylalkyne ED-2 and, in this way, is prepared by R¹A substituted triazole ring (A-2). Finally, the ester A-2 obtained is saponified to give the free acid A-3 (for example ethyl ester, using LiOH or NaOH), and the amide coupling is carried out using the amino component ED-3.

Alternatively (Synthesis method 2), starting from azide A-1, first a saponification reaction and an amide coupling are carried out to give azide A-6, and then finally the compound I of the example is obtained by a1, 3-dipolar cycloaddition reaction with the alkyne ED-2.

Starting from ED-1, the reaction sequence can also be completed by first carrying out a saponification reaction to give the free acid A-4, followed by amide coupling with ED-3 to give the amide A-5 (Synthesis method 3), followed by formation of the triazole ring via intermediate A-6 (sequence).

Examples I-1 to I-207 syntheses

a) Process for the synthesis of A-Ia

The ester ED-1a (743mg, 2.65mmol) was suspended in 12.5N aqueous hydrochloric acid (2.5mL), and the mixture was stirred at room temperature for 2 hours. 13mL of H was added₂O, cooling the mixture to 0 ℃, and slowly adding cooled NaNO into the mixture₂Aqueous solution (219mg, 3.18mmol in 3.5mL H₂O) and the mixture was stirred for 30 minutes. Adding NaN at 0 deg.C₃Aqueous solution (209mg, 31.8mmol in 3.5mL H₂O) and the mixture is stirred for a further 30 minutes. Diluted with water and extracted three times with DCM (30mL each). The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness. Azide A-1a thus obtained (HPLC-MS: t)_Ret.1.42 minutes; MS (M + H)⁺207) can be directly reacted further without any further washing steps.

Similar to the method for the synthesis of A-1a, other azides A-1 can be obtained from their corresponding starting materials ED-1.

b) Method for synthesizing A-2a

1, 5-dimethyl-4-trimethylsilylethynyl-1H-pyrazole ED-2a (760mg, 3.95mmol) was placed in MeOH (10mL) and stirred at RT with KF (374mg, 6.43mmol) overnight to remove the trimethylsilyl group. Then, A-1a (546mg, 2.65mmol), sodium ascorbate (577mg, 2.91mmol in 2mL H, respectively) were added₂In O) and 1.2mL of 0.8M CuSO₄Aqueous solution, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness using a rotary evaporator and dissolved in H₂O, and extracted three times with DCM. The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness. The residue was dissolved in a small amount of DMF and purified by preparative HPLC. The product-containing fraction of A-2a was freeze-dried.

Similar to the process for the synthesis of A-2a, other intermediates A-2 can be obtained from their corresponding components A-1 and ED-2.

c) Process for the synthesis of A-3a

A-2a (530mg, 1.70mmol) was dissolved in H₂O (3mL) was mixed with MeOH (1.5mL), mixed with 1.0M sodium hydroxide solution (6.0mL), and stirred at 40 ℃ for 2 h. The mixture was neutralized with hydrochloric acid and evaporated to dryness using a rotary evaporator. The residue was dissolved in a small amount of DMF and purified by preparative HPLC. Freeze-drying the product-containing fraction of A-3a (HPLC-MS: t)_Ret.: 0.36 min; MS (M + H)⁺＝299)。

Similar to this method, other free acids A-3 can be obtained from their corresponding esters A-2.

d) Method for synthesizing example compound I-1 (method a: activation with GHOSEZ reagent)

A-3a (55.8mg, 0.19mmol) was placed in DCM (3mL), mixed with 1-chloro-N, N, 2-trimethylpropenylamine (43 μ L, 0.19mmol), and stirred at room temperature overnight. 5-tert-butyl-iso-butyl dissolved in DCM and DIPEA (79. mu.L, 0.46mmol) was addedOxazol-3-ylamine ED-3a (25.5mg, 0.18mmol), and the mixture was stirred at room temperature for 3 hours. Then, it was evaporated to dryness using a rotary evaporator, the residue was dissolved in a small amount of DMF and purified by preparative HPLC. Freeze-drying the product-containing fraction of I-1 (HPLC-MS: t)_Ret.1.47 minutes; MS (M + H)⁺＝421)。

e) Method for synthesizing example compound I-4 (method B: using HATU activation)

A-3a (75.2mg, 0.25mmol) was taken up in THF (3mL), mixed with HATU (112mg, 0.35mmol) and DIPEA (50. mu.L, 0.30mmol) and stirred at room temperature for 30 min. Then 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine ED-3b (47.1mg, 0.31mmol) was added, and the mixture was left overnight at room temperature and stirred at 50 ℃ for another 24 hours. Subsequently, it was evaporated to dryness using a rotary evaporator, the residue was dissolved in a small amount of DMF and purified by preparative HPLC. Freeze-drying the product-containing fraction of I-4 (HPLC-MS: t)_Ret.1.38 minutes; MS (M + H)⁺＝434)。

f) Method for synthesizing example Compounds I-56 and I-61

Activation of A-3a (1.30g, 3.05mmol) as described in reaction method d) and reaction with ED-3c (1.00g, 3.07 mmol). Freeze drying the product-containing fraction of I-56 (HPLC-MS: t)_Ret.2.02 minutes; MS (M + H)⁺＝534/536)。

Mixing I-56(75mg, 0.14mmol) with NaOtBu (55mg, 0.56mmol) and Pd₂(dba)₃(25mg, 0.03mmol) and biphenyl-2-yl-di-tert-butyl-phosphine (19mg, 0.06mmol) were placed in a1, 4-bisIn an alkane (2mL), mixed with morpholine (50. mu.L, 0.57mmol) and stirred in a sealed vial under argon at 45 ℃ overnight. The reaction mixture was then filtered and washed with DMF and H₂Diluted O and purified by preparative HPLC. Freeze-drying the product-containing fraction of I-61 (HPLC-MS: t)_Ret.1.86 minutes; MS (M + H)⁺＝541)。

g) Method for the Synthesis of example Compounds I-126 and I-97

3-bromo-5-trifluoromethyl-4-methyl-nitrobenzene (1.01g, 3.55mmol), 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.38g, 4.45mmol), Pd (dppf) Cl₂·CH₂Cl₂(434mg, 0.53mmol) and K₂CO₃(1.61g, 11.6mmol) was placed in a1, 4-di-columnAlkane (10mL) and H₂O (3mL) and stirred at 100 ℃ for 1.5 hours. After cooling, the reaction mixture was washed with DCM and H₂O dilution and removal of the aqueous phase. The organic phase was filtered through silica gel, evaporated to dryness using a rotary evaporator, the residue was dissolved in EtOAc and washed with saturated NaCl solutionAnd (6) washing. The organic phase was washed with MgSO₄Dried, filtered, and evaporated to dryness using a rotary evaporator. The intermediate compound thus obtained (HPLC-MS: t)_Ret.2.34 min) can be used further without any further purification steps.

The intermediate compound obtained (1.30g, 2.36mmol) was placed in EtOH (15mL) with NH₄Cl solution (67mg, 1.26mmol in 20mL H₂O) and heated to 75 ℃. Fe dust (1.36g, 24.4mmol) was added portionwise and the mixture was stirred at 75 ℃ for 30 min. The reaction mixture was filtered through a glass fiber filter, washed with MeOH, and the filtrate was evaporated to dryness using a rotary evaporator. The ED-3d thus obtained can be used further without any further purification steps.

A-3a (839mg, 2.35mmol) and ED-3d (609mg, 2.04mmol) were placed in THF (8mL) and reacted with NEt₃(1.6mL, 11.5mmol) were mixed. Propylphosphonic acid cyclic anhydride (3.1mL, 50% solution in DMF, 5.31mmol) was added and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was evaporated to dryness using a rotary evaporator, the residue was dissolved in a small amount of DMF and purified by preparative HPLC. Freeze-drying the product-containing fraction of example Compound I-126, still Boc-protected (HPLC-MS: t)_Ret.2.20 min: MS (M + H)⁺＝635)。

The example compound still protected by Boc-was placed in 1, 4-bis (241mg, 0.38mmol)In an alkane (5mL), combined with concentrated HCl (1mL) and stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness using a rotary evaporator and the residue was dissolved in a small amount of DMF and H₂O, and purified by preparative HPLC. Freeze drying the product-containing fraction of I-126 (HPLC-MS: t)_Ret.1.79 minutes; MS (M + H)⁺＝537)。

I-126(75mg, 0.14mmol) was placed in DCM (1.5mL), mixed with AcOH (40. mu.L, 0.70mmol) and acetaldehyde (16. mu.L, 0.28mmol), and stirred for 30 min. Then, sodium triacetoxyborohydride (51mg, 0.24mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness using a rotary evaporator and the residue was dissolved in a small amount of MeOH and H₂O, and purified by preparative HPLC. Freeze drying of the product-containing fraction of I-97 (HPLC-MS: t)_Ret.1.98 minutes; MS (M + H)⁺＝565)。

h) Process for the synthesis of A-6a

A-1a (1.49g, 7.08mmol) was dissolved in water (1mL) and EtOH (7.5mL), mixed with sodium hydroxide solution (8M, 3.5mL) and stirred at 40 ℃ for 2 h. The reaction mixture was evaporated to dryness and the still moist residue was dissolved in hydrochloric acid and filtered. The filtrate was evaporated to dryness again, dissolved in a small amount of DMF and purified by preparative HPLC. The product-containing fraction of the free carboxylic acid is lyophilized.

Free nicotinic acid (75mg, 0.42mmol) was placed in DCM (2.5mL), mixed with 1-chloro-N, N, 2-trimethylpropenylamine (145. mu.L, 1.10mmol), and stirred at room temperature for 3.5 h. Aniline ED-3e (104mg, 0.43mmol) and DIPEA (108. mu.L, 0.63mmol) were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness, dissolved in a small amount of DMF and purified by preparative HPLC. Freeze-drying the product-containing fraction of A-6a (HPLC-MS: t)_Ret.2.10 minutes; MS (M + H)⁺405) freeze drying.

In analogy to this procedure, further azides A-6 can be obtained from their corresponding azides A-1.

i) Method for synthesizing example Compound I-15

ED-2b (66.2mg, 0.26mmol) was dissolved in MeOH (3mL), mixed with KF (29.4mg, 0.51mmol), and stirred at 30 ℃ for 3 h. Then, A-6a (71.0mg, 0.18mmol), 0.8M CuSO were added₄Aqueous solution (22. mu.L, 0.02mmol) and sodium ascorbate (36.3mg, 0.18mmol), and the mixture was stirred at 40 ℃ for an additional 4 days. The reaction mixture was evaporated to dryness using a rotary evaporator, the residue was dissolved in a small amount of DMF and purified by preparative HPLC. Freeze-drying the product-containing fraction of I-15 (HPLC-MS: t)_Ret.1.84 minutes; MS (M + H)⁺＝571)。

j) Process for the synthesis of A-4a

ED-1a (28.4g, 101mmol) was dissolved in MeOH (120mL) and H₂O (100mL), with sodium hydroxide solution (80mL, 2M H₂O solution) and stirred at 120 ℃ for 8 hours. The volatile constituents are then removed using a rotary evaporator and the residue is slowly acidified to pH 4 with hydrochloric acid (2N) over a period of time in which the alkyl fraction A-4a is present (HPLC-MS: t)_Ret.0.34 min; MS (M + H)⁺253) was precipitated as a solid, which was isolated by filtration. The filtrate was extracted three times with EtOAc over MgSO₄Dried, filtered and evaporated to dryness using a rotary evaporator while isolating additional product a-4 a.

k) Process for the synthesis of A-5a

Propylphosphonic acid cyclic anhydride (52.5mL, 50% EtOAc solution) was slowly added dropwise to A-4a (14.7g, 58.4mmol), ED-3a (9.06g, 62.7mmol) and NEt₃(27mL, 195mmol) in THF (159mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was subsequently evaporated to dryness using a rotary evaporator, and the residue was taken up with H₂O, during which time A-5a (HPLC-MS: t)_Ret.1.83 minutes; MS (M + H)⁺375) was precipitated as a solid, which was filtered off and used further without any further purification steps.

l) method for the synthesis of A-6b

A-5a (20.5g, 54.8mmol) was placed in 12.5N hydrochloric acid (15mL) and stirred overnight at room temperature to remove the Boc protecting group. Then, the reaction mixture was cooled to 0 ℃ and pre-cooled NaNO was slowly added dropwise thereto₂(4.88g, 70.8mmol) of H₂O solution and the mixture is stirred for another 90 minutes. Then, the dissolved H is slowly added at 0 DEG C₂NaN in O₃(4.39g, 66.9mmol) and the reaction mixture was stirred for 30 minutes. By H₂O diluted and a precipitate formed, which was filtered off and dissolved in DCM. The organic phase is treated with H₂O was extracted twice and evaporated to dryness using a rotary evaporator. A-6b (HPLC-MS: t) with a small amount of isopropanol_Ret.1.70 minutes; MS (M + H)⁺301) and purified.

Analogously to processes k) and I), further azides A-6 are obtainable from their corresponding carboxylic acids A-4 with amines ED-3 via amides A-5 as intermediate compounds.

m) method for synthesizing example Compound I-34

5-bromo-pyridine-3-carbaldehyde (1.48g, 7.71mmol) and das BESTMANN-OHIRA reagent (2.03g, 10.6mmol) were placed in MeOH (20mL) with K₂CO₃(1.16g, 8.37mmol) were mixed and stirred at room temperature for 12 hours. The reaction mixture was then evaporated to dryness using a rotary evaporator, the residue was dissolved in DCM and taken up with H₂And extracting for three times. The organic phase was washed with MgSO₄Dried, filtered and evaporated to dryness using a rotary evaporator. ED-2c obtained (HPLC-MS: t)_Ret.1.37 minutes) can be used further without any further purification steps.

ED-2c (1.67g, 9.15mmol) was placed in MeOH (40mL), mixed first with A-6b (2.00g, 6.66mmol), and after 5 minutes, successively with aqueous sodium ascorbate (6.0mL, 1M) and CuSO₄The aqueous solution (14mL, 0.1M) was mixed and stirred at 45 ℃ for 48 hours. The reaction mixture was then evaporated to dryness using a rotary evaporator and the residue was dissolved in H₂O and filtering off the precipitate formed. The solid was stirred with a saturated EDTA solution, filtered again and I-34 (HPLC-MS: t) was obtained_Ret.1.79 minutes; MS (M + H)⁺482/484). Some of the solid was dissolved in DMF and purified by preparative HPLC for further purification. The product-containing fraction of I-34 was freeze-dried.

n) method for synthesizing example Compound I-39

Under protective gas, I-34(66mg, 0.14mmol), NaOtBu (65mg, 0.65mmol), biphenyl-2-yl-di-tert-butyl-phosphine (16mg, 0.06mmol) and Pd₂(dba)₃(35mg, 0.04mmol) was placed in a1, 4-di-flaskIn an alkane (2mL), was mixed with N-methylpiperazine (60mg, 0.60mmol) and stirred overnight at 45 ℃ in a sealed reaction vessel. Then, the reaction mixture is washed with H₂O was diluted with DMF and purified by preparative HPLC. Freeze drying the product-containing fraction of I-39 (HPLC-MS: t)_Ret.1.62 minutes; MS (M + H)⁺＝502)。

o) method for the Synthesis of example Compound I-187

5-Bromonicotinic acid (3.44g, 17.0mmol) was placed in THF (40mL), mixed with CDI (3.00g, 18.5mmol), and stirred at 50 ℃ for 2 h. The reaction mixture was then poured into NaBH, cooled with ice₄Aqueous solution (600mg, 15.9mmol in 100mL H₂O), stirred at room temperature for 3 days and extracted seven times with DCM. The combined organic phases were washed with Na₂SO₄Dried, filtered and evaporated to dryness using a rotary evaporator. (5-bromo-pyridin-3-yl) -methanol thus obtained (HPLC-MS: t)_Ret.0.21 min; MS (M + H)⁺188/190) can be used further without any further purification steps.

(5-bromo-pyridin-3-yl) -methanol (3.00g, 16.0mmol) was placed in THF (60mL) and NEt under a protective gas₃(6mL) with CuI (100mg, 0.53mmol), (PPh)₃)₂Cl₂(430mg，0.61mmol)、PPh₃(180mg, 0.69mmol) and TMS-acetylene (2.9mL, 20.9mmol) were mixed and stirred at 80 ℃ for 1 hour. The reaction mixture was evaporated down using a rotary evaporator and purified by normal phase chromatography (DCM/MeOH; 90: 10). The product-containing fractions of ED-2d were evaporated to dryness using a rotary evaporator (HPLC-MS: t)_Ret.1.81 minutes; MS (M + H)⁺＝206)。

ED-2d (1.00g, 3.30mmol) was placed in MeOH (20mL), mixed with KF (310mg, 5.33mmol), and stirred at room temperature for 2 h. Then, a solution of A-6b (300mg, 1.00mmol) in MeOH (20mL), aqueous sodium ascorbate (2.5mL, 1M), and CuSO were added successively₄Aqueous solution (788. mu.L, 0.8M) and the mixture was stirred at 50 ℃ for 4 hours. MeOH was removed using a rotary evaporator and the residue was taken up with H₂And (4) mixing the materials. The resulting precipitate of hydroxymethyl compound was filtered off and dried in a vacuum desiccator for further use without any further purification steps.

The crude hydroxymethyl compound (1.4g, 3.23mmol) was placed in DCM (30mL) and DMF (3mL) with SOCl₂(3.0mL) were mixed and refluxed for 1 hour. The reaction mixture was then evaporated down using a rotary evaporator, dissolved in DCM/MeOH and the precipitate formed of the product was filtered off and purified by normal phase chromatography (DCM/MeOH; gradient from 100: 0 to 40: 60). The product-containing fraction of the chloromethyl compound (HPLC-MS: t) was purified using a rotary evaporator_Ret.1.68 minutes; MS (M + H)⁺452) was evaporated to dryness, the compound was initially obtained as additional intermediate product.

The chloromethyl compound obtained (80.0mg, 0.18mmol) was taken up in DCM (3mL) and DMF (1mL), mixed with dimethylamine (17mg, 0.35mmol) and stirred at 50 ℃ overnight. The reaction mixture was then evaporated to dryness using a rotary evaporator and purified by preparative HPLC. Freeze-drying the product-containing fraction of I-187 (HPLC-MS: t)_Ret.1.57 minutes; MS (M + H)⁺＝461)。

Reaction methods a) to g) (synthesis method 1) analogous to the synthesis example compounds I-1, I-4, I-56, I-61, I-97 and I-126 described above, or a), h) and I) (synthesis method 2) of the synthesis example compounds I-15, or j) to o) (synthesis method 3) of the synthesis example compounds I-34, I-39 and I-187, further example compounds of type I in Table 1 below (examples I-1 to I-207) or comparable further examples can be obtained by their corresponding precursors, which are either commercially available or can be prepared by methods known in the literature.

TABLE 1

Examples Compounds I-1 to I-207

Reaction scheme B

Example compounds of type II:

compounds with N-linked pyrrole, pyrazole or imidazole rings (type II) can be prepared, for example, by one of the synthetic routes shown in reaction scheme B (synthetic methods 1 and 2).

The starting material used is likewise a heteroaromatic, protected amino acid ester ED-1. After the amino protecting group is removed, it is then converted to the iodide Z-1 in sodium nitrite sulfate solution in the presence of copper iodide and potassium iodide (SANDMEYER reaction).

The iodide Z-1 may then be first saponified (Synthesis method 1) and then substituted with pyrrole, imidazole or pyrazole using a copper-catalyzed ULLMANN reaction to give the acid B-1. Selective halogenation using, for example, bromine, iodine, N-bromosuccinimide, N-iodosuccinimide or other halogenating agents known in the literature, followed by reaction with a heteroaryl boronic acid R¹B(OH)₂Or heteroarylboronic acid derivatives R¹B(OR”)₂(ED-4) performing a palladium-catalyzed SUZUKI cross-coupling reaction to obtain the free acid B-2. If necessaryThe saponification of the carboxylic ester-C (O) OR' may also be carried out only after the ULLMANN-like substitution, halogenation and SUZUKI reactions, since these three conversions may also be carried out with esters. Finally, compounds of type II are obtained by coupling with amides of the component ED-3.

Or (synthetic method 2), changing the reaction sequence, firstly, directly carrying out amide coupling with the amino component ED-3 after saponification reaction of Z-1 to obtain the iodide B-3. ULLMANN-like substitutions were made in a manner analogous to synthetic method 1 to obtain B-4, followed by selective halogenation and SUZUKI reactions to also obtain compounds of type II.

Reaction scheme C

Example compounds of type III:

compounds having a C-linked triazole ring (type III) can be prepared, for example, by one of the synthetic routes shown in reaction scheme C (synthetic methods 1 and 2).

Starting from the iodide Z-1 (cf. reaction scheme B), the ester function is first removed (method 1 for synthesis) and then subjected to a palladium-catalyzed SONOGASHIRA cross-coupling reaction with trimethylsilylacetylene and CuI to give the alkyne C-1. Followed by a copper-catalyzed 1, 3-dipolar cycloaddition reaction between C-1 and heteroaryl azide ED-5 to form a C-linked triazole ring. The reactivity of the "1, 3-dipole" introduced into the group is exactly opposite to that of the "dipole-philic" compared to the formation of an N-linked triazole ring according to reaction scheme a. Amide coupling with amine ED-3 finally gives compound III. If desired, the saponification reaction of Synthesis method 1 can also be carried out prior to the amide coupling, since all conversions using ester functions are similar. According to synthesis method 2, the example compound III can also be prepared by a different reaction sequence than in synthesis method 1.

Reaction scheme D

Example compounds of type IV:

compounds having C-linked pyrrole, pyrazole or imidazole rings (type IV) can be prepared, for example, by one of the synthetic routes shown in reaction scheme D (synthetic methods 1 and 2).

Starting from iodide Z-1, a palladium-catalyzed cross-coupling reaction with boronic acid derivative Z-3 is carried out after the saponification reaction (Synthesis method 1), giving intermediate D-1. Finally, the final compound IV is obtained through amidation reaction. If desired, the saponification reaction can also be carried out just before the amidation reaction. The desired component Z-3 in this sequence is prepared beforehand, starting from pyrrole, imidazole or pyrazole, by copper-catalyzed cross-coupling with its corresponding heteroaryl halide ED-6, followed by halogenation on the heteroaryl group using, for example, bromine, iodine, N-bromosuccinimide, N-iodosuccinimide or other halogenating agents known from the literature, and finally by palladium-catalyzed cross-coupling with bis-pinacolborane.

For synthesis method 2, the order of the reaction steps of synthesis method 1 was rearranged, and compound IV was obtained via intermediate C-3 (see reaction scheme C).

Reaction scheme E

Example compounds of types V, VI-A and VI-B:

in each case, compounds having an imidazole ring (type V) attached via C-at the 4-position or having a thiazole ring (types VI-A and VI-B) attached via C-at the 4-or 2-position can be obtained by cyclization of iodide Z-1 (scheme E). To synthesize the example compounds of types V and VI-A (part 1), iodide Z-1 was metallated by iPrMgCl in the presence of CuCN in a first reaction step, and then reacted with chloroacetyl chloride to obtain α -chloroketone E-1.

E-1 was reacted with heteroaryl amidine ED-7 to give imidazole intermediate E-2 (Synthesis method 1), and with heteroaryl thioamide ED-8 to give thiazole intermediate E-3 (Synthesis method 2). Both E-2 and E-3 can be amidated after saponification to form the final compound.

To synthesize example compounds of type VI-B (part 2), the iodide Z-1 is saponified in a first reaction step and then converted to the boronic acid derivative E-4 using a palladium-catalyzed reaction (e.g., via reaction with bis-pinacolborane). By two successive palladium-catalyzed SUZUKI reactions, the thiazole ring is first introduced using 2, 4-dibromothiazole (intermediate E-5) and the group R is then introduced via boronic acid or boronic acid derivative ED-4¹(intermediate E-6). Finally, the final compound of type VI-B is obtained by amide linkage with the amine ED-3. If desired, the saponification reaction can also be carried out just before the amidation reaction.

Reaction scheme F

Example compounds of type VII (reaction scheme F, part 1):

compounds having an imidazole ring attached via a C-at the 2-position (type VII) can be obtained by cyclization of iodide Z-1. The latter is substituted in a first reaction step by CuCN to form the nitrile F-1 and converted by ammonolysis to the amidine F-2. The imidazole ring is formed by reaction with heteroaryl- α -bromomethyl ketone ED-9, and finally saponification and amidation of intermediate F-3. The reactivity of the introduced group "α -haloketone" is exactly opposite to that of the "amidine", compared to the synthesis of the C-linked imidazole ring (type V) in position 4 according to reaction scheme E.

Example compounds of type VIII-A (reaction scheme F, part 2):

compounds having a thiazole ring attached via a C-linkage in the 2-position can be obtained from the boronic acid derivative E-4 (cf. reaction scheme E). By two successive palladium-catalyzed SUZUKI reactions, the thiazole ring is first introduced using 2, 5-dibromothiazole (intermediate F-4) and the group R is then introduced via boronic acid or boronic acid derivative ED-4¹(intermediate F-5). Finally amide linkage with amine ED-3 to obtain the final compound of type VIII-A. If desired, the saponification reaction described for the synthesis of E-4 can also be carried out just before this amidation reaction (cf. scheme E).

Example compounds of type VIII-B (reaction scheme F, part 3):

compounds having a thiazole ring linked via a C-linkage in the 5-position (type VIII-B) can be obtained from boronic acids or boronic acid derivatives E-4.

First, in a first palladium-catalyzed SUZUKI cross-coupling reaction, boronic acid or boronic acid derivative ED-4 is reacted with 2, 5-dibromothiazole to introduce R¹. In another SUZUKI reaction with boronic acid derivative E-4, carboxylic acid F-6 is obtained, which is then converted to the final compound of type VIII-B by amide coupling with amine ED-3.

Reaction scheme G

Example compounds of type IX:

compounds having a pyrazole ring C-linked in the 5-position (type IX) can be obtained by cyclization of an alkyne C-4 (cf. reaction scheme C) using tosylhydrazone cycloaddition. Tosylhydrazone is generated in situ from its corresponding heteroaryl aldehyde ED-10 and tosylhydrazide.

Alternatively, the cycloaddition reaction can also be carried out on alkyne C-1. In this case, the amidation reaction must be carried out using the amine ED-3.

Reaction scheme H

Example compounds of type X:

having 2, 4-bonds via C-bonds at the 3-positionThe compound of the diazole ring (type X) can be obtained by cyclization reaction of nitrile F-1 (refer to reaction scheme F). In the first step, F-1 is saponified and the free acid is amidated with the amine ED-3 (H-1). Subsequent addition of hydroxylamine affords intermediate H-2, which is subsequently cyclized using heteroaryl carboxylic acid ED-11 to give compound X.

Example compounds of type XI:

having 2, 4-bonds via C-bonds at the 5-positionThe compounds of the diazole ring (type XI) can be obtained by cyclization of the carboxylic acid ED-12 by condensation with the heteroaryl hydroxyamidine ED-13. The intermediate H-3 thus obtained is subjected to saponification and amidation to give the compound XI.

Reaction scheme I

Example compounds of type XII:

the compounds of the invention having an N-linked triazole ring (type XII) can be prepared, for example, by one of the synthetic routes shown in reaction scheme I (synthetic methods 1 and 2). Compounds of type XII have an inverted (inverted) amide bond compared to compounds of type I.

Starting from the nitrocarboxylic acid ED-14, first a conversion using DPPA with tert-butanol and a base (e.g. N-methylmorpholine) in a Curtius reaction gives Boc-protected aniline Z-4.

Removal of the Boc protecting group using, for example, TFA or HCl, diazotization in a hydrochloric acid solution of sodium nitrite, and reaction of the diazonium salt with sodium azide gives azide I-1 (Synthesis method 1). The triazole ring is synthesized by copper-catalyzed 1, 3-dipolar cycloaddition with an alkyne ED-2, and the intermediate I-2 obtained is then reduced to the aniline I-3. The nitro group can be reduced using methods known in the literature, for example using hydrogen in the presence of palladium on activated carbon or using iron in the presence of ammonium chloride. Finally, aniline I-3 is amidated with carboxylic acid ED-15.

For synthesis method 2, the reaction steps in synthesis method 1 are permuted.

Examples Synthesis of XII-1 to XII-78

a) Process for the synthesis of I-1a

ED-14a (1.01g, 5.52mmol) was placed in tBuOH (50mL), mixed with DPPA (1.8mL, 8.35mmol) and NMM (724. mu.L, 6.59mmol), and refluxed for 15 hours. After cooling, a saturated sodium chloride solution was added, and the mixture was extracted several times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution over MgSO₄Dried, filtered and evaporated to dryness using a rotary evaporator. The residue was dissolved in some water and freeze dried. Z-4a thus obtained (HPLC-MS: t)_Ret.1.73 minutes; MS (M + H)⁺254) was used without further purification.

Z-4a (1.25g, 4.94mmol) was placed in DCM (15mL), mixed with TFA (7mL), and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (20mL) and H₂O (2X 40mL) was extracted with 2N hydrochloric acid (3X 40 mL). The combined aqueous phases were made basic with sodium hydroxide solution and extracted with ethyl acetate (3X 75 mL). The combined organic phases were washed with saturated NaHCO₃The solution is washed over MgSO₄Dried, filtered and evaporated to dryness. The residue (730mg, 4.77mmol) was taken up in 2N hydrochloric acid (25mL), cooled to 0 ℃ and reacted with NaNO₂Solution (395mg, 5.72mmol in 2mL H₂O) was mixed dropwise. After 30 minutes, NaN was added at 0 deg.C₃(341mg, 5.25mmol, dissolved in 2mL H₂O) and the mixture is stirred for a further 30 minutes. Subjecting the reaction mixture to hydrogenation with H₂Diluted with O and extracted three times with ethyl acetate. The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness. Azide I-1a obtained (HPLC-MS: t)_Ret.1.30 min) was used without further purification.

Analogously to the process for the synthesis of I-1a, further azides I-1 are obtained from their corresponding starting materials ED-13.

b) Method for synthesizing I-2a

1, 5-dimethyl-4-trimethylsilylethynyl-1H-pyrazole ED-2a (1.65g, 8.61mmol) was placed in MeOH (20mL) and reacted with K at room temperature₂CO₃(1.22g, 8.85mmol) were stirred together for 1.5 hours to remove trimethylsilyl groups. Then, I-1a (854mg, 4.77mmol), sodium ascorbate (594mg, 3.00mmol in 2mL H₂In O) and 2.2mL of 0.8M CuSO₄Aqueous solution, and the mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness using a rotary evaporator and dissolved in H₂O, and extracted three times with ethyl acetate. The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness. Removing residuesThe residue was dissolved in a small amount of DMF and water, and during this time part I-2a precipitated and was filtered off. The mother liquor was purified by normal phase chromatography. Fraction containing the product of I-2a evaporated to dryness (HPLC-MS: t)_Ret.1.35 minutes; MS (M + H)⁺＝300)。

Similar to the process for the synthesis of I-2a, the other intermediate I-2 is obtained from its corresponding component I-1 and ED-2.

c) Process for the synthesis of I-3a

I-2a (485mg, 1.62mmol) was dissolved in MeOH (10mL), mixed with Pd/C (10%, 186mg, 1.75mmol), and hydrogenated in a hydrogenation autoclave at 50PSI for 3 h. The catalyst is filtered off, the mother liquor is evaporated to dryness, dissolved in a small amount of 2N hydrochloric acid and freeze-dried. I-3a thus obtained (HPLC-MS: t)_Ret.0.99 min; MS (M + H)⁺270) can be used further without any further purification steps.

In analogy to this process, further anilines I-3 can also be obtained by reduction of their corresponding nitro compounds I-2.

d) Method for synthesizing example Compound XII-1

Benzoic acid ED-15a (56.6mg, 0.20mmol) was taken up in THF, mixed with HATU (73.7mg, 0.23mmol) and DIPEA (88. mu.L, 0.52mmol) and stirred at room temperature for 30 min. Then, I-3a (50.0mg, 0.16mmol) was added, and the mixture was stirred at 50 ℃ for 3 days. The reaction mixture was evaporated to dryness using a rotary evaporator and the residue was dissolved in a small amount of DMF and H₂O, and purified by preparative HPLC. The product-containing fractions of XII-1 were combined and lyophilized (HPLC-MS: t)_Ret.1.79 minutes; MS (M + H)⁺540) and freeze-dried.

e) Method for synthesizing I-5a

Z-4a (1.79g, 7.07mmol) was taken up in MeOH (80mL), mixed with Pd/C (188mg, 10%) and hydrogenated at room temperature under 4 bar of hydrogen pressure for 2 h. The catalyst was filtered off and the filtrate was evaporated to dryness using a rotary evaporator. The residue was dissolved in a small amount of MeCN and H₂O, and freeze-drying. To obtain I-4a (HPLC-MS: t)_Ret.1.20 minutes; MS (M + H)⁺224) was used without any further purification.

I-4a (1.51g, 6.76mmol) and ED-15b (1.52g, 7.31mmol) were placed in THF (20mL) and NEt₃(3.0mL) and mixed. Then, propylphosphonic acid cyclic anhydride (5.9mL, 50% EtOAc solution) was added dropwise and the mixture was stirred at rt for 2 h. Then, it was evaporated to dryness using a rotary evaporator, and the residue was dissolved in H₂O, and extracted three times with DCM. The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness using a rotary evaporator. I-5a thus obtained (HPLC-MS: t)_Ret.1.93 minutes; MS (M + H)⁺412) can be used further without any further purification steps.

In analogy to this procedure, further amides I-5 can also be obtained from their corresponding aminopyridine I-4 by amidation with further carboxylic acids ED-15.

f) Process for the synthesis of I-6a

I-5a (3.36g, 6.78mmol) was stirred at 50 ℃ in 12.5N hydrochloric acid (10mL) overnight.After cooling, the reaction mixture is reacted with H₂O (10mL) was mixed, neutralized with sodium hydroxide solution (8N), and extracted three times with DCM. The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness using a rotary evaporator. The residue (HPLC-MS: t)_Ret.1.43 minutes; MS (M + H)⁺312) dissolved in small amounts of H₂O with MeCN and freeze-dried.

The free amine thus obtained (1.60g, 5.15mmol) was placed in a1, 4-bisAlkane (20mL), with TMS-N₃(0.7mL, 8.60mmol) and tert-butyl nitrite (3.0mL, 25.3mmol) were mixed continuously and stirred at room temperature overnight. The mixture was then diluted with DCM and saturated NaHCO₃The solution was washed three times. The organic phase was washed with MgSO₄Dried, filtered and evaporated to dryness using a rotary evaporator. The I-6a thus obtained can be further used without any further purification step.

In analogy to this procedure, further azides I-6 can also be obtained from protected aminopyridine I-5.

g) Method for synthesizing ED-2f

3-bromo-5-fluoro-pyridine (4.26g, 23.5mmol) and isopropylpiperazine (7.58g, 59.1mmol) were placed in n-BuOH (16mL) and stirred at 100 ℃ for 6 days. After cooling, the reaction mixture was acidified with 0.1N hydrochloric acid and extracted three times with EtOAc. The aqueous phase was adjusted to pH 10 with sodium hydroxide solution and extracted three times with DCM. The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness using a rotary evaporator. The residue was dissolved in a small amount of DCM and added to 4g of polymer-bound isocyanate (manufactured by Argonaut, part No. 800260) which had been previously swollen in DCM, and the mixture was stirred at room temperature for 2 hours. However, the device is not suitable for use in a kitchenAfter this time, the polymer resin was filtered off, the mixture was washed with DCM and evaporated to dryness using a rotary evaporator. Thus obtained substituted 3-bromo-pyridines (HPLC-MS: t)_Ret.1.59 minutes; MS (M + H)⁺284) can be further used without any further purification steps.

The resulting substituted 3-bromo-pyridine (3.88g, 8.18mmol), CuI (124mg, 0.65mmol) and (PPh) were combined under a protective atmosphere₃)₂PdCl₂(95.0mg, 0.14mmol) was placed in diisopropylamine (5mL), mixed with TMS-acetylene (1.5mL, 10.6mmol) and stirred in a microwave at 100 ℃ for 30 min. After cooling, the reaction mixture was diluted with 1N hydrochloric acid and extracted three times with DCM. The acidic aqueous phase was adjusted to pH 9 and extracted three times with DCM. The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness using a rotary evaporator. The residue was purified by normal phase chromatography. Fraction containing product from ED-2f evaporated to dryness (HPLC-MS: t)_Ret.2.13 minutes; MS (M + H)⁺203) and dried under high vacuum.

In analogy to this method, other TMS-protected acetylenes ED-2 were obtained from 3-bromo-5-fluoro-pyridine.

h) Method for the Synthesis of example Compound XII-42

ED-2f (140mg, 0.46mmol) was placed in MeOH (10mL), mixed with KF (60mg, 1.03mmol), and stirred at room temperature overnight. Then, I-6a (132mg, 0.31mmol) was added, the mixture was stirred for 5 minutes, and an aqueous solution of sodium ascorbate (180. mu.L, 1M) and CuSO were added successively₄Aqueous solution (150. mu.L, 1M) and the mixture was stirred at 45 ℃ for 48 hours. Subsequently, it was made basic with 1N sodium hydroxide solution and extracted three times with EtOAc. The combined organic phases were washed with water and brine₄Dried, filtered and evaporated to dryness using a rotary evaporator. The residue was dissolved in small amounts of DMF and H₂O, and by preparationPurification by HPLC. The product-containing fractions of XII-42 are combined (HPLC-MS: t)_Ret.1.92 minutes; MS (M + H)⁺567) and freeze-dried.

Analogous to the above-described reaction processes a) to d) (synthesis process 1) for the synthesis of the compound XII-1 of the example, or e) to h) (synthesis process 2) for the synthesis of the compound XII-42 of the example, the following examples XII-2 to XII-41 and XII-43 to XII-78 (Table 2) or comparable further examples can be obtained from the corresponding precursors, which are either commercially available or can be prepared by processes known from the literature.

TABLE 2

Examples Compounds XII-1 to XII-78

Reaction scheme J

Example compounds of type XIII:

compounds with N-linked pyrrole, pyrazole or imidazole rings (type XIII) can be prepared, for example, using one of the synthetic routes shown in reaction scheme J (synthetic methods 1 and 2). Compounds of type XIII have an inverted amide bond compared to compounds of type II.

Starting from Boc-protected nitroaniline Z-4 (reference scheme I), it was first converted to iodide Z-5 by removal of the protecting group, diazotization and SANDMEYER reaction.

The iodide Z-5 can then be substituted with pyrrole, imidazole or pyrazole using a copper-catalyzed reaction in a ULLMANN-like manner (Synthesis method 1) to afford the nitro compound J-1. Selective halogenation using, for example, bromine, iodine, N-bromosuccinimide, N-iodosuccinimide, or other halogenating agents known in the literature followed by palladium catalyzed SUZUKI cross-coupling with heteroaryl boronic acid or derivative ED-4 provides intermediate J-2 which is finally reduced and amidated with acid ED-15 to provide final compound XIII.

For synthesis method 2, the reaction steps in synthesis method I are performed in a different order.

Reaction scheme K

Example compounds of type XIV:

compounds having a C-linked triazole ring (form XIV) can be prepared, for example, by one of the synthetic routes shown in reaction scheme K (synthetic methods 1 and 2). Compounds of type XIV have an inverted amide bond compared to compounds of type III.

Starting from iodide Z-5 (see reaction scheme J), palladium-catalyzed SONOGASHIRA cross-coupling was first performed (Synthesis method 1) with trimethylsilylacetylene and CuI to obtain alkyne K-1. Followed by a copper-catalyzed 1, 3-dipolar cycloaddition reaction between K-1 and heteroaryl azide ED-5, thereby synthesizing a C-linked triazole ring. The "1, 3-dipole" introduced into the group is quite opposite in reactivity to the "dipole-philic" compared to the synthesis of the N-linked triazole ring of reaction scheme A or I. After reduction, the final amide coupling with the acid ED-14 gives the compound XIV.

In contrast to synthesis method 1, in synthesis method 2 example compound XIV can be prepared by changing the order of the reaction sequence.

Reaction scheme L

Example compounds of type XV:

compounds having C-linked pyrrole, pyrazole or imidazole rings (type XV) can be prepared, for example, using one of the synthetic routes shown in reaction scheme L (synthetic methods 1 and 2). Compounds of type XV have an inverted amide bond compared to compounds of type IV.

Starting from iodide Z-5 (reference scheme J), first (Synthesis method 1) a palladium-catalyzed SUZUKI cross-coupling reaction was carried out with boronic acid derivative Z-3 (reference scheme D) to obtain nitro compound L-1. This was converted to the example compound of type XV by reduction of the nitro group and subsequent amide coupling with the acid ED-15.

In contrast to synthesis method 1, in synthesis method 2 the example compound XV can be prepared by changing the order of the reaction sequence.

Reaction scheme M

Example compounds of types XVI and XVII-A (reaction scheme M, part 1):

in each case, compounds having an imidazole ring (type XVI) or a C-linked thiazole ring (type XVII-A) which are C-linked in the 4-position can be obtained from the iodide Z-5. In contrast to compounds of types V, VI-A and VI-B (see reaction scheme E), types XVI and XVII-A have inverted amide bonds.

First, the iodide Z-5 is reduced and the resulting amino group is protected by two Boc-protecting groups. The iodide Z-6 thus obtained was metallated by iPrMgCl in the presence of CuCN and then reacted with chloroacetyl chloride to give α -chloroketone M-1. M-1 reacts with heteroaryl amidine ED-7 to give imidazole intermediate M-2 (method 1), and reacts with heteroaryl thioamide ED-8 to give thiazole intermediate M-3 (method 2). Both M-2 and M-3 can be amidated after saponification to give the final compound.

Example compounds of type XVII-B (reaction scheme M, part 2):

compounds having a thiazole ring attached via a C-linkage in the 2-position (type XVII-B) can be obtained from carboxylic acid ED-14. Compounds of type XVII-B have an inverted amide bond compared to compounds of type VI-B.

First, carboxylic acid ED-14 is converted to thioamide M-4 by amide coupling and reaction with a LAWESSON reagent. Cyclization with α -bromoketone ED-9 followed by nitro reduction and finally amide coupling with carboxylic acid ED-15 gives the final compounds of type XVII-B.

Reaction scheme N

Compounds of types XVIII, IXX-A and IXX-B have inverted amide bonds compared to compounds of types VII, VIII-A and VIII-B (see reaction scheme F).

Example compounds of type XVIII (reaction scheme N, part 1):

compounds having an imidazole ring attached via a C-at the 2-position (type XVIII) are obtainable by cyclization of iodide Z-5. Compounds of type XVIII have an inverted amide bond compared to compounds of type VII.

The iodide Z-5 is substituted with CuCN in the first reaction step to give the nitrile N-1 and converted to the amidine N-2 by aminolysis. Imidazole ring formation by reaction with heteroaryl- α -bromomethyl ketone ED-9, and finally reduction and amidation of intermediate N-3.

Example compounds of type IXX-A (reaction scheme N, part 2):

compounds having a thiazole ring linked via a C-linkage in the 2-position (type IXX-A) are also obtainable starting from iodide Z-5. The synthesis was carried out by: boronic acid derivatives N-4 are first prepared from Z-5, for example by reaction with bis-pinacolborane under palladium catalysis followed by SUZUKI cross-coupling with 2, 4-dibromothiazole or 2, 5-dibromothiazole under palladium catalysis to give intermediates N-5. The group R is then introduced by a further SUZUKI reaction with a boronic acid or boronic acid derivative ED-4¹(intermediate N-6), after reduction and amidation with ED-15, the final compound is finally obtained.

Example compounds of type IXX-B (reaction scheme N, part 3):

starting from boronic acids or boronic acid derivatives N-4, compounds with a thiazole ring linked via a C-linkage in the 5-position (type IXX-B) are available. Firstly, in the first palladium-catalyzed SUZUKI cross-coupling reaction, boric acid or boric acid derivative ED-4 is reacted with 2, 5-dibromothiazole to introduce R¹. In another SUZUKI reaction with boronic acid derivative N-4, nitro compound N-7 is obtained, which is then converted to the final compound of type IXX-B by reduction and finally amide coupling with carboxylic acid ED-15.

Reaction scheme O

Example compounds of type XX:

compounds having a pyrazole ring C-linked in the 5-position (type XX) can be obtained by cyclization of an alkyne K-4 (cf. reaction scheme K), which undergoes cycloaddition with tosylhydrazone. Tosylhydrazones are prepared in situ from their corresponding heteroaryl aldehydes ED-10 and tosylhydrazide. Compounds of type XX have an inverted amide bond compared to compounds of type IX.

Reaction scheme P

Example compounds of type XXI:

having 2, 4-bonds via C-bonds at the 3-positionThe compound of the diazole ring (type XXI) can be obtained by cyclization of nitrile N-1 (see reaction scheme N). In the first step, the nitro group in N-1 is reduced and the free amino group is amidated with the carboxylic acid ED-15 (O-1). Hydroxylamine is then added to intermediate O-2 and cyclized with heteroaryl carboxylic acid ED-11 to provide compound XXI. Compounds of type XXI have an inverted amide bond compared to compounds of type X.

Example compounds of type XXII:

having 2, 4-bonds via C-bonds at the 5-positionThe compounds of the diazole ring (type XXII) can be obtained by cyclisation of the carboxylic acid ED-14 by reaction with the heteroaryl hydroxyamidine ED-13. The intermediate O-3 thus obtained is reduced and amidated with the carboxylic acid ED-15 to give compound XXII. Type XXII has an inverted amide bond compared to the compound of type XI.

Reaction scheme Q

Example compounds of type XXIII:

having 1, 2-hetero-rings linked via a C-link in the 3-positionThe azole ring compounds (type XXIII) can be obtained by cyclization of the diester ED-16 by first monosaponifying it and then amidating it with the amine ED-3. The ester Q-1 obtained is subsequently converted in a reduction-oxidation sequence into the aldehyde Q-2 and then into the oxime Q-3 with hydroxylamine, followed by 1, 3-dipolar cycloaddition with the alkyne ED-2 to give the final compound XXIII. To ensure that only the carboxylic ester-COOR ' is selectively saponified in the diester ED-16, the groups R ' and R ' "must have orthogonal reactivity (e.g., -COOR ' is saponified in a basic manner, -COOR '" is saponified in an acidic manner) corresponding to the saponification reaction conditions.

Example compounds of type XXIV:

having 1, 2-hetero-rings linked via a C-link in the 3-positionCompounds of the azole ring with a reversed amide bond (type XXIV) can be obtained by cyclization of carboxylic acid ED-14 by first esterifying the acid function, reducing the nitro group and then amidating with carboxylic acid ED-15. The ester Q-4 thus obtained is subsequently converted in a reduction-oxidation reaction sequence into the aldehyde Q-5, which is then converted with hydroxylamine into the oxime Q-6, which is subsequently subjected to a1, 3-dipolar cycloaddition reaction with the alkyne ED-2 to give the final compound XXIV.

Reaction scheme R

Example compounds of types XXV and XXVI:

having 1, 2-hetero-rings linked via a C-link in the 5-positionThe compounds of the azole ring (type XXV) are obtainable by 1, 3-dipolar cycloaddition of an alkyne C-4 to an oxime ED-17. The corresponding compound with a reversed amide bond (type XXVI) can be obtained in the same way from alkyne K-4.

Further references for reaction schemes a to R and all types of example compounds (I to XXVI):

for the amide coupling reaction, the methods known in the literature for activating carboxylic acids are used. Thus, for example, SOCl may be used₂Oxalyl chloride/DMF or GHOSEZ reagent (1-chloro-N, 2-trimethylpropenylamine) converts the acid to the acid chloride, reacts it with the corresponding amine, and adds an auxiliary base such as TEA, DIPEA, pyridine or other common organic bases to give the amide. Alternatively, the carboxylic acid can be activated using special coupling reagents such as HATU, TBTU, DCC, EDC, PyBOP, CDI and others known in the literature and reacted with an amine and an auxiliary base as described above to give the amide.

Radicals R of the compounds I to XXVI according to the invention¹With the radical R²Can be modified in further reaction steps not shown in the scheme to obtain further compounds I to XXVI according to the invention. These reaction steps may be substitution, alkylation, acylation or addition reactions. These modified examples are compounds I-35 to I-41 of the invention (Table 1), which were prepared from compound I-34 of the invention by the BUCHWALD-HARTWIG reaction.

Many representative starting materials ED-1 to ED-17 required for the synthesis of the compounds of the present invention are commercially available or routinely prepared using well known methods. Furthermore, it can be prepared according to or analogously to the literature cited below.

Heteroaryl alkynes ED-2 can be prepared from their corresponding halides using methods known in the literature: palladium catalyzed SONOGASHIRA cross-coupling reaction with trimethylsilylacetylene in the presence of copper (I) iodide. Trimethylsilyl-protected alkynes thus formed by reaction with K₂CO₃Or KF to remove trimethylsilyl groups in situ to obtain terminal alkynes. Alternatively, the alkyne ED-2 can also be reacted from its corresponding heteroaryl aldehyde R by the BESTMANN-OHIRA reaction¹CHO (ED-10) preparation. For the desired aldehyde ED-10 can be synthesized according to methods known in the literature, for example by VILSMAIER-HAACK formylation of its corresponding heteroaromatic group.

The heteroaryl boronic acid or boronic acid derivative ED-4 used in the SUZUKI reaction is prepared from its corresponding heteroaryl halide ED-6, which is obtained by halogenation of the heteroaromatic group.

Heteroaryl azides ED-5 from heteroarylamines R¹-NH₂Obtained by diazotization with hydrochloric acid and substitution with sodium azide.

The heteroarylamidines ED-7 can be prepared by reacting heteroarylnitriles R¹-CN, while the heteroaryl thioamide ED-8 can be obtained by amidation of a heteroaryl carboxylic acid and reaction with a LAWESSON reagent.

Heteroaryl bromomethyl ketone ED-9 can be obtained from heteroaryl halide ED-6 in the following manner: metallation with magnesium and acylation with bromoacetyl chloride or bromine, or from heteroarylcarboxylic acid ED-11, by: WEINREB amidation with N, O-dimethylhydroxylamine, followed by reaction with methyllithium or methyl-GRIGNARD compound, and optionally, α -bromination.

Heteroaryl Hydroxyamidines ED-13 by addition of a hydroxylamine to heteroaryl nitriles R¹-CN.

Heteroaryl oxime ED-17 is obtained from aldehyde ED-10 with hydroxylamine.

Furthermore, with regard to the synthesis of other starting materials or the method of cyclization, reference is made to the following publications: WO 2004/050642, WO 2005/056535, WO 2005/090333, WO 2005/115991, US 2006/100204, WO 2008/003770, WO 2009/003999, WO 2009/003998, WO 2008/089034, WO 2007/056016, WO 2007/075896, WO 2008/021388, WO 2005/023761.

The six-membered cyclic heteroaryl component ED-16 (diester) can be converted into the component ED-12 or ED-1 by a monosaponification reaction and subsequent Curtius degradation:

the following examples are intended to illustrate the biological activity of the compounds of the invention and are not intended to limit the invention thereto.

The compounds of general formula (1) are characterized by a multiplicity of possible applications in the therapeutic field. In particular, the use thereof for inhibiting specific signaling enzymes should be mentioned, in particular the inhibitory effect on the proliferation of cultured human tumor cells and on the proliferation of other cells such as endothelial cells.

Kinase test B-Raf (V600E)

10 μ L of the test substance solution was placed in a multiwell plate in serial dilutions. Serial dilutions were chosen so that a concentration range of 2 μ M to 0.119nM or 0.017nM should typically be included. If desired, the initial concentration of 2. mu.M can be changed to 50. mu.M, 10. mu.M or 0.4. mu.M or 0.2857. mu.M, and further dilutions made accordingly. The final concentration of DMSO was 5%. Mu. L B-Raf (V600E) -kinase solution (0.5 ng B-Raf (V600E) -kinase in 20mM Tris-HCl pH 7.5, 0.1mM EDTA, 0.1mM EGTA, 0.286mM sodium orthovanadate, 10% glycerol, 1mg/mL bovine serum albumin, 1mM dithiothreitol) was pipetted and the mixture was incubated at room temperature for 1 hour with shaking. By adding 20 μ L ATP solution [ final concentration: 250 μ M ATP, 30mM Tris-HCl pH 7.5, 0.02% Brij, 0.2mM sodium orthovanadate, 10mM magnesium acetate, 0.1mM mixture of EGTA and phosphatase (Sigma, code P2850, manufacturer's recommended dilution), 0.1mM EGTA ] and 10 μ L MEK1 solution [ containing 50ng biotinylated MEK1 (prepared by standard procedures from purified MEK1, e.g.using Z-Link sulfo-NHS-LC-Biotin reagent, Pierce, code 21335) were started for the kinase reaction and run at RT for 60 min with constant shaking. The reaction was stopped by adding 12. mu.L of 100mM EDTA solution and incubation continued for 5 minutes. mu.L of the reaction solution was transferred to streptavidin-coated plates (e.g., Streptawell HighBond, Roche, No. 11989685001) and slowly shaken at room temperature for 1 hour to bind biotinylated MEK1 to the plates. After removal of the liquid, the plates were washed five times with 200. mu.L of 1xPBS and 100. mu.L of a solution of primary and europium-labeled secondary antibodies [ anti-phospho-MEK (Ser217/221), CellSignaling, No. 9121 and Eu-N1-labeled goat anti-rabbit antibodies, Perkin Elmer, No. AD0105], the primary antibodies were diluted 1: 2000 in Delfia assay buffer (Perkin Elmer, No. 1244-. After shaking at room temperature for 1 hour, the solution was decanted and washed five times with 200. mu.L of Delfia wash buffer (Perkin Elmer, No. 4010-0010/No. 1244-114). 200 μ L of enhancing solution (Perkin Elmer, code 4001-. IC50 values were obtained from the dose-activity curves using a software program (graphpadpizm).

Most of the example compounds of types I to XXVI show good to excellent inhibition in the B-Raf (V600E) inhibition assay, i.e., IC₅₀Values below 5. mu.M, generally below 1. mu.M.

To confirm that the compounds of the invention of different building blocks have inhibitory activity, table 3 shows the% CTL values of the example compounds at a concentration of 2 μ M (with exceptions indicated). A value of 100% indicates no inhibition, while a value of 0% indicates total inhibition. The% CTL-values represent the residual activity of the enzyme in the solvent DMSO after addition of the inhibiting compound, in relation to the activity of the enzyme in the solvent DMSO without addition of the compound (control). These values were determined using the B-Raf (V600E) -kinase assay described above.

#	％CTL
		I-1	7.6
I-2	8.0
		I-3	8.7
I-4	1.7
		I-6	2.1
I-7	2.0
		I-8	1.6
I-9	1.4
		I-10	1.1
I-12	1.8
		I-13	2.3
I-14	1.4

I-15	1.4
		I-16	2.0^*
I-18	2.4
		I-20	1.9
I-21	2.2
		I-23	5.9
I-24	1.0
		I-25	2.2
I-26	1.4
		I-27	3.3
I-29	2.5
		I-30	6.9
I-32	1.5
		I-33	1.4
I-34	1.5
		I-35	1.7
I-36	1.8
		I-37	2.5
I-38	2.4
		I-39	1.5
I-40	1.4
		I-41	1.1
I-42	1.6
		I-43	1.1

I-44	3.3
		I-45	3.2
I-46	6.1
		I-47	2.0
I-48	1.7
		I-49	6.2
I-50	2.2

#	％CTL
		I-51	4.0
I-52	1.6
		I-53	1.4
I-54	1.2
		I-55	1.2
I-56	1.4
		I-57	2.3
I-58	5.5
		I-59	13.4
I-60	7.2
		I-61	8.1
I-62	2.8
		I-63	4.6
I-64	6.6
		I-65	7.1

I-66	6.4
		I-67	2.9
I-68	4.7
		I-69	2.8
I-70	10.4
		I-71	5.5
I-72	5.1
		I-73	1.7
I-74	9.0
		I-75	7.3
I-76	2.0^***
		I-77	1.9
I-78	2.8
		I-79	3.6
I-80	1.9
		I-81	1.2
I-82	1.6
		I-83	1.1
I-84	2.4
		I-85	1.1
I-86	1.4
		I-87	1.7
I-88	1.3
		I-89	1.5

I-90	2.1
		I-91	2.5
I-92	2.5
		I-93	3.5

#	％CTL
		I-94	3.5
I-95	3.1
		I-96	3.4
I-97	3.3
		I-98	3.0
I-99	1.9
		I-100	3.0
I-101	1.3^***
		I-102	4.6
I-103	3.8
		I-104	2.1
I-105	2.0^***
		I-106	1.3
I-107	1.6
		I-108	1.7
I-109	1.8
		I-110	1.3
I-111	1.8

I-112	2.0
		I-113	2.9
I-114	15.6^**
		I-115	1.9
I-116	3.1
		I-117	3.1
I-118	2.6
		I-119	1.8
I-120	1.7
		I-121	2.3^***
I-122	1.8
		I-123	5.8
I-124	1.9
		I-125	1.2
I-126	5.7
		I-127	6.1
I-128	5.3
		I-130	2.2
I-131	2.2
		I-132	1.0
I-134	2.6
		I-135	2.6
I-136	2.5
		I-137	2.5

I-138	2.5
		#	％CTL
I-139	2.5
		I-140	2.2
I-141	2.1
		I-142	1.5
I-143	2.2
		I-144	1.9
I-145	2.2
		I-146	2.0
I-147	3.1
		I-148	4.0
I-149	2.1
		I-150	4.1
I-151	4.5
		I-152	2.4
I-153	1.8
		I-154	2.9
I-155	2.6
		I-164	9.9
I-165	8.9
		I-166	7.9
I-167	7.9
		I-168	9.8

I-169	8.4
		I-170	7.5
I-171	7.7
		I-172	8.0
I-173	2.4
		I-174	8.1
I-175	8.1
		I-176	6.7
I-177	1.9
		I-178	2.3
I-179	2.6
		I-180	2.9
I-181	2.3
		I-182	2.1
I-183	1.8
		I-184	2.5
I-185	1.7
		I-186	1.5
I-187	4.1
		I-188	1.5
I-189	3.8

#

％CTL

I-190	4.1
		I-191	3.0
I-192	1.9
		I-193	3.6
I-194	2.1
		I-195	0.8
I-196	1.0
		I-197	1.0
I-198	1.7
		I-199	1.6
I-200	1.0
		I-201	1.6
I-202	1.6
		I-204	1.0
I-205	0.8
		I-206	0.9
XII-1	4.4
		XII-2	4.6
XII-3	4.7
		XII-5	1.8
XII-6	4.7
		XII-7	4.7
XII-8	6.4
		XII-9	6.6

XII-10	2.5
		XII-11	1.5^***
XII-12	5.2
		XII-13	0.9
XII-14	0.9^*
		XII-15	0.8
XII-16	0.7
		XII-17	0.9
XII-18	2.1
		XII-19	6.5
XII-20	1.6
		XII-21	1.5
XII-22	3.4
		XII-23	7.2
XII-24	3.8
		XII-25	3.9
XII-26	2.2
		XII-27	2.4
XII-28	2.0

#	％CTL
		XII-29	1.6
XII-30	1.8
		XII-31	1.9

XII-32	2.9
		XII-33	1.7
XII-34	0.8
		XII-35	1.7
XII-36	1.3
		XII-37	2.3
XII-38	2.1
		XII-39	2.5
XII-40	3.0^*
		XII-41	3.1
XII-42	4.3
		XII-43	2.1
XII-44	1.9
		XII-45	2.9
XII-46	1.8
		XII-47	4.0
XII-48	2.4
		XII-49	2.3
XII-50	6.8
		XII-51	2.3
XII-52	7.0
		XII-53	7.0
XII-54	10.8
		XII-55	1.8

XII-57	0.9
		XII-63	3.8
XII-64	0.9
		XII-65	0.9

^*Measurement at 0.29. mu.M

^**Measurement at 1.02. mu.M

^***Measurement at 1.43. mu.M

Measurement of cultured human melanoma cells (SK-MEL-28, B-RAF)^V600EMutation) inhibition of proliferation

To measure the proliferation of cultured human tumor cells, melanoma cell line SK-MEL-28[ American Type Culture Collection) (ATCC) was cultured in MEM medium]The cell of (a), the medium being supplemented with 10% fetal bovine serum, 2% sodium bicarbonate, 1mM sodium pyruvate, 1% non-essential amino acids (e.g., from Cambrex, No. BE13-114E), and 2mM glutamine. SK-MEL28 cells were plated at a density of 2500 cells/well in 96-well plates with MEM medium (see above) and incubated overnight (at 37 ℃ and 5% CO) in an incubator₂Below). The active substance is added to the cells at various concentrations, ranging from 50. mu.M to 3.2 nM. If desired, the initial concentration of 50. mu.M can be changed to 10. mu.M or 2. mu.M and further dilutions made accordingly (to 0.6nM or 0.12 nM). After an additional incubation time of 72 hours, 20 μ L of AlamarBlue reagent (Serotec ltd. inc., number BUF012B) was added to each well and the cells were incubated for an additional 3-6 hours. The color change of AlamarBlue reagent is measured in a fluorescence spectrometer (e.g., Gemini, molecular devices). EC was calculated using the software program (GraphPadPrizm)₅₀The value is obtained.

Most of the example compounds of types I to XXVI showed good to excellent activity in the intracellular SK-MEL-28 test, i.e.the example compounds of types I and XII (Table 3) showed EC of less than 10. mu.M, typically less than 3. mu.M₅₀The value is obtained.

Measuring the person being culturedMelanoma cells (A375, B-RAF)^V600EMutation) inhibition of proliferation

To measure the proliferation of cultured human tumor cells, cells of melanoma cell line A375[ ATCC ] were cultured in DMEM medium supplemented with 10% fetal bovine serum and 2% sodium bicarbonate. The test substances were tested with A375 cells but seeded at 5000 cells/well according to the procedures described for SK-MEL28 cells (see above).

Most of the example compounds of forms I to XXVI show good to excellent activity in the A375 test, i.e. the example compounds of forms I and XII (Table 3) show an EC of less than 10. mu.M, typically less than 3. mu.M₅₀The value is obtained.

Said active substance being characterized in that its antiproliferative effect on cell lines not having a B-RAF mutation is significantly reduced, i.e. the EC₅₀Values generally compare EC for B-RAF mutant cell lines₅₀The value is ten times higher.

The cell selectivity of the active substance is manifested by the following facts: reduced phosphate-ERK EC₅₀EC values and antiproliferative activity in B-RAF mutant cell lines₅₀The values are correlated.

Measurement of cultured human melanoma cells (SK-MEL-28, B-RAF)^V600EMutation) reduction of phospho-ERK signal

To measure the decrease in phospho-ERK signaling in cultured human tumor cells, melanoma cell line SK-MEL-28[ ATCC ] was cultured in MEM medium]The cell of (1), the medium being supplemented with 10% fetal bovine serum, 2% sodium bicarbonate, 1mM sodium pyruvate, 1% non-essential amino acids (e.g., from Cambrex, code BE13-114E), and 2mM glutamine. SK-MEL28 cells were placed in 96-well plates supplemented with MEM medium (see above) at a density of 7500 cells/well and incubated overnight (at 37 ℃ and 5% CO) in an incubator₂Below). The active substance is added to the cells at various concentrations, ranging from 10. mu.M to 2.4 nM. If desired, the initial concentration of 10. mu.M can be changed to 50. mu.M or 2.5. mu.M, and further dilutions made accordingly (to 12.2nM or 0.6 nM). Re-cultivation 2After hours, cells were fixed with 4% formaldehyde and made permeable with 0.1% Triton X-100 in PBS. Nonspecific antibody binding was reduced by incubation with 5% skim milk powder in TBS-T.

Phosphorylated ERK was detected with the mouse monoclonal anti-diphosphorylated ERK1/2 antibody (from Sigma, accession number M8159). Bound primary antibody was detected by a secondary antibody (polyclonal rabbit anti-mouse IgG coupled to peroxidase, from DAKO, No. P0161) after washing with 0.1% Tween 20 in PBS. After further washing, substrate (TMB peroxidase substrate solution from bendermed systems, accession BMS406) was added. After a few minutes, the color reaction was stopped with 1M phosphoric acid. Color was measured at 450nm with a Spectra max Plus reader from Molecular Devices. EC was calculated using the software program (GraphPadPrizm)₅₀The value is obtained.

The compounds of the invention are B-RAF-kinase inhibitors. The inhibition of proliferation achieved by the compounds of the invention was achieved mainly by preventing entry into the DNA synthesis phase, as demonstrated by FACS or Cellomics Array Scan analysis after DNA staining. The treated cells arrested in the G1 phase of the cell cycle.

Thus, other tumor cells may also be used to test the compounds of the invention. For example, the compounds are effective against colon cancer cell lines (e.g., Colo205), and may be used in this and other indications. This indicates that the compounds of the present invention are useful for the treatment of different types of tumors.

The compounds of general formula (1) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the aforementioned forms can be used, depending on their biological properties, for diseases associated with excessive or abnormal cell proliferation.

Such diseases include, for example: viral infections (e.g., HIV and kaposi's sarcoma); inflammatory and autoimmune diseases (e.g., colitis, arthritis, alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukemias, lymphomas and solid tumors (e.g., carcinomas and sarcomas), skin diseases (e.g., psoriasis); proliferative diseases associated with an increased number of cells, such as fibroblasts, hepatocytes, bone and bone marrow cells, cartilage or smooth muscle cells, or epithelial cells (e.g., endometrial hyperplasia); bone diseases and cardiovascular diseases (e.g., restenosis and hypertrophy). It is also suitable for protecting proliferating cells (e.g., hair cells, intestinal cells, blood cells, and progenitor cells) from DNA damage caused by radiation, UV treatment, and/or cell proliferation inhibition treatment.

For example, the following (but not limited to) cancers may be treated with the compounds of the present invention: brain tumors, such as acoustic neuroma, astrocytoma (e.g., fibrocytoastrocytoma, fibrillar astrocytoma, protoplasmic astrocytoma, fertigoblastoma, glioblastoma multiforme, and glioblastoma), brain lymphoma, brain metastases, pituitary tumors (e.g., prolactinoma, HGH (human growth hormone) -producing tumor, and ACTH (adrenocorticotropic hormone) -producing tumor), craniopharyngeal tumor, medulloblastoma, meningioma, and oligodendroglioma; tumors of the nervous system (neoplasms), such as tumors of the vegetative nervous system (e.g., sympathogenic cytoma, ganglioneuroma (pheochromocytoma), paraganglioma (chromaffinoma)) and carotid glomus), tumors of the peripheral nervous system (e.g., truncated neuroma, neurofibroma, neurinoma (neurinoma), and malignant neurinoma), and tumors of the central nervous system (e.g., brain tumor and bone marrow tumor); intestinal cancer such as rectal cancer, colon cancer, anal cancer, small intestine cancer, and duodenal cancer; eyelid tumors, such as basal cell carcinoma (basalioma) or basal cell carcinoma (basal cell carcinoma); pancreatic or pancreatic cancer; bladder cancer or bladder cancer; lung cancer (bronchial cancer), such as small cell bronchial cancer (oat cell cancer) and non-small cell bronchial cancer, such as squamous cell carcinoma, adenocarcinoma, and large cell bronchial cancer; breast cancers, such as breast cancer (e.g., invasive ductal carcinoma), colloidal cancer, lobular invasive carcinoma, tubular cancer, cystic adenoid cancer, and papillary carcinoma; non-Hodgkin's lymphoma (NHL), such as Burkitt's lymphoma, low grade malignant non-Hodgkin's lymphoma (NHL), and mycosis fungoides; uterine cancer or endometrial cancer or uterine body cancer; CUP syndrome (cancer with unknown primary site); ovarian cancer or ovarian cancer, such as mucinous, endometrial, or serous carcinoma; gallbladder cancer; bile duct cancer, such as hepatoportal bile duct tumor (Klatskin tumor); testicular cancers, such as seminoma and non-seminoma; lymphomas (lymphosarcomas), such as malignant lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (NHL) (e.g., chronic lymphocytic leukemia), leukemic reticuloendotheliosis, immune cell tumors, plasmacytoma (multiple myeloma), immunoblastoma, burkitt's lymphoma, T-zone mycosis fungoides, large cell anaplastic lymphoblastomas, and lymphoblastomas; laryngeal cancers, such as vocal cord tumors, supraglottic tumors, glottic tumors, and subglottic laryngeal tumors; bone cancers such as osteochondroma, chondroma, chondroblastoma, chondroromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumor, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulocytoma, plasmacytoma, fibrodysplasia, juvenile bone cyst, and aneurysm bone cyst; head and neck tumors, such as tumors located in the lip, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, pharynx, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer, such as hepatocellular carcinoma (HCC) or hepatocellular carcinoma; leukemias, such as acute leukemia (e.g., Acute Lymphangioblastic Leukemia (ALL), Acute Myeloid Leukemia (AML)); chronic leukemias, e.g., Chronic Lymphatic Leukemia (CLL), Chronic Myeloid Leukemia (CML); gastric or stomach cancers, such as papillary adenocarcinoma, tubular adenocarcinoma, and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small cell carcinoma, and undifferentiated carcinoma; melanomas such as superficial spreading melanoma, nodular melanoma, black nevus melanoma, and acromelasma melanoma; kidney cancers, such as renal cell carcinoma or suprarenal adenoid or adrenal-like tumors (Grawitz's tumor); esophageal cancer or esophageal cancer; penile cancer; prostate cancer; laryngeal or pharyngeal cancer, such as nasopharyngeal, oropharyngeal, and hypopharyngeal cancers; retinoblastoma, such as vaginal cancer or vaginal cancer; squamous carcinoma, adenocarcinoma, carcinoma in situ (in situ carcinomas), malignant melanoma, and sarcoma; thyroid cancer such as papillary carcinoma, follicular carcinoma, and medullary thyroid carcinoma, and anaplastic carcinoma; spinal cord cancer, epidermoid carcinoma of the skin, and squamous carcinoma; thymoma, cancer of the urethra and cancer of the vulva.

The novel compounds are useful for the prophylaxis, short-term or long-term treatment of the abovementioned diseases and optionally also in combination with radiotherapy or other "existing" compounds, for example cytostatic or cytotoxic substances, cytostatic agents, antiangiogenic substances, steroids or antibodies.

The compounds of the general formula (1) can be used alone 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 of the invention include, but are not limited to, hormones, hormone analogs and anti-hormonal agents (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liazole, vorozolozole, exemestane, atamet), LHRH agonists and antagonists (e.g., capromorelin acetate, leuprolide), growth factor inhibitors (e.g., "platelet-derived growth factor" and "hepatocyte growth factor", inhibitors (e.g., "growth factor" antibodies, "growth factor receptor" antibodies and tyrosine kinase inhibitors), such as cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g., antifolates such as methotrexate, raltitrexed; pyrimidine analogs such as 5-fluorouracil, capecitabine and gemcitabine; purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumor antibiotics (e.g., anthracycline antibiotics such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, actinomycin D, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, mecloethymene (mecloethamine), melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas (e.g., carmustine and lomustine, thiotepa), antimitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine (vindesin), vinorelbine (vinorelbine) and vincristine; and taxanes such as paclitaxel, docetaxel), topoisomerase inhibitors (e.g., epidophyllotoxins such as etoposide and viniboside, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone) and various chemotherapeutic agents such as amifostine, anagrelide, clodronate, filgrastim, interferon alpha, calcium folinate, rituximab, procarbazine, levamisole, mesteine, mitotane, mellitorine, meclizine, mellitorine, meclizine, and other, Pamidronate and porfiiel sodium.

Suitable formulations include, for example, tablets, capsules, suppositories, elixirs of solutions, in particular for injection (subcutaneous, intravenous, intramuscular) and infusion solutions, emulsions or dispersible powders. The amount of pharmaceutically active compound should be from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight, of the total composition, i.e. an amount sufficient to achieve the dosage ranges described below. If desired, the indicated dose may be administered several times per day.

Suitable tablets may be obtained by mixing the active substance with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose; disintegrating agents, such as corn starch or alginic acid; binders, such as starch or gelatin; lubricants, for example magnesium stearate or talc, and/or release-retarding agents, for example carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise several layers.

Coated tablets may thus be prepared by coating a core obtained in a manner analogous to tablets with substances conventionally used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of multiple layers for delayed release or to prevent incompatibility. Likewise, the tablet coating may consist of multiple layers to achieve delayed release, wherein the excipients described above for tablets may be used.

A syrup or elixir containing an active substance or a combination thereof according to the invention may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerol or sugar, and a taste-enhancing agent, such as a flavoring agent, such as vanillin or citrus extract. It may also contain suspension adjuvants or thickeners (e.g. sodium carboxymethylcellulose), wetting agents (e.g. condensation products of fatty alcohols with ethylene oxide) or preservatives (e.g. parabens).

Solutions for injection and infusion are prepared in a conventional manner, for example by adding isotonic agents, preservatives (e.g. parabens) or stabilizers (e.g. alkali metal salts of ethylenediamine tetraacetic acid), optionally with emulsifiers and/or dispersants, optionally with organic solvents as dissolving agents or dissolving aids, for example if water is used as diluent, and transferring the solution to injection bottles or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may be prepared, for example, by mixing the active substances with inert carriers, for example lactose or sorbitol, and encapsulating them in gelatin capsules.

Suitable suppositories may be prepared, for example, by mixing them with carriers provided for this purpose, for example neutral fats or polyethylene glycols or derivatives thereof.

Useful excipients include, for example, water; pharmaceutically acceptable organic solvents, for example paraffins (e.g. petroleum fractions), vegetable oils (e.g. arachis oil or sesame oil), mono-or polyhydric alcohols (e.g. ethanol or glycerol); carriers such as natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. sucrose, lactose and glucose), emulsifiers (e.g. lignin, spent sulfite liquors (spent sulfite liquors), methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The formulations are administered by conventional means, preferably by the oral or transdermal route, more preferably by oral administration. For oral administration, the tablets may of course contain, in addition to the above-mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, as well as various additives such as starch (preferably potato starch), gelatin and the like. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used simultaneously in the tableting process. In the case of aqueous suspensions, the active substance may be combined with various flavoring or coloring agents in addition to the excipients described above.

For parenteral use, solutions of the active substance in a suitable liquid carrier may be employed.

The dose used intravenously is between 1 and 1000 mg/hour, preferably between 5 and 500 mg/hour.

However, depending on the body weight, route of administration, individual response to the drug, nature of the pharmaceutical formulation, and time or interval of drug administration, it may sometimes be desirable to deviate from the amounts specified. Thus, in some cases it may be sufficient to use an amount lower than the minimum dose mentioned above, while in other cases the upper limit of the dose mentioned above may have to be exceeded. When administered in large amounts, they may suitably be divided into a number of smaller doses to be administered at different times of the day.

The following formulation examples are intended to illustrate the invention without limiting its scope:

examples of pharmaceutical formulations:

the finely ground active substance, lactose and a portion of the corn starch are mixed together. The mixture is sieved and then moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet-granulated and dried. The granules, the remaining corn starch and magnesium stearate are sieved and mixed. The mixture is compressed to produce tablets of suitable shape and size.

The finely ground active substance, part of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed, the mixture is sieved and treated with the remaining corn starch and water to form granules, which are dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is compressed to form tablets of appropriate size.

C) Ampoule solution

50mg of active substance of formula (1)

50mg of sodium chloride

5mL of water for injection

The active substance is dissolved in water at the pH of the water itself or optionally at a pH of 5.5 to 6.5 and made isotonic by the addition of sodium chloride. The resulting solution is filtered free of pyrogens and the filtrate is transferred under aseptic conditions to ampoules, which are then sterilized and sealed by melting. Ampoules contain 5mg, 25mg and 50mg of active substance.

Claims

1. A compound of the general formula (1)

Wherein R is¹Represents optionally substituted by one or more identical or different R^bAnd/or R^cA substituted 5-or 6-membered monocyclic or 9-or 10-membered bicyclic heteroaryl having the alkyl moiety structure (i)

Wherein the ring directly bonded to Q is a heteroaromatic ring;

q is selected from

L¹is selected from (R)²) -C (O) NH-and (R)²)-NHC(O)-；

each R^fAre suitable substituents and are selected, independently of one another, from: OR (OR)^g、-SR^g、-NR^gR^g、-ONR^gR^g、-N(OR^g)R^g、-N(R^h)NR^gR^gHalogen, -CN, -NO₂、-N₃、-C(O)R^g、-C(O)OR^g、-C(O)NR^gR^g、-C(O)NR^hNR^gR^g、-C(O)NR^hOR^g、-C(NR^h)R^g、-N＝CR^gR^g、-C(NR^h)OR^g、-C(NR^h)NR^gR^g、-C(NR^h)NR^hNR^gR^g、-C(NOR^h)R^g、-C(NOR^h)NR^gR^g、-C(NNR^hR^h)R^g、-OS(O)R^g、-OS(O)OR^g、-OS(O)NR^gR^g、-OS(O)₂R^g、-OS(O)₂OR^g、-OS(O)₂NR^gR^g、-OC(O)R^g、-OC(O)OR^g、-OC(O)NR^gR^g、-OC(NR^h)R^g、-OC(NR^h)NR^gR^g、-ONR^hC(O)R^g、-S(O)R^g、-S(O)OR^g、-S(O)NR^gR^g、-S(O)₂R^g、-S(O)₂OR^g、-S(O)₂NR^gR^g、-NR^hC(O)R^g、-NR^hC(O)OR^g、-NR^hC(O)NR^gR^g、-NR^hC(O)NR^hNR^gR^g、-NR^hC(NR^h)R^g、-N＝CR^gNR^gR^g、-NR^hC(NR^h)OR^g、-NR^hC(NR^h)NR^gR^g、-NR^hC(NOR^h)R^g、-NR^hS(O)R^g、-NR^hS(O)OR^g、-NR^hS(O)₂R^g、-NR^hS(O)₂OR^g、-NR^hS(O)₂NR^gR^g、-NR^hNR^hC(O)R^g、-NR^hNR^hC(O)NR^gR^g、-NR^hNR^hC(NR^h)R^gand-N (OR)^h)C(O)R^gAnd divalent substituents ═ O, ═ S, ═ NR^h、＝NOR^h、＝NNR^hR^hAnd NNR^hC(O)NR^hR^hWherein these divalent substituents may only be substituents in non-aromatic ring systems;

each R^gIndependently of one another represent hydrogen orSelected from the group consisting of^hSubstituted of the following groups: c_1-6Alkyl, 2-6 membered heteroalkyl, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl;

2. A compound of the general formula (1)

Wherein R is¹Is optionally substituted by one or more identical or different R^bAnd/or R^cSubstituted 5-10 membered heteroaryl;

L¹is selected from (R)²) -C (O) NH-and (R)²)-NHC(O)-；

Each R^bAre suitable substituents and are selected, independently of one another, from-OR^c、-SR^c、-NR^cR^c、-ONR^cR^c、-N(OR^c)R^c、-NR^gNR^cR^cHalogen, -CN, -NO₂、-N₃、-C(O)R^c、-C(O)OR^c、-C(O)NR^cR^c、-C(O)NR^gNR^cR^c、-C(O)NR^gOR^c、-C(NR^g)R^c、-N＝CR^cR^c、-C(NR^g)OR^c、-C(NR^g)NR^cR^c、-C(NR^g)NR^gNR^cR^c、-C(NOR^g)R^c、-C(NOR^g)NR^cR^c、-C(NNR^gR^g)R^c、-OS(O)R^c、-OS(O)OR^c、-OS(O)NR^cR^c、-OS(O)₂R^c、-OS(O)₂OR^c、-OS(O)₂NR^cR^c、-OC(O)R^c、-OC(O)OR^c、-OC(O)NR^cR^c、-OC(NR^g)R^c、-OC(NR^g)NR^cR^c、-ONR^gC(O)R^c、-S(O)R^c、-S(O)OR^c、-S(O)NR^cR^c、-S(O)₂R^c、-S(O)₂OR^c、-S(O)₂NR^cR^c、-NR^gC(O)R^c、-NR^gC(O)OR^c、-NR^gC(O)NR^cR^c、-NR^gC(O)NR^gNR^cR^c、-NR^gC(NR^g)R^c、-N＝CR^cNR^cR^c、-NR^gC(NR^g)OR^c、-NR^gC(NR^g)NR^cR^c、-NR^gC(NOR^g)R^c、-NR^gS(O)R^c、-NR^gS(O)OR^c、-NR^gS(O)₂R^c、-NR^gS(O)₂OR^c、-NR^gS(O)₂NR^cR^c、-NR^gNR^gC(O)R^c、-NR^gNR^gC(O)NR^cR^c、-NR^gNR^gC(NR^g)R^cand-N (OR)^g)C(O)R^cAnd divalent substituents ═ O, ═ S, ═ NR^g、＝NOR^g、＝NNR^gR^gAnd (NNR)^gC(O)NR^gR^gWherein these divalent substituents may only be substituents in non-aromatic ring systems;

each R^fAre suitable substituents and are selected, independently of one another, from-OR^g、-SR^g、-NR^gR^g、-ONR^gR^g、-N(OR^g)R^g、-N(R^h)NR^gR^gHalogen, -CN, -NO₂、-N₃、-C(O)R^g、-C(O)OR^g、-C(O)NR^gR^g、-C(O)NR^hNR^gR^g、-C(O)NR^hOR^g、-C(NR^h)R^g、-N＝CR^gR^g、-C(NR^h)OR^g、-C(NR^h)NR^gR^g、-C(NR^h)NR^hNR^gR^g、-C(NOR^h)R^g、-C(NOR^h)NR^gR^g、-C(NNR^hR^h)R^g、-OS(O)R^g、-OS(O)OR^g、-OS(O)NR^gR^g、-OS(O)₂R^g、-OS(O)₂OR^g、-OS(O)₂NR^gR^g、-OC(O)R^g、-OC(O)OR^g、-OC(O)NR^gR^g、-OC(NR^h)R^g、-OC(NR^h)NR^gR^g、-ONR^hC(O)R^g、-S(O)R^g、-S(O)OR^g、-S(O)NR^gR^g、-S(O)₂R^g、-S(O)₂OR^g、-S(O)₂NR^gR^g、-NR^hC(O)R^g、-NR^hC(O)OR^g、-NR^hC(O)NR^gR^g、-NR^hC(O)NR^hNR^gR^g、-NR^hC(NR^h)R^g、-N＝CR^gNR^gR^g、-NR^hC(NR^h)OR^g、-NR^hC(NR^h)NR^gR^g、-NR^hC(NOR^h)R^g、-NR^hS(O)R^g、-NR^hS(O)OR^g、-NR^hS(O)₂R^g、-NR^hS(O)₂OR^g、-NR^hS(O)₂NR^gR^g、-NR^hNR^hC(O)R^g、-NR^hNR^hC(O)NR^gR^g、-NR^hNR^hC(NR^h)R^gand-N (OR)^h)C(O)R^gAnd divalent substituents ═ O, ═ S, ═ NR^h、＝NOR^h、＝NNR^hR^hAnd NNR^hC(O)NR^hR^hWherein these divalent substituents may only be substituents in non-aromatic ring systems;

3. The compound of claim 2, wherein

Q is selected from

4. A compound according to claim 2 or 3, wherein

R^band R^cAs defined in claim 2.

5. The compound of claim 1 or 2 or 4,

wherein R is¹Is represented by one or more identical or different R^b2And/or R^c2Substituted heteroaryl;

each R^c2Independently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^d2And/or R^e2Substituted of the following groups: c_1-6Alkyl radical, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl;

each R^g2Independently of one another, from hydrogen, C_1-6Alkyl radical, C_3-10Cycloalkyl and C_6-10And (4) an aryl group.

6. The compound of claim 5, wherein

R¹To represent

the above groups may optionally be substituted, wherever possible, by one or more of the following substituents, which may be the same or different: -OH, -OC_1-6Alkyl, -C_1-6Haloalkyl, -OC_3-6Cycloalkyl radical, C_3-6Cycloalkyl, -CN, -C (O) NH₂、-C(O)NH(C_1-6Alkyl) and-C (O) N (C)_1-6Alkyl radical)₂。

7. The compound of claim 5, wherein R¹To represent

8. The compound of any one of claims 1 to 7, wherein

X¹Denotes nitrogen, X²Represents CR^4-1And X³Represents CR^4-2And is and

R^4-1and R^4-2Each independently of the others, selected from hydrogen, fluorine, chlorine and methyl, and the radical R^4-1And R^4-2At least one of them represents hydrogen.

9. The compound of any one of claims 1 to 8, wherein

R²Is optionally substituted by one or more identical or different R^bAnd/or R^cSubstituted of the following groups: a phenyl 5-6 membered heteroaryl group,

and R is^bAnd R^cAs defined in claim 1.

10. A compound according to claim 9, which is a pharmaceutically acceptable salt thereof,

wherein R is²Is heteroaryl selected from the group consisting of furyl, thienyl, pyrrolyl,Azolyl, thiazolyl, triazolyl, isoylAzolyl, isothiazolyl, pyrazolyl, imidazolyl,Oxadiazolyl, thiadiazolyl, pyridinyl, and pyrimidinyl, and optionally substituted with one or two substituents each independently selected from C_3-7Cycloalkyl, phenyl, 4-to 7-membered heterocycloalkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 1-ethylpropyl, isopentyl, neopentyl, trifluoromethyl, difluoromethyl, fluoromethyl, tert-butoxy, trifluoromethoxy,

11. the compound of claim 9, wherein

R²Represents a phenyl group

R⁷selected from hydrogen, -OC_1-6Alkyl, halogen, -NHS (O)₂C_1-6Alkyl, -S (O)₂NH₂、-S(O)₂NHC_1-6Alkyl, -S (O)₂N(C_1-6Alkyl radical)₂，

R⁹Selected from hydrogen and C_1-6An alkyl group;

R^c1represents hydrogen or is selected from the group consisting of R optionally substituted by one or more, the same or different^d1And/or R^e1Substituted of the following groups: c_1-6Alkyl and 3-14 membered heterocycloalkyl;

each R^e1Independently of one another, represents hydrogen or is selected from the group consisting of R which are optionally identical or different^f1And/or R^g1SubstitutionThe following groups of (a): c_1-6Alkyl radical, C_1-6Haloalkyl, C_3-10Cycloalkyl radical, C_6-10Aryl, 5-12 membered heteroaryl, and 3-14 membered heterocycloalkyl:

or

12. The compound of claim 11, wherein

R⁵Is selected from

13. The compound of claim 1 selected from the group consisting of:

I-1N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl]-6-methyl-nicotinamide;

1-25- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (4-trifluoromethyl-pyridin-2-yl) -nicotinamide;

1-35- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-4N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-5N- (5-tert-butyl-2H-pyrazol-3-yl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-65- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- [ 4-methyl-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-75- [4- (1, 5-dimethyl-1 II-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- (4-methoxy-3-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-85- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (2-methyl-5-trifluoromethyl-phenyl) -nicotinamide;

1-9N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-105- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- [ 4-fluoro-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-115- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- (3-fluoro-5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-125- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -nicotinamide;

1-135- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (isopropylamino-methyl) -2-methoxy-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-145- [4- (2-acetylamino-thiazol-5-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-N- (4-trifluoromethyl-pyridin-2-yl) -nicotinamide;

1-155- [4- (2-acetylamino-thiazol-5-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-N- (3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -nicotinamide;

1-165- (4- (2-acetylamino-thiazol-5-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-N- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

i-175- [4- (2-acetylamino-thiazol-5-yl) -1, 2, 3-triazol-1-yl ] -methyl-acetamide]-N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-nicotinamide;

1-186-methyl-N- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-19N- [ 4-fluoro-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -6-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-20N- [3- (4-ethyl-piperazin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

I-21N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-22N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -6-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-236-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -N- (4-trifluoromethyl-pyridin-2-yl) -nicotinamide;

1-245- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-N- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-25N- [ 4-fluoro-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -5- (4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-26N- [3- (4-ethyl-piperazin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -5- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

I-27N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-6-methyl-nicotinamide;

1-28N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -5- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-295- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-N- (4-trifluoromethyl-pyridin-2-yl) -nicotinamide;

1-30N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -6-methyl-5- [4- (6-methyl-imidazo [1, 2-a ] pyrazin-3-yl) -1, 2, 3-triazol-1-yl ] -nicotinamide;

I-31N- (5-tert-butyl-iso-butyl)Azol-3-yl) -6-methyl-5- [4- (6-methyl-imidazo [1, 2-a ]]Pyrazin-3-yl) -1, 2, 3-triazol-1-yl]-nicotinamide;

1-326-methyl-5- [4- (6-methyl-imidazo [1, 2-a ] pyrazin-3-yl) -1, 2, 3-triazol-1-yl ] -N- (4-trifluoromethyl-pyridin-2-yl) -nicotinamide;

1-33N- (4-methoxy-3-trifluoromethyl-phenyl) -6-methyl-5- [4- (6-methyl-imidazo [1, 2-a ] pyrazin-3-yl) -1, 2, 3-triazol-1-yl ] -nicotinamide;

i-345- [4- (5-bromo-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-nicotinamide;

I-35N- (5-tert-butyl-iso-butyl)Azol-3-yl) -6-methyl-5- [4- (5-morpholin-4-yl-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-nicotinamide;

I-36N- (5-tert-butyl-iso-butyl)Azol-3-yl) -6-methyl-5- [4- (5-perhydro-1, 4-oxazepan-4-yl-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-nicotinamide;

I-37N- (5-tert-butyl-iso-butyl)Azol-3-yl) -6-methyl-5- {4- [5- (tetrahydro-furan-3-ylamino) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -nicotinamide;

I-38N- (5-tert-butyl-iso-butyl)Azol-3-yl) -6-methyl-5- (4- {5- [ methyl- (tetrahydro-furan-3-yl) -amino]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -nicotinamide;

I-39N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl) -nicotinamide;

I-40N- (5-tert-butyl-iso-butyl)Azol-3-yl) -6-methyl-5- {4- [5- (tetrahydro-pyran-4-ylamino) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -nicotinamide;

I-41N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- {4- [5- (2-methoxy-ethylamino) -pyridin-3-yl]-1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-42N- (3-tert-butyl-iso-butyl)Oxazol-5-yl) -5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl]-6-methyl-nicotinamide;

1-43N- [3 (-4-ethyl-piperazin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-446-methyl-5- [4- (6-methyl-imidazo [1, 2-a ] pyrazin-3-yl) -1, 2, 3-triazol-1-yl ] -N- [ 4-methyl-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-456-methyl-5- [4- (6-methyl-imidazo [1, 2-a ] pyrazin-3-yl) -1, 2, 3-triazol-1-yl ] -N- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-46N- [3- (4-ethyl-piperazin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-5- (4-pyridin-3-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-475- [4- (6-acetylamino-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -N- [3- (4-ethyl-piperazin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-485- [4- (2-acetylamino-thiazol-5-yl) -1, 2, 3-triazol-1-yl ] -N- [3- (4-ethyl-piperazin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-495- [4- (5-cyano-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -N- [3- (4-ethyl-piperazin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-50N- [3- (isopropylamino-methyl) -4-methoxy-5-trifluoromethyl-phenyl ] -6-methyl-5- [4- (6-methyl-imidazo [1, 2-a ] pyrazin-3-yl) -1, 2, 3-triazol-1-yl ] -nicotinamide;

1-516-methyl-N- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethoxy-phenyl ] -5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-52N- (4-chloro-3-dimethylaminomethyl-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-53N- (4-chloro-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-54N- [ 4-chloro-3- (isopropylamino-methyl) -5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-55N- [ 4-chloro-3- (isobutylamino-methyl) -5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-56N- (3-bromo-4-methyl-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-575- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- [3- (4-ethyl-piperazin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-585- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (4-isopropyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-595- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (4-ethyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-60N- {3- [ (2-dimethylamino-ethyl) -methyl-amino ] -5-trifluoromethyl-phenyl } -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-615- (4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (4-methyl-3-morpholin-4-yl-5-trifluoromethyl-phenyl) -nicotinamide;

1-62N- (3-bromo-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-63N- [3- ((S) -3-dimethylamino-pyrrolidin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-64N- (4-methoxy-3-trifluoromethyl-phenyl) -6-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-65N- [3- ((R) -3-dimethylamino-pyrrolidin-1-yl) -4-methyl-5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-665- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (4-methyl-3-piperidin-1-yl-5-trifluoromethyl-phenyl) -nicotinamide;

1-676-methyl-N- [ 4-methyl-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-685- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- (3-ethylamino-4-methyl-5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-695- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (3-morpholin-4-yl-5-trifluoromethyl-phenyl) -nicotinamide;

1-70N- [3- (2-dimethylamino-ethylamino) -4-methyl-5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-71N- {3- [ (2-dimethylamino-ethyl) -methyl-amino ] -4-methyl-5-trifluoromethyl-phenyl } -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-726-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -N- (3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -nicotinamide;

1-73N- (3-diethylamino-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-745- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (3-piperidin-1-yl-5-trifluoromethyl-phenyl) -nicotinamide;

1-755- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- (3-ethylamino-5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-76N- [3- ((R) -3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-77N- [3- ((S) -3-dimethylamino-pyrrolidin-1-yl) -5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-78N- [3- (2-dimethylamino-ethylamino) -5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-796-methyl-N- [3- (4-methyl-imidazol-1-yl) -5-trifluoromethyl-phenyl ] -5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

I-80N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- (4-pyridin-3-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-816-methyl-5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -N- (4-trifluoromethyl-pyridin-2-yl) -nicotinamide;

I-82N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-83N- (5-tert-butyl-2H-pyrazol-3-yl) -6-methyl-5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-84N- (5-tert-butyl-2H-pyrazol-3-yl) -5- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-855- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-N- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethoxy-phenyl ] -nicotinamide;

1-865- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-lh- Λ/- [3- (1-methyl-piperidin-4-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-875- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- [3- (1-methyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-885- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- [3- (1, 2, 3, 6-tetrahydro-pyridin-4-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-89N- (4-methoxy-3-trifluoromethyl-phenyl) -6-methyl-5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-90N- (4-chloro-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -5- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-915- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-N- (3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -nicotinamide;

1-925- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -N- (4-methoxy-3-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-93N- (3-dimethylaminomethyl-4-methyl-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-945- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- (3- { [ (2-methoxy-ethyl) -methyl-amino ] -methyl } -4-methyl-5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-955- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- [3- (isobutylamino-methyl) -4-methoxy-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-965- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- (4-methoxy-3- { [ (2-methoxy-ethyl) -methyl-amino ] -methyl) -5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-975- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- [3- (1-ethyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-98N- [3- (1-cyclopropylmethyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl) -4-methyl-5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-99N- [3- (1-sec-butyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl) -4-methyl-5-trifluoromethyl-phenyl ] -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-100N- (3-bromo-2-methyl-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-1015- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- [ 2-methyl-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-102N- (3-dimethylaminomethyl-2-methoxy-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-1035- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- [3- (isopropylamino-methyl) -4-methoxy-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-1045- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- (2-methoxy-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-1055- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (isobutylamino-methyl) -2-methoxy-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-106N- (3-dimethylaminomethyl-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-1075- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (isopropylamino-methyl) -5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-1085- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (isobutylamino-methyl) -5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-1095- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- (3- { [ (2-methoxy-ethyl) -methyl-amino ] -methyl } -5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-1105- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (3-methylaminomethyl-5-trifluoromethyl-phenyl) -nicotinamide;

1-111N- (3-cyclopropylaminomethyl-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-1125- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -N- (2-methoxy-3- { [ (2-methoxy-ethyl) -methyl-amino ] -methyl } -5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-1135- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- (3-hydroxymethyl-4-methoxy-5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-1145- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (2-methyl-3-piperidin-1-yl-5-trifluoromethyl-phenyl) -nicotinamide;

1-115N- (4-chloro-3-hydroxymethyl-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-1165- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- (4-methoxy-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -6-methyl-nicotinamide;

1-117N- (3-dimethylaminomethyl-4-methoxy-5-trifluoromethyl-phenyl) -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-1185- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (2-methyl-3-perhydro-1, 4-oxazepan-4-yl-5-trifluoromethyl-phenyl) -nicotinamide;

1-119N- {3- [ (2-dimethylamino-ethyl) -methyl-amino ] -2-methyl-5-trifluoromethyl-phenyl } -5- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-nicotinamide;

1-1205- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (4-ethyl-piperazin-1-yl) -2-methyl-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-1215- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (2-methyl-3-pyrrolidin-1-yl-5-trifluoromethyl-phenyl) -nicotinamide;

1-1225- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (2-methyl-3-morpholin-4-yl-5-trifluoromethyl-phenyl) -nicotinamide;

1-1236-methyl-N- (3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-1246-methyl-N- [3- (4-methyl-piperazin-1-yl) -5-trifluoromethoxy-phenyl ] -5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-1255- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- [ 4-methyl-3- (1-methyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-1265- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- [ 4-methyl-3- (1, 2, 3, 6-tetrahydro-pyridin-4-yl) -5-trifluoromethyl-phenyl ] -nicotinamide;

1-127N- (4-chloro-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -6-methyl-5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-128N- [ 4-fluoro-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-phenyl ] -6-methyl-5- (4-thiazol-5-yl-1, 2, 3-triazol-1-yl) -nicotinamide;

1-129N- (4-methoxy-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -6-methyl-5- [4- (6-methyl-imidazo [1, 2-a ] pyrazin-3-yl) -1, 2, 3-triazol-1-yl ] -nicotinamide;

1-1305- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl- Λ/- (4-methyl-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl) -nicotinamide;

1-1315- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (isobutylamino-methyl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

1-1325- [4- (1, 5-dimethyl-lh-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] - Λ/- [3- (isopropylamino-methyl) -4-methyl-5-trifluoromethyl-phenyl ] -6-methyl-nicotinamide;

I-133N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- [4- (5-fluoro-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-6-methyl-nicotinamide;

I-134N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-ethyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-135N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- (4- {5- [4- (2-methoxy-ethyl) -piperazin-1-yl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-136N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- [4- (4-morpholin-4-yl-3, 4, 5, 6-tetrahydro-2H-1.3 '-bipyridin-5' -yl) -1, 2, 3-triazol-1-yl]-nicotinamide;

I-137N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- {4- [5- (4-cyclopropylmethyl-piperazineOxazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-138N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- {4- [5- (2-dimethylamino-ethylamino) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-139N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- [4- (3, 4, 5, 6, 3 ', 4', 5 ', 6' -octahydro-2H, 2 'H-1, 4'; 1', 3 "-terpyridin-5" -yl) -1, 2, 3-triazol-1-yl]-nicotinamide;

I-140N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-141N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- (4- {5- [ (2-dimethylamino-ethyl) -methyl-amino]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

1-142N- (4-chloro-3-trifluoromethyl-phenyl) -6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -nicotinamide;

I-143N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- ((R) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-1446-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -N- (4-trifluoromethyl-pyridin-2-yl) -nicotinamide;

I-145N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- ((S) -3-dimethylamino-pyrrolidin-1-yl) -pyridin-3-yl) -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-146N- (4-methoxy-3-trifluoromethyl-phenyl) -6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -nicotinamide;

1-147N- (3-tert-butyl-4-chloro-phenyl) -6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -nicotinamide;

1-148N- (4-tert-butyl-thiazol-2-yl) -5- (4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-1495- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -N- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) -6-methyl-nicotinamide;

1-1505- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -N- (1-isopropyl-1H-pyrazol-4-yl) -6-methyl-nicotinamide;

1-151N- (1-isopropyl-5-methyl-1H-pyrazol-4-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-1525- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-N- (4-trifluoromethyl-pyridin-2-yl) -nicotinamide;

1-153N- (5-tert-butyl-1, 3, 4-thiadiazol-2-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-154N- (3-isopropyl-iso)Oxazol-5-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl) -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-155N- (6-tert-butyl-pyrimidin-4-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

i-1565- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-N- (3-trifluoromethyl-isoOxazol-5-yl) -nicotinamide;

I-157N- [3- (1-fluoro-1-methyl-ethyl) -isoAzol-5-yl]-5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-158N- [3- (1, 1-dimethyl-propyl) -isoAzol-5-yl]-5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-159N- (3-tert-butyl-iso-butyl)Oxazol-5-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-160N- [3- (2, 2-dimethyl-propyl) -isoAzol-5-yl]-5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-161N- (2-tert-butyl-pyridin-4-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-162N- (3-tert-butyl-1, 2, 4-thiadiazol-5-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-163N- (5-tert-butyl-4-methyl-4H-1, 2, 4-triazol-3-yl) -5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-164N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- {4- [5- (4-propyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -nicotinamide;

I-165N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-cyclopropyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-166N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-167N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-tert-butyl-piperazin-1-yl) -pyridin-3-yl) -1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-168N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- (4- {5- [4- (3-hydroxy-propyl) -piperazin-1-yl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-169N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- (4- {5- [4- (3-methoxy-propyl) -piperazin-1-yl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-170N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- (4- {5- [4- (2-ethoxyethyl) -piperazin-1-yl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-171N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-isobutyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-172N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-butyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-173N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-cyclohexylmethyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

i-1745- {4- [5- (4-allyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-nicotinamide;

I-175N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- (4- {5- [4- (2-cyano-ethyl) -piperazin-1-yl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-176N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- {4- [5- (4-dimethylcarbamoylmethyl) amideRadical-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

1-177N- (6-tert-butyl-pyrimidin-4-yl) -6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -nicotinamide;

1-178N- (2-tert-butyl-pyridin-4-yl) -6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -nicotinamide;

I-179N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- (4- {5- [4- (2-hydroxy-ethyl) -piperazin-1-yl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-180N- (3-tert-butyl-iso-butyl)Oxazol-5-yl) -6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl) -nicotinamide;

I-181N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- (4- {5- (4- (2, 2-difluoro-ethyl) -piperazin-1-yl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-182N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- (4- {5- [4- (2, 2, 2-trifluoro-ethyl) -piperazin-1-yl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -nicotinamide;

I-183N- (5-tert-butyl-iso-butyl)Azol-3-yl) -6-methyl-5- [4- (5-piperazin-1-yl-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-nicotinamide;

I-184N- (5-tert-butyliso-butyl)Azol-3-yl) -6-methyl-5- [4- (5-morpholin-4-ylmethyl-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-nicotinamide;

I-185N- (5-tert-butyl-iso-butyl)Azol-3-yl) -6-methyl-5- [4- (5-pyrrolidin-1-ylmethyl-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-nicotinamide;

I-186N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-5- {4- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl) -nicotinamide;

I-187N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- [4- (5-dimethylaminomethyl-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-6-methyl-nicotinamide;

I-188N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-ethyl-piperazin-1-ylmethyl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-189N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (3, 3-difluoro-pyrrolidin-1-ylmethyl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-190N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- (4-isopropyl-piperazin-1-ylmethyl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-191N- (5-tert-butyl-iso-butyl)Azol-3-yl) -5- (4- {5- [ (ethyl-methyl-amino) -methyl]-pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-nicotinamide;

I-192N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- ((R) -3-fluoro-pyrrolidin-1-ylmethyl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

I-193N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -5- {4- [5- ((S) -3-fluoro-pyrrolidin-1-ylmethyl) -pyridin-3-yl]-1, 2, 3-triazol-1-yl } -6-methyl-nicotinamide;

i-1945- [4- (5-aminomethyl-pyridin-3-yl) -1, 2, 3-triazol-1-yl]-N- (5-tert-butyl-iso-butyl)Oxazol-3-yl) -6-methyl-nicotinamide;

XII-1N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-benzamide;

XII-24-trifluoromethyl-pyridine-2-carboxylic acid {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -amide;

XII-35-tert-butyl-isoAzole-3-carboxylic acid {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl]-6-methyl-pyridin-3-yl } -amide;

XII-45-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -amide;

XII-5N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -4-fluoro-3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-benzamide;

XII-63- (cyano-dimethyl-methyl) -N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -benzamide;

XII-7N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl ] -4-methoxy-3-trifluoromethyl-benzamide;

XII-8N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3-trifluoromethoxy-benzamide;

XII-9N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -2-methyl-5-trifluoromethyl-benzamide;

XII-103- (cyano-dimethyl-methyl) -N- [ 6-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -pyridin-3-yl ] -benzamide;

XII-113- (cyano-dimethyl-methyl) -N- [ 6-methyl-5- (4-pyridin-3-yl-1, 2, 3-triazol-1-yl) -pyridin-3-yl ] -benzamide;

XII-123- (cyano-dimethyl-methyl) -N- {5- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -benzamide;

XII-133- (cyano-dimethyl-methyl) -N- {5- [4- (5-cyano-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -benzamide;

XII-14N- {5- [4- (2-acetylamino-thiazol-5-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- (cyano-dimethyl-methyl) -benzamide;

XII-15N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- (4-methyl-piperazin-1-yl) -5-trifluoromethoxy-benzamide;

XII-16N- {5- [4- (5-methoxy-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- (4-methyl-piperazin-1-yl) -5-trifluoromethoxy-benzamide;

XII-173- (4-methyl-piperazin-1-yl) -N- [ 6-methyl-5- (4-pyridin-3-yl-1, 2, 3-triazol-1-yl) -pyridin-3-yl ] -5-trifluoromethoxy-benzamide;

XII-184-methyl-N- { 6-methyl-5- (4- (6-methyl-imidazo [1, 2-a ] pyrazin-3-yl) -1, 2, 3-triazol-1-yl ] -pyridin-3-yl } -3- (4-methyl-piperazin-1-yl) -5-trifluoromethyl-benzamide;

XII-19N- {5- [4- (2-acetylamino-thiazol-5-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl) -3- (4-methyl-piperazin-1-yl) -5-trifluoromethoxy-benzamide;

XII-203- [ (2-dimethylamino-ethyl) -methyl-amino ] -N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -5-trifluoromethoxy-benzamide;

XII-213- (2-dimethylamino-ethylamino) -N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -5-trifluoromethoxy-benzamide;

XII-22N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- (4-ethyl-piperazin-1-yl) -5-trifluoromethoxy-benzamide;

XII-23N- { 6-methyl-5- [4- (2-methyl-thiazol-5-yl) -1, 2, 3-triazol-1-yl ] -pyridin-3 yl } -3- (4-methyl-piperazin-1-yl) -5-trifluoromethoxy-benzamide;

XII-24N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- [4- (2-methoxy-ethyl) -piperazin-1-yl ] -5-trifluoromethoxy-benzamide;

XII-25N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3-morpholin-4-yl-5-trifluoromethoxy-benzamide:

XII-263- (4-methyl-piperazin-1-yl) -N- [ 6-methyl-5- (4-pyrimidin-5-yl-1, 2, 3-triazol-1-yl) -pyridin-3-yl ] -5-trifluoromethoxy-benzamide;

XII-27N- {5- [4- (5-cyano-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- (4-methyl-piperazin-1-yl) -5-trifluoromethoxy-benzamide;

XII-28N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- [ methyl- (1-methyl-pyrrolidin-3-yl) -amino ] -5-trifluoromethoxy-benzamide;

XII-293- (3-dimethylamino-pyrrolidin-1-yl) -N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -5-trifluoromethoxy-benzamide;

XII-30N- {5- [4- (1, 5-dimethyl-1H-pyrazol-4-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -3- (1, 2, 3, 6-tetrahydro-pyridin-4-yl) -5-trifluoromethoxy-benzamide;

XII-314-trifluoromethyl-pyridine-2-carboxylic acid [5- (4- {5- [4- (3-methoxy-propyl) -piperazin-1-yl ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -amide;

XII-324-trifluoromethyl-pyridine-2-carboxylic acid (5- {4- [5- (4-tert-butyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -amide;

XII-334-trifluoromethyl-pyridine-2-carboxylic acid [5- (4- {5- [4- (2-ethoxy-ethyl) -piperazin-1-yl ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -amide;

XII-343- (cyano-dimethyl-methyl) -N- (6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -pyridin-3-yl) -benzamide;

XII-354-trifluoromethyl-pyridine-2-carboxylic acid (5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -amide;

XII-36N- (6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -pyridin-3-yl) -3-trifluoromethoxy-benzamide;

XII-374-trifluoromethyl-pyridine-2-carboxylic acid (5- {4- [5- (4-isobutyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl) -amide;

XII-384-trifluoromethyl-pyridine-2-carboxylic acid (5- {4- [5- (4-ethyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -amide;

XII-39N- (5- {4- [5- (4-ethyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl) -4-methoxy-3-trifluoromethyl-benzamide;

XII-404-methoxy-N- (6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -pyridin-3-yl) -3-trifluoromethyl-benzamide;

XII-414-trifluoromethyl-pyridine-2-carboxylic acid (6-methyl-5- {4- [5- (4-propyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -pyridin-3-yl) -amide;

XII-42N- (5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -3-trifluoromethoxy-benzamide;

XII-43N- (5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -4-methoxy-3-trifluoromethyl-benzamide;

XII-44N- [5- (4- {5- [4- (2-ethoxy-ethyl) -piperazin-1-yl ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -4-methoxy-3-trifluoromethyl-benzamide;

XII-45N- (5- {4- [5- (4-tert-butyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -4-methoxy-3-trifluoromethyl-benzamide;

XII-464-methoxy-N- [5- (4- {5- [4- (3-methoxy-propyl) -piperazin-1-yl ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -3-trifluoromethyl-benzamide;

XII-47N- (5- {4- [5- (4-tert-butyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -3-trifluoromethoxy-benzamide;

XII-48N- [5- (4- {5- [4- (3-methoxy-propyl) -piperazin-1-yl ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -3-trifluoromethoxy-benzamide;

XII-493- (cyano-dimethyl-methyl) -N- (5- {4- [5- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -benzamide;

XII-503- (cyano-dimethyl-methyl) -N- (5- {4- [5- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -benzamide;

XII-513- (cyano-dimethyl-methyl) -N- (5- {4- [5- (4-ethyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl) -benzamide;

XII-523- (cyano-dimethyl-methyl) -N- (5- {4- [5- (2-dimethylamino-ethylamino) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -benzamide;

XII-533- (cyano-dimethyl-methyl) -N- [5- (4- {5- [ (2-dimethylamino-ethyl) -methyl-amino ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -benzamide;

XII-54N- [5- (4- {5- [4- (2-ethoxy-ethyl) -piperazin-1-yl ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -3-trifluoromethoxy-benzamide;

XII-55N- (5- {4- [5- (4-ethyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -3-trifluoromethoxy-benzamide;

XII-56N- (5- {4- [5- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -3-trifluoromethoxy-benzamide;

XII-574-trifluoromethyl-pyridine-2-carboxylic acid (6-methyl-5- {4- [5- (4-methyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -pyridin-3-yl) -amide;

XII-583- (cyano-dimethyl-methyl) -N- [5- (4- {5- [4- (3-methoxy-propyl) -piperazin-1-yl ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -benzamide;

XII-594-methoxy-N- (6-methyl-5- {4- [5- (4-propyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -pyridin-3-yl) -3-trifluoromethyl-benzamide;

XIIA-60N- (5- {4- [5- (4-cyclopropylmethyl-piperazin-1-yl) -pyridin-3-yl ] -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -4-methoxy-3-trifluoromethyl-benzamide;

XII-613- (cyano-dimethyl-methyl) -N- [5- (4- {5- [4- (2-ethoxy-ethyl) -piperazin-1-yl ] -pyridin-3-yl } -1, 2, 3-triazol-1-yl) -6-methyl-pyridin-3-yl ] -benzamide;

XII-62N- (5- {4- [5- (4-tert-butyl-piperazin-1-yl) -pyridin-3-yl) -1, 2, 3-triazol-1-yl } -6-methyl-pyridin-3-yl) -3- (cyano-dimethyl-methyl) -benzamide;

XII-633- (cyano-dimethyl-methyl) -N- {5- [4- (5-hydroxymethyl-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -benzamide;

XII-643- (cyano-dimethyl-methyl) -N- {5- [4- (5-dimethylaminomethyl-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -6-methyl-pyridin-3-yl } -benzamide;

XII-653- (cyano-dimethyl-methyl) -N- { 6-methyl-5- [4- (5-pyrrolidin-1-ylmethyl-pyridin-3-yl) -1, 2, 3-triazol-1-yl ] -pyridin-3-yl } -benzamide;

14. a compound of the general formula (1) or a pharmacologically acceptable salt thereof according to any one of claims 1 to 13 as a medicament.

15. Pharmaceutical preparation comprising one or more compounds of general formula (1) according to any one of claims 1 to 13 or a pharmacologically acceptable salt thereof as active substance, optionally in combination with conventional excipients and/or carriers.

16. A compound of general formula (1) according to any one of claims 1 to 13 for use in the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.

17. A compound according to claim 16 for use in the treatment and/or prevention of cancer.

18. Pharmaceutical preparation comprising a compound of the general formula (1) according to any one of claims 1 to 13 and at least one further cytostatic or cytotoxic active substance different from formula (1), wherein the compound (1) may also optionally be present in the form of its tautomers, racemates, enantiomers, diastereomers and mixtures thereof or in the form of pharmacologically acceptable salts of all the aforementioned forms.