Bicyclic triazine derivatives for the treatment of cancer - Patents.com

Abstract

The present invention relates to compounds of general formula (I): JPEG2025502240000140.jpg10658 (In the formula, A, B, X, Y, R 1 , R 2 and R 3 as described and defined herein), processes for preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds, as the sole agent or in combination with other active ingredients, for the manufacture of a pharmaceutical composition for the treatment and / or prevention of diseases, particularly hyperproliferative disorders such as cancer disorders.

Description

[Technical Field]

[0001] The present invention provides compounds of general formula (I) that impair the activity of CDK12. In particular, the present invention provides compositions and methods for treating cancer and other CDK12-dependent diseases. Accordingly, the present invention provides compounds that can inhibit the kinase activity of CDK12 / cyclin K for treating breast cancer, liver cancer, lung cancer, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, prostate cancer, Ewing's sarcoma, glioblastoma, and acute myeloid leukemia. Even more particularly, the present invention provides compounds that can inhibit CDK12 / cyclin K for treating lung cancer, breast cancer, liver cancer, colorectal cancer, gastric cancer, prostate cancer, and leukemia. [Background technology]

[0002] Cyclin-dependent kinase (CDK) 12 (CDK12, gene id 51755) is a member of a subset of the CDK serine / threonine kinase family that phosphorylates the C-terminal domain (CTD) of RNA polymerase II. CDK12, which forms a complex with cyclin K (CCNK, gene id 8812), regulates transcriptional, co-transcriptional, and post-transcriptional processes by phosphorylating Ser2 and Ser5 of the CTD of the RNA polymerase II complex, which is important during the elongation phase of pre-mRNA synthesis. CDK12 / cyclin K has been reported to regulate transcription elongation and mRNA processing, particularly co-transcriptional and post-transcriptional pre-mRNA splicing, alternative splicing, 3'-end processing, and repression of intron polyadenylation. CDK13 (CDK13, gene id 8621), a kinase closely related to CDK12, also forms a complex with cyclin K and regulates the transcription of a diverse set of genes (Bartkowiak et al. Genes Dev. 2010;24:2303-16; Dubbury et al. Nature. 2018;564:141-5; Greenleaf Transcription. 2018;10:91-110; Greifenberg et al. Cell Rep. 2016;14:320-31; Liang et al. Mol. Cell. Biol. 2015;35:928-38; Lui et al. J. Clin. Pathol. 2018;71:957-62; Tien et al. Nuc. Acids Res. 2017;45:6698-716).Transcription of genes encoding components of DNA damage signaling and repair pathways, such as the homologous recombination and replication stress response genes BRCA1, FANCD2, FANCI, and ATR, as well as genes encoding components of other stress response pathways, such as NF-κB and oxidative stress response, has been reported to be specifically regulated by CDK12 / cyclin K, as demonstrated by gene knockdown and chemoproteomic studies (Blazek et al. Genes Dev. 2011;25:2158-72. Henry et al. Sci. Signal. 2018;11:eaam8216. Li et al. Sci. Rep. 2016;6:21455.). Additionally, CDK12 / cyclin K has been reported to regulate the translation of a subset of mRNAs, including CHK1 mRNA, by directly phosphorylating the mRNA 5' cap-binding translational repressor 4E-BP1, leading to its release from the mRNA cap (Choi et al. Genes Dev. 2019;33:418-35). The recent discovery of rare biallelic CDK12 inactivating mutations in high-grade serous ovarian cancer and primary and castration-resistant prostate cancer, which result in a specific type of genomic instability characterized by the occurrence of multiple tandem duplications indicative of major defects in DNA repair, highlights the role of CDK12 in the DNA damage response and genome maintenance (Ekumi et al. Nucl. Acids Res. 2015;43:2575-89; Grasso et al. Nature. 2012;487:239-43; Joshi et al. J. Biol. Chem. 2014;289:9247-53; Menghi et al. Cancer Cell. 2018;34:197-210;e5; Popova et al. Cancer Res. 2016;76:1882-91; Quigley et al. al.Cell.2018;174:758-69.e9.Robinson et al.2015;162:454.Viswanathan et al.Cell.2018;174:433-47.e19.Wu et al.Cell.2018;173:1770-82.e14).The CDK12 gene is located on chromosome 17, approximately 200 kb proximal to the ERBB2 gene, and is frequently coamplified in breast cancer. Furthermore, CDK12 gene amplification has been observed in other cancer types, including gastric, esophageal, pancreatic, uterine, endometrial, prostate, and bladder cancers (Lui et al. J Clin Pathol. 2018;71:957-62; Gupta et al. Clin. Cancer Res. 2017;23:1346-57). CDK12 amplification and elevated expression levels suggest a tumor-promoting role for CDK12, based at least in part on alternatively spliced ​​mRNA, increased DNA repair capacity, and increased stress resistance (Lui et al. J Clin Pathol. 2018;71:957-62; Tien et al. Nucl. Acids Res. 2017;45:6698-716). Collectively, these data validate CDK12 as a potential target for developing drugs to treat cancer and other diseases, such as myotonic dystrophy type 1. Several inhibitors of CDK12 kinase activity are known:

[0003] Flavopiridol, a micromolar, nonselective inhibitor of CDK12 that inhibits other kinases, including CDK9, CDK1, and CDK4 (Bosken et al. Nat. Comm. 2014;5:3505); dinaciclib, a pan-CDK inhibitor (Johnson et al. Cell Rep. 2016;17:2367-81); THZ531, a dual inhibitor of CDK12 and CDK13 (Zhang et al. Nat. Chem. Biol. 2016;12:876-84); SR-3029 and related purine compounds (Johannes et al. Chem. Med. Chem. 2018;13:231-5); and SR-4835, a dual inhibitor of CDK12 and CDK13 (Quereda et al. Cancer Cell 2019;36:1-14). Compound 919278, a micromolar CDK12 inhibitor (Henry et al. Science Signal. 2018;11:eaam8216), is an aryl urea derivative (Ito et al. J. Med. Chem. 2018;61:7710-28).

[0004] Additionally, compounds that induce proteolysis of CDK12 and / or CCNK in cells have been described (Slabicki et al. Nature 2020;585:293-297; Lv et al. eLife 2020;9:e59994; Jiang et al. Nat. Chem. Biol. 2021;17:675-683; Dieter et al. Cell Reports 2021;36:109394; WO 2021 / 116178; WO 2021 / 176045; WO 2021 / 176049).

[0005] There is a need for the development of compounds that selectively impair CDK12 / cyclin K function to treat cancer and other diseases. Covalent inhibitors of CDK12 and CDK13 kinase function, as well as CDK12 / cyclin K degrader compounds, have been described to induce tumor cell mutations that are resistant to such inhibitors or degrader compounds, thereby limiting their potential therapeutic use (Jiang et al. Nat. Chem. Biol. 2021;17:675-683). Surprisingly, the compounds described in the present invention overcome cellular resistance to CDK12 / cyclin K degrader compounds and exhibit comparable antitumor activity against resistant cells and their corresponding parental cells. CDK12 inhibitors that have high kinase inhibitory potency at physiological ATP concentrations but weak or no CDK12 degrading potency are selective against other kinases. Therefore, there is a need to provide compounds that impair CDK12 / cyclin K activity in cells and exhibit a good degree of selectivity for targeting other CDKs and other kinases. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention relates to compounds of general formula (I): [ka] (In the formula, A, B, X, Y, R 1 , R 2 and R 3 as described and defined herein), processes for preparing the compounds, intermediate compounds useful in preparing the compounds, pharmaceutical compositions and combinations comprising the compounds, and the use of the compounds, as the sole agent or in combination with other active ingredients, for the manufacture of a pharmaceutical composition for the treatment and / or prevention of diseases, particularly hyperproliferative disorders such as cancer disorders. [Means for solving the problem]

[0007] It has now been found that the compounds of the present invention effectively impair the activity of CDK12 / cyclin K (data shown in the Biological Experimental Section) and can therefore be used for the treatment and / or prevention of hyperproliferative disorders, such as cancer disorders. In particular, the compounds of the present invention are CDK12 inhibitors that have high kinase inhibitory potency at physiological ATP concentrations, but weak or no potency for proteolytic CDK12 and / or cyclin K degradation in cells, and are selective over other kinases.

[0008] According to a first aspect, the present invention provides compounds of general formula (I): [ka] (In the formula, A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R 1 is selected from halogen atoms and C1-C3-haloalkyl groups, R 2 is selected from C1-C3-alkyl groups, C1-C3-alkoxy groups, C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom. or a tautomer thereof, or an N-oxide thereof, or a salt thereof, or a salt of the tautomer thereof, or a salt of the N-oxide thereof, or a mixture thereof. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition The term "substituted" means that one or more hydrogen atoms on the specified atom or group are replaced with a selection from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom under the existing circumstances. Combinations of substituents and / or variables are permissible.

[0010] The term "optionally substituted" means that the number of substituents can be equal to or different from 0. Unless otherwise specified, an optionally substituted group can be substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Generally, if present, the number of optional substituents can be 1, 2, 3, 4, or 5, particularly 1, 2, or 3, more particularly 1 or 2, and even more particularly 1.

[0011] As used herein, for example in the definition of substituents of compounds of general formula (I) of the present invention, the term "one or more" means "1, 2, 3, 4 or 5, in particular 1, 2, 3 or 4, more in particular 1, 2 or 3, and even more in particular 1 or 2".

[0012] When the group in the compound according to the present invention is substituted, unless otherwise specified, this group can be mono- or polysubstituted by substituents.Within the scope of the present invention, the meanings of all repeating groups are independent of each other.The group in the compound according to the present invention can be substituted by 1, 2 or 3 identical or different substituents, particularly by 1, 2 or 3 substituents, more particularly by 1 substituent.

[0013] The term "oxo," "oxo group," or "oxo substituent" refers to a doubly bonded oxygen atom, ═O. The oxo may be attached to an atom of suitable valence, such as a saturated carbon atom, or to a sulfur atom. For example, but not limited to, one oxo group can be attached to a carbon atom to form a carbonyl group, C(═O), or two oxo groups can be attached to one sulfur atom to form a sulfonyl group, -S(═O)2.

[0014] The term "ring substituent" means a substituent attached to an aromatic or non-aromatic ring that replaces an available hydrogen atom on the ring.

[0015] When a composite substituent is composed of multiple moieties, e.g., (C1-C4-alkoxy)-(C1-C4-alkyl)-, the position of a given moiety can be at any suitable position of the composite substituent; i.e., a C1-C4-alkoxy moiety can be bonded to any carbon atom of the C1-C4-alkyl moiety of the (C1-C4-alkoxy)-(C1-C4-alkyl)- group. The first or last hyphen of such a composite substituent indicates the point of attachment of the composite substituent to the rest of the molecule. For example, when a ring containing carbon atoms and, optionally, one or more heteroatoms, e.g., nitrogen, oxygen, or sulfur atoms, is substituted with a substituent, the substituent can be bonded to any suitable position of the ring, regardless of whether it is bonded to a suitable carbon atom and / or a suitable heteroatom.

[0016] The term "comprising" as used herein includes "consisting of."

[0017] When any item is referred to in the text as "mentioned in this specification", it means that it may be mentioned anywhere in the text.

[0018] When any item in the description is referred to as "above" in the text, it refers to either the preceding page or the respective disclosure made herein above on the same page.

[0019] When any item in the description is referred to as "below" in the text, it refers to either one of the subsequent pages or the respective disclosure made herein at the bottom of the same page.

[0020] Terms referred to in this document have the following meanings:

[0021] The term "halogen atom" means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom, more in particular a fluorine atom.

[0022] The term "C1-C6-alkyl" means a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, -, 1,1-dimethylpropyl-, hexyl-, 1-methylpentyl-, 2-methylpentyl-, 3-methylpentyl-, 4-methylpentyl-, 1-ethylbutyl-, 2-ethylbutyl-, 1,1-dimethylbutyl-, 2,2-dimethylbutyl-, 3,3-dimethylbutyl-, 2,3-dimethylbutyl-, 1,2-dimethylbutyl- or 1,3-dimethylbutyl- or an isomer thereof. In particular, it has 1, 2, 3 or 4 carbon atoms ("C1-C4-alkyl"), such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, sec-butyl-, isobutyl- or tert-butyl, more in particular 1, 2 or 3 carbon atoms ("C1-C3-alkyl"), such as methyl-, ethyl-, n-propyl- or isopropyl.

[0023] The term "C1-C6-hydroxyalkyl" means a linear or branched saturated monovalent hydrocarbon radical, wherein the term "C1-C6-alkyl" is defined above and in which one or more hydrogen atoms have been replaced by hydroxy groups, such as, for example, a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl or 1-hydroxy-2-methyl-propyl group.

[0024] The term "C1-C6-alkylsulfanyl" means a linear or branched saturated monovalent radical of the formula (C1-C6-alkyl)-S-, wherein the term "C1-C6-alkyl" is as defined above, such as a methylsulfanyl-, ethylsulfanyl-, propylsulfanyl-, isopropylsulfanyl-, butylsulfanyl-, sec-butylsulfanyl-, isobutylsulfanyl-, tert-butylsulfanyl-, pentylsulfanyl-, isopentylsulfanyl- or hexylsulfanyl- group.

[0025] The term "C1-C6-haloalkyl" refers to a linear or branched saturated monovalent hydrocarbon group in which the term "C1-C6-alkyl" is defined as above, and in which one or more hydrogen atoms are replaced, identically or differently, by halogen atoms. Preferably, the halogen atoms are fluorine atoms. The C1-C6-haloalkyl, in particular the C1-C3-haloalkyl, is, for example, a fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, or 1,3-difluoropropan-2-yl group.

[0026] The term "C1-C6-alkoxy" means a linear or branched saturated monovalent radical of the formula (C1-C6-alkyl)-O-, wherein the term "C1-C6-alkyl" is as defined above, such as a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, or n-hexyloxy radical or an isomer thereof.

[0027] The term "C1-C6-haloalkoxy" means a linear or branched saturated monovalent C1-C6-alkoxy group as defined above, in which one or more of the hydrogen atoms are replaced, identically or differently, by a halogen atom. Preferably, the halogen atom in "C1-C6-haloalkoxy-" is fluorine, resulting in a group referred to herein as "C1-C6-fluoroalkoxy-". Representative C1-C6-fluoroalkoxy- groups include, for example, -OCF3, -OCHF2, -OCH2F, -OCF2CF3, and -OCH2CF3.

[0028] The term "C2-C6-alkenyl-" means a straight-chain or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms, preferably 2, 3, or 4 carbon atoms ("C2-C4-alkenyl-") or 2 or 3 carbon atoms ("C2-C3-alkenyl-"), it being understood that if the alkenyl-group contains more than one double bond, the double bonds can be isolated from one another or conjugated. Representative alkenyl groups include, for example, ethenyl, prop-2-enyl, (E)-prop-1-enyl, (Z)-prop-1-enyl, iso-propenyl, but-3-enyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl. group, (E)-1-methylprop-1-enyl- group, (Z)-1-methylprop-1-enyl- group, buta-1,3-dienyl- group, pent-4-enyl- group, (E)-pent-3-enyl- group, (Z)-pent-3-enyl- group, (E)-pent-2-enyl- group, (Z)-pent-2-enyl- group, (E)-pent-1-enyl- group, (Z)-pent-1-enyl- group, 3-methylbut-3-enyl- group, 2-methylbut-3-enyl- group, 1- Methylbut-3-enyl group, 3-methylbut-2-enyl group, (E)-2-methylbut-2-enyl group, (Z)-2-methylbut-2-enyl group, (E)-1-methylbut-2-enyl group, (Z)-1-methylbut-2-enyl group, (E)-3-methylbut-1-enyl group, (Z)-3-methylbut-1-enyl group, (E)-2-methylbut-1-enyl group, (Z)-2-methylbut-1-enyl group, (E)-1-methylbut- a 1-phenyl-1-enyl group, a (Z)-1-methylbut-1-enyl group, a 1,1-dimethylprop-2-enyl group, a 1-ethylprop-1-enyl group, a 1-propylvinyl group, a 1-isopropylvinyl group, an (E)-3,3-dimethylprop-1-enyl group, a (Z)-3,3-dimethylprop-1-enyl group, a penta-1,4-dienyl group, a hex-5-enyl group, an (E)-hex-4-enyl group, a (Z)-hex-4-enyl group,(E)-hex-3-enyl-group, (Z)-hex-3-enyl-group, (E)-hex-2-enyl-group, (Z)-hex-2-enyl-group, (E)-hex-1-enyl-group, (Z)-hex-1-enyl-group, 4-methylpent-4-enyl-group, 3-methylpent-4-enyl-group, 2-methylpent-4-enyl-group, 1-methylpent-4-enyl-group, 4-methylpent-3-enyl-group, (E)-3-methylpent-3-enyl-group, (Z)-3-methylpent-3-enyl-group, (E)-2-methylpent-3-enyl-group, ( Z)-2-methylpent-3-enyl group, (E)-1-methylpent-3-enyl group, (Z)-1-methylpent-3-enyl group, (E)-4-methylpent-2-enyl group, (Z)-4-methylpent-2-enyl group, (E)-3-methylpent-2-enyl group, (Z)-3-methylpent-2-enyl group, (E)-2-methylpent-2-enyl group, (Z)-2-methylpent-2-enyl group, (E)-1-methylpent-2-enyl group, (Z)-1-methylpent-2-enyl group, (E)-4-methylpent-1-enyl nyl- group, (Z)-4-methylpent-1-enyl- group, (E)-3-methylpent-1-enyl- group, (Z)-3-methylpent-1-enyl- group, (E)-2-methylpent-1-enyl- group, (Z)-2-methylpent-1-enyl- group, (E)-1-methylpent-1-enyl- group, (Z)-1-methylpent-1-enyl- group, 3-ethylbut-3-enyl- group, 2-ethylbut-3-enyl- group, 1-ethylbut-3-enyl- group, (E)-3-ethylbut-2-enyl- group, (Z)-3-ethylbut-2-enyl- group, (E)-2- ethylbut-2-enyl-group, (Z)-2-ethylbut-2-enyl-group, (E)-1-ethylbut-2-enyl-group, (Z)-1-ethylbut-2-enyl-group, (E)-3-ethylbut-1-enyl-group, (Z)-3-ethylbut-1-enyl-group, 2-ethylbut-1-enyl-group, (E)-1-ethylbut-1-enyl-group, (Z)-1-ethylbut-1-enyl-group, 2-propylprop-2-enyl-group, 1-propylprop-2-enyl-group, 2-isopropylprop-2-enyl-group, 1-isopropylprop-2-enyl-group,These include (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, (Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl, (Z)-1-isopropylprop-1-enyl, hexa-1,5-dienyl, and 1-(1,1-dimethylethyl)ethenyl. In particular, the groups are ethenyl or prop-2-enyl.

[0029] The same definition can be applied when the alkenyl group is arranged in a chain as a divalent "C2-C6-alkenylene" moiety. Any of the names mentioned above will have an "ene" added to its end, thus, for example, "pentenyl" becomes a divalent "pentenylene" group.

[0030] The term "C2-C6-haloalkenyl-" refers to a straight-chain or branched hydrocarbon group in which one or more hydrogen atoms of the above-defined "C2-C6-alkenyl-" have been replaced by halogen atoms, each identical or different. Preferably, the halogen atom is fluorine, resulting in a group referred to herein as "C2-C6-fluoroalkenyl-". Representative C2-C6-fluoroalkenyl- groups include, for example, -CH=CF2, -CF=CH2, -CF=CF2, -C(CH3)=CF2, -CH=C(F)-CH3, -CH2-CF=CF 2、 and -CF2-CH=CH2.

[0031] The term "C2-C6-alkynyl-" refers to a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and containing 2, 3, 4, 5, or 6 carbon atoms, preferably 2, 3, or 4 carbon atoms ("C2-C4-alkynyl-") or 2 or 3 carbon atoms ("C2-C3-alkynyl-"). Representative C2-C6-alkynyl- groups include, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, hex-6-ynyl, hex-7-ynyl, hex-8-ynyl, hex-9-ynyl, hex-10-ynyl, hex-11-ynyl, hex-12-ynyl, hex-13-ynyl, hex-14-ynyl, hex-15-ynyl, hex-16-ynyl, hex-17-ynyl, hex-18-ynyl, hex-19-ynyl, hex-20-ynyl, hex-21-ynyl, hex-22-ynyl, hex-23-ynyl, hex-24-ynyl, hex-25-ynyl, hex-26-ynyl, hex-27-ynyl, hex-28-ynyl, hex-29 ... nyl group, hex-3-ynyl group, hex-4-ynyl group, hex-5-ynyl group, 1-methylprop-2-ynyl group, 2-methylbut-3-ynyl group, 1-methylbut-3-ynyl group, 1-methylbut-2-ynyl group, 3-methylbut-1-ynyl group, 1-ethylprop-2-ynyl group, 3-methylpent-4-ynyl group groups, 2-methylpent-4-ynyl-group, 1-methyl-pent-4-ynyl-group, 2-methylpent-3-ynyl-group, 1-methylpent-3-ynyl-group, 4-methylpent-2-ynyl-group, 1-methyl-pent-2-ynyl-group, 4-methylpent-1-ynyl-group, 3-methylpent-1-ynyl-group, 2-ethylbut-3-ynyl-group, 1-ethylbut-3-ynyl-group, 1-ethylbut-2-ynyl-group, 1-propylprop-2-ynyl-group, 1-isopropylprop-2-ynyl-group, 2,2-dimethylbut-3-ynyl-group, 1,1-dimethylbut-3-ynyl-group, 1,1-dimethylbut-2-ynyl-group and 3,3-dimethylbut-1-ynyl-group. In particular, the alkynyl group is an ethynyl group, a prop-1-ynyl group or a prop-2-ynyl group.

[0032] The term "C3-C8-cycloalkyl" denotes a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7, or 8 carbon atoms ("C3-C8-cycloalkyl"). Similarly, the term "C3-C6-cycloalkyl" denotes a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, or 6 carbon atoms ("C3-C6-cycloalkyl"). The C3-C8-cycloalkyl or C3-C6-cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl group, or a bicyclic hydrocarbon ring, such as a bicyclo[4.2.0]octyl or octahydropentalenyl group.

[0033] The term "C3-C6-halocycloalkyl" means a saturated monovalent hydrocarbon ring containing 3, 4, 5 or 6 carbon atoms, in which the term "C3-C6-cycloalkyl" is defined as above, and in which one or more of the hydrogen atoms of the hydrocarbon ring have been replaced, identically or differently, by halogen atoms. Preferably, the halogen atoms are fluorine atoms. A "C3-C6-cycloalkyl" group as defined above in which one or more of the hydrogen atoms have been replaced, identically or differently, by halogen atoms, preferably fluorine atoms, is, for example and preferably, a monocyclic hydrocarbon ring, such as a cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexyl-group.

[0034] The term "C4-C8-cycloalkenyl" denotes a monovalent monocyclic or bicyclic hydrocarbon ring containing 4, 5, 6, 7, or 8 carbon atoms and one double bond. In particular, the ring contains 4, 5, or 6 carbon atoms ("C4-C6-cycloalkenyl"). The C4-C8-cycloalkenyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, or cyclooctenyl group, or a bicyclic hydrocarbon ring, such as a bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl group.

[0035] The term "C3-C8-cycloalkoxy" means a saturated monovalent monocyclic or bicyclic radical of the formula (C3-C8-cycloalkyl)-O-, containing 3, 4, 5, 6, 7 or 8 carbon atoms, where the term "C3-C8-cycloalkyl" is defined above, such as a cyclopropyloxy-, cyclobutyloxy-, cyclopentyloxy-, cyclohexyloxy-, cycloheptyloxy- or cyclooctyloxy- group.

[0036] When the term "heterocycloalkyl" is used without specifying the number of atoms, it refers to a "4- to 10-membered heterocycloalkyl-" group, more particularly a 5- to 6-membered heterocycloalkyl group. The terms "4- to 7-membered heterocycloalkyl," "4- to 6-membered heterocycloalkyl," and "5- to 7-membered heterocycloalkyl" refer to a monocyclic saturated heterocycle having a total of "4, 5, 6, or 7," or "4, 5, or 6," or "5, 6, or 7," ring atoms, respectively, which may be saturated or partially unsaturated monocyclic, bicyclic, or polycyclic, containing one or two identical or different ring heteroatoms selected from nitrogen, oxygen, and sulfur, or one group selected from -S(=O)-, -S(=O)2-, and -S(=O)(=NH)-.

[0037] The heterocycloalkyl group can be attached to the remainder of the molecule through any one of the carbon atoms or, if present, the nitrogen atom.

[0038] Illustratively, but not limited to, the "4- to 7-membered heterocycloalkyl" may be, for example, a 4-membered ring, a "4-membered heterocycloalkyl-" group, such as an azetidinyl group or an oxetanyl group; or a 5-membered ring, a "5-membered heterocycloalkyl-" group, such as a tetrahydrofuranyl group, a dioxolinyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, or a pyrrolinyl group; or a 6-membered ring, a "6-membered heterocycloalkyl-" group, such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a 3-oxomorpholin-4-yl group, a dithianyl group, a thiomorpholinyl group, or a piperazinyl group; or a 7-membered ring, a "7-membered heterocycloalkyl-" group, such as an azepanyl group, a diazepanyl group, or an oxazepanyl group. Heterocycloalkyl groups may be substituted independently one or more times by C1-C3-alkyl, C1-C3-alkoxy, hydroxy, halogen or carbonyl groups.

[0039] In particular, "4- to 6-membered heterocycloalkyl" refers to a 4- to 6-membered heterocycloalkyl as defined above containing one ring nitrogen atom and, optionally, one additional ring heteroatom selected from nitrogen, oxygen, and sulfur. In particular, "5- to 7-membered heterocycloalkyl" refers to a 5- to 7-membered heterocycloalkyl as defined above containing one ring nitrogen atom and, optionally, one additional ring heteroatom selected from nitrogen, oxygen, and sulfur. Even more particularly, "5- or 6-membered heterocycloalkyl" refers to a monocyclic saturated heterocycle having a total of 5 or 6 ring atoms, containing one ring nitrogen atom and, optionally, one additional ring heteroatom selected from nitrogen and oxygen.

[0040] The term "heteroaryl-" means a monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (a "5- to 14-membered heteroaryl-" group), preferably 5, 6, 9, or 10 ring atoms, and containing 1, 2, 3, or 4 heteroatoms, which may be the same or different, and which are selected from oxygen, nitrogen, and sulfur. The heteroaryl group may be a 5-membered heteroaryl group, such as a thienyl group, a furanyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, an isoxazolyl group, an isothiazolyl group, an oxadiazolyl group, a triazolyl group, a thiadiazolyl group or a tetrazolyl group; or a 6-membered heteroaryl group, such as a pyridyl group, a pyridazinyl group, a pyrimidyl group, a pyrazinyl group or a triazinyl group; or a benzo-fused 5-membered heteroaryl group, such as a benzo It may be a benzofuranyl group, a benzothienyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzimidazolyl group, a benzothiazolyl group, a benzotriazolyl group, an indazolyl group, an indolyl group or an isoindolyl group; or a benzo-fused 6-membered heteroaryl group, such as quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl or quinoxalinyl; or another bicyclic group, such as an indolizinyl group, a purinyl group or a pteridinyl group.

[0041] Preferably, "heteroaryl-" is a monocyclic aromatic ring system having 5 or 6 ring atoms and containing one or more heteroatoms (if more than one, the heteroatoms may be the same or different and are selected from oxygen, nitrogen and sulfur), ("5- to 6-membered monocyclic heteroaryl-"), such as a thienyl-, furanyl-, pyrrolyl-, oxazolyl-, thiazolyl-, imidazolyl-, pyrazolyl-, isoxazolyl-, isothiazolyl-, oxadiazolyl-, triazolyl-, thiadiazolyl-, tetrazolyl-, pyridyl-, pyridazinyl-, pyrimidyl-, pyrazinyl- or triazinyl group.

[0042] In particular, in the context of the present invention, the term "heteroaryl", when applied to any of the substituents of the compounds of general formula (I), should be understood to mean a monocyclic aromatic ring system, preferably having 5 or 6 ring atoms and containing 1, 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, which may be the same or different, said heteroatoms being independently selected from oxygen, sulfur and nitrogen, preferably oxygen and nitrogen, i.e., a ("5-6 membered monocyclic heteroaryl-") group.

[0043] Generally, unless otherwise specified, the heteroaryl group includes all possible isomeric forms thereof, for example, positional isomers thereof.Thus, in some illustrative non-limiting examples, the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl, the term thienyl includes thien-2-yl, and thien-3-yl, and heteroarylene groups can be inserted into the chain in the opposite way, for example, 2,3-pyridinylene includes pyridin-2,3-yl, and pyridin-3,2-yl.Furthermore, the heteroaryl group can be bonded to the rest of the molecule via a carbon atom, or, if applicable, a nitrogen atom, for example, a pyrrol-1-yl group, a pyrazol-1-yl group, or an imidazol-1-yl group.

[0044] In particular, the heteroaryl group is a pyridyl- or pyrimidyl- or imidazolyl-group, which includes hydroxy substitution of the pyridyl group, resulting in 2-hydroxy-pyridine, which is the tautomeric form of, for example, 2-oxo-2(1H)-pyridine. In some embodiments, the heteroaryl group is an oxazolyl group.

[0045] Furthermore, as used herein and throughout the text, the term "C3-C8", for example, as used in the context of the definition of "C3-C8-cycloalkyl-", is to be understood to mean a cycloalkyl- group having a total number of carbon atoms from 3 to 8, i.e., 3, 4, 5, 6, 7 or 8 carbon atoms. It is further to be understood that the term "C3-C8" is to be interpreted as disclosing any subrange contained therein, for example, C3-C6, C4-C5, C3-C5, C3-C4, C4-C6, C5-C7, preferably C3-C6.

[0046] Similarly, as used herein and throughout the text, for example, the term "C2-C6" as used in the context of the definitions of "C2-C6-alkenyl-" and "C2-C6-alkynyl-" shall be understood to mean an alkenyl- or alkynyl- group having a total number of carbon atoms from 2 to 6, i.e., 2, 3, 4, 5 or 6 carbon atoms. It shall further be understood that the term "C2-C6" shall be interpreted as disclosing any subrange contained therein, for example, C2-C6, C3-C5, C3-C4, C2-C3, C2-C4, C2-C5, preferably C2-C3.

[0047] Throughout the text, the term "C1-C6" as used in the context of the definitions of, for example, "C1-C6-alkyl-", "C1-C6-haloalkyl-", "C1-C6-alkoxy-" or "C1-C6-haloalkoxy-" is to be understood to mean an alkyl group having a total carbon number of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is further to be understood that the term "C1-C6" is to be interpreted as disclosing any subrange contained therein, for example, C1-C6, C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, preferably C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, even more preferably C1-C4, and in the case of "C1-C6-haloalkyl-" or "C1-C6-haloalkoxy-", even more preferably C1-C2.

[0048] When a range of values ​​is given, the range includes each value and subrange within the range.

[0049] For example: "C1~C6" means C1, C2, C3, C4, C5, C6, C1~C6, C1~C5, C1~C4, C1~C3, C1~C2, C2~C6 , C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6.

[0050] "C2 to C6" includes C2, C3, C4, C5, C6, C2 to C6, C2 to C5, C2 to C4, C2 to C3, C3 to C6, C3 to C5, C3 to C4, C4 to C6, C4 to C5, and C5 to C6.

[0051] "C3~C 10 ” is C3, C4, C5, C6, C7, C8, C9, C 10 , C3~C 10 , C3~C9, C3~C8, C3~C7, C3~C6, C3~C5, C3~C4, C4~C 10 , C4~C9, C4~C8, C4~C7, C4~C6, C4~C5, C5~C 10 , C5~C9, C5~C8, C5~C7, C5~C6, C6~C 10 , C6~C9, C6~C8, C6~C7, C7~C 10 , C7~C9, C7~C8, C8~C 10 , C8 to C9, and C9 to C 10 Includes.

[0052] "C3 to C8" includes C3, C4, C5, C6, C7, C8, C3 to C8, C3 to C7, C3 to C6, C3 to C5, C3 to C4, C4 to C8, C4 to C7, C4 to C6, C4 to C5, C5 to C8, C5 to C7, C5 to C6, C6 to C8, C6 to C7, and C7 to C8.

[0053] "C3 to C6" includes C3, C4, C5, C6, C3 to C6, C3 to C5, C3 to C4, C4 to C6, C4 to C5, and C5 to C6.

[0054] "C4 to C8" includes C4, C5, C6, C7, C8, C4 to C8, C4 to C7, C4 to C6, C4 to C5, C5 to C8, C5 to C7, C5 to C6, C6 to C8, C6 to C7, and C7 to C8.

[0055] "C4 to C7" includes C4, C5, C6, C7, C4 to C7, C4 to C6, C4 to C5, C5 to C7, C5 to C6, and C6 to C7.

[0056] "C4 to C6" includes C4, C5, C6, C4 to C6, C4 to C5, and C5 to C6.

[0057] "C5~C 10 ” is C5, C6, C7, C8, C9, C 10 , C5~C 10 , C5~C9, C5~C8, C5~C7, C5~C6, C6~C 10 , C6~C9, C6~C8, C6~C7, C7~C 10 , C7~C9, C7~C8, C8~C 10 , C8 to C9, and C9 to C 10 Includes.

[0058] "C6~C 10 " is C6, C7, C8, C9, C 10 , C6~C 10 , C6~C9, C6~C8, C6~C7, C7~C 10 , C7~C9, C7~C8, C8~C 10 , C8 to C9, and C9 to C 10 Includes.

[0059] As used herein, the term "leaving group" refers to an atom or group of atoms that takes up the bonding electrons and is displaced in a chemical reaction as a stable species, typically forming, for example, an anion. Preferably, the leaving group is selected from the group comprising a halo group, in particular a chloro group, a bromo group or an iodo group, a (methylsulfonyl)oxy- group, a [(4-methylphenyl)sulfonyl]oxy- group, a [(trifluoromethyl)sulfonyl]oxy- group, a [(nona-fluorobutyl)sulfonyl]oxy- group, a [(4-bromophenyl)sulfonyl]oxy- group, a [(4-nitrophenyl)sulfonyl]oxy- group, a [(2-nitro-phenyl)sulfonyl]oxy- group, a [(4-isopropylphenyl)sulfonyl]oxy- group, a [(2,4,6-triisopropylphenyl)sulfonyl]oxy- group, a [(2,4,6-trimethylphenyl)sulfonyl]oxy- group, a [(4-tert-butylphenyl)sulfonyl]oxy- group, a (phenylsulfonyl)oxy- group and a [(4-methoxyphenyl)sulfonyl]oxy group.

[0060] As used herein, the term "protecting group" refers to a protecting group attached to an oxygen or nitrogen atom in an intermediate used in the preparation of a compound of general formula (I). Such groups are introduced, for example, by chemical modification of the respective hydroxy or amino group to obtain chemoselectivity in subsequent chemical reactions. Protecting groups for hydroxy and amino groups are described, for example, in T.W. Greene and P.G.M.Wuts in Protective Groups in Organic Synthesis, 4 thedition, Wiley 2006. More particularly, the protecting group for the amino group can be selected from substituted sulfonyl groups, such as mesyl, tosyl, or phenylsulfonyl groups, acyl groups, such as benzoyl, acetyl, or tetrahydropyranoyl groups, or carbamate-based groups, such as tert-butoxycarbonyl (Boc). The protecting group for the hydroxy group can be selected from acyl groups, such as benzoyl, acetyl, pivaloyl, or tetrahydropyranoyl groups, or can contain silicon, such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, or triisopropylsilyl groups.

[0061] The term "substituents" refers to a "substituted" group on an alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group, for example, replacing one or more hydrogen atoms of any atom of that group. In one aspect, the substituents on a group are independently any one, or any combination of two or more, of the permissible atoms or groups of atoms described for that substituent. In another aspect, a substituent may itself be substituted with any one of the above substituents. Furthermore, as used herein, the phrase "optionally substituted" means unsubstituted (e.g., substituted by H) or substituted.

[0062] It is understood that the description of compounds herein is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more of several substituents, such substitutions are selected to obtain a compound that is in accordance with the principles of chemical bonding, such as valence, and is not inherently unstable.For example, any carbon atom is bonded to two, three, or four other atoms, in accordance with the four valence electrons of carbon.

[0063] "Subject" means a mammal, including, but not limited to, a human or non-human mammal, for example, a cow, horse, dog, sheep, rodent, or cat.

[0064] Compounds of general formula (I) can exist as isotopic variations. Thus, the present invention includes one or more isotopic variations of compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).

[0065] The present invention also includes all suitable isotopic variations of the compounds of the invention.

[0066] The term "isotopic variant" of a compound or reagent is defined as a compound that exhibits an unnatural proportion of one or more of the isotopes that constitute such compound.

[0067] The expression "unnatural proportion" with respect to an isotope means a proportion of such isotope that is higher than its natural abundance. The natural abundance of an isotope as applied in this context is described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1), 217-235, 1998.

[0068] An isotopic variant of a compound of the invention is defined as one in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that may be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as, for example, 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 33 P, 33 S, 34 S, 35 S, 36 S,18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 Therefore, the recitation of "hydrogen" or "H" includes, unless otherwise specified, 1 H (protium), 2 H (deuterium), and 3 H (tritium). Specific isotopic variations of the compounds of the invention, such as 3 H or 14 Those incorporating one or more radioactive isotopes, such as C, are useful for drug and / or substrate tissue distribution studies. Tritiated and carbon-14 labeled, i.e., 14 C isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with isotopes such as deuterium may be preferred in some circumstances because it may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced administration requirements. Isotopic variants of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art, for example, by the exemplary method or by the preparations described in the following examples using appropriate isotopic variants of suitable reagents.

[0069] For the treatment and / or prevention of the disorders specified herein, isotopic variants of the compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). 3 H or 14 Isotopic variations of compounds of general formula (I), into which one or more radioactive isotopes, such as C, are incorporated, are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred for their ease of incorporation and detectability. 18 F or 11 Positron-emitting isotopes, such as C, may be incorporated into the compounds of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing compounds of general formula (I) and 13C-containing compounds may be used in mass spectrometry in preclinical or clinical trial settings.

[0070] Isotopic variants of compounds of general formula (I) can generally be prepared by substituting a reagent for an isotopic variant of the reagent, preferably a deuterium-containing reagent, by methods known to those skilled in the art, such as those described in the schemes and / or examples herein. Depending on the desired deuteration site, deuterium from DO can be incorporated directly into the compound or into a reagent useful for synthesizing such a compound, in some cases. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic and acetylenic bonds is a rapid route for incorporating deuterium. Metal catalysts (i.e., Pd, Pt, and Rh) can be used in the presence of deuterium gas to directly exchange deuterium for hydrogen in hydrocarbon-containing functional groups. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as, for example, C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.

[0071] The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I) in which one or more hydrogen atoms have been replaced by one or more deuterium atoms, and the abundance of deuterium at each deuterated position of the compound of general formula (I) is greater than the natural abundance of deuterium, which is about 0.015%. In particular, in a deuterium-containing compound of general formula (I), the abundance of deuterium at each deuterated position of the compound of general formula (I) is greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% at that position, preferably greater than 90%, 95%, 96%, or 97%, and even more preferably greater than 98% or 99%. It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated positions.

[0072] Selective incorporation of one or more deuterium atoms into compounds of general formula (I) can alter the physicochemical properties of the molecule (e.g., acidity [CL Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271], etc.) and / or metabolic profile, resulting in changes in the ratio of parent compound to metabolites or the amount of metabolites formed. Such changes may be desirable in some circumstances, as they may confer certain therapeutic benefits. Decreased rates of metabolism and metabolic switching, resulting in altered metabolite ratios, have been reported (AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure to the parent drug and metabolites can have important consequences regarding the pharmacokinetics, tolerability, and efficacy of deuterium-containing compounds of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of undesired or toxic metabolites and enhances the formation of desirable metabolites (e.g., Nevirapine: AM Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: AEMutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the primary effect of deuteration is to decrease the rate of systemic clearance. As a result, the biological half-life of the compound increases. Potential clinical benefits include the ability to maintain similar systemic exposure with reduced peak levels and increased trough levels. This can reduce side effects and enhance efficacy, depending on the pharmacokinetic / pharmacodynamic relationship of the particular compound. mL-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208) and odanacatib (K. Kassahun et al., WO 2012 / 112363) are examples of this deuterium effect.Still other cases have been reported in which a decrease in metabolic rate results in increased drug exposure without altering the rate of systemic clearance (e.g., rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs that exhibit this effect may have reduced dosing requirements (e.g., fewer doses or fewer doses to achieve the desired effect) and / or reduced metabolite amounts.

[0073] Compounds of general formula (I) may have multiple potential attack sites for metabolism. To optimize the above effects on physicochemical properties and metabolic profiles, deuterium-containing compounds of general formula (I) can be selected with one or more specific patterns of deuterium-hydrogen exchange. In particular, the deuterium atoms of deuterium-containing compounds of general formula (I) are bonded to carbon atoms and / or to, for example, cytochrome P. 450 It is located at the position of the compound of general formula (I) which is the attack site for metabolizing enzymes such as

[0074] When the plural of words such as compounds, salts, polymorphs, hydrates, solvates, etc. is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate, etc.

[0075] By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0076] The compounds of the present invention optionally contain one or more asymmetric centers, depending on the position and nature of the various desired substituents. One or more asymmetric carbon atoms can be in the (R) or (S) configuration, which can result in a racemic mixture in the case of a single asymmetric center, or a diastereomeric mixture in the case of multiple asymmetric centers. In certain cases, asymmetry can exist due to restricted rotation around a given bond, for example, the central bond adjacent to the two substituted aromatic rings of a specified compound.

[0077] Preferred compounds are those that exhibit the additional desired biological activity. Also included within the scope of the invention are separated, pure or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures, of the compounds of the invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

[0078] Preferred isomers are those which result in the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of the present invention are also included within the scope of the present invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

[0079] Optical isomers can be obtained by resolution of racemic mixtures by conventional processes, for example, by the formation of diastereomeric salts using optically active acids or bases, or by the formation of covalent diastereomers. Examples of suitable acids include tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into individual diastereomers based on their physical and / or chemical differences by methods known in the art, for example, chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. Different processes for the separation of optical isomers include the use of chiral chromatography (e.g., HPLC columns using chiral phases) optimally selected to maximize the separation of enantiomers, with or without prior derivatization. Suitable HPLC columns using chiral phases are commercially available, for example, those manufactured by Daicel, among others, such as Chiracel OD and Chiracel OJ, both of which are routinely selectable. Enzymatic separations, with or without derivatization, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

[0080] To distinguish different types of isomers from one another, reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0081] In the context of the present invention, A and B are selected independently from one another from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom. Thus, when A is a nitrogen atom and B is a carbon atom, the compound of formula (I) is a compound of the formula

[0082] [ka]

[0083] Similarly, in the context of the present invention, when A is a carbon atom and B is a nitrogen atom, the compound of formula (I) is a compound of the formula

[0084] [ka]

[0085] The present invention includes all possible stereoisomers of the compounds of the present invention, either as a single stereoisomer or as any mixture of said stereoisomers, e.g., as (R)- or (S)-isomers, in any ratio. Isolation of a single stereoisomer of a compound of the present invention, e.g., a single enantiomer or a single diastereomer, is achieved by any suitable prior art method, such as, for example, chromatography, especially chiral chromatography.

[0086] Additionally, compounds of the present invention may be capable of existing as tautomers. For example, any compound of the present invention containing an imidazopyridine moiety as a heteroaryl group can exist as, for example, a 1H tautomer, or a 3H tautomer, or even a mixture of the two tautomers, i.e., any of the following amounts:

[0087] [ka]

[0088] The present invention includes all possible tautomers of the compounds of the present invention as single tautomers or as any mixture of said tautomers, in any ratio.

[0089] Furthermore, in the context of the present invention, compounds of formula (I) may be able to exist as tautomers. For example, as shown below, compounds of formula (I) according to the present invention may exist as 1H tautomers, or 3H tautomers, or even as mixtures of any amount of two or more of the possible tautomers. [ka]

[0090] The present invention includes all possible tautomers of the compounds of formula (I) of the present invention, either as a single tautomer or as any mixture of any two or more of any possible tautomers, in any ratio.

[0091] Furthermore, in the context of the present invention, it may be possible for compounds of formula (I) in which X is a nitrogen atom to exist as tautomers. For example, as shown below, compounds of formula (I) according to the present invention in which X is a nitrogen atom can exist as the 1H tautomer, or the 4H tautomer, or even as a mixture of any amount of two or more of the possible tautomers. [ka]

[0092] The present invention includes all possible tautomers of the compounds of formula (I) of the present invention, where X is a nitrogen atom, either as a single tautomer or as any mixture of two or more possible tautomers in any ratio.

[0093] Furthermore, in the context of the present invention, X is CR 3 It may be possible for compounds of formula (I) where X is a group to exist as tautomers. For example, when X is CR 3 The compounds of formula (I) according to the invention, which are a group, can exist as two different 1H tautomers or even as a mixture of any amount of two or more of the possible tautomers. [ka]

[0094] The present invention is 3The group includes all possible tautomers of the compounds of formula (I) of the present invention, either as a single tautomer or as any mixture of two or more possible tautomers in any ratio.

[0095] Furthermore, in the context of the present invention, the triazine core of the compounds of formula (I) may exhibit tautomerism, allowing the compounds to exist as a single tautomer or even as a mixture of any amount of two or more of the possible tautomers. [ka]

[0096] Additionally, compounds of the present invention can exist as N-oxides, which are defined in that one or more of the nitrogens in a compound of the present invention are oxidized. The present invention includes all such possible N-oxides.

[0097] The present invention also provides useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, particularly pharmaceutically acceptable salts, and / or coprecipitates.

[0098] The compounds of the present invention can exist as hydrates or solvates, and for example, the compounds of the present invention contain polar solvents, particularly water, methanol, or ethanol, as structural elements of the crystal lattice of the compounds. The amount of polar solvent, particularly water, can be stoichiometric or non-stoichiometric. In the case of stoichiometric solvates, for example, hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are possible. The present invention includes all such hydrates or solvates.

[0099] Furthermore, the compounds of the present invention can exist in free form, for example as a free base or as a free acid or as a zwitterion, or in the form of a salt, which may be any salt, organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt conventionally used in pharmacy or used, for example, to isolate or purify the compounds of the present invention.

[0100] The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. See, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0101] Physiologically acceptable salts of the compounds according to the invention are, for example, acid addition salts of mineral acids, carboxylic acids and sulfonic acids, such as, for example, salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid, nitric acid, or organic acids, such as, for example, salts of formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, piva acid, and 2-hydroxyethanesulfonate, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

[0102] "Pharmaceutically acceptable anion" refers to the deprotonated form of a conventional acid, such as, for example, hydroxide, carboxylate, sulfate, halide, phosphate, or nitrate.

[0103] Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and preferably, alkali metal salts (e.g., lithium salts, sodium salts and potassium salts), alkaline earth metal salts (e.g., calcium salts, strontium salts and magnesium salts), and ammonium salts derived from ammonia or organic amines having 1 to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyl-diisopropyl-amine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylamino-ethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methyl-piperidine, N-methylglucamine, dimethylglucamine, ethylglucamine, 1,6-hexadiamine, glucosamine, sarcosine, serinol, tris(hydroxymethyl)aminomethane, aminopropanediol, Sovak's base, and 1-amino-2,3,4-butanetriol.

[0104] Furthermore, the compounds according to the invention may form salts with quaternary ammonium ions, which may be obtained by the quaternization of basic nitrogen-containing groups with agents such as lower alkyl halides, e.g., methyl chloride, methyl bromide and methyl iodide, ethyl chloride, ethyl bromide and ethyl iodide, propyl chloride, propyl bromide and propyl iodide, and butyl chloride, butyl bromide and butyl iodide; dialkyl sulfates, e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long-chain halides, e.g., decyl chloride, decyl bromide and decyl iodide, lauryl chloride, lauryl bromide and lauryl iodide, myristyl chloride, myristyl bromide and myristyl iodide, and stearyl chloride, stearyl bromide and stearyl iodide; aralkyl halides, e.g., benzyl bromide and phenethyl bromide. Examples of suitable quaternary ammonium ions include tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, or N-benzyl-N,N,N-trimethylammonium.

[0105] The present invention includes all possible salts of the compounds of the present invention, either as a single salt or as any mixture of said salts in any ratio.

[0106] In the present text, particularly in the experimental section, for the synthesis of intermediates and examples of the present invention, when compounds are referred to in salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form obtained by the respective preparation and / or purification process is in most cases unknown.

[0107] Unless otherwise specified, for example, "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF3COOH", "x Na + A suffix to a chemical name or structural formula for a salt, such as "," refers to the salt form and does not specify the stoichiometry of that salt form.

[0108] This also applies if the synthetic intermediates or example compounds or salts thereof are obtained by the described preparation and / or purification processes as solvates, e.g., hydrates, with unknown stoichiometric composition (if defined).

[0109] Unless otherwise specified, for example, "hydrochloride", "trifluoroacetate", "sodium salt" or "x HCl", "x CF3COOH", "x Na + A suffix to a chemical name or structural formula for a salt, such as "," refers to the salt form and does not specify the stoichiometry of that salt form.

[0110] Solvates and hydrates of the disclosed intermediates or example compounds or salts thereof obtained by the preparation and / or purification processes described herein may be formed in any ratio.

[0111] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as single polymorphs or as mixtures of multiple polymorphs in any ratio.

[0112] Furthermore, the present invention also includes prodrugs of the compounds according to the present invention. The term "prodrug" refers to a compound that may be biologically active or inactive itself, but is converted (e.g., metabolically or hydrolytically) into a compound according to the present invention during its residence in the body. For example, a prodrug may be in the form of an in vivo hydrolyzable ester of a particular compound. Derivatives of the compound of formula (I) and its salts that are converted into the compound of formula (I) or its salts in a biological system (biological precursor or prodrug) are encompassed by the present invention. The biological system may be, for example, a mammalian organism, particularly a human subject. The biological precursor is, for example, converted into the compound of formula (I) or its salts by a metabolic process.

[0113] Furthermore, in the context of the present invention, when referring to the inhibitory and / or degrading activity of the compounds of formula (I) according to the invention, the following terms are defined as follows:

[0114] As used herein and within the context of the present invention, the term "IC50 CDK12 hATP" refers to the IC obtained according to the assay described in section 2.2 of the Experimental Section herein below. 50 value, i.e., IC for inhibition of CDK12 at high ATP 50 Points to a value.

[0115] As used herein and within the context of the present invention, the term "DC50 CDK12" refers to DC obtained according to the assay described in Section 7 of the Experimental Section herein below. 50 value, i.e., DC for CDK12 degradation 50 Points to a value.

[0116] explanation Further embodiments of the first aspect of the invention According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R 1 is a halogen atom, R 2 is selected from C1-C3-alkyl groups, C1-C3-alkoxy groups, C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of the above general formula (I).

[0117] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R 1 is a C1-C3-haloalkyl group, R 2 is selected from C1-C3-alkyl groups, C1-C3-alkoxy groups, C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of the above general formula (I).

[0118] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R 1 is a halogen atom, R 2 is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of the above general formula (I).

[0119] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R 1 is a C1-C3-haloalkyl group, R 2 is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of the above general formula (I).

[0120] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R 1 is a halogen atom, R 2 is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Provided is a compound of the above general formula (I), or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein Y is a carbon atom.

[0121] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R 1 is a C1-C3-haloalkyl group, R 2 is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Provided is a compound of the above general formula (I), or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein Y is a carbon atom.

[0122] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A is a nitrogen atom and B is a carbon atom, R 1 is a halogen atom, R 2 is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of the above general formula (I).

[0123] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A is a nitrogen atom and B is a carbon atom, R 1 is a C1-C3-haloalkyl group, R 2is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of the above general formula (I).

[0124] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A is a carbon atom and B is a nitrogen atom, R 1 is a halogen atom, R 2 is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of the above general formula (I).

[0125] According to a further embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis, comprising: A is a carbon atom and B is a nitrogen atom, R 1 is a C1-C3-haloalkyl group, R 2 is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups, X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of the above general formula (I).

[0126] The present invention provides compounds of general formula (I), which are disclosed in the Examples section of the text below.

[0127] In some embodiments, the present invention includes a compound of general formula (I) selected from the following:

[0128] 8-bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0129] 8-bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0130] 8-bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0131] 8-bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0132] 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0133] 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0134] 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0135] 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0136] 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0137] 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0138] 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0139] 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0140] N-{[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0141] 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0142] N-{[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0143] 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0144] 2-(morpholin-4-yl)-N-({5-[6-(trifluoromethoxy)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0145] N-{[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0146] 2-(morpholin-4-yl)-N-({5-[6-(trifluoromethoxy)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0147] 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine,

[0148] N-{[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0149] N-{[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine,

[0150] N-{[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine, and

[0151] 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine.

[0152] Further embodiments of the first aspect of the invention In some embodiments, the present invention provides a compound of formula (I) above, or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein A and B are, independently of each other, selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom.

[0153] In some embodiments, the present invention provides a compound of formula (I) above, or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein A is a nitrogen atom and B is a carbon atom.

[0154] In some embodiments, the present invention provides a compound of formula (I) above, wherein A is a carbon atom and B is a nitrogen atom, or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

[0155] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 1 is selected from a halogen atom and a C1-C3-haloalkyl group, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, of the compound of formula (I) above.

[0156] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 1 is a halogen atom, or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

[0157] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 1 is a C1-C3-haloalkyl group, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

[0158] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 2 provides a compound of the above formula (I), or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein the N-oxide is selected from a C1-C3-alkyl group, a C1-C3-alkoxy group, a C1-C3-haloalkyl group, and a C1-C3-haloalkoxy group.

[0159] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 2 provides a compound of the above formula (I), or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein the group is selected from C1-C3-haloalkyl groups and C1-C3-haloalkoxy groups.

[0160] In some embodiments, the present invention provides a method for treating a cancer comprising administering to a patient a cancer-related disorder, ... 2 is a C1-C3-haloalkyl group, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

[0161] In some embodiments, the present invention provides X is a nitrogen atom and CR 3 is selected from the group R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

[0162] In some embodiments, the present invention provides a compound of formula (I) above, or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein X is a nitrogen atom.

[0163] In some embodiments, the present invention provides X is CR 3 It is the basis, R 3 is selected from a hydrogen atom, a C1-C3-alkyl group and a C1-C3-haloalkyl group, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

[0164] In some embodiments, the present invention provides a compound of formula (I) above, or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein Y is selected from a nitrogen atom or a carbon atom.

[0165] In some embodiments, the present invention provides a compound of formula (I) above, or a tautomer, or N-oxide, or salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof, wherein Y is a carbon atom.

[0166] In a further embodiment, the present invention includes a compound of formula (I), or a tautomer, N-oxide or salt thereof, or a salt of a tautomer or N-oxide, or a mixture thereof.

[0167] In a further embodiment, the present invention comprises a compound of formula (I) or a salt thereof:

[0168] In a further embodiment, the present invention comprises a compound of formula (I) or a tautomer or salt thereof, or a salt of a tautomer, or a mixture thereof.

[0169] In a further embodiment, the present invention includes a compound of formula (I) that is a salt.

[0170] In a further embodiment, the present invention includes a compound of formula (I) that is a tautomer or a salt thereof, or a salt of a tautomer, or a mixture thereof.

[0171] In a further embodiment, the present invention includes a compound of formula (I) as its N-oxide or salt, or a salt of an N-oxide, or a mixture thereof.

[0172] In further embodiments of the first aspect, the invention provides combinations of two or more of the above-described embodiments under the heading "Further embodiments of the first aspect of the invention".

[0173] Furthermore, it is understood that the present invention includes any subcombination of the single embodiments disclosed herein with respect to particular residues, or subcombinations of residues, of formula (I).

[0174] The present invention includes any subcombination within any embodiment or aspect of the invention of compounds of general formula (I) above.

[0175] The present invention includes compounds of general formula (I) or any subcombination within any embodiment or aspect of the invention of intermediate compounds. The present invention includes compounds of general formula (I) disclosed in the Examples section of the text below.

[0176] (General synthesis of compounds of general formula (I) of the present invention)

[0177] The following paragraphs outline various synthetic methods suitable for preparing compounds of general formula (I) and intermediates useful in their synthesis.

[0178] In addition to the routes described below, other routes may be used to synthesize the target compounds, according to the general knowledge of one skilled in the art of organic synthesis. Thus, the sequence of transformations illustrated in the following schemes is not intended to be limiting, and suitable synthetic steps from the various schemes may be combined to form additional synthetic sequences. In addition, any of the substituents, particularly R 1 , R 2 , R 3 or R 4Interconversion of the following groups can be achieved. These modifications can be, for example, the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, metal-catalyzed coupling reactions exemplified by, but not limited to, Suzuki, Sonogashira, and Ullmann couplings, ester saponification, amide coupling reactions, and / or substitution or other reactions known to those skilled in the art. These transformations include those that introduce functional groups that allow further interconversion of substituents. Suitable protecting groups, and their introduction and cleavage, are well known to those skilled in the art (see, for example, T.W. Greene and P.G.M. Buts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999).

[0179] (pyrazolotriazine) [ka] Scheme 1: Preparation of compounds of general formula (Ia) from sulfone derivatives of formula (IIa).

[0180] R 1 , R 2 Pyrazolotriazines of general formula (Ia), where X and Y are as defined for compounds of general formula (I), can be converted to R 1 , R 2 It can be assembled from a sulfone derivative of formula (IIa), where X and Y are as defined for compounds of general formula (I), and an amine such as morpholine. The nucleophilic reaction can be carried out in a suitable solvent in the presence of a suitable base such as sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate, N,N-diisopropylethylamine, triethylamine or 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), and in the case of aromatic amines, in the presence of an acid such as 4-methylbenzenesulfonic acid.

[0181] Herein it is preferred to carry out the nucleophilic reaction in the case of amines using N,N-diisopropylethylamine as base in acetonitrile as solvent within the temperature range of 20°C to 80°C.

[0182] [ka] Scheme 2: Preparation of intermediates of general formula (IIa).

[0183] The intermediate sulfone derivatives of formula (IIa) are available, for example, by the sequence shown in Scheme 2. This procedure involves the use of ethyl carbonisothiocyanatidate in ethyl acetate to form R 1 Starting from an amino-pyrazole derivative of formula (IV), commercially available or synthesized (e.g., according to WO 2018 / 195397), where R is as defined for the compound of general formula (I), intermediate (V) is obtained, which under basic conditions, such as aqueous sodium hydroxide, forms a pyrazolotriazine derivative of formula (VI). Using methyl iodide under basic conditions, such as sodium hydroxide, forms the methylsulfanyl derivative (VII). In compound (VII), R 1 In the case of =H, halogens such as bromo, chloro, or iodo can be introduced using the corresponding N-halo-succinimide reagent. Reaction of the derivative (VII) with phosphorus oxychloride gave the chloro intermediate (VIII). The reaction of (VIII) with R under basic conditions, such as N,N-diisopropylethylamine, in a suitable solvent, such as acetonitrile, at a temperature range of 20°C to 80°C, afforded the chloro intermediate (VIII). 3 and a commercially available or prepared amine of general formula (IX), where X is as defined for compounds of general formula (I), followed by oxidation of the sulfur atom with meta-chloroperbenzoic acid (mCPBA) provides sulfone (IIa).

[0184] [ka] Scheme 3: Preparation of different types of amines of general formula (IX).

[0185] The synthesis of different types of amines of general formula (IX) is shown in Scheme 3. When X=N and R 2 is as defined for compounds of general formula (I) in the first step, commercially available protected ethyl 2-aminoethanimidate (XI) can be reacted with R 2 is as defined for compounds of general formula (I) according to US 2010 / 22599 to give protected amines (XIII), which are deprotected in a subsequent step using conditions known to those skilled in the art to give amines of formula (IX) where X=N. The acyl hydrazides (XII) used are either commercially available or can be easily prepared using the corresponding acids or esters by procedures known to those skilled in the art.

[0186] X=CR 3 and R 3 is as defined for compounds of general formula (I), commercially available protected aminoacetaldehyde (XIV) is reacted with 1,2-diketone (XV) (for preparation, see Landais, Y.; Vincent, JM, Science of Synthesis, (2005) 26, 647) in the presence of a methanol / tetrahydrofuran solution of ammonium acetate according to Bioorganic and Medicinal Chemistry, 2012, 7128, to give protected amine (XVI), which is subsequently deprotected using conditions known to those skilled in the art to give X = CR 3 to obtain an amine of formula (IX):

[0187] These amines can also be prepared according to Bioorganic and Medicinal Chemistry Letters, 2013, 4374, starting from the 1,2-diamino compound (XVII) by reaction with the commercially available protected glycine derivative of formula (XVIII) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and hydroxybenzotriazole monohydrate followed by acetic acid to give the protected amine (XVI), which can be deprotected in a subsequent step using conditions known to those skilled in the art to give X=CR 3 The compound can be prepared by obtaining an amine of formula (IX)

[0188] Alternatively, 1,2-diamino compounds (XVII) can be reacted with glycine (XIX) using acid conditions such as aqueous HCl, according to EP 1135374 (2006), where X=CR 3 An amine of formula (IX) can be obtained,

[0189] [ka] Scheme 4: X = CR 3 An alternative preparation of compounds of general formula (Ia) wherein:

[0190] Alternatively, compounds of formula (VIII) can be reacted with 2-aminoethanol (XX) to give compounds of formula (XXI), which can be oxidized with meta-chloroperbenzoic acid (mCPBA) to give sulfones of formula (XXII). These sulfones of formula (XXII) and amines can be reacted in aromatic nucleophilic substitutions well known to those skilled in the art, and as described for Scheme 1, to give compounds of formula (XXIII), which can be oxidized to the corresponding aldehydes of formula (XXIV) using methods well known to those skilled in the art. X=CR 3 and R 3Compounds of formula (Ia), wherein is as defined for compounds of general formula (I), can be assembled by reaction of an aldehyde of formula (XXIV) with a 1,2-diketone of formula (XV), as described for Scheme 3.

[0191] [ka] Scheme 5: X = CR 4 An additional alternative preparation of compounds of general formula (Ia) wherein:

[0192] Alternatively, compounds of formula (VIII) can be reacted with aminoacetonitrile (XXVI) to give compounds of formula (XXVII), which can be oxidized with meta-chloroperbenzoic acid (mCPBA) to give sulfones of formula (XXVIII). These sulfones of formula (XXVIII) and amines can be reacted with aromatic nucleophilic substitutions well known to those skilled in the art, and as described for Scheme 1, to give compounds of formula (XXXIX), which can be reacted with the corresponding imidamides of formula (XXX) using methods well known to those skilled in the art. X=CR 3 and R 3 Compounds of formula (Ia), wherein is as defined for compounds of general formula (I), can be assembled by reaction of an imidamide of formula (XXX) with an alpha-halogenated ketone of formula (XXXI), using methods well known to those skilled in the art.

[0193] [ka] Scheme 6: Alternative preparation of compounds of general formula (Ia) where X=N.

[0194] Alternatively, a compound of formula (VIII) can be reacted with a glycinate of formula (XXXII) to give a compound of formula (XXXIII), which can be oxidized with meta-chloroperbenzoic acid (mCPBA) to give a sulfone of formula (XXXIV). These sulfones of formula (XXXIV) and amines can be reacted by aromatic nucleophilic substitution, as well known to those skilled in the art, and as described for Scheme 1, to give a compound of formula (XXXV), which can be reacted with the corresponding hydrazide of formula (XXXVI) using methods well known to those skilled in the art. Alternatively, a compound of formula (XXXV) can be first hydrolyzed to the corresponding carbonic acid, which can be reacted with the corresponding hydrazide of formula (XXXVI) using methods well known to those skilled in the art. When X=N and R 3 Compounds of formula (Ia), wherein is as defined for compounds of general formula (I), can be assembled by reaction of a hydrazide of formula (XXXVI) with an imidamide of formula (XXXVII), using methods well known to those skilled in the art.

[0195] [ka] Scheme 7: Alternative preparation of compounds of general formula (Ia) where X=N.

[0196] Alternatively, compounds of formula (XXXVII) can be halogenated and reacted with phosphorus oxychloride to give compounds of formula (VIII), which can be reacted with amines bearing two protecting groups (PG), for example, para-methoxybenzyl, and oxidized to sulfones of formula (XXXIX) using meta-chloroperbenzoic acid (mCPBA). These sulfones of formula (XXXIX) and amines can be reacted with aromatic nucleophilic substitutions, as well known to those skilled in the art, and as described for Scheme 1, to give compounds of formula (XL), which can be reacted with the corresponding CF3 derivative of formula (XLI) using methods well known to those skilled in the art. After deprotection, compounds of formula (XLII) can be alkylated with chloroacetic ester to give compounds of formula (XXXV), which can be hydrolyzed to the corresponding carbonic acid and then reacted with the corresponding hydrazide of formula (XXXVI) using methods well known to those skilled in the art. When X=N and R 3 Compounds of formula (Ia), wherein is as defined for compounds of general formula (I), can be assembled by reaction of a hydrazide of formula (XXXVI) with an imidamide of formula (XXXVII), using methods well known to those skilled in the art.

[0197] (imidazotriazine) [ka] Scheme 8: Preparation of compounds of general formula (Ib).

[0198] R 1 , R 2 , R 3 Imidazotriazines of general formula (Ib), where X and Y are as defined for compounds of general formula (I), can be converted to R by aromatic nucleophilic substitution, as known to those skilled in the art, according to Scheme 8. 1 , R 2 , R 3, a sulfone derivative of formula (IIb), in which X and Y are as defined for compounds of general formula (I), and an amine. The nucleophilic reaction can be carried out by reaction of compounds of formula (IIb) and (III) in a suitable solvent in the presence of a suitable base such as sodium hydroxide, sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate, N,N-diisopropylethylamine, triethylamine or 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), and in the case of aromatic amines in the presence of an acid such as 4-methylbenzenesulfonic acid.

[0199] Herein it is preferred to carry out the nucleophilic reaction in the case of amines using N,N-diisopropylethylamine as base in acetonitrile as solvent within the temperature range of 20°C to 80°C.

[0200] [ka] Scheme 9: Preparation of intermediates of general formula (IIb).

[0201] The intermediate sulfone derivative of formula (IIb) can be obtained, for example, by the sequence shown in Scheme 9. This method starts from 2-(methanesulfonyl)-4-(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine of formula (III) (see Dudfield, Philip J.; Le, Van-Due; Lindell, Stephen D.; Rees, Charles W. Journal of the Chemical Society. Perkin transactions I, 1999, #20, pp. 2929-2936). A halogen such as bromo, chloro, or iodo is introduced using the corresponding N-halo-succinimide reagent to form R 1 It is possible to obtain compounds of formula (IV) in which is bromo, chloro or iodo. Reaction of the derivative (IV) with a compound of formula (V) gives sulfones of formula (IIb).

[0202] [ka] Scheme 10: Alternative preparation of compounds of general formula (Ib) where X=N.

[0203] Alternatively, compounds of formula (XLIII) can be reacted with phosphorus oxychloride to give compounds of formula (XLIV), which can be reacted with methanethiol to give compounds of formula (XLV). These disulfanes of formula (XLV) can be halogenated to give compounds of formula (XLVI), which can be reacted with the corresponding CF3 derivatives of formula (XLVI) using methods well known to those skilled in the art. These compounds of formula (XLVI) and amines can be reacted in a nucleophilic aromatic substitution well known to those skilled in the art to give compounds of formula (XLVIII). After oxidation, sulfones of formula (XLIX) can be reacted in a nucleophilic aromatic substitution well known to those skilled in the art to give compounds of formula (L), which can be hydrolyzed to the corresponding carbonic acid using methods well known to those skilled in the art and then reacted with the corresponding hydrazide of formula (LI). When X=N and R 3 Compounds of formula (Ib), wherein is as defined for compounds of general formula (I), can be assembled by reaction of a hydrazide of formula (LI) with an imidamide of formula (XXXVII), using methods well known to those skilled in the art.

[0204] [ka] Scheme 11: Alternative preparation of compounds of general formula (Ib) where X=N.

[0205] Alternatively, these compounds of formula (XLVI) and amines can be reacted in a nucleophilic aromatic substitution well known to those skilled in the art to give compounds of formula (LII). After oxidation, sulfones of formula (LIII) can be reacted with amines such as morpholines in a nucleophilic aromatic substitution well known to those skilled in the art to give compounds of formula (Ib).

[0206] The present invention includes intermediate compounds disclosed in the Examples section of the text below.

[0207] The compound of the present invention represented by general formula (I) can be converted into any salt, preferably a pharmaceutically acceptable salt, by any method known to those skilled in the art.Similarly, any salt of the compound of the present invention represented by general formula (I) can be converted into the free compound by any method known to those skilled in the art.

[0208] The compounds of general formula (I) of the present invention exhibit an unexpectedly beneficial pharmacological spectrum. The compounds of the present invention effectively inhibit the activity of CDK12 (data shown in the Biological Experiments section) and can therefore be used for the treatment and / or prevention of hyperproliferative disorders, such as cancer disorders, in humans and animals.

[0209] Methods and Administration The compounds of general formula (I) of the present invention exhibit advantageous pharmacological action spectrum and pharmacokinetic profile that could not be predicted.The compounds of the present invention have surprisingly been found to effectively inhibit the activity of CDK12, induce proteolysis of CDK12 protein in cells, and exhibit strong CDK12 degradation potency, which increases selectivity against other kinases.Therefore, the compounds can be used for the treatment and / or prevention of diseases, preferably hyperproliferative disorders, in humans and animals.

[0210] Furthermore, CDK12 has been identified as a potential target for the development of new drugs to treat the RNA-based disease myotonic dystrophy type 1 (DM1) (Ketley et al., Sci. Transl. Med. 12, eaaz2415 (2020)). Therefore, the compounds of general formula (I) of the present invention can be used for the treatment and / or prevention of diseases in which CDK12 is involved, such as myotonic dystrophy type 1 (DM1).

[0211] As used herein, "prevention" includes the use of a compound that, when administered prior to the onset of a disorder or condition in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0212] The compounds of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and / or cell division and / or cause apoptosis, all of which are types of “treatment.” The method comprises administering to a mammal, including a human, in need thereof, a compound of general formula (I) of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate, or ester thereof, in an amount effective to treat the disorder.

[0213] Hyperproliferative disorders include, but are not limited to, psoriasis, keloids, and other hyperplasias affecting the skin, benign prostatic hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, gastrointestinal tract, urinary tract, eye, liver, skin, head and neck, thyroid, and parathyroid glands, and their distant metastases. These disorders also include lymphomas, sarcomas, and leukemias.

[0214] Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0215] Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

[0216] Examples of brain cancers include, but are not limited to, brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.

[0217] Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.

[0218] Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.

[0219] Tumors of the digestive tract include, but are not limited to anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

[0220] Tumors of the urinary tract include, but are not limited to bladder cancer, penile cancer, kidney cancer, renal pelvis cancer, ureter cancer, urethral cancer, and human papillary renal carcinoma.

[0221] Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

[0222] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar transformation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular-cholangiocarcinoma.

[0223] Skin cancer includes, but is not limited to basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0224] Head and neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal, lip and oral cavity cancer, and squamous cell.

[0225] Lymphomas include, but are not limited to, AIDS-related lymphoma, chronic lymphocytic lymphoma (CLL), non-Hodgkin's lymphoma (NHL), T-non-Hodgkin's lymphoma (T-NHL), subtypes of NHL such as diffuse large cell lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell lymphoma DLBCL, double-hit lymphoma and double-expression lymphoma; anaplastic large cell lymphoma, B-cell lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, hairy cell lymphoma, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoma of the central nervous system, small lymphocytic lymphoma and chronic lymphocytic lymphoma, and Sézary syndrome.

[0226] Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0227] Leukemias include, but are not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, (acute) T-cell leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia (ALL), acute monocytic leukemia (AML), acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and myelodysplastic syndromes (MDS) which can progress to acute myeloid leukemia.

[0228] The present invention also provides methods for treating angiogenic disorders, including diseases associated with excessive and / or aberrant angiogenesis.

[0229] Inappropriate and ectopic angiogenesis can be harmful to an organism. Several pathological conditions are associated with the proliferation of exogenous blood vessels. These include, for example, diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity [Aiello et al., New Engl. J. Med., 1994, 331, 1480; Peer et al., Lab. Invest., 1995, 72, 638], age-related macular degeneration (AMD) [Lopez et al., Invest. Ophthalmol. Vis. Sci., 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, and vascular graft restenosis. In addition, the increased blood supply associated with cancerous and neoplastic tissue promotes proliferation, leading to rapid tumor expansion and metastasis. Furthermore, the growth of new blood and lymphatic vessels within tumors provides an escape route for mutated cells, facilitating the metastasis and consequent spread of cancer. Thus, the compounds of general formula (I) of the present invention may be utilized to treat and / or prevent any of the aforementioned angiogenic disorders, for example, by inhibiting and / or reducing angiogenesis, inhibiting, blocking, reducing, decreasing, etc., endothelial cell proliferation, or other types involved in angiogenesis, and inducing cell death or apoptosis of such cell types.

[0230] These disorders are well characterized in humans, but also exist in other mammals with similar etiologies and can be treated by administering the pharmaceutical compositions of the present invention.

[0231] The terms "treating" or "treatment" as referred to throughout this specification are used conventionally and refer to the management or care of a subject for the purpose of combating, alleviating, reducing, ameliorating and / or ameliorating the condition of a disease or disorder, e.g., cancer.

[0232] The compounds of the present invention may be used in particular for the treatment and prevention of tumor growth and metastasis, i.e., prophylaxis, particularly for solid tumors of all indications and stages, with or without prior treatment of tumor growth.

[0233] Generally, the use of chemotherapeutic and / or anti-cancer agents in combination with the compounds or pharmaceutical compositions of the present invention includes: 1. Provides better efficacy in reducing tumor growth or even eliminating tumors compared to administration of either agent alone; 2. Providing for administration of even smaller amounts of chemotherapeutic agents; 3. Providing chemotherapy treatments that are well tolerated in patients with fewer adverse pharmacological complications than those observed with single agent chemotherapy and certain other combination therapies; 4. In mammals, particularly humans, to provide treatment for a wide range of different cancer types; 5. Increase response rates among treated patients; 6. Extend survival among treated patients compared to standard chemotherapy treatment; 7. Prolonging the time for tumor progression, and / or 8. Helps produce efficacy and tolerability results that are at least as good as those of the drugs used alone, compared with known instances where combinations of other cancer drugs result in antagonism.

[0234] In addition, the compounds of general formula (I) of the present invention may also be used in combination with radiotherapy and / or surgical intervention.

[0235] In a further embodiment of the present invention, the compounds of general formula (I) of the present invention may be used to sensitize cells to radiation, i.e., treating cells with a compound of the present invention prior to radiation treatment of the cells makes the cells more susceptible to DNA damage and cell death than if they were not treated with a compound of the present invention. In one aspect, cells are treated with one or more compounds of general formula (I) of the present invention.

[0236] Thus, the present invention also provides a method of killing cells, in which the cells are administered one or more compounds of the present invention in combination with conventional radiation therapy.

[0237] The present invention also provides a method for predisposing cells to cell death, comprising treating the cells with one or more compounds of general formula (I) of the present invention prior to treating the cells to cause or induce cell death. In one aspect, after treating the cells with one or more compounds of general formula (I) of the present invention, the cells are treated with one or more compounds, or one or more methods, or a combination thereof, to cause DNA damage in order to inhibit the function of the cells or kill the cells.

[0238] In another embodiment of the present invention, cells are killed by treating them with one or more DNA damaging agents, i.e., after treating the cells with one or more compounds of general formula (I) of the present invention to sensitize the cells to cell death, the cells are then treated with one or more DNA damaging agents to kill the cells. DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, UV light), carcinogens, and mutagens.

[0239] In other embodiments, cells are killed by treating cells with one or more methods to cause or induce DNA damage.Such methods include, but are not limited to, activating cell signaling pathways that cause DNA damage when the pathway is activated, inhibiting cell signaling pathways that cause DNA damage when the pathway is inhibited, and inducing biochemical changes in cells that cause DNA damage.Non-limiting examples include inhibiting intracellular DNA repair pathways, thereby preventing DNA damage repair and causing abnormal accumulation of DNA damage in cells.

[0240] In some embodiments, the compound of general formula (I) of the present invention is administered to a cell prior to radiation or other induction of DNA damage in the cell. In some embodiments of the present invention, the compound of general formula (I) of the present invention is administered to a cell simultaneously with radiation or other induction of DNA damage in the cell. In further embodiments of the present invention, the compound of general formula (I) of the present invention is administered to a cell after radiation or other induction of DNA damage in the cell has begun. In still further embodiments of the present invention, the compound of general formula (I) of the present invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.

[0241] In some embodiments, the cell is in vitro. In other embodiments, the cell is in vivo.

[0242] Thus, in some embodiments, the present invention includes methods of inhibiting proliferation of a cell and / or inducing apoptosis in a cell, comprising contacting the cell with a compound of formula (I).

[0243] Another aspect of the present invention is a method of treating, preventing, or prophylaxing cancer (i.e., a method for treating, preventing, or prophylaxis of cancer) in a subject (e.g., a human, other mammal, such as a rat, etc.) by administering to the subject an effective amount of one or more compounds of general formula (I) or a pharmaceutically acceptable salt, polymorph, metabolite, hydrate, solvate, or ester thereof.

[0244] In some embodiments, a subject may be administered a medicament comprising one or more compounds of general formula (I) and one or more pharmaceutically acceptable carriers, formulation additives and / or diluents.

[0245] Additionally, in some embodiments, the present invention includes methods of using compounds of general formula (I) for the treatment of diseases.

[0246] In particular, in some embodiments, the present invention includes methods of treating hyperproliferative diseases, more particularly cancer, comprising administering to a subject in need thereof an effective amount of one or more compounds of general formula (I).

[0247] In some embodiments, a method for treating and / or preventing a hyperproliferative disorder in a subject can include administering to the subject an effective amount of a compound of general formula (I). The hyperproliferative disorder can be, for example, cancer (e.g., lung cancer, breast cancer, acute myeloid leukemia, lymphoma, glioblastoma, prostate cancer, etc.).

[0248] Additionally, in some embodiments, the present invention includes methods of treating cancer, particularly lymphoma, non-Hodgkin's lymphoma types, diffuse large B-cell lymphoma subtypes, acute leukemia, acute myeloid leukemia types, multiple myeloma, and ovarian cancer, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0249] Furthermore, in some embodiments, the present invention includes methods of treating cancer, particularly multiple myeloma, ovarian cancer, acute monocytic leukemia, melanoma, and lung cancer, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0250] Furthermore, in some embodiments, the present invention includes a method for treating cancer, particularly breast cancer; lung cancer; lymphoma, including non-Hodgkin's lymphoma type, diffuse large B-cell lymphoma subtypes, including GC-DLBCL* subtype and ABC-DLBCL** subtype, and mantle cell lymphoma; acute leukemia, acute myeloid leukemia type, acute monocytic leukemia; melanoma; multiple myeloma; ovarian cancer; and pancreatic cancer, comprising administering an effective amount of one or more compounds of formula (I) as defined in any one of claims 1 to 9 to a subject in need thereof. GC-DLBCL refers to germinal B-cell diffuse large B-cell lymphoma, and ABC-DLBCL refers to activated B-cell diffuse large B-cell lymphoma.

[0251] Furthermore, in some embodiments, the present invention includes a method of treating cancer, particularly breast cancer, lung cancer, diffuse large B-cell lymphoma subtypes including GC-DLBCL* and ABC-DLBCL** subtypes, mantle cell lymphoma, acute monocytic leukemia, melanoma, ovarian cancer, and pancreatic cancer, comprising administering to a subject in need thereof an effective amount of one or more compounds of formula (I) as defined in any one of claims 1 to 9. Furthermore, in some embodiments, the present invention provides a compound of formula (I) for use in treating a disease.

[0252] Additionally, in some embodiments, the present invention includes methods of treating cancer, particularly breast cancer; lymphoma, leukemia, multiple myeloma; and ovarian cancer, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0253] Additionally, in some embodiments, the present invention includes methods of treating cancer, particularly lymphoma, non-Hodgkin's lymphoma types, diffuse large B-cell lymphoma subtypes, acute leukemia, acute myeloid leukemia types, multiple myeloma, and ovarian cancer, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0254] Furthermore, in some embodiments, the present invention includes methods of treating cancer, particularly breast cancer, lymphoma (including non-Hodgkin's lymphoma types, diffuse large B-cell lymphoma subtypes, and mantle cell lymphoma), leukemia (including acute monocytic leukemia), liver cancer, multiple myeloma, melanoma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, ovarian carcinoma, gastric cancer, and squamous cell carcinoma, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0255] Furthermore, in some embodiments, the present invention includes methods of treating cancer, particularly breast cancer, diffuse large B-cell lymphoma subtype, mantle cell lymphoma, acute monocytic leukemia, liver cancer, multiple myeloma, melanoma, non-small cell lung cancer, small cell lung cancer, ovarian cancer, ovarian carcinoma, prostate cancer, gastric cancer, and squamous cell carcinoma, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0256] Furthermore, in some embodiments, the present invention includes a method of treating cancer, particularly bladder cancer, bone cancer, brain cancer, breast cancer, colon cancer (colorectal cancer), endometrial (uterine) cancer, stomach cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, lung cancer, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, rhabdoid tumor, sarcoma, and skin cancer, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0257] Furthermore, in some embodiments, the present invention includes a method of treating cancer, particularly breast cancer, liver cancer, lung cancer, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, prostate cancer, sarcoma, glioblastoma, and acute myeloid leukemia, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0258] Furthermore, in some embodiments, the present invention includes a method of treating cancer, particularly lung cancer, breast cancer, liver cancer, colorectal cancer, gastric cancer, prostate cancer, and leukemia, comprising administering to a subject in need thereof an effective amount of one or more compounds of Formula (I).

[0259] Additionally, in some embodiments, the present invention includes a method of treating myotonic dystrophy type 1 (DM1), comprising administering to a subject in need thereof an effective amount of one or more compounds of general formula (I).

[0260] According to some embodiments, the present invention provides a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate and salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for use in the treatment and / or prevention of a disease, in particular a hyperproliferative disorder.

[0261] Furthermore, according to a further aspect, the present invention provides a compound of formula (I) for use in the treatment of disease.

[0262] According to a further aspect, the present invention comprises a compound of general formula (I) for use in a method of inhibiting proliferation of a cell and / or the induction of apoptosis in a cell, comprising contacting the cell with a compound of formula (I).

[0263] In particular, in some embodiments, the present invention comprises a compound of general formula (I) for use in a method of treating a hyperproliferative disease, more particularly, the hyperproliferative disease is cancer, and even more particularly, the cancer disease is selected from lymphoma, non-Hodgkin's lymphoma type, diffuse large B-cell lymphoma subtype, ovarian cancer, multiple myeloma, acute leukemia, and acute myeloid leukemia.

[0264] More particularly, in some embodiments, the present invention comprises a compound of general formula (I) for use in a method of treating a hyperproliferative disease, more particularly, the hyperproliferative disease is cancer, and even more particularly, the cancer disease is selected from breast cancer; lymphoma, leukemia, multiple myeloma; and ovarian cancer.

[0265] In particular, in some embodiments, the present invention comprises compounds of general formula (I) for use in a method of treating a hyperproliferative disease, more particularly wherein the hyperproliferative disease is cancer, and even more particularly wherein the cancer is selected from breast cancer; esophageal cancer; liver cancer; lung cancer; lymphoma, including non-Hodgkin's lymphoma types, diffuse large B-cell lymphoma subtypes, including GC-DLBCL* subtypes and ABC-DLBCL** subtypes, and mantle cell lymphoma; acute leukemia, acute myeloid leukemia types, acute monocytic leukemia; melanoma; multiple myeloma; melanoma; ovarian cancer; or pancreatic cancer.

[0266] More particularly, in some embodiments, the present invention comprises a compound of general formula (I) for use in a method of treating cancer, wherein the cancer disease is selected from breast cancer; lymphoma, leukemia, multiple myeloma; and ovarian cancer.

[0267] More particularly, in some embodiments, the present invention comprises a compound of general formula (I) for use in a method of treating cancer, wherein the cancer disease is selected from breast cancer, liver cancer, lung cancer, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, prostate cancer, sarcoma, glioblastoma, and acute myeloid leukemia.

[0268] More particularly, in some embodiments, the present invention comprises a compound of general formula (I) for use in a method of treating cancer, wherein the cancer disease is selected from lung cancer, breast cancer, liver cancer, colorectal cancer, gastric cancer, prostate cancer, and leukemia.

[0269] Additionally, in some embodiments, the present invention includes compounds of general formula (I) for use in methods for treating myotonic dystrophy type 1 (DM1).

[0270] In some embodiments, the present invention comprises the use of a compound of general formula (I) for the manufacture of a medicament for treating and / or preventing a hyperproliferative disease.

[0271] In some embodiments, the present invention comprises the use of a compound of general formula (I) for the manufacture of a medicament for treating and / or preventing a hyperproliferative disease, wherein the hyperproliferative disease is cancer.

[0272] In some embodiments, the present invention comprises the use of a compound of general formula (I) for the manufacture of a medicament for the treatment of hyperproliferative diseases, particularly cancer, more particularly lymphoma, non-Hodgkin's lymphoma type, diffuse large B-cell lymphoma subtype, ovarian cancer, multiple myeloma, acute leukemia and acute myeloid leukemia type.

[0273] In some embodiments, the present invention comprises the use of a compound of general formula (I) for the manufacture of a medicament for the treatment of a hyperproliferative disease, particularly cancer, more particularly breast cancer, liver cancer, lung cancer, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, prostate cancer, sarcoma, glioblastoma, and acute myeloid leukemia.

[0274] In some embodiments, the present invention comprises the use of a compound of general formula (I) for the manufacture of a medicament for the treatment of a hyperproliferative disease, particularly cancer, more particularly lung cancer, breast cancer, liver cancer, colorectal cancer, gastric cancer, prostate cancer and leukemia.

[0275] In some embodiments, the present invention provides the use of a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate and salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture thereof, for preparing a pharmaceutical composition, preferably a medicament, for preventing or treating a disease, particularly a hyperproliferative disorder, especially cancer.

[0276] In some embodiments, the present invention provides the use of a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate and salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture thereof, for the preparation of a pharmaceutical composition, preferably a medicament, for the prevention or treatment of a disease, particularly a hyperproliferative disorder, in particular cancer, more particularly breast cancer, liver cancer, lung cancer, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, prostate cancer, sarcoma, glioblastoma and acute myeloid leukemia.

[0277] Additionally, in some embodiments, the present invention includes the use of a compound of general formula (I) for the manufacture of a medicament for treating myotonic dystrophy type 1 (DM1).

[0278] In some embodiments, the present invention provides a method for treating and / or preventing a disease, particularly a hyperproliferative disorder, especially cancer, comprising administering to a subject in need thereof an effective amount of a compound of the above general formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate and salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture thereof.

[0279] In some embodiments, the present invention provides a method for treating and / or preventing a disease, in particular a hyperproliferative disorder, in particular cancer, more in particular breast cancer, liver cancer, lung cancer, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, prostate cancer, sarcoma, glioblastoma and acute myeloid leukemia, comprising administering to a subject in need thereof an effective amount of a compound of general formula (I) above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof.

[0280] Furthermore, in some embodiments, the present invention provides a method for treating myotonic dystrophy type 1 (DM1), comprising administering to a subject in need thereof an effective amount of a compound of the above general formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture thereof.

[0281] In some embodiments, the present invention provides a pharmaceutical composition, particularly a medicament, comprising a compound of the above general formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt, particularly a pharmaceutically acceptable salt thereof, or a mixture thereof, and one or more formulation additives), particularly one or more pharmaceutically acceptable formulation additives. Conventional procedures can be used to prepare such pharmaceutical compositions in suitable dosage forms.

[0282] The present invention further provides pharmaceutical compositions, in particular medicaments, comprising one or more compounds according to the invention, conventionally together with one or more pharmaceutically suitable formulation excipients, and their use for the above-mentioned purposes.

[0283] The compounds according to the invention can have systemic and / or local activity, and for this purpose they can be suitably administered, for example via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, cutaneous, transdermal, conjunctival, otic route, or as an implant or stent.

[0284] For these administration routes, the compounds according to the invention can be administered in suitable dosage forms.

[0285] For oral administration, the compounds according to the invention can be formulated into dosage forms known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as tablets (uncoated or coated, e.g., with a delayed-dissolving or insoluble enteric or controlled-release coating), orally disintegrating tablets, films / wafers, films / lyophilisates, capsules (e.g., hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions, etc. The compounds according to the invention can be incorporated into the dosage form in crystalline and / or amorphous and / or dissolved form.

[0286] Parenteral administration can be carried out either avoiding the absorption step (for example, intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or including absorption (for example, intramuscularly, subcutaneously, intradermally, transdermally or intraperitoneally). Suitable dosage forms for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0287] Examples of suitable forms for other administration routes are pharmaceutical forms for inhalation (in particular powder inhalers, nebulizers), nose drops, nose solutions or nasal sprays; tablets / films / wafers / capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, stirred mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as patches), milks, pastes, foams, powders, implants or stents.

[0288] The compounds according to the invention can be incorporated into the described dosage forms. This can be done in a manner known per se by mixing with pharmaceutically suitable formulation additives. Pharmaceutically suitable formulation additives include, inter alia: fillers and carriers (e.g., cellulose, microcrystalline cellulose (e.g., Avicel®, etc.), lactose, mannitol, starch, calcium phosphate (e.g., Di-Cafos®, etc.)); Ointment bases (e.g., yellow petrolatum, paraffin, triglycerides, wax, wool wax, wool wax alcohol, lanolin, hydrophilic ointments, polyethylene glycol), Suppository bases (e.g., polyethylene glycol, cocoa butter, hard fats), solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin), surfactants, emulsifiers, dispersing agents or wetting agents (e.g. sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (e.g. Lanette®, etc.), sorbitan fatty acid esters (e.g. Span®, etc.), polyoxyethylene sorbitan fatty acid esters (e.g. Tween®, etc.), polyoxyethylene fatty acid glycerides (e.g. Cremophor®, etc.), polyoxyethylene fatty acid esters, polyoxyethylene fatty acid alcohol ethers, glycerol fatty acid esters, poloxamers (e.g. Pluronic®, etc.), buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), isotonic agents (e.g., glucose, sodium chloride), Adsorbents (e.g., highly dispersible silica), thickening agents, gel-forming agents, thickeners and / or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl-cellulose, carboxymethylcellulose-sodium, starch, carbomer, polyacrylic acid (e.g., Carbopol®, etc.); alginates, gelatin), disintegrants (e.g., modified starch, sodium carboxymethylcellulose, sodium starch glycolate (e.g., Explotab®, etc.), cross-linked polyvinylpyrrolidone, croscarmellose sodium (e.g., AcDiSol®, etc.)); Flow regulators, lubricants, glidants and release agents (e.g., magnesium stearate, stearic acid, talc, highly disperse silica (e.g., Aerosil®, etc.)), coating materials (e.g. sugars, shellac) and film-forming agents for rapidly or modified dissolving films or diffusion membranes (e.g. polyvinylpyrrolidone (e.g. Kollidon®), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl-methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates (e.g. Eudragit®), etc.), capsule materials (e.g., gelatin, hydroxypropyl methylcellulose), synthetic polymers (e.g. polylactides, polyglycolides, polyacrylates, polymethacrylates (e.g. Eudragit®, etc.), polyvinylpyrrolidones (e.g. Kollidon®, etc.), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols, and copolymers and block copolymers thereof); Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilizers (e.g., antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, etc.); Preservatives (e.g., parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), colorants (e.g., inorganic pigments, e.g., iron oxide, titanium dioxide, etc.); Flavorings, sweeteners, flavor masking agents and / or odor masking agents.

[0289] The present invention further relates to pharmaceutical compositions comprising one or more compounds according to the invention, conventionally together with one or more pharmaceutically suitable formulation excipients, and to their uses according to the invention.

[0290] In some embodiments, the present invention provides pharmaceutical combinations, particularly medicaments, comprising one or more compounds of general formula (I) according to the present invention and at least one or more further active ingredients, particularly for the treatment and / or prevention of hyperproliferative disorders, especially cancer.

[0291] In particular, the present invention provides a pharmaceutical combination comprising: one or more first active ingredients, in particular compounds of general formula (I) as defined above, and one or more further active ingredients, in particular for the treatment and / or prevention of hyperproliferative disorders, in particular cancer.

[0292] The term "combination" in the present invention is used as known to those skilled in the art, and the combination can be a fixed combination, a loose combination, or a kit of parts.

[0293] "Fixed combination" in the present invention is used as known to those skilled in the art, and is defined as, for example, a combination in which a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and an additional active ingredient are present together in one unit dosage or one single entity.One example of "fixed combination" is a pharmaceutical composition in which the first active ingredient and the additional active ingredient are present in a mixture, such as a formulation, for simultaneous administration.Another example of "fixed combination" is a pharmaceutical combination in which the first active ingredient and the additional active ingredient are not present in a mixture but are present in one unit.

[0294] In the present invention, a non-fixed combination or "kit of parts" is used as known to those skilled in the art and is defined as a combination in which a first active ingredient and an additional active ingredient are present in multiple units. An example of a non-fixed combination or kit of parts is a combination in which the first active ingredient and the additional active ingredient are present separately. The components of a non-fixed combination or kit of parts can be administered separately, sequentially, simultaneously, concurrently, or chronologically staggered.

[0295] The compound of the present invention can be administered as the only pharmaceutical or in combination with one or more other pharmaceutically active ingredients, provided that the combination does not cause unacceptable adverse effects.The present invention also provides such pharmaceutical combinations.For example, the compound of the present invention can be combined with a known anti-cancer drug.

[0296] Examples of anti-cancer drugs include: 131I-chTNT, abarelix, abemaciclib, abiraterone, acalabrutinib, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronate, alitretinoin, altretamine, amifostine, aminoglutethimide, hexylaminolevulinic acid, amrubicin, amsacrine, anastrozole, ancestim, anetholedithiolthione, anetuzumab emtansine, angiotensin II, antithrombin III, aflibercept Palutamide, aprepitant, arcitumomab, aruglavin, arsenic trioxide, asparaginase, atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, bosutinib, buserelin, brentuximab vedotin, brigatinib, busulfan, cabazitaxel, cabozantinib, calcitonin, calcium folinate, levo Calcium folinate, capecitabine, capromab, carbamazepine, carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, cermoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronate, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbe Poetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, durvalumab, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, enasidenib,Endostatin, enocitabine, enzalutamide, epirubicin, epithiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinyl estradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine , fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoterate meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoxime, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine amine dihydrochloride, histrelin, hydroxycarbamide, I-125 species, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, inotuzumab ozogamicin, interferon alpha, interferon beta, interferon gamma, iobitridol , Iobenguane (123I), Iomeprol, Ipilimumab, Irinotecan, Itraconazole, Ixabepilone, Ixazomib, Lanreotide, Lansoprazole, Lapatinib, Lasocorrin, Lenalidomide, Lenvatinib, Lenograstim, Lentinan, Letrozole, Leuprorelin, Levamisole, Levonorgestrel, Levothyroxine Sodium, Lisuride, Lobaplatin, Lomustine, Lonidamine, Lutetium Lu 177 Dotatate, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methyl aminolevulinate, methylprednisolone, methyltestosterone, metyrosine, midostaurin, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab,Molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, mvasi, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neratinib, neridronic acid, netupitant / palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, niraparib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olatamazumab, omase Taxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103, palonosetron, pamidronate, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxyPEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterf Seron alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutan, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusum, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol , quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib, regorafenib, ribociclib, risedronate, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, rucaparib, samarium (153Sm) lexidronam, sargramostim, sarilumab, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran,Sobuzoxane, glycididazole sodium, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentane, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, thioguanine, tisagenlecleucel, tociliz Mab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, baratinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microparticles, zinostatin, zinostatin stimalamer, zoledronic acid and zorubicin.

[0297] Based on known standard laboratory techniques for evaluating compounds useful in the treatment of hyperproliferative disorders, by standard toxicity tests and by standard pharmacological assays for determining the treatment of the above-identified conditions in mammals, and by comparing these results with those of known active ingredients or pharmaceuticals used to treat these conditions, the effective dosage of the compounds of the present invention for the treatment of each desired indication can be readily determined. The amount of active ingredient administered in the treatment of one of these conditions can vary widely, depending on such considerations as the particular compound and dosage unit used, the mode of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and severity of the condition being treated.

[0298] The total amount of active ingredient administered generally ranges from about 0.001 mg / kg to about 200 mg / kg body weight per day, preferably from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules range from one to three times daily to once every four weeks. In addition, a "drug holiday" in which the patient is not administered the drug for a period of time may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered one or more times per day, or less than once per day. For administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and for use with infusion techniques, the average daily dosage is preferably 0.01 to 200 mg per kg of total body weight. The average daily rectal dosing regimen is preferably 0.01 to 200 mg per kg of total body weight. The average daily vaginal dosage regimen is preferably 0.01 to 200 mg / kg of total body weight. The average daily topical dosage regimen is preferably 0.1 to 200 mg administered 1 to 4 times daily. The transdermal concentration is preferably that required to maintain a daily dose of 0.01 to 200 mg / kg. The average daily inhalation dosage regimen is preferably 0.01 to 100 mg / kg of total body weight.

[0299] Of course, the specific initial and subsequent dosing regimens for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, the drug combination, etc. The desired mode of treatment and frequency of administration of the compounds of the invention or pharmaceutically acceptable salts or esters thereof or compositions can be ascertained by one skilled in the art using conventional therapeutic trials.

[0300] (Experimental Section) (Experimental Section - NMR Spectra) To the extent that NMR peak shapes and multiplicities are specified, they are stated as they appear in the spectrum, without consideration of possible higher order effects.

[0301] Selected Examples 1 H-NMR data is 1 The peaks are listed in the form of a H-NMR peak list. For each signal peak, the δ value (ppm) is given, followed by the signal intensity reported in parentheses. δ value-signal intensity pairs from different peaks are separated by commas. Thus, the peak list has the general form: δ1 (intensity 1), δ2 (intensity 2), ..., δ i (strength i ), ..., δ n (strength n ) is described by

[0302] The intensity of a sharp signal correlates with the signal height (cm) in the printed NMR spectrum. When compared to other signals, this data can be correlated with the actual ratio of signal intensities. In the case of a broad signal, multiple peaks or signal centers are shown along with their relative intensities compared to the most intense signal displayed in the spectrum. 1 The H-NMR peak list is a classic 1 H-NMR readings are similar and therefore typically contain all the peaks listed in the classical NMR interpretation. 1 Similar to a H-NMR printout, the peak list may show solvent signals, signals originating from stereoisomers of the target compound (also the subject of the present invention), and / or impurity peaks. Stereoisomers' and / or impurity peaks are typically shown at lower intensities compared to the peaks of the target compound (e.g., with a purity of >90%). Since such stereoisomers and / or impurities may be typical for a particular manufacturing process, these peaks may be useful for identifying the reproduction of our manufacturing process based on the "by-product fingerprint." Experts who calculate the peaks of the target compound by known methods (MestReC, ACD simulation, or using empirically evaluated expectation values) can optionally use additional intensity filters to isolate the peaks of the target compound as needed. Such operations are performed in a classical manner. 1This is similar to peak picking in H-NMR interpretation. A detailed description of the reporting of NMR data in the form of a peak list can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or see http: / / www.researchdisclosure.com / searching-disclosures). In the peak picking procedure described in Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. Depending on the chemical structure and / or concentration of the compound being measured, it may be reasonable to set the parameter "MinimumHeight" to <1%.

[0303] (Experimental Section - Abbreviations) The following table lists the abbreviations used in this paragraph, as well as in the Intermediates and Examples section, unless explained in the text. Other abbreviations have their customary meanings to those skilled in the art. A comprehensive list of abbreviations utilized by organic chemists of ordinary skill in the art is presented in the first issue of each volume of the Journal of Organic Chemistry. This list is typically presented in a table entitled "Standard List of Abbreviations." In case of doubt, the abbreviations and / or their meanings from the following table shall prevail.

[0304] [Table 1]

[0305] Other abbreviations have their customary meanings to those skilled in the art.

[0306] Various aspects of the invention described in this application are illustrated by the following examples, which are not meant to limit the invention in any way.

[0307] The exemplary test experiments described herein serve to illustrate the invention, and the invention is not limited to the examples shown.

[0308] (Experimental section - general part) Any reagents whose synthesis is not described in the experimental section are commercially available, known compounds, or can be prepared from known compounds by known methods by those skilled in the art. Reactions were set up and started, for example, by adding reagents, at the temperatures specified in the protocols. If no temperature was specified, each work step was carried out at ambient temperature, i.e., 18-25°C.

[0309] "Silicone filters" or "water-resistant filters" refer to filter papers that have been made hydrophobic (impermeable to water) by impregnation with silicone. These filters can be used to separate water from water-immiscible organic solvents by filtration (i.e., filter paper type MN 617 WA, Macherey-Nagel).

[0310] The compounds and intermediates produced according to the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several ways to purify the compounds. In some cases, purification may not be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be removed by trituration with a suitable solvent or solvent mixture. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using a pre-packed silica gel cartridge, such as a Biotage SNAP cartridge KP-Sil® or KP-NH®, in combination with, for example, a Biotage automated purification system (SP4® or Isolera Four®) and an eluent, such as a gradient of hexane / ethyl acetate or dichloromethane / ethanol. For flash column chromatography, unmodified ("normal") silica gel and amino-phase functionalized silica gel may be used. As used herein, "Biotage SNAP cartridge silica" refers to the use of normal silica gel. "Biotage SNAP cartridge NH2 silica" refers to the use of amino-phase functionalized silica gel. Where no stationary phase is specified and reference is made to flash column chromatography or flash chromatography in the experimental section, regular silica gel was used.

[0311] In some cases, compounds may be purified by preparative HPLC using, for example, a Waters automated purification system equipped with a diode array detector and / or an on-line electrospray ionization mass spectrometer in combination with a suitable pre-packed reverse-phase column and an eluent, for example, a gradient of water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, diethylamine, or aqueous ammonia.

[0312] In some cases, the above purification methods can provide compounds of the present invention having sufficiently basic or acidic functional groups in the form of a salt, such as trifluoroacetate or formate salts in the case of sufficiently basic compounds of the present invention, or ammonium salts in the case of sufficiently acidic compounds of the present invention. Such salts can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or can be used as salts in subsequent biological assays. It should be understood that the specific forms (e.g., salts, free bases, etc.) of the isolated compounds of the present invention described herein are not necessarily the only forms in which the compounds can be applied to biological assays to quantify specific biological activity.

[0313] UPLC-MS standard procedure Analytical UPLC-MS was performed as described below. Masses (m / z) are reported from positive mode electrospray ionization unless negative mode (ESI-) is indicated.

[0314] Analytical UPLC method: (Method 1:) Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm; Eluent A: water + 0.1% by volume formic acid (99%), Eluent B: acetonitrile; Gradient: 0–1.6 min, 1–99% B, 1.6–2.0 min, 99% B; Flow rate: 0.8 mL / min; Temperature: 60 °C; DAD scan: 210–400 nm.

[0315] (Method 2:) Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm; Eluent A: water + 0.2% (v / v) aqueous ammonia (32%), Eluent B: acetonitrile; Gradient: 0–1.6 min, 1–99% B, 1.6–2.0 min, 99% B; Flow rate: 0.8 mL / min; Temperature: 60 °C; DAD scan: 210–400 nm.

[0316] (Method 3:) Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm; Eluent A: water + 0.2% (v / v) aqueous ammonia (32%), Eluent B: acetonitrile; Gradient: 0–1.6 min, 1–99% B, 1.6–2.0 min, 99% B; Flow rate: 0.8 mL / min; Temperature: 60 °C; DAD scan: 210–400 nm.

[0317] (Method C): 5~95AB, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; Eluent A: water + 0.0375 vol% trifluoroacetic acid, Eluent B: acetonitrile + 0.01875 vol% trifluoroacetic acid; Gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min 95% B; Flow rate: 1.5 mL / min; Temperature: 50 °C; PDA: 220 nm and 254 nm.

[0318] (Method D): 5~95AB, Agilent Instrument: Agilent 1100\G1956A SingleQuad; Column: Kinetex@5μm EVO C18 30*2.1mm; Eluent A: water + 0.0375% vol. trifluoroacetic acid, Eluent B: acetonitrile + 0.01875% vol. trifluoroacetic acid; Gradient: 0~0.8 min, 5~95% B, 0.8~1.2 min 95% B; Flow rate: 1.5mL / min; Temperature: 50℃; PDA: 220nm and 254nm.

[0319] Preparative HPLC method: (Method HT Acid:) Instrument: Waters Autopurification system; Column: Waters XBrigde C18 5μ 100 × 30 mm; Eluent A: water + 0.1% by volume formic acid (99%), Eluent B: acetonitrile; Gradient; DAD scan: 210–400 nm.

[0320] (Method HT Basic:) Instrument: Waters Autopurification system; Column: Waters XBrigde C18 5μ 100 × 30 mm; Eluent A: water + 0.2% (v / v) aqueous ammonia (32%), Eluent B: acetonitrile; Gradient; DAD scan: 210–400 nm.

[0321] Specific rotation method: Method O1: Instrument: JASCO P2000 Polarimeter; Wavelength: 589 nm; Temperature: 20°C; Integration time: 10 seconds; Path length: 100 mm.

[0322] (Intermediate 1) Ethyl [(1H-pyrazol-5-yl)carbamothioyl]carbamate [ka]

[0323] 1H-Pyrazol-5-amine (58.7 g, 706 mmol; CAS 1820-80-0) was dissolved in ethyl acetate (420 mL) under nitrogen and stirred at 75° C. C12-isothiocyanatidic acid ethyl ester (88 mL, 750 mmol; CAS 16182-04-0) was added dropwise at 75° C., and the mixture was stirred at 75° C. for 1 hour. The mixture was cooled to 0° C., filtered, washed with ethyl acetate, and the solid was dried under reduced pressure at 50° C. to give 124 g (77% yield) of the title compound.

[0324] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.232(7.32),1.250(16.00),1.267(7.44),2.518(0.40),4.18 4(2.18),4.201(6.76),4.219(6.67),4.237(2.07),5.889(0.89),5.89 3(0.82),6.998(1.81),7.003(2.83),7.008(1.72),7.697(2.70),7.8 67(0.72),7.872(0.75),11.317(2.61),12.036(2.75),12.709(1.55).

[0325] (Intermediate 2) 2-Sulfanylpyrazolo[1,5-a][1,3,5]triazin-4-ol [ka]

[0326] Ethyl [(1H-pyrazol-5-yl)carbamothioyl]carbamate ((Intermediate 1), 124 g, 580 mmol) was stirred in sodium hydroxide (550 mL, 2.0 M, 1.1 mol) at room temperature for 3 hours. The mixture was cooled to 0° C., and sulfuric acid (580 mL, 2.0 M, 1.2 mol) was added dropwise. The suspension was filtered, washed with water, and the solid was dried under reduced pressure at 50° C. to give 85.2 g (87% yield) of the title compound.

[0327] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.518(0.54),3.349(0.66),5.888(14.42),5.892(16.00),7.866(14.93),7.870(13.98),12.730(0.83),13.450(0.66).

[0328] (Intermediate 3) 2-(Methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol [ka]

[0329] 2-Sulfanylpyrazolo[1,5-a][1,3,5]triazin-4-ol ((Intermediate 2), 85.2 g, 507 mmol) was dissolved in ethanol (2.0 L) and sodium hydroxide (580 mL, 1.7 M, 1.0 mol). Iodomethane (32 mL, 510 mmol; CAS 74-88-4) was added dropwise at room temperature, and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0°C, and sulfuric acid (510 mL, 1.0 M, 510 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with water dried under reduced pressure at 50°C. The solid was stirred twice in acetonitrile, the liquid phase was filtered off, and the solid was washed with hexane and dried to give 60.5 g (65% yield) of the title compound.

[0330] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.530(16.00),6.351(3.35),6.355(3.08),7.970(2.67),7.976(3.22).

[0331] (Intermediate 4) 8-Bromo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol [ka]

[0332] 2-(Methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol ((Intermediate 3), 59.0 g, 324 mmol) was dissolved in DMF (690 mL) and cooled to 0° C. NBS (63.4 g, 356 mmol; CAS 128-08-5) dissolved in DMF (200 mL) was added dropwise, and the mixture was stirred at 0° C. for 1 h. The mixture was poured into water, stirred for 15 min, filtered, and washed with water, acetonitrile, and hexane. The solid was dried under reduced pressure at 50° C. to give 71.7 g (85% yield) of the title compound.

[0333] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:8.113(16.00).

[0334] (Intermediate 5) 8-Iodo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol [ka]

[0335] 2-(Methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol ((Intermediate 3), 25.0 g, 137 mmol) was dissolved in N,N-dimethylformamide (200 mL) and cooled to 0 °C. N-iodosuccinimide (32.4 g, 144 mmol; CAS-RN: [516-12-1]) was added within 10 min and the mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into water. The precipitate was collected by filtration, washed with water, and dried overnight to give 41.5 g (98% yield) of the title compound.

[0336] LC-MS (Method 1):R t =0.86min;MS(ESIpos):m / z=309[M+H] +

[0337] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.523(0.53),2.575(16.00),8.048(5.89).

[0338] (Intermediate 6) 8-Bromo-4-chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine [ka]

[0339] 8-Bromo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol ((Intermediate 4), 33.3 g, 128 mmol) was dissolved in phosphorus oxychloride (170 mL, 1.8 mol; CAS 10025-87-3), and N,N-dimethylaniline (16 mL, 130 mmol; CAS 121-69-7) was added. The mixture was stirred at 105 °C for 3 h. The mixture was carefully poured into ice water and neutralized with sodium bicarbonate. The suspension was filtered and washed with water and hexane to give 24.0 g (67% yield) of the title compound.

[0340] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.518(0.49),2.567(16.00),8.116(6.88).

[0341] (Intermediate 7) Methyl N-[8-bromo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycinate [ka]

[0342] 8-Bromo-4-chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 6), 3.53 g, 12.6 mmol) and methyl glycinate hydrochloride (1 / 1) (2.38 g, 18.9 mmol) were dissolved in n-butanol (71 mL), N,N-diisopropylethylamine (8.8 mL, 51 mmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 90 °C for 30 min. The mixture was diluted with ethanol and water, and the precipitate was collected by filtration, washed with water and ethanol, and dried under reduced pressure at 50 °C to give 3.18 g (72% yield) of the title compound.

[0343] LC-MS (Method 2):R t =1.09min;MS(ESIpos):m / z=332[M+H] +

[0344] 1 H-NMR(400 MHz,CHLOROFORM-d)δ [ppm]:1.537(5.12),2.524(16.00),3.764(12.91),4.330(3.05),4.344(3.18),7.821(4.46).

[0345] (Intermediate 8) Methyl N-[8-bromo-2-(methanesulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycinate [ka]

[0346] Methyl N-[8-bromo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycinate ((Intermediate 7), 3.18 g, 9.56 mmol) was dissolved in dichloromethane (60 mL) and cooled to 0 °C. mCPBA (4.95 g, 70% purity, 28.7 mmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature over the weekend. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 3.33 g (86% yield) of the title compound, which was used without further purification.

[0347] LC-MS (Method 2):R t =0.61 min;MS(ESIpos):m / z=364[M+H] +

[0348] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.084(0.68),2.323(0.42),2.327(0.60),2.332(0.44),2.523(1.92),2.665(0.44),2.669(0.59),3.695 (16.00),4.366(3.18),4.381(3.18),5.758(1.65),8.576(7.06),10.062(0.59),10.077(1.20),10.091(0.59).

[0349] (Intermediate 9) Methyl N-[8-bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycinate [ka]

[0350] Methyl N-[8-bromo-2-(methanesulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycinate ((Intermediate 8), 1.00 g, 2.75 mmol) and morpholine (720 μL, 8.2 mmol; CAS-RN: [110-91-8]) were dissolved in acetonitrile (10 mL, 190 mmol; CAS-RN: [75-05-8]). N,N-Diisopropylethylamine (1.4 mL, 8.2 mmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 70 °C overnight. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The residue was stirred with ethanol, and the precipitate was collected by filtration and dried to give 647 mg (55% yield) of the title compound.

[0351] LC-MS (Method 2):R t =1.01min;MS(ESIneg):m / z=371[M+H] +

[0352] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.075(0.96),2.518(1.88),2.523(1.22),3.613(1.63),3.623(3.49),3.636(3.26),3.659(16. 00),3.677(2.97),3.689(3.10),3.700(1.55),4.170(2.77),5.758(0.68),8.028(6.59),8.977(0.75).

[0353] (Intermediate 10) N-[8-bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycine [ka]

[0354] Methyl N-[8-bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycinate (Intermediate 9, 647 mg, 1.74 mmol) was prepared in a mixture of ethanol (8 mL) and tetrahydrofuran (4.0 mL). Aqueous lithium hydroxide solution (4.4 mL, 1.0 M, 4.4 mmol; CAS-RN: [1310-65-2]) was added, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was diluted with water and citric acid (837 mg, 4.36 mmol; CAS-RN: [77-92-9]) and stirred for 15 minutes. The mixture was concentrated, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure at 50 °C to give 585 mg (90% yield) of the title compound.

[0355] LC-MS (Method 2):R t =0.57min;MS(ESIpos):m / z=357[M+H] +

[0356] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.951(10.46),1.052(0.76),2.323(0.81),2.327(1.10),2.331(0.85),2.665(0.83),2.669(1.10),2.673 (0.83),3.616(6.66),3.627(12.47),3.638(11.31),3.695(11.20),3.707(12.43),3.717(6.79),4.069(8.67),4 .084(8.62), 6.553(0.83), 7.374(1.39), 7.379(1.54), 7.387(2.82), 7.391(2.50), 7.671(1.27), 7.683(1.18), 7.690(1.38), 7.695(1.03), 8.019(16.00), 8.033(0.62), 8.786(1.85), 8.801(3.84), 8.816(1.86), 12.840(0.71).

[0357] (Intermediate 11) 2-{[8-bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide [ka]

[0358] N-[8-Bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycine ((Intermediate 10), 1.63 g, 4.56 mmol) was prepared in tetrahydrofuran (60 mL). Di(1H-imidazol-1-yl)methanone (1.48 g, 9.13 mmol; CAS 530-62-1) was added, and the mixture was stirred at reflux for 6 hours. A solution of hydrazine in tetrahydrofuran (23 mL, 1.0 M, 23 mmol) was added at room temperature, and the mixture was stirred at room temperature for 24 hours. The precipitate was collected by filtration, washed with ethanol and water, and dried under reduced pressure at 50 °C to give 1.46 g (84% yield) of the title compound.

[0359] LC-MS (Method 1):Rt =0.76 min;MS(ESIpos):m / z=371[M+H] +

[0360] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.758(1.19),1.774(0.41),2.518(3.54),2.523(2.59),3.582(0.56),3.59 3(0.48),3.599(1.08),3.606(0.70),3.616(3.57),3.627(6.63),3.638(5.87),3.6 93 (5.53), 3.705 (6.63), 3.715 (3.66), 3.974 (7.92), 4.232 (2.21), 4.345 (0.50), 4.491 (0.59), 7.989 (16.00), 7.994 (1.45), 8.003 (0.43), 8.658 (0.43), 9.199 (1.81).

[0361] (Intermediate 12) {[8-bromo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile [ka]

[0362] 8-Bromo-4-chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 6), 9.20 g, 32.9 mmol) was prepared in n-butanol (200 mL).

[0363] Aminoacetonitrile hydrogen chloride (1 / 1) (4.57 g, 49.4 mmol) and N,N-diisopropylethylamine (23.0 mL, 130 mmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 100° C. for 2.5 h. The mixture was concentrated, the residue was stirred with water, and the precipitate was collected by filtration and dried under reduced pressure at 50° C. to give 9.67 g (88% yield) of the title compound.

[0364] LC-MS (Method 1):R t =1.00min;MS(ESIpos):m / z=299[M+H] +

[0365] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.238(0.45),2.518(1.20),2.522(0.83),2.561(16.00),4.539(2.34),8.287(6.18),8.300(1.06),9.651(0.55).

[0366] (Intermediate 13) {[8-Bromo-2-(methanesulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile [ka]

[0367] {[8-Bromo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile ((Intermediate 12), 722 mg, 2.41 mmol) was dissolved in acetonitrile (50 mL) and cooled to 0 °C. mCPBA (1.11 g, 75% purity, 4.83 mmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane, the layers were separated, and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were dried and evaporated to give 1.54 g (193% yield) of the title compound, which was used without further purification.

[0368] LC-MS (method 1): Rt=0.75 min; MS (ESIpos): m / z=331[M+H] +

[0369] (Intermediate 14) {[8-bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile [ka]

[0370] {[8-Bromo-2-(methanesulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile ((Intermediate 13), 3.80 g, 11.5 mmol) and morpholine (3.0 mL, 34 mmol; CAS-RN: [110-91-8]) were prepared in acetonitrile (100 mL). N,N-Diisopropylethylamine (6.0 mL, 34 mmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 70 °C overnight. The reaction mixture was poured into water, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure at 50 °C to give 3.26 g (82% yield) of the title compound.

[0371] LC-MS (Method 2):R t =0.95min;MS(ESIneg):m / z=338[M+H] +

[0372] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.075(3.84),2.518(3.54),2.523(2.39),3.651(4.82),3.662(8.33),3.67 5(7.03),3.788(4.97),4.505(15.43),8.043(16.00),8.057(2.60),9.215(1.09).

[0373] (Intermediate 15) {[8-Bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}ethanimidamide hydrochloride [ka]

[0374] Ammonium chloride (1.11 g, 20.8 mmol) was suspended in toluene (100 mL), trimethylaluminum (10 mL, 2.0 M in toluene, 20.8 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. {[8-Bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile ((Intermediate 14), 2.34 g, 6.92 mmol) was added, and the mixture was stirred at 80 °C for 16 hours. Ammonium chloride (1.11 g, 20.8 mmol) and trimethylaluminum (10 mL, 2.0 M in toluene, 20.8 mmol) were added, and the mixture was stirred at 80 °C for 6 hours. After the reaction mixture cooled, 10 g of silica gel and 20 mL of methanol were added, and the mixture was stirred at room temperature for 1 hour. The solid was removed by filtration and washed with methanol. The filtrate was concentrated to give 2.80 g (95% yield) of the title compound.

[0375] LC-MS (Method 1):R t =0.65min;MS(ESIpos):m / z=355[M+H] +

[0376] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.109(2.94),2.331(0.80),2.518(3.71),2.522(2.59),2.669(1 .15),2.673(0.82),3.153(7.04),3.166(7.08),3.622(4.14),3.631(7. 31),3.644(6.43),3.660(1.28),3.673(0.86),3.695(1.05),3.711(6.5 7),3.723(6.77),3.734(3.62),3.785(0.43),4.111(0.52),4.125(1.28 ), 4.138(1.22), 4.151(0.43), 4.413(10.30), 4.476(0.76), 4.490(0.74), 4.509(1.21), 7.210(1.13), 7.216(1.26), 7.228(1.42), 7.238(1.42), 7.303(5.54), 7.313(3.27), 7.316(3.46), 7.354(2.62), 7.955(0.66), 8.033(16.00), 8.041(0.45), 8.045(1.71), 8.049(3.25), 8.059(0.41).

[0377] (Intermediate 16) 4-chloro-8-iodo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine [ka]

[0378] To a mixture of 8-iodo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol ((Intermediate 5), 7.00 g, 22.7 mmol) in phosphorus oxychloride (70 mL) was added N,N-dimethylaniline (8.6 mL, 68 mmol; CAS-RN: [121-69-7]) in one portion. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (200-300 mesh, petroleum ether:ethyl acetate = 40:1) to give 6.00 g (81% yield) of the title compound as a yellow solid.

[0379] (Intermediate 17) 8-Iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0380] To a mixture of 4-chloro-8-iodo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 16), 3.00 g, 9.19 mmol) and 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (2.84 g, 11.0 mmol, CAS-RN: [17061-62-0]) in tetrahydrofuran (20 mL) was added N,N-diisopropylethylamine (4.8 mL, 28 mmol; CAS-RN: [7087-68-5]) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 2.00 g (40% yield) of the title compound as a white solid.

[0381] LC-MS (Method D):R t =1.075min;MS(ESIpos):m / z=548.1[M+H] + .

[0382] (Intermediate 18) 8-Iodo-2-(methanesulfonyl)-N,N-bis[(4-methoxyphenyl)methyl]pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0383] To a solution of 8-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 17), 2.00 g, 3.65 mmol) in dichloromethane (15 mL) was added meta-chloroperbenzoic acid (1.89 g, 11.0 mmol; CAS-RN: [937-14-4]) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 3.30 g (crude) of the title compound as a white solid.

[0384] LC-MS (Method D):R t =1.033min;MS(ESIpos):m / z=580.3[M+H] + .

[0385] (Intermediate 19) 8-Iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0386] To a solution of 8-iodo-2-(methanesulfonyl)-N,N-bis[(4-methoxyphenyl)methyl]pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 18), 3.30 g, 60% purity, 3.42 mmol) and morpholine (893 mg, 10.3 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (1.8 mL, 10 mmol; CAS-RN: [7087-68-5]) at room temperature. The reaction mixture was stirred at 70 °C for 16 hours. The reaction mixture was filtered, and the filter cake was dried to give 2.40 g (crude) of the title compound as an off-white solid.

[0387] LC-MS (Method D):R t =1.142min;MS(ESIpos):m / z=587.3[M+H] + .

[0388] (Intermediate 20) N,N-Bis[(4-methoxyphenyl)methyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0389] To a solution of 8-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 19), 820 mg, 1.40 mmol) in N,N-dimethylformamide (40 mL) was added methyl difluoro(fluorosulfonyl)acetate (1.07 g, 5.59 mmol) and copper(I) iodide (1.07 g, 5.59 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography (200-300 mesh, petroleum ether:ethyl acetate=50:1) to give 650 mg (88% yield) of the title compound as a white solid.

[0390] LC-MS (Method D):R t =1.139min;MS(ESIpos):m / z=529.4[M+H] + .

[0391] (Intermediate 21) 2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0392] A solution of N,N-bis[(4-methoxyphenyl)methyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 20), 650 mg, 1.23 mmol) in trifluoromethanesulfonic acid (23 mL) was stirred at 70 °C for 16 h. The reaction mixture was poured into ice water and basified to pH = 8 with sodium carbonate. The mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (200-300 mesh, petroleum ether:ethyl acetate = 5:1) to give 400 mg (crude) of the title compound as a yellow solid.

[0393] LC-MS (Method D):R t =0.856min;MS(ESIpos):m / z=289.5[M+H] + .

[0394] (Intermediate 22) Methyl N-[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycinate [ka]

[0395] To a solution of 2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 21), 900 mg, 3.12 mmol) in 5 mL of DMF, sodium hydride (74.9 mg, 60% in mineral oil, 1.87 mmol; CAS-RN: [7646-69-7]) was added, and the mixture was stirred at 60 °C for 20 min. Then, methyl chloroacetate (300 μL, 3.44 mmol) was added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, filtered through a hydrophobic filter, and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane / ethanol gradient), and the product was stirred with methyl tert-butyl ether. The precipitate was filtered off and dried to give 383 mg (34% yield) of the title compound.

[0396] LC-MS (Method 2):R t =1.15 min;MS(ESIpos):m / z=361[M+H] +

[0397] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:3.618(2.08),3.628(4.14),3.639(3.58),3.664(16.00),3.695(3.32),3.706(3.73),4.184(4.60),8.252(4.23),9.131(1.34).

[0398] (Intermediate 23) N-[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycine [ka]

[0399] To a solution of methyl N-[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycinate ((Intermediate 22), 380 mg, 1.05 mmol) in 5.0 mL of tetrahydrofuran and 2.0 mL of ethanol, aqueous lithium hydroxide solution (2.6 mL, 1.0 M, 2.60 mmol; CAS-RN: [1310-65-2]) was added. The mixture was stirred at room temperature for 72 h. Water was added, and the mixture was acidified with aqueous citric acid (10%) until a pH of 3-4 was reached. The precipitate was filtered off, washed with water, and dried to give 319 mg (79% yield) of the title compound.

[0400] LC-MS (Method 2):R t =0.63min;MS(ESIpos):m / z=347[M+H] +

[0401] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.102(14.43),1.154(0.44),1.166(0.41),1.171(0.89),1.189(0.46),1.230(0.48),1.250(0.43),1.268(0.87),1.907( 0.43),1.987(1.15),2.322(0.74),2.327(1.02),2.332(0.78),2.522(3.88),2.664(0.78),2.669(1.07),2.673(0.80),3.072(4 .57), 3.620(10.43), 3.630(15.37), 3.642(14.34), 3.711(14.32), 3.724(16.00), 3.734(8.88), 4.084(10.40), 4.099(10.43), 5.757(1.02), 8.173(3.03), 8.184(0.70), 8.221(0.76), 8.243(15.02), 8.948(2.13), 8.963(4.66), 8.978(2.18), 12.860(0.52).

[0402] (Intermediate 24) 2-{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide [ka]

[0403] N-[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]glycine ((Intermediate 23), 315 mg, 819 μmol) was dissolved in 8.0 mL of THF, and di-1H-imidazol-1-ylmethanone (266 mg, 1.64 mmol; CAS-RN: [530-62-1]) was added. The reaction mixture was stirred under reflux for 6 hours. The solution was cooled to room temperature, and a THF solution of hydrazine (4.1 mL, 1.0 M, 4.1 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, filtered, and concentrated. The residue was stirred in methyl tert-butyl ether, and the precipitate was filtered off, washed with methyl tert-butyl ether, and dried to give 244 mg (66% yield) of the title compound.

[0404] LC-MS (Method 2):R t =0.90min;MS(ESIpos):m / z=361[M+H] +

[0405] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.154(2.21),1.172(4.53),1.189(2.21),1.266(0.40),1.757(0.65),1.987(7.98),2.322(0.88),2.326(1.20),2.331(0.88), 2.518(7.94),2.522(5.37),2.664(0.95),2.668(1.26),2.673(0.91),3.599(0.99),3.620(7.83),3.629(15.47),3.642(14.97),3.70 7 (13.09), 3.719 (15.12), 3.730 (8.97), 3.986 (11.87), 4.016 (2.00), 4.034 (1.77), 4.052 (0.55), 4.240 (5.03), 4.357 (0.67), 4.499 (1.24), 7.633 (0.42), 8.141 (0.46), 8.174 (0.88), 8.194 (0.51), 8.209 (16.00), 8.217 (1.94), 8.669 (0.63), 8.811 (1.71), 9.204 (4.74).

[0406] (Intermediate 25) Ethyl 1-amino-1H-imidazole-2-carboxylate [ka]

[0407] Ethyl 1H-imidazole-2-carboxylate (100 g, 678 mmol) was dissolved in N,N-dimethylformamide (1500 mL) and cooled to 0 °C. Lithium bis(trimethylsilyl)amide (810 mL, 1.0 M, 810 mmol; CAS-RN: [4039-32-1]) was added dropwise. The mixture was stirred for 10 minutes, and O-(diphenylphosphinoyl)hydroxylamine (213 g, 915 mmol; CAS-RN: [72804-96-7]) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was cooled using an ice bath, diluted with water, and extracted with ethyl acetate and dichloromethane. The combined organic layers were dried, filtered, and evaporated. The aqueous layer was extracted three more times with ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to give 92.2 g (88% yield) of the title compound, which was used without further purification.

[0408] LC-MS (Method 1):R t =0.53min;MS(ESIpos):m / z=156[M+H] +

[0409] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.285(7.37),1.303(16.00),1.320(7.52),2.728(5.51),2.888(6.51),3.823(0.91),4.270(2.20),4.288(6. 95),4.305(6.91),4.323(2.14),6.575(5.16),6.966(4.72),6.968(4.95),7.375(4.92),7.377(4.90),7.951(0.84).

[0410] (Intermediate 26) Ethyl 1-[(benzoylcarbamothioyl)amino]-1H-imidazole-2-carboxylate [ka]

[0411] To a solution of ethyl 1-amino-1H-imidazole-2-carboxylate ((Intermediate 25), 92.0 g, 593 mmol) in tetrahydrofuran (2 L) was added a solution of benzoyl isothiocyanate (80 mL, 590 mmol; CAS-RN: [532-55-8]) in tetrahydrofuran (2.5 L) under cooling. The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate gradient) to give 162 g (86% yield) of the title compound as an orange solid.

[0412] LC-MS (Method 2):R t =0.50min;MS(ESIpos):m / z=319[M+H] +

[0413] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.202(7.05),1.220(16.00),1.238(7.34),3.772(0.72),4.194(2.17),4.211(7.40),4.229(7.32),4.247(2 .10),7.151(6.55),7.154(6.82),7.541(2.55),7.546(1.00),7.559(5.33),7.573(8.93),7.576(9.95),7.580(4.0 6), 7.664(1.11), 7.667(2.08), 7.670(1.22), 7.682(0.96), 7.686(2.78), 7.691(0.83), 7.701(0.69), 7.705(1.15), 7.708(0.60), 7.975(3.96), 7.979(5.11), 7.983(1.36), 7.996(4.49), 7.999(3.66), 12.072(0.85), 13.041(0.87).

[0414] (Intermediate 27) 2-Sulfanylimidazo[2,1-f][1,2,4]triazin-4-ol [ka]

[0415] Ethyl 1-[(benzoylcarbamothioyl)amino]-1H-imidazole-2-carboxylate ((Intermediate 26), 110 g, 346 mmol) was prepared in aqueous NaOH (860 mL, 1.0 M, 860 mmol). The mixture was stirred at 85° C. for 2 h. The reaction mixture was diluted with ethanol (280 mL), cooled to 0° C., and acetic acid (79 mL) was added. The suspension was stirred at 0° C. for 30 min. The precipitate was collected by filtration, washed with water and cold ethanol, and dried under reduced pressure at 40° C. to give 53.2 g (92% yield) of the title compound as a white solid.

[0416] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.906(0.65),7.543(12.57),7.546(13.17),7.679(15.73),7.682(16.00),11.376(0.88).

[0417] (Intermediate 28) 2-(Methylsulfanyl)imidazo[2,1-f][1,2,4]triazin-4-ol [ka]

[0418] 2-Sulfanylimidazo[2,1-f][1,2,4]triazin-4-ol ((Intermediate 27), 53.2 g, 316 mmol) was suspended in tetrahydrofuran (800 mL). Iodomethane (26 mL, 410 mmol; CAS-RN: [74-88-4]) ​​was added and the mixture was stirred at 45 °C for 2 h. The reaction mixture was concentrated to give 55.9 g (97% yield) of the title compound, which was used without further purification.

[0419] LC-MS (Method 1):R t =0.60min;MS(ESIpos):m / z=183[M+H] +

[0420] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.548(16.00),3.722(0.67),7.594(2.71),7.597(2.74),8.020(3.15),8.023(3.15).

[0421] (Intermediate 29) 4-chloro-2-(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine [ka]

[0422] 2-(Methylsulfanyl)imidazo[2,1-f][1,2,4]triazin-4-ol ((Intermediate 28), 18.0 g, 98.8 mmol) was prepared in toluene (340 mL). N,N-Diisopropylethylamine (22 mL, 130 mmol; CAS-RN: [7087-68-5]) and phosphoroxychloride (28 mL, 300 mmol; CAS-RN: [10025-87-3]) were added, and the mixture was stirred at 120 °C for 2 h. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate, poured into sodium bicarbonate solution, and stirred for 15 min. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, hexane / ethyl acetate gradient) to give 17.7 g (89% yield) of the title compound.

[0423] 1 H-NMR(400 MHz,CHLOROFORM-d)δ [ppm]:2.609(16.00),7.839(2.25),7.841(2.36),7.960(2.80),7.963(2.73).

[0424] (Intermediate 30) 2,4-Bis(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine [ka]

[0425] 4-Chloro-2-(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 29), 17.7 g, 88.2 mmol) was dissolved in tetrahydrofuran (400 mL). Sodium methanethiolate (9.76 g, 95% purity, 132 mmol; CAS-RN: [5188-07-8]) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed, dried, filtered, and concentrated to give 18.6 g (99% yield) of the title compound.

[0426] LC-MS (Method 1):R t =1.05min;MS(ESIpos):m / z=213[M+H] +

[0427] 1 H-NMR(400 MHz,CHLOROFORM-d)δ [ppm]:2.591(16.00),2.679(14.38),7.624(2.41),7.627(2.43),7.765(2.80),7.767(2.87).

[0428] (Intermediate 31) 7-Iodo-2,4-bis(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine [ka]

[0429] 2,4-Bis(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 30), 150 mg, 707 μmol) was dissolved in N,N-dimethylformamide (3 mL). N-Iodosuccinimide (397 mg, 1.77 mmol; CAS-RN: [516-12-1]) was added, and the mixture was stirred at 85° C. overnight. The reaction mixture was poured into ice water and stirred for 30 minutes. The precipitate was collected by filtration and dried under reduced pressure at 40° C. to give 216 mg (90% yield) of the title compound.

[0430] LC-MS (Method 1):R t =1.30min;MS(ESIpos):m / z=339[M+H] +

[0431] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.619(15.41),2.637(16.00),2.646(0.47),7.814(7.28).

[0432] (Intermediate 32) 2,4-Bis(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine [ka]

[0433] To a suspension of 7-iodo-2,4-bis(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 31), 2.93 g, 8.68 mmol) and copper(I) iodide (4.96 g, 26.0 mmol; CAS-RN: [7681-65-4]) in N,N-dimethylformamide (55 mL) was added methyl difluoro(fluorosulfonyl)acetate (3.3 mL, 26 mmol; CAS-RN: [680-15-9]) at 110 °C. The mixture was stirred at 110 °C for 75 min. The reaction mixture was concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane / ethyl acetate gradient) to give 2.22 g (83% yield) of the title compound.

[0434] LC-MS (Method 2):R t =1.31min;MS(ESIpos):m / z=281[M+H] +

[0435] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.518(0.71),2.523(0.47),2.580(15.12),2.668(16.00),2.876(2.08),3.173(2.02),8.221(2.12),8.224(2.25).

[0436] (Intermediate 33) 2-(Methanesulfonyl)-4-(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine [ka]

[0437] 2,4-Bis(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 32), 568 mg, 2.03 mmol) was prepared in dichloromethane and cooled using a water bath. mCPBA (2.27 g, 77% purity, 10.1 mmol; CAS-RN: [937-14-4]) was added over 45 min, and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane, stirred with sodium thiosulfate, and filtered through a hydrophobic filter. The organic phase was purified by flash chromatography (silica gel, dichloromethane / ethanol gradient). The product was stirred in ethanol, and the precipitate was filtered off. The filtrate was concentrated, and the residue was diluted with water and 1% acetonitrile. The precipitate was collected by filtration, washed with water, and dried to give 108 mg (15% yield) of the title compound.

[0438] LC-MS (Method 2):R t =0.97min;MS(ESIpos):m / z=313[M+H] +

[0439] (Intermediate 34) tert-Butyl (2-amino-2-iminoethyl)carbamate hydrogen chloride [ka]

[0440] To a solution of tert-butyl(cyanomethyl)carbamate (25.0 g, 160 mmol) in methanol (300 mL) was added a suspension of sodium methoxide (1.73 g, 32.0 mmol; CAS-RN: [124-41-4]) in methanol (50 mL) at 50° C. The reaction mixture was stirred at 50° C. for 12 hours. Ammonium chloride (11.1 g, 208 mmol) was added to the reaction mixture at 50° C. The reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was concentrated and diluted with ethyl acetate. The suspension was concentrated and diluted with ethyl acetate. The suspension was filtered, and the solid was dried under reduced pressure to give 20.0 g (95% purity, 57% yield) of the title compound as a white solid.

[0441] (Intermediate 35) tert-Butyl ({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)carbamate [ka]

[0442] tert-Butyl (2-amino-2-iminoethyl)carbamate hydrochloride ((Intermediate 34), 750 mg, 3.58 mmol) and 2-bromo-1-[4-(trifluoromethyl)phenyl]ethan-1-one (955 mg, 3.58 mmol; CAS-RN: [383-53-9]) were prepared in acetonitrile (22 mL). Potassium carbonate (1.98 g, 14.3 mmol; CAS-RN: [584-08-7]) was added, and the mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography (silica gel, dichloromethane / ethanol gradient) to give 219 mg (18% yield) of the title compound.

[0443] LC-MS (Method 2):R t =1.17min;MS(ESIpos):m / z=342[M+H] +

[0444] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]:1.311(0.63),1.322(0.60),1.353(0.66),1.401(16.00),2.518(2.20 ),2.523(1.45),2.674(0.43),4.178(1.90),4.193(1.92),7.313(0.62),7.6 52(2.02),7.673(2.38),7.692(1.83),7.697(1.83),7.830(0.47),7.850(0. 62),7.936(2.22),7.957(1.88),8.049(0.50),8.070(0.43),12.045(0.59).

[0445] (Intermediate 36) 1-{5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methanamine [ka]

[0446] tert-Butyl ({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)carbamate ((Intermediate 35), 218 mg, 639 μmol) was prepared in methanol (2.6 mL). HCl in dioxane (1.6 mL, 4.0 M, 6.4 mmol; CAS-RN: [7647-01-0]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, adjusted to pH 8-9 with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The combined organic layers were filtered through a hydrophobic filter and concentrated to give 64.0 mg (42% yield) of the title compound.

[0447] LC-MS (Method 2):R t =0.91 min;MS(ESIpos):m / z=242[M+H] +

[0448] 1 H-NMR(400 MHz,CHLOROFORM-d)δ [ppm]:1.172(0.57),1.183(1.64),1.189(1.07),1.208(0.48),1.977(0.84),3.636(16.00),3.890(2.26),4.014(7.77),7. 265(5.98),7.522(3.58),7.543(4.36),7.647(0.85),7.667(0.94),7.732(3.45),7.752(2.85),7.848(0.78),7.868(0.65).

[0449] (Intermediate 37) tert-Butyl ({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)carbamate [ka]

[0450] tert-Butyl (2-amino-2-iminoethyl)carbamate hydrochloride ((Intermediate 34), 500 mg, 2.38 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethan-1-one (675 mg, 2.38 mmol; CAS-RN: [103962-10-3]) were prepared in acetonitrile (15 mL). Potassium carbonate (1.32 g, 9.54 mmol; CAS-RN: [584-08-7]) was added, and the mixture was stirred at 100 °C for 90 min. The reaction mixture was concentrated, and the residue was purified by flash chromatography (silica gel, dichloromethane / ethanol gradient). The product was stirred in methyl tert-butyl ether. The precipitate was collected by filtration and dried to give 44.0 mg (5% yield) of the title compound.

[0451] LC-MS (Method 2):R t =1.21 min;MS(ESIpos):m / z=358[M+H] +

[0452] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.104(0.52),1.233(0.46),1.400(16.00),2.518(2.92),2.523(1.95),4.164(2.04),4.178(2.08),7.295(2.5 8),7.315(2.37),7.556(1.93),7.821(0.46),7.828(3.92),7.833(1.20),7.845(1.14),7.850(3.48),11.934(0.64).

[0453] (Intermediate 38) 1-{5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methanamine [ka]

[0454] First batch tert-Butyl ({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)carbamate ((Intermediate 37), 218.0 mg, 0.6 mmol) was prepared in methanol (2.4 mL). A solution of HCl in dioxane (1.5 mL, 4.0 M, 61.0 mmol; CAS-RN: [7647-01-0]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were dried over a hydrophobic filter and concentrated.

[0455] Second batch tert-Butyl ({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)carbamate ((Intermediate 37), 60.0 mg, 168 μmol) was prepared in methanol (680 μL). A solution of HCl in dioxane (420 μL, 4.0 M, 1.7 mmol; CAS-RN: [7647-01-0]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated.

[0456] The first and second batches were combined and purified by flash chromatography (silica gel, dichloromethane / ethyl acetate gradient) to give 142 mg of the title compound.

[0457] LC-MS (Method 2):R t =0.94min;MS(ESIpos):m / z=258[M+H] +

[0458] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.798(0.47),0.814(0.96),0.821(0.63),0.830(0.70),0.840 (0.47),0.846(0.72),0.852(0.95),0.868(0.80),0.892(0.84),0.90 1(0.43),0.904(0.61),0.910(0.44),1.005(0.47),1.024(1.02),1.0 44(1.06),1.052(0.66),1.064(0.46),1.232(1.20),1.895(2.45),1.9 17(0.64), 2.336(0.71), 2.518(9.20), 2.523(6.57), 2.678(0.69), 3.385(0.50), 3.763(16.00), 3.828(1.97), 4.496(0.69), 7.298(2.89), 7.318(2.80), 7.466(0.62), 7.486(0.67), 7.564(1.23), 7.593(0.57), 7.647(1.19), 7.812(1.91), 7.822(2.45), 7.834(2.62), 7.842(2.31).

[0459] (Intermediate 39) 2-(Methanesulfonyl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0460] 2-(Methanesulfonyl)-4-(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 33), 96.6 mg, 247 μmol) and 1-{5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methanamine ((Intermediate 38), 70.0 mg, 272 μmol) were prepared in acetonitrile (4.6 mL). N,N-Diisopropylethylamine (170 μL, 990 μmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 50 °C for 90 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, dichloromethane / ethyl acetate gradient) to give 34.0 mg (26% yield) of the title compound.

[0461] LC-MS (Method 2):R t =1.16 min;MS(ESIpos):m / z=522[M+H] +

[0462] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.153(0.44),1.171(0.85),1.189(0.41),1.986(1.49),2.518(1.94),2.523(1.29),3.332(16.00),4.890(3.0 0),7.304(0.99),7.325(1.09),7.642(0.93),7.836(1.16),7.858(1.03),8.347(1.94),8.350(2.07),11.993(0.43).

[0463] (Intermediate 40) 4-chloro-8-iodo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine [ka]

[0464] To a mixture of 8-iodo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazin-4-ol ((Intermediate 5), 7.00 g, 22.7 mmol) in phosphorus oxychloride (70 mL) was added N,N-dimethylaniline (8.6 mL, 68 mmol; CAS-RN: [121-69-7]) in one portion. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (200-300 mesh, petroleum ether:ethyl acetate = 40:1) to give 6.00 g (81% yield) of the title compound as a yellow solid.

[0465] (Intermediate 41) 8-Iodo-2,4-bis(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine [ka]

[0466] To a solution of 4-chloro-8-iodo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 40), 9.98 g, 30.6 mmol) in tetrahydrofuran (200 mL) was added sodium methanethiolate (2.62 g, 90% purity, 33.6 mmol; CAS-RN: [5188-07-8]). The mixture was stirred at room temperature for 16 hours. Sodium methanethiolate (952 mg, 90% purity, 12.2 mmol; CAS-RN: [5188-07-8]) was added, and the mixture was stirred at room temperature for 3 days. The mixture was concentrated, and water was added. The precipitate was isolated by filtration to give 7.01 g (66% yield) of the title compound.

[0467] LC-MS (Method 1):R t =1.33min;MS(ESIpos):m / z=339[M+H] +

[0468] H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.518(1.43),2.523(0.97),2.603(16.00),2.668(15.72),8.307(6.49).

[0469] (Intermediate 42) 2,4-Bis(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine [ka]

[0470] To a suspension of 8-iodo-2,4-bis(methylsulfanyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 41), 4.65 g, 13.8 mmol) and copper(I) iodide (10.6 g, 55.0 mmol; CAS-RN: [7681-65-4]) in N,N-dimethylformamide (87 mL), methyl difluoro(fluorosulfonyl)acetate (7.0 mL, 55.0 mmol; CAS-RN: [680-15-9]) was added at room temperature under an argon atmosphere. The reaction mixture was stirred at 80 °C for 20 hours. Methyl difluoro(fluorosulfonyl)acetate (3.5 mL, 22.5 mmol; CAS-RN: [680-15-9]) was added, and the mixture was stirred at 80 °C for 24 hours and at room temperature for 3 days. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, hexane / dichloromethane / ethyl acetate gradient) to give 2.85 g (72% yield) of the title compound.

[0471] LC-MS (Method 2):R t =1.35min;MS(ESIpos):m / z=281[M+H] +

[0472] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.518(0.74),2.523(0.50),2.603(16.00),2.693(15.54),8.622(2.65).

[0473] (Intermediate 43) Benzyl ({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)carbamate [ka]

[0474] N-[(benzyloxy)carbonyl]glycine (1.00 g, 4.78 mmol) and cesium carbonate (779 mg, 2.39 mmol; CAS-RN: [534-17-8]) were prepared in N-methylpyrrolidinone (10 mL) and stirred at room temperature for 1 h. 2-Bromo-1-[4-(trifluoromethyl)phenyl]ethan-1-one (1.28 g, 4.78 mmol) was added, and the mixture was stirred at room temperature for 30 min. Xylene (30 mL) and ammonium acetate (9.21 g, 120 mmol; CAS-RN: [631-61-8]) were then added, and the mixture was stirred at 120 °C for 9 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium carbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The residue was stirred in dichloromethane. The precipitate was collected by filtration and dried to give 284 mg (16% yield) of the title compound.

[0475] LC-MS (Method 1):R t =1.00min;MS(ESIneg):m / z=374[MH] -

[0476] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.518(4.78),2.523(3.22),4.269(6.00),4.283(6.27),5.056(2.04),5.065(16.00),7.257(0 .63),7.304(0.88),7.315(1.56),7.326(1.78),7.336(1.43),7.345(1.28),7.366(11.50),7.377(8. 92), 7.465(0.42), 7.656(4.85), 7.677(5.70), 7.713(4.36), 7.719(4.51), 7.731(0.63), 7.752(0.68), 7.792(0.98), 7.806(1.89), 7.820(0.98), 7.848(0.52), 7.941(4.98), 7.962(4.33), 12.148(1.48).

[0477] (Intermediate 44) 1-{5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methanamine hydrobromide [ka]

[0478] Benzyl ({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)carbamate ((Intermediate 43), 284 mg, 757 μmol) was stirred in a solution of hydrogen bromide (32% purity; CAS-RN: [10035-10-6]) in acetic acid at room temperature overnight. The reaction mixture was concentrated, toluene was added, and the mixture was concentrated. The residue was stirred in toluene, and the precipitate was collected by filtration and dried under reduced pressure at 50 °C to give 277 mg (91% yield) of the title compound.

[0479] LC-MS (Method 1):R t =0.76min;MS(ESIpos):m / z=242[M+H] +

[0480] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.905(0.52),2.295(1.25),2.336(0.74),2.518(11.19),2.522(7.52),2.678(0.77),4.040(3.45),4.177 (8.60),4.705(0.40),7.770(10.82),7.790(13.15),7.966(16.00),7.991(14.25),8.011(11.50),8.411(4.83).

[0481] (Intermediate 45) 2-(Methylsulfanyl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0482] 2,4-Bis(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 42), 159 mg, 569 μmol) was dissolved in acetonitrile (5 mL). 1-{5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methanamine hydrobromide ((Intermediate 44), 275 mg, 682 μmol) and N,N-diisopropylethylamine (400 μL, 2.3 mmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at reflux for 3 hours. 2,4-Bis(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 42), 20 mg, 71 μmol) was added, and the mixture was stirred at reflux for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated to give the crude product. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 310 mg of the title compound.

[0483] LC-MS (Method 2):Rt =1.41 min;MS(ESIpos):m / z=474[M+H] +

[0484] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.884(0.41),0.902(0.82),1.035(1.06),1.052(2.55),1.070(1. 35),2.065(1.12),2.084(1.40),2.454(0.72),2.469(16.00),2.518(2.0 0),2.523(1.28),4.810(6.26),5.758(0.40),7.665(1.69),7.685(1.97) ,7.765(1.54),7.941(1.68),7.961(1.42),8.505(4.32),12.128(0.44).

[0485] (Intermediate 46) 2-(Methanesulfonyl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0486] 2-(Methylsulfanyl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 45), 300 mg, 634 μmol) was prepared in dichloromethane (5 mL) and cooled to 2 °C. mCPBA (426 mg, 77% purity, 1.90 mmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with saturated aqueous sodium thiosulfate and stirred at room temperature for 1 h. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were extracted with saturated aqueous sodium thiosulfate, saturated sodium bicarbonate, and washed with saturated aqueous sodium chloride. The organic phase was filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 205 mg (38% yield) of the title compound.

[0487] LC-MS (Method 2):R t =1.05min;MS(ESIpos):m / z=506[M+H] +

[0488] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.103(16.00),2.518(0.64),2.523(0.42),3.073(5.25),3.345(1.04),7.547(0. 63),7.695(0.47),7.698(0.41),7.892(0.48),7.896(0.45),7.902(0.64),8.821(0.40).

[0489] (Intermediate 47) Benzyl ({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)carbamate [ka]

[0490] N-[(benzyloxy)carbonyl]glycine (1.00 g, 4.78 mmol) and cesium carbonate (779 mg, 2.39 mmol; CAS-RN: [534-17-8]) were dissolved in N-methylpyrrolidinone (10 mL) and stirred at room temperature for 1 hour. 2-Bromo-1-[4-(trifluoromethoxy)phenyl]ethan-1-one (1.35 g, 4.78 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Xylene (30 mL) and ammonium acetate (9.21 g, 120 mmol; CAS-RN: [631-61-8]) were added, and the mixture was stirred at 120 °C for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium carbonate. The organic phase was washed with saturated aqueous sodium chloride, dried on a hydrophobic filter, and concentrated to give the crude product. The residue was stirred in methyl tert-butyl ether. The precipitate was collected by filtration and dried to give 954 mg (48% yield) of the title compound.

[0491] LC-MS (Method 2):R t =1.23min;MS(ESIpos):m / z=392[M+H] +

[0492] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.206(0.74),2.327(0.98),2.332(0.72),2.518(3.70),2.523(2.27),2.669(0.99),2.673(0.72),2.729 (0.42),2.822(0.41),2.888(0.53),3.535(3.66),3.551(3.67),4.255(6.38),4.270(6.54),5.023(7.43),5.061 (15.25), 7.003 (0.76), 7.259 (0.78), 7.298 (6.11), 7.319 (7.04), 7.343 (2.77), 7.355 (11.59), 7.364 (16.00), 7.374 (10.86), 7.578 (5.30), 7.778 (1.12), 7.793 (1.89), 7.807 (1.08), 7.833 (5.51), 7.855 (5.05), 12.049 (1.51).

[0493] (Intermediate 48) 1-{5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methanamine hydrobromide [ka]

[0494] Benzyl ({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)carbamate ((Intermediate 47), 950 mg, 2.43 mmol) was stirred with a solution of hydrogen bromide (6.0 mL, 32% purity, 35 mmol; CAS-RN: [10035-10-6]) in acetic acid at room temperature for 22 hours. The reaction mixture was concentrated, toluene was added, and the mixture was concentrated. The residue was stirred in methyl tert-butyl ether. The precipitate was collected by filtration, washed with methyl tert-butyl ether, and dried under reduced pressure to give 950 mg (91% yield) of the title compound.

[0495] LC-MS (Method 2):R t =0.95min;MS(ESIneg):m / z=256[MH] -

[0496] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.101(9.83),1.905(0.45),1.938(0.52),2.518(3.76),2.523(2.31),2. 848(0.56),3.071(3.25),3.482(1.48),3.496(3.88),3.511(3.85),3.525(1.55 ), 4.221(5.85), 7.453(6.45), 7.474(7.09), 7.752(0.92), 7.888(2.42), 7.895(16.00), 7.900(5.61), 7.912(5.92), 7.917(14.80), 7.930(7.51), 8.454(2.95).

[0497] (Intermediate 49) 2-(Methylsulfanyl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0498] 2,4-Bis(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 42), 265 mg, 945 μmol) was prepared in acetonitrile (6 mL). 1-{5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methanamine hydrobromide ((Intermediate 48), 475 mg, 1.13 mmol) and N,N-diisopropylethylamine (660 μL, 3.8 mmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at reflux for 21 hours. 2,4-Bis(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 42), 53 mg, 189 μmol) was added, and the mixture was stirred at reflux for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried on a hydrophobic filter, and concentrated to give the crude product. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient). The combined fractions were stirred in methyl tert-butyl ether. The precipitate was removed by filtration, and the filtrate was concentrated and dried under reduced pressure to give 403 mg (73% yield) of the title compound.

[0499] LC-MS (Method 2):R t =1.38min;MS(ESIpos):m / z=490[M+H] +

[0500] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.103(16.00),2.456(0.36),2.470(8.62),2.518(1.05),2.523(0.68),3.073(5.39),4.016(0.20),4.797(3.07),7.3 05(1.30),7.325(1.42),7.627(1.34),7.835(2.07),7.857(1.85),8.482(0.20),8.506(2.53),9.661(0.47),12.019(0.56).

[0501] (Intermediate 50) 2-(Methanesulfonyl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0502] 2-(Methylsulfanyl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 49), 400 mg, 687 μmol) was dissolved in dichloromethane (6 mL) and cooled to 2 °C. mCPBA (462 mg, 77% purity, 2.06 mmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature for 23 h. The reaction mixture was diluted with saturated aqueous sodium thiosulfate solution and stirred at room temperature for 1 h. The precipitate was removed by filtration. The phases of the filtrate were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were extracted with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution, and washed with saturated aqueous sodium chloride solution. The organic phase was filtered through a hydrophobic filter and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 186 mg (purity 66%, yield 34%) of the title compound.

[0503] LC-MS (Method 2):R t =1.03min;MS(ESIpos):m / z=522[M+H] +

[0504] (Intermediate 51) Ethyl 4-(trifluoromethyl)benzene-1-carboxyimidate [ka]

[0505] 4-(Trifluoromethyl)benzonitrile (1.00 g, 5.84 mmol; CAS-RN: [455-18-5]) was prepared in ethanol (5 mL) and cooled in an ice bath. Acetyl chloride (2.9 mL, 41 mmol; CAS-RN: [75-36-5]) was added dropwise. The mixture was stirred at room temperature overnight and at 50 °C for 90 minutes. The reaction mixture was poured into ice water, and the precipitate was removed by filtration. The filtrate was neutralized with sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was stirred in hexane, and the precipitate was removed by filtration. The filtrate was purified by column chromatography (silica gel, dichloromethane / ethyl acetate gradient) to give 533 mg (42% yield) of the title compound.

[0506] LC-MS (Method 1):R t =0.86min;MS(ESIpos):m / z=218[M+H] +

[0507] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.312(7.33),1.320(1.77),1.330(16.00),1.337(3.67),1.347(7.38),1.355(1.71),2.518( 1.06),2.523(0.76),4.084(0.40),4.102(1.25),4.119(1.23),4.240(2.17),4.258(6.84),4.275(6. 76), 4.292(2.07), 7.789(0.81), 7.810(0.95), 7.823(3.04), 7.825(3.53), 7.845(4.33), 8.019(3.52), 8.021(4.07), 8.041(3.36), 8.043(2.79), 8.116(0.87), 8.136(0.75), 8.347(0.49), 9.241(3.90).

[0508] (Intermediate 52) tert-Butyl ({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)carbamate [ka]

[0509] Ethyl 4-(trifluoromethyl)benzene-1-carboxyimidate ((Intermediate 51), 100 mg, 373 μmol) was dissolved in acetonitrile (3 mL), tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate (70.6 mg, 373 μmol) was added, and the mixture was stirred at 50° C. overnight and at 105° C. for 16 hours. The reaction mixture was evaporated and purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 119 mg (93% yield) of the title compound.

[0510] LC-MS (Method 2):R t =0.88 min;MS(ESIpos):m / z=343[M+H] +

[0511] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.035(0.94),1.052(2.01),1.070(1.04),1.285(0.46),1.400(16.00),2.518(2.67),2.523(1.77),2.673(0. 43),4.282(1.58),4.296(1.52),5.759(0.44),7.454(0.44),7.828(1.72),7.848(1.91),8.173(2.38),8.194(2.06).

[0512] (Intermediate 53) 1-{5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methanamine [ka]

[0513] tert-Butyl ({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)carbamate ((Intermediate 52), 117 mg, 342 μmol) was dissolved in methanol (1.4 mL). HCl in dioxane (850 μL, 8 mmol, 4 M; CAS-RN: [7647-01-0]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, the residue was taken up in dichloromethane, triethylamine (1 mL) was added, and the mixture was concentrated. The residue was purified by column chromatography (silica gel, amino phase, dichloromethane / ethanol gradient) to give 77.0 mg (93% yield) of the title compound.

[0514] LC-MS (Method 2):R t =0.63min;MS(ESIpos):m / z=243[M+H] +

[0515] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.232(0.42),2.518(5.36),2.522(3.49),2.673(0.89),3.874(16. 00),7.807(3.11),7.827(3.43),8.179(3.34),8.199(2.96),8.201(2.50).

[0516] (Intermediate 54) 2-(Methylsulfanyl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0517] 2,4-Bis(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 32), 75.0 mg, 268 μmol) and 1-{5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methanamine ((Intermediate 53), 71.3 mg, 294 μmol) were prepared in acetonitrile (5 mL). N,N-Diisopropylethylamine (190 μL, 1.1 mmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred in a microwave at 150 °C for 2 h, 160 °C for 2 h, and 180 °C for 1 h. The precipitate was collected by filtration and washed with acetonitrile to give 65.0 mg (51% yield) of the title compound.

[0518] LC-MS (Method 2):R t =1.02min;MS(ESIpos):m / z=475[M+H] +

[0519] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.332(0.40),2.416(16.00),2.518(2.28),2.522(1.49),2.673(0.41),4.886(4. 44),7.823(2.32),7.844(2.57),8.118(2.86),8.121(2.97),8.173(2.88),8.193(2.47).

[0520] (Intermediate 55) 2-(Methanesulfonyl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0521] 2-(Methylsulfanyl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 54), 60.0 mg, 126 μmol) was prepared in dichloromethane (3.0 mL) and cooled using a water bath. mCPBA (113 mg, 77% purity, 506 μmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic layer was dried on a hydrophobic filter and evaporated. The crude product was purified by column chromatography (silica gel, amino phase, dichloromethane / ethanol gradient) to give 62.0 mg (97% yield) of the title compound.

[0522] LC-MS (Method 2):R t =0.84min;MS(ESIpos):m / z=507[M+H] +

[0523] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.904(0.41),1.052(0.52),2.518(3.63),2.522(2.40),3.313(16.00),3.330(10.73),3.390(0.61),4. 986(3.13),5.758(0.56),7.830(1.71),7.851(1.94),8.173(2.32),8.193(2.01),8.360(2.02),8.362(2.14).

[0524] (Intermediate 56) Benzyl ({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)carbamate [ka]

[0525] N-[(benzyloxy)carbonyl]glycine (1.50 g, 7.17 mmol) and cesium carbonate (1.17 g, 3.59 mmol; CAS-RN: [534-17-8]) were dissolved in N,N-dimethylformamide (13 mL) and stirred at room temperature for 1 hour. 2-Bromo-1-[6-(trifluoromethyl)pyridin-3-yl]ethan-1-one (1.92 g, 7.17 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Xylene (45 mL) and ammonium acetate (13.8 g, 179 mmol; CAS-RN: [631-61-8]) were then added, and the mixture was stirred at 120 °C for 19 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, filtered through a hydrophobic filter, and concentrated to give the crude product. The residue was stirred in methyl tert-butyl ether. The precipitate was removed by filtration. The filtrate was purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 278 mg (11% yield) of the title compound.

[0526] LC-MS (Method 2):Rt =1.07min;MS(ESIpos):m / z=377[M+H] +

[0527] (Intermediate 57) 1-{5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methanamine [ka]

[0528] Benzyl ({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)carbamate ((Intermediate 56), 275 mg, 658 μmol) was stirred with a solution of hydrogen bromide (5.0 mL, 32% purity, 29 mmol; CAS-RN: [10035-10-6]) in acetic acid at room temperature for 22 hours. The reaction mixture was concentrated, toluene was added, and the mixture was concentrated. The residue was stirred in methyl tert-butyl ether. The precipitate was collected by filtration, washed with methyl tert-butyl ether, dried, and purified by column chromatography (silica gel, amino phase, dichloromethane / ethanol gradient) to give 98.0 mg (57% yield) of the title compound.

[0529] LC-MS (Method 2):R t =0.76min;MS(ESIpos):m / z=243[M+H] +

[0530] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.226(0.44),1.792(0.45),1.884(1.47),1.953(2.27),2.080(9.69),2.332(1.14),2.518(6.94),2.522(4.26),2.711(1.16),2.778(2.12),2.938(3.01),3.161(2.07),3.624(6.36),3.639(7.52),3.654(6.65),3.668(3.80),3.741(2.06),3.931(0.90),4.157(4.95),4.209(0.75),4.224(0.71),4.478(3.46),4.492(3.47),6.997(1.44),7.125(1.48),7.252(1.41),7.872(0.41),7.887(2.24),7.908(3.59),7.928(5.35),7.948(5.75),7.975(2.32),7.995(2.53),8.011(2.32),8.026(1.79),8.031(1.94),8.043(16.00),8.090(0.42),8.128(0.87),8.169(0.54),8.189(0.48),8.364(3.81),8.368(3.86),8.385(4.18),8.388(4.29),8.473(0.63),8.706(2.53),8.848(0.59),8.978(0.77),8.993(1.48),9.008(0.78),9.159(0.50),9.179(5.36),9.184(5.22).

[0531] Alternatively, in the first batch, tert-butyl [(5-bromo-1H-imidazol-2-yl)methyl]carbamate ((Intermediate 74), 707 mg, 2.56 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (839 mg, 3.07 mmol; CAS-RN: [1218790-39-6]), and potassium carbonate (1.06 g, 7.67 mmol) were prepared in 1,4-dioxane (15 mL) and water (5 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride (187 mg, 256 μmol; CAS-RN: [72287-26-4]) was added. The mixture was flushed with argon and stirred in a microwave at 130 °C for 1 h. A second batch of tert-butyl [(5-bromo-1H-imidazol-2-yl)methyl]carbamate ((Intermediate 74), 605 mg, 2.19 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (718 mg, 2.63 mmol; CAS-RN: [1218790-39-6]), and potassium carbonate (908 mg, 6.57 mmol) was dissolved in 1,4-dioxane (15 mL) and water (5 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride (160 mg, 219 μmol; CAS-RN: [72287-26-4]) was added. The mixture was flushed with argon and stirred in a microwave at 130° C. for 1 hour. The two reaction mixtures were combined, concentrated, and stirred in a mixture of dichloromethane and ethanol. The precipitate was removed by filtration. The filtrate was concentrated and purified by column chromatography (silica gel, amino phase, dichloromethane / ethyl acetate gradient) to give 1340 mg of tert-butyl ({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)carbamate.

[0532] LC-MS (Method 1):R t =0.89min;MS(ESIpos):m / z=343[M+H] +

[0533] To a solution of tert-butyl ({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)carbamate (1.33 g, 3.89 mmol) in methanol (16 L) was added a solution of HCl in 1,4-dioxane (9.7 mL, 4.0 M, 38.9 mmol CAS-RN: [7647-01-0]). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and stirred with dichloromethane. The precipitate was collected by filtration to give 946 mg of the title compound as the crude hydrochloride salt, which was used without further purification.

[0534] (Intermediate 58) 2-(Methylsulfanyl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0535] 2,4-Bis(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 32), 99.9 mg, 357 μmol) and 1-{5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methanamine ((Intermediate 57), 95.0 mg, 392 μmol) were prepared in acetonitrile (3 mL). N,N-Diisopropylethylamine (250 μL, 1.4 mmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 150 °C in a microwave for 2 h. The reaction mixture was diluted with water. The precipitate was collected by filtration, washed with water, and stirred in methyl tert-butyl ether at 50 °C. The precipitate was collected by filtration, washed with methyl tert-butyl ether, and dried to give 64.0 mg (34% yield) of the title compound.

[0536] LC-MS (Method 2):R t=1.25min;MS(ESIpos):m / z=475[M+H] +

[0537] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.102(0.32),2.073(0.62),2.323(0.34),2.327(0.48),2.331(0.35),2.440(16.00),2.452(1.21 ),2.461(0.34),2.518(2.28),2.523(1.45),2.579(0.23),2.665(0.40),2.669(0.56),2.673(0.38),4.8 16 (4.71), 5.094 (0.25), 5.931 (0.19), 7.844 (1.26), 7.865 (1.39), 7.901 (1.92), 7.933 (0.17), 8.104 (3.00), 8.106 (3.13), 8.146 (0.20), 8.314 (0.89), 8.334 (0.80), 9.124 (1.66), 9.731 (0.23), 12.231 (0.22).

[0538] (Intermediate 59) 2-(Methanesulfonyl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0539] 2-(Methylsulfanyl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 58), 60.0 mg, 126 μmol) was prepared in dichloromethane (2 mL) and cooled to 2 °C. mCPBA (65.5 mg, 77% purity, 379 μmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with sodium thiosulfate solution (50%, aqueous) and stirred at room temperature for 1 h. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were extracted with sodium thiosulfate solution (50%, aqueous), saturated aqueous sodium bicarbonate, and washed with saturated aqueous sodium chloride. The organic phase was filtered through a hydrophobic filter and concentrated to give 62.5 mg of the title compound, which was used without further purification.

[0540] LC-MS (Method 2):R t =1.07min;MS(ESIpos):m / z=507[M+H] +

[0541] (Intermediate 60) Benzyl {[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methyl}carbamate [ka]

[0542] N-[(benzyloxy)carbonyl]glycine (1.50 g, 7.17 mmol) and cesium carbonate (1.17 g, 3.59 mmol; CAS-RN: [534-17-8]) were dissolved in N,N-dimethylformamide (15 mL) and stirred at room temperature for 1 hour. 2-Bromo-1-(4-methoxyphenyl)ethan-1-one (1.64 g, 7.17 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Xylene (45 mL) and ammonium acetate (9.21 g, 120 mmol; CAS-RN: [631-61-8]) were then added, and the mixture was stirred at 120 °C for 19 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, filtered through a hydrophobic filter, and concentrated to give the crude product. The residue was stirred in methyl tert-butyl ether. The precipitate was collected by filtration, washed with methyl tert-butyl ether and purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 1.28 g (48% yield) of the title compound.

[0543] LC-MS (Method 2):R t =1.05min;MS(ESIpos):m / z=338[M+H] +

[0544] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]:2.332(0.22),2.518(0.99),2.523(0.64),2.819(0.31),2.931(0.24) ,3.307(0.24),3.384(0.19),3.747(16.00),3.764(2.00),3.798(0.23),3.84 0(0.83),3.848(0.30),4.236(2.90),4.251(3.02),5.028(0.26),5.059(6.0 2),6.880(2.99),6.903(3.17),6.949(0.50),6.970(0.51),7.092(0.19),7.1 14(0.31), 7.122(0.42), 7.270(0.37), 7.290(0.36), 7.302(0.57), 7.312(0.92), 7.323(1.06), 7.333(0.86), 7.343(0.82), 7.363(8.48), 7.374(5.26), 7.543(0.48), 7.565(0.47), 7.644(2.52), 7.665(2.46), 7.749(0.47), 7.763(0.87), 7.777(0.45), 8.128(0.16), 9.202(0.27), 11.851(0.72), 12.184(0.18).

[0545] (Intermediate 61) 1-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methanamine hydrobromide [ka]

[0546] Benzyl {[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methyl}carbamate ((Intermediate 60), 1.28 g, 3.79 mmol) was stirred with a solution of hydrogen bromide (5.0 mL, 32% purity, 29 mmol; CAS-RN: [10035-10-6]) in acetic acid at room temperature for 23 hours. The reaction mixture was concentrated, toluene was added, and the mixture was concentrated. The residue was stirred in methyl tert-butyl ether. The precipitate was collected by filtration, washed with methyl tert-butyl ether, and dried under reduced pressure to give 1.37 g (93% yield) of the title compound.

[0547] LC-MS (Method 2):R t =0.68min;MS(ESIpos):m / z=204[M+H] +

[0548] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.905(6.34),2.332(0.74),2.518(4.59),2.522(2.87),2.888(0.96),2.933(1.39),3.622(2.15),3.696(2.20) ,3.745(2.18),3.772(2.07),3.826(1.92),3.838(3.46),3.847(1.73),3.896(1.02),3.983(0.84),4.291(7.41),4.70 5(0.39), 7.070(9.40), 7.091(10.13), 7.113(0.74), 7.707(1.85), 7.714(16.00), 7.719(4.92), 7.731(4.80), 7.736(14.47), 7.744(1.63), 7.851(0.19), 7.913(3.62), 8.127(0.44), 8.133(0.44), 8.149(0.43), 8.495(2.55), 9.202(0.68).

[0549] (Intermediate 62) N-{[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methyl}-2-(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0550] 2,4-Bis(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 32), 454 mg, 1.62 mmol) and 1-[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methanamine hydrobromide ((Intermediate 61), 650 mg, 1.78 mmol) were prepared in acetonitrile (12 mL). N,N-Diisopropylethylamine (1.1 mL, 6.5 mmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 150 °C in a microwave for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and filtered through a hydrophobic filter to give the crude product. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 480 mg (57% yield) of the title compound.

[0551] LC-MS (Method 2):R t =1.18 min;MS(ESIpos):m / z=436[M+H] +

[0552] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.782(0.31),0.801(0.79),0.814(0.19),0.820(0.44),0.883(0.46),0.901(1.02),0.920(0.48),0.991(0 .22),1.009(0.24),1.035(0.35),1.053(1.32),1.071(1.87),1.088(0.79),1.159(1.03),1.525(0.20),1.544(0. 20), 2.065(1.25), 2.079(0.46), 2.091(0.17), 2.336(0.18), 2.418(0.30), 2.438(0.55), 2.451(16.00), 2.461(0.61), 2.518(1.90), 2.522(1.23), 2.660(0.19), 2.917(0.21), 3.349(1.14), 3.363(0.51), 3.367(0.28), 3.381(0.17 ), 3.705(0.23), 3.732(2.22), 3.745(14.66), 3.756(1.74), 3.784(0.47), 3.798(0.41), 3.822(0.49), 4.764(2.35), 4.777(2.28), 4.940(0.20), 5.378(0.35), 6.881(3.21), 6.903(3.28), 6.947(0.41), 6.969(0.41), 7.128(0.33) ,7.397(2.14),7.401(2.01),7.497(0.61),7.514(0.37),7.535(0.38),7.603(0.48),7.608(0.17),7.625(0.47),7.644(3.19),7.666(2.81),8.063(0.25),8.092(3.42),8.094(3.49),9.663(0.76),11.791(0.85),12.100(0.19).

[0553] (Intermediate 63) N-{[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methyl}-2-(methylsulfinyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0554] N-{[5-(4-Methoxyphenyl)-1H-imidazol-2-yl]methyl}-2-(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 62), 480 mg, 882 μmol) was prepared in dichloromethane (8 mL) and cooled to 2 °C. mCPBA (457 mg, 77% purity, 2.65 mmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature for 22 h. The reaction mixture was diluted with sodium thiosulfate solution (50%, aqueous) and stirred at room temperature for 30 min. The layers were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were extracted with sodium thiosulfate solution (50%, aqueous), saturated aqueous sodium bicarbonate, and washed with saturated aqueous sodium chloride. The organic phase was filtered through a hydrophobic filter and concentrated to give 494 mg of the title compound, which was used without further purification.

[0555] LC-MS (Method 2):R t =1.01min;MS(ESIneg):m / z=450[MH] -

[0556] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.231(0.45),2.518(3.20),2.523(2.03),2.673(0.69),2.869(16.00),2.888(2.57 ),2.895(0.59),2.918(0.49),3.164(0.63),3.646(0.54),3.730(1.06),3.744(15.91),3. 797(0.45), 3.811(0.41), 3.863(0.55), 4.819(3.39), 4.824(3.70), 4.862(0.66), 6.882(1.68), 6.903(1.89), 7.408(1.25), 7.641(1.63), 7.662(1.42), 8.271(3.18), 11.824(0.59).

[0557] (Intermediate 64) Ethyl 4-(trifluoromethoxy)benzene-1-carboxyimidate [ka]

[0558] First batch 4-(Trifluoromethoxy)benzonitrile (780 μL, 5.3 mmol; CAS-RN: [332-25-2]) was prepared in ethanol (5 mL) and cooled using an ice bath. Acetyl chloride (2.7 mL, 37 mmol; CAS-RN: [75-36-5]) was added dropwise, and the mixture was stirred overnight at room temperature and for 2 days at 50° C. The reaction mixture was concentrated, dichloromethane and triethylamine were added, and the mixture was concentrated again.

[0559] Second batch 4-(Trifluoromethoxy)benzonitrile (780 μL, 5.3 mmol; CAS-RN: [332-25-2]) was prepared in ethanol (4.6 mL) and cooled using an ice bath. Acetyl chloride (2.7 mL, 37 mmol; CAS-RN: [75-36-5]) was added dropwise, and the mixture was stirred at 50 °C for 29 h. The reaction mixture was concentrated, dichloromethane and triethylamine were added, and the mixture was concentrated again.

[0560] The first and second batches were combined and purified by flash chromatography (silica gel, dichloromethane / ethyl acetate gradient) to give 1.75 g (70% yield) of the title compound.

[0561] LC-MS (method 1): Rt=0.81 min; MS (ESIpos): m / z=234[M+H] +

[0562] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.297(7.12),1.305(1.43),1.314(16.00),1.323(2.97),1.332(7.27),1.340(1.32),2.518(0.89),2.522(0.5 8),4.074(0.95),4.091(0.96),4.218(2.01),4.235(6.40),4.253(6.21),4.270(1.88),7.396(0.51),7.399(0.58),7. 419 (0.63), 7.421 (0.59), 7.428 (0.41), 7.435 (2.70), 7.438 (2.98), 7.455 (2.11), 7.457 (3.38), 7.460 (2.99), 7.932 (0.74), 7.939 (7.34), 7.944 (1.98), 7.956 (2.01), 7.961 (6.42), 7.969 (0.65), 8.028 (1.21), 8.050 (1.18), 9.057 (3.85).

[0563] (Intermediate 65) tert-Butyl ({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)carbamate [ka]

[0564] Ethyl 4-(trifluoromethoxy)benzene-1-carboxyimidate ((Intermediate 64), 750 mg, 87% purity, 2.80 mmol) was dissolved in acetonitrile (15 mL). tert-Butyl (2-hydrazinyl-2-oxoethyl)carbamate (529 mg, 2.80 mmol; CAS-RN: [6926-09-6]) was added, and the mixture was stirred at 50° C. overnight, at 105° C. for 32 hours, and at room temperature over the weekend. The precipitate was collected by filtration and washed with acetonitrile to give 546 mg (54% yield) of the title compound.

[0565] LC-MS (Method 1):R t=1.17min;MS(ESIneg):m / z=357[MH] -

[0566] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.287(0.41),1.397(16.00),2.518(1.25),2.522(0.83),4.260(1.23),4.275(1.18),7.457(1. 23),7.478(1.22),8.065(0.49),8.072(4.47),8.077(1.29),8.089(1.25),8.094(4.02),8.101(0.43).

[0567] (Intermediate 66) 1-{5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methanamine [ka]

[0568] tert-Butyl ({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)carbamate ((Intermediate 65), 483 mg, 1.35 mmol) was dissolved in methanol (5.5 mL). HCl in dioxane (3.4 mL, 13 mmol, 4 M; CAS-RN: [7647-01-0]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated. Dichloromethane and triethylamine (1 mL) were added, the mixture was concentrated, and the residue was purified by column chromatography (silica gel, amino phase, dichloromethane / ethanol gradient) to give 328 mg (78% yield) of the title compound.

[0569] LC-MS (Method 2):R t =0.70min;MS(ESIneg):m / z=257[MH] -

[0570] 1H-NMR (400 MHz, DMSO-d6) δ [ppm]:0.883(0.78),0.901(1.67),0.920(0.86),1.013(0.62),1.022(0.64) ,1.032(1.18),1.035(1.01),1.040(0.58),1.052(1.83),1.058(0.48),1.070 (0.82),1.171(0.52),1.227(1.53),1.798(1.01),1.808(0.46),1.826(0.42) ,1.930(1.19),2.064(1.85),2.244(1.17),2.419(0.41),2.437(0.44),2.518 (6.55), 2.523 (4.62), 3.349 (2.10), 3.367 (1.93), 3.386 (2.16), 3.411 (1.45), 3.428 (1.68), 3.446 (1.59), 3.464 (0.96), 4.284 (0.44), 4.298 (0.44), 4.382 (0.55), 4.451 (1.27), 7.386 (0.52), 7.406 (0.64), 7.437 (12.52), 7.457 (13.77), 8.080 (16.00), 8.090 (3.90), 8.101 (14.96), 8.131 (1.19), 8.179 (0.40).

[0571] (Intermediate 67) 2-(Methylsulfanyl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0572] 2,4-Bis(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 32), 150 mg, 535 μmol) and 1-{5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methanamine ((Intermediate 66), 166 mg, 642 μmol) were dissolved in acetonitrile (10 mL). N,N-Diisopropylethylamine (370 μL, 2.1 mmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 180 °C in a microwave for 3 h. The reaction mixture was concentrated to give the crude product. The residue was purified by column chromatography (silica gel, dichloromethane / ethyl acetate gradient). The resulting precipitate was collected by filtration to give 104 mg (39% yield) of the title compound.

[0573] LC-MS (Method 1):R t =1.37min;MS(ESIpos):m / z=491[M+H] +

[0574] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]:0.840(0.41),0.852(0.57),0.857(1.13),1.237(0.92),2.318(0.48) ,2.419(16.00),2.518(14.05),2.523(10.18),2.678(0.64),4.865(2.66),5 .759(0.58),7.456(1.79),7.476(1.93),8.066(0.81),8.073(7.35),8.078( 2.61),8.089(2.18),8.095(6.92),8.102(1.00),8.117(4.38),9.808(0.65).

[0575] (Intermediate 68) 2-(Methanesulfonyl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0576] 2-(Methylsulfanyl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 67), 102 mg, 208 μmol) was prepared in dichloromethane (5 mL) and cooled using a water bath. mCPBA (186 mg, 77% purity, 832 μmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic layer was dried over a hydrophobic filter and concentrated. The crude product was purified by column chromatography (silica gel, dichloromethane / ethyl acetate gradient) to give 94.0 mg (87% yield) of the title compound.

[0577] LC-MS (Method 2):R t =0.89min;MS(ESIpos):m / z=523[M+H] +

[0578] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.154(1.08),1.172(2.36),1.190(1.24),1.987(4.66),2.518(1.54),2.522(1.01),3.316(2.22),3.3 30(16.00),3.345(0.43),4.017(0.99),4.034(0.98),5.758(1.50),8.071(1.35),8.093(1.22),8.368(0.64).

[0579] (Intermediate 69) Ethyl N-[2-(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]glycinate [ka]

[0580] 2,4-Bis(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 32), 2.00 g, 7.14 mmol) was dissolved in acetonitrile (40 mL). Ethyl glycinate hydrochloride (1 / 1) (1.49 g, 10.7 mmol) and N,N-diisopropylethylamine (5.0 mL, 29 mmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70 °C for 5 days. The reaction mixture was concentrated, and the residue was diluted with water. The precipitate was collected by filtration and dried under reduced pressure at 60 °C to give 2.11 g (87% yield) of the title compound.

[0581] LC-MS (Method 1):R t =1.26 min;MS(ESIpos):m / z=336[M+H] +

[0582] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.183(4.82),1.189(0.46),1.201(10.88),1.218(4.91),2.459(1 6.00),2.468(0.48),2.482(1.01),2.518(1.41),2.523(1.04),4.117(1. 32),4.135(4.13),4.152(4.04),4.170(1.22),4.209(2.92),4.223(2.92 ),8.110(2.36),8.112(2.43),9.604(0.46),9.620(0.95),9.634(0.44).

[0583] (Intermediate 70) Ethyl N-[2-(methanesulfonyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]glycinate [ka]

[0584] Ethyl N-[2-(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]glycinate ((Intermediate 69), 2.11 g, 6.29 mmol) was dissolved in dichloromethane (50 mL) and cooled using an ice bath. 3-Chlorobenzene-1-carboperoxoic acid (2.82 g, 77% purity, 12.6 mmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted to basic pH by adding saturated aqueous sodium bicarbonate solution. The organic layer was washed with aqueous sodium thiosulfate and brine, dried on a hydrophobic filter, and concentrated to give 2.08 g (90% yield) of the title compound.

[0585] LC-MS (Method 1):R t =0.97min;MS(ESIpos):m / z=368[M+H] +

[0586] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.184(0.30),1.189(1.77),1.201(0.26),1.207(3.93),1.225(1. 76),2.518(0.60),2.523(0.42),2.879(0.31),3.331(16.00),3.347(7.1 3),3.380(0.42),4.127(0.47),4.144(1.47),4.162(1.47),4.180(0.44) ,4.343(1.49),5.758(0.31),8.366(0.88),8.369(0.93),10.257(0.25).

[0587] (Intermediate 71) Ethyl N-[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]glycinate [ka]

[0588] Ethyl N-[2-(methanesulfonyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]glycinate ((Intermediate 70), 2.08 g, 5.66 mmol) was dissolved in acetonitrile (40 mL). Morpholine (1.5 mL, 17 mmol; CAS-RN: [110-91-8]) and N,N-diisopropylethylamine (3.0 mL, 17 mmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70 °C for 7 days. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic phase was dried on a hydrophobic filter and concentrated to give the crude product. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate gradient) to give 450 mg (21% yield) of the title compound.

[0589] LC-MS (Method 1):R t =1.19min;MS(ESIneg):m / z=373[MH] -

[0590] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.163(7.21),1.180(16.00),1.194(0.95),1.198(7.26),2.518(2.66), 2.523(1.93),3.504(3.12),3.514(5.18),3.528(4.63),3.638(4.65),3.651(5. 48), 3.662(3.34), 4.097(2.08), 4.114(6.76), 4.132(6.70), 4.148(5.00), 4.162(4.49), 7.938(3.97), 7.940(4.10), 9.276(0.76), 9.290(1.65), 9.305(0.77).

[0591] (Intermediate 72) N-[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]glycine [ka]

[0592] Ethyl N-[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]glycinate ((Intermediate 71), 450 mg, 1.20 mmol) was dissolved in tetrahydrofuran (25 mL) and ethanol (10 mL). Aqueous lithium hydroxide solution (3.0 mL, 1.0 M, 3.0 mmol; CAS-RN: [1310-65-2]) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was diluted with water. The aqueous phase was adjusted to a slightly acidic pH with citric acid solution (50%, aq.). The resulting precipitate was filtered off, washed with water, and the solid was dried to give 381 mg (90% yield) of the title compound.

[0593] LC-MS (Method 1):R t =0.99min;MS(ESIpos):m / z=347[M+H] +

[0594] 1 H-NMR(500 MHz,DMSO-d6)δ [ppm]:1.232(0.44),2.365(1.56),2.369(0.70),2.515(7.16),2.518(7.04),2.522(5.54),3.521(9.69),3.530(15.21),3.540(13.44) ,3.644(13.74),3.655(16.00),3.664(10.34),4.070(11.53),4.082(11.51),7.927(11.79),9.058(1.63),9.069(2.98),9.080(1.57).

[0595] (Intermediate 73) 2-{[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]amino}acetohydrazide [ka]

[0596] N-[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]glycine ((Intermediate 72), 380 mg, 1.10 mmol) was dissolved in tetrahydrofuran (20 mL). Di(1H-imidazol-1-yl)methanone (356 mg, 2.19 mmol; CAS-RN: [530-62-1]) was added, and the mixture was stirred at reflux for 6 hours. The reaction mixture was cooled to room temperature, and a solution of hydrazine in tetrahydrofuran (5.5 mL, 1.0 M, 5.5 mmol; CAS-RN: [302-01-2]) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried on a hydrophobic filter, and concentrated. The crude product was stirred in methyl tert-butyl ether. The precipitate was collected by filtration, washed with methyl tert-butyl ether and dried to give 330 mg (79% yield) of the title compound.

[0597] LC-MS (Method 1):R t =0.90min;MS(ESIneg):m / z=359[MH] -

[0598] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.154(0.80),1.173(1.59),1.190(0.84),1.758(0.40),1.988(3.18),2.337(0.76),2.518(10. 46),2.523(7.42),3.516(8.95),3.527(15.32),3.540(13.47),3.599(0.55),3.643(13.36),3.656(16 .00), 3.667(9.74), 3.996(9.49), 4.010(9.36), 4.035(0.87), 4.222(5.55), 4.373(0.78), 4.388(0.76), 4.496(1.16), 7.906(11.75), 8.631(0.55), 8.948(1.85), 8.963(3.75), 8.977(1.80), 9.167(4.32).

[0599] (Intermediate 74) tert-Butyl [(5-bromo-1H-imidazol-2-yl)methyl]carbamate [ka]

[0600] tert-Butyl [(1H-imidazol-2-yl)methyl]carbamate (654 mg, 3.32 mmol; CAS-RN: [203664-05-5]) was prepared in N,N-dimethylformamide (30 mL) and cooled to -50 °C. 1-Bromopyrrolidine-2,5-dione (590 mg, 3.32 mmol; CAS-RN: [128-08-5]) was added, and the mixture was allowed to warm to room temperature. The reaction mixture was concentrated, and the residue was purified twice by column chromatography (1. silica gel, dichloromethane / ethanol gradient; 2. silica gel amino phase, dichloromethane / ethanol gradient) to give 313 mg (34% yield) of the title compound.

[0601] LC-MS (method 1): Rt=0.78 min; MS (ESIpos): m / z=276[M+H] +

[0602] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.323(0.41),1.363(0.92),1.384(16.00),2.518(0.90),2.523(0 .71),2.563(0.78),2.728(0.40),2.889(0.47),4.077(2.12),4.091(2.0 5),4.248(0.16),5.758(0.19),7.019(0.20),7.022(0.20),7.112(2.09) ,7.116(2.09),7.259(0.32),7.273(0.56),7.287(0.30),12.127(0.39).

[0603] (Intermediate 75) tert-Butyl {[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]methyl}carbamate [ka]

[0604] The first batch of tert-butyl [(5-bromo-1H-imidazol-2-yl)methyl]carbamate ((Intermediate 74), 50.0 mg, 181 μmol), (6-methoxypyridin-3-yl)boronic acid (22.2 mg, 145 μmol; CAS-RN: [163105-89-3]), and potassium carbonate (62.6 mg, 435 μmol) was dissolved in 1,4-dioxane (3 mL) and water (1 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride (6.6 mg, 9 μmol; CAS-RN: [72287-26-4]) was added. The mixture was flushed with argon and stirred at 80 °C overnight. A second batch of tert-butyl [(5-bromo-1H-imidazol-2-yl)methyl]carbamate ((Intermediate 74), 101 mg, 366 μmol), (6-methoxypyridin-3-yl)boronic acid (67.1 mg, 439 μmol; CAS-RN: [163105-89-3]), and potassium carbonate (153 mg, 1.10 mmol) was dissolved in 1,4-dioxane (6.1 mL) and water (2 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride (13.4 mg, 18.3 μmol; CAS-RN: [72287-26-4]) was added. The mixture was flushed with argon and stirred at 80 °C for 3 h. The two reaction mixtures were combined, concentrated and purified by column chromatography (silica gel NH2, dichloromethane / ethyl acetate gradient) to give 116 mg of the title compound.

[0605] LC-MS (method 2): Rt=0.93 min; MS (ESIpos): m / z=305[M+H] +

[0606] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.066(0.97),1.154(0.42),1.172(0.89),1.190(0.45),1.233(0.41),1.385 (11.05),1.399(16.00),1.987(1.44),2.336(0.21),2.518(3.43),2.522(2.24),2.6 60(0.22), 3.842(15.36), 3.857(0.91), 4.017(0.31), 4.035(0.32), 4.077(0.89), 4.091(0.88), 4.114(0.67), 4.128(0.70), 4.157(1.97), 4.171(2.02), 4.209(0.18), 4. 214(0.18), 6.780(1.93), 6.801(1.86), 6.855(0.16), 6.875(0.17), 6.976(0.16), 7.114(1.05), 7.190(0.20), 7.208(0.28), 7.274(0.58), 7.289(0.74), 7.302(0.35), 7. 461(2.04), 7.466(2.00), 7.480(0.16), 7.552(0.22), 7.987(1.49), 7.993(1.38), 8.009(1.34), 8.014(1.38), 8.515(1.73), 8.519(1.73), 11.870(0.62), 12.132(0.17).

[0607] (Intermediate 76) 1-[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]methanamine [ka]

[0608] To tert-butyl {[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]methyl}carbamate ((Intermediate 75), 110 mg, 361 μmol) was added a solution of HCl in 1,4-dioxane (1.8 mL, 4.0 M, 7.2 mmol CAS-RN: [7647-01-0]). 1,4-Dioxane (5.0 mL) was added, and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated and diluted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate, dried on a hydrophobic filter, and concentrated to give the crude product. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 44 mg (59% yield) of the title compound.

[0609] LC-MS (method 2): Rt=0.62 min; MS (ESIpos): m / z=205[M+H] +

[0610] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.052(0.17),1.231(0.77),1.840(2.05),2.332(0.50),2.336(0.25),2.518(2.76),2.523(1.97 ),2.678(0.24),3.333(2.17),3.428(0.34),3.445(0.25),3.461(0.21),3.641(3.62),3.657(0.17),3.6 79 (3.27), 3.727 (16.00), 3.860 (0.33), 5.760 (0.88), 6.782 (1.89), 6.804 (1.99), 6.867 (0.23), 7.101 (1.90), 7.430 (0.59), 7.978 (1.70), 7.984 (1.83), 8.000 (1.66), 8.006 (1.75), 8.505 (2.23), 8.509 (2.35).

[0611] (Intermediate 77) N-{[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]methyl}-2-(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0612] 2,4-Bis(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 42), 69.2 mg, 247 μmol) and 1-[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]methanamine ((Intermediate 76), 42.0 mg, 206 μmol) were dissolved in acetonitrile (2 mL). N,N-Diisopropylethylamine (110 μL, 620 μmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 60° C. for 1 hour and at 50° C. overnight. The reaction mixture was concentrated to give the crude product. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 54 mg (50% yield) of the title compound.

[0613] LC-MS (method 2): Rt=1.16 min; MS (ESIpos): m / z=437[M+H] +

[0614] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.035(1.34),1.053(2.72),1.070(1.22),1.232(0.64),2.318(0.55),2.337(0.52),2.464(4.56),2.474(16.00 ),2.518(6.97),2.523(5.36),2.660(0.56),2.679(0.55),3.422(0.43),3.435(0.44),3.845(15.64),4.355(0.43),4.7 39 (0.99), 4.791 (3.81), 5.759 (14.97), 6.791 (1.60), 6.812 (1.72), 7.526 (1.83), 7.530 (1.82), 7.993 (1.18), 8.000 (1.25), 8.015 (1.11), 8.021 (1.19), 8.489 (0.80), 8.502 (3.44), 8.523 (1.71), 8.528 (1.70), 9.651 (0.51), 11.953 (0.75).

[0615] (Intermediate 78) {[2-(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile [ka]

[0616] 2,4-Bis(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazine ((Intermediate 42), 1.93 g, 6.89 mmol) was prepared in acetonitrile (50 mL). Aminoacetonitrile hydrogen chloride (956 mg, 10.3 mmol) and N,N-diisopropylethylamine (4.8 mL, 28 mmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70 °C for 24 h. Aminoacetonitrile hydrogen chloride (637 mg, 6.8 mmol) was added, and the mixture was stirred at 70 °C for 3 h and at 80 °C for 18 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated to give the crude product. The residue was purified by column chromatography (silica gel, dichloromethane / ethyl acetate gradient). The product was stirred in pentane. The precipitate was collected by filtration and dried to give 1.30 g (60% yield) of the title compound.

[0617] LC-MS (Method 1):R t =1.12 min;MS(ESIpos):m / z=289[M+H] +

[0618] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.102(0.48),1.349(0.79),1.366(0.84),2.518(1.47),2.523(1.00),2.5 47(0.43),2.567(16.00),4.564(6.50),8.437(0.58),8.527(3.56),9.819(0.53).

[0619] (Intermediate 79) {[2-(methylsulfinyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile [ka]

[0620] {[2-(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile ((Intermediate 78), 4.01 g, 13.9 mmol) was prepared in dichloromethane (100 mL) and cooled using an ice bath. 3-Chlorobenzene-1-carboperoxoic acid (4.68 g, 77% purity, 20.9 mmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with dichloromethane. The solid was dried and stirred in aqueous sodium bicarbonate solution. The precipitate was filtered and dried to give 1.91 g (43% yield) of the title compound.

[0621] LC-MS (method 1): Rt=0.74 min; MS (ESIpos): m / z=305[M+H] +

[0622] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.518(0.96),2.523(0.67),2.961(16.00),3.420(0.64),4.600(0.4 0),4.644(3.43),4.653(3.34),4.697(0.44),8.750(3.35),10.300(0.74).

[0623] (Intermediate 80) {[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile [ka]

[0624] {[2-(methanesulfinyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile ((Intermediate 79), 1.90 g, 6.24 mmol) and morpholine (1.6 mL, 19 mmol; CAS-RN: [110-91-8]) were prepared in acetonitrile (75 mL). N,N-Diisopropylethylamine (3.3 mL, 19 mmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 70 °C overnight. The reaction mixture was poured into water. The precipitate was collected by filtration, washed with water, and dried to give 1.89 g (92% yield) of the title compound.

[0625] LC-MS (Method 1):R t =1.07min;MS(ESIneg):m / z=326[MH] -

[0626] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.073(4.21),2.332(0.70),2.518(3.63),2.522(2.49),2.673(0.71),3.655(4.7 8),3.666(8.17),3.679(6.81),3.803(2.80),4.521(16.00),8.262(9.35),9.354(1.01).

[0627] (Intermediate 81) N-Hydroxy{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}ethanimidamide [ka]

[0628] {[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetonitrile ((Intermediate 80), 1.89 g, 5.78 mmol) was dissolved in methanol (100 mL). Hydroxylamine hydrochloride (1.81 g, 26.0 mmol) and triethylamine (3.6 mL, 26 mmol; CAS-RN: [121-44-8]) were added, and the mixture was stirred at room temperature for 72 hours. The solid was collected by filtration, washed with methanol, and dried to give 1.94 g (91% yield) of the title compound.

[0629] LC-MS (Method 1):R t =0.80min;MS(ESIneg):m / z=359[MH] -

[0630] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.331(0.67),2.518(4.09),2.523(2.78),2.673(0.67),3.632(4.35),3.642(7.80),3.655(6.70),3.7 06(0.42),3.750(5.09),4.063(3.75),4.070(3.70),5.475(6.09),8.205(8.75),8.668(1.51),9.144(16.00).

[0631] (Intermediate 82) {[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}ethanimidamide hydrochloride [ka]

[0632] N-Hydroxy{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}ethanimidamide ((Intermediate 81), 264 mg, 733 μmol) was prepared in 10 mL of a 1:1 mixture of ethanol and water. Iron (246 mg, 4.40 mmol; CAS-RN: [7439-89-6]) was added, and the mixture was heated to 100 °C. 3 mL of a 1:1 solution of 1 N HCl in ethanol and water was added dropwise, and the mixture was stirred at 100 °C for 1 h. The reaction mixture was hot filtered over Celite and washed with ethanol. The filtrate was concentrated. The residue was diluted with ethanol, concentrated several times, and dried to give the crude product. The crude product was purified by preparative HPLC [Waters Autopurification system; column: Waters XBridge C18 100*30 mm*5 μm; eluent A: water (0.1% TFA (99%)), eluent B: acetonitrile; gradient: 0.0-0.5 min 14% B (25-70 mL / min), 0.51-5.5 min 14-34% B; flow rate 70 mL / min; detector: DAD scan 210-400 nm] to give 112 mg (39% yield) of the title compound.

[0633] LC-MS (Method 1):R t =0.77min;MS(ESIneg):m / z=343[MH] -

[0634] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.232(0.67),2.075(1.36),2.332(2.81),2.336(1.20),2.518(16.00),2.523(11.27 ),2.673(2.82),2.678(1.24),3.651(13.08),3.678(5.48),3.728(13.39),3.741(13.95),3 .751(9.46), 4.395(7.41), 4.410(6.68), 6.964(2.00), 7.091(2.31), 7.219(2.01), 8.208(3.24), 8.265(12.16), 8.803(7.71), 8.938(7.68), 9.023(1.72), 9.037(3.67), 9.052(1.66).

[0635] Example 1 8-Bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0636] 2-{[8-Bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide ((Intermediate 11), 80.0 mg, 216 μmol), 4-(trifluoromethyl)benzene-1-carboximidamide hydrochloride (1 / 1) (58.1 mg, 259 μmol), and sodium ethylate (29.3 mg, 431 μmol; CAS-RN: [141-52-6]) were dissolved in N,N-dimethylformamide (2.5 mL). The mixture was stirred in a microwave at 180 °C for 45 min. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT basic) to give 34.0 mg (29% yield) of the title compound.

[0637] LC-MS (Method 2):R t=0.91 min;MS(ESIpos):m / z=526[M+H] +

[0638] H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.232(0.62),1.249(0.43),2.337(1.11),2.518(13.96),2.52 3(9.58),2.679(1.11),3.539(8.34),3.650(8.96),4.818(3.09),7.8 38(3.09),7.976(0.80),7.996(1.11),8.031(16.00),8.111(0.99),8 .130(0.74),8.167(7.41),8.187(6.42),9.176(1.30),14.117(0.62).

[0639] Example 2 8-Bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0640] 2-{[8-Bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide ((Intermediate 11), 80.0 mg, 216 μmol), 4-(trifluoromethoxy)benzene-1-carboximidamide hydrochloride (1 / 1) (62.2 mg, 259 μmol; CAS-RN: [121219-95-2]), and sodium ethylate (29.3 mg, 431 μmol; CAS-RN: [141-52-6]) were dissolved in N,N-dimethylformamide (2.5 mL). The mixture was stirred at 180 °C in a microwave oven for 45 min. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT basic) to give 38.7 mg (32% yield) of the title compound.

[0641] LC-MS (Method 2):Rt =0.97min;MS(ESIpos):m / z=540[M+H] +

[0642] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]:2.332(1.21),2.336(0.52),2.518(9.19),2.523(6.70),2.540(1.41 ),2.673(1.21),3.542(5.02),3.642(5.41),3.654(6.40),4.787(4.52),7.4 53(3.37),7.473(3.59),8.025(16.00),8.039(0.41),8.058(1.05),8.064(9 .35),8.070(2.92),8.081(2.76),8.087(8.39),8.093(1.02),9.141(0.63).

[0643] Example 3 8-Bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0644] {[8-Bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}ethanimidamide hydrogen chloride (1 / 1) ((Intermediate 15), 150 mg, 383 μmol) and 2-bromo-1-[4-(trifluoromethyl)phenyl]ethan-1-one (133 mg, 498 μmol) were dissolved in N,N-dimethylformamide (2.5 mL). Cesium carbonate (499 mg, 1.53 mmol; CAS-RN: [534-17-8]) was added, and the reaction mixture was stirred at 90 °C overnight. The mixture was filtered, and the filtrate was purified by preparative HPLC (HT basic) to give 20.5 mg (9% yield) of the title compound.

[0645] LC-MS (Method 2):R t =1.26 min;MS(ESIpos):m / z=523[M+H] +

[0646] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.331(1.20),2.336(0.53),2.518(5.84),2.522(3.97),2.539(0.45),2.669(1.63),2. 673(1.20),3.561(5.09),3.669(6.27),3.682(6.83),3.693(3.87),3.903(0.43),4.716(3.81 ),4.729(3.55),7.656(4.56),7.676(5.15),7.729(4.29),7.733(4.35),7.755(0.45),7.815(0.43),7.931(5.12),7.952(4.24),8.013(16.00),8.026(0.99),9.024(1.44),12.125(1.71).

[0647] Example 4 8-Bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0648] {[8-Bromo-2-(morpholin-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}ethanimidamide hydrogen chloride (1 / 1) ((Intermediate 15), 150 mg, 383 μmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethan-1-one (141 mg, 498 μmol) were dissolved in N,N-dimethylformamide (2.5 mL). Cesium carbonate (499 mg, 1.53 mmol; CAS-RN: [534-17-8]) was added, and the reaction mixture was stirred at 90 °C overnight. The mixture was filtered, and the filtrate was purified by preparative HPLC (HT basic) to give 22.7 mg (10% yield) of the title compound.

[0649] LC-MS (Method 2):R t =1.28 min;MS(ESIpos):m / z=539[M+H] +

[0650] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.327(1.81),2.331(1.33),2.336(0.60),2.518(6.27),2.523(4.19),2.669(1.87),2.673(1.33),2. 678(0.63),3.564(4.91),3.670(6.03),3.683(6.54),3.693(3.62),4.702(3.68),4.715(3.40),7.298(3.95 ),7.318(4.43),7.591(4.25),7.596(4.19),7.706(0.51),7.728(0.45),7.818(0.90),7.825(7.44),7.830(2.38),7.841(2.23),7.846(6.51),7.854(0.72),8.009(16.00),8.023(1.11),9.007(1.42),12.022(1.66).

[0651] Example 5 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0652] 2-{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide ((Intermediate 24), 125 mg, 347 μmol) and 4-(trifluoromethoxy)benzene-1-carboximidamide hydrogen chloride (1 / 1) (100 mg, 416 μmol) were dissolved in N,N-dimethylformamide (3.0 mL). Sodium ethylate (47.2 mg, 694 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 45 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified by preparative HPLC (HT acid) to give 87.2 mg (47% yield) of the title compound.

[0653] LC-MS (Method 1):R t =1.33min;MS(ESIpos):m / z=530[M+H] +

[0654] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.336(0.86),2.518(12.00),2.523(8.22),2.674(1.86),2.678(0.86),3.548(5.90),3.669(9.47),4.804(4.11),7.455(3.75 ),7.474(3.89),8.061(1.96),8.068(16.00),8.073(4.95),8.085(4.88),8.090(13.84),8.097(1.68),8.247(15.14),9.300(1.42).

[0655] Example 6 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0656] 2-{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide ((Intermediate 24), 125 mg, 347 μmol) and 4-(trifluoromethyl)benzene-1-carboximidamide hydrogen chloride (1 / 1) (93.5 mg, 416 μmol) were dissolved in N,N-dimethylformamide (3.0 mL). Sodium ethylate (47.2 mg, 694 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 45 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified by preparative HPLC (HT acid) to give 49.6 mg (28% yield) of the title compound.

[0657] LC-MS (Method 1):R t =1.31 min;MS(ESIpos):m / z=514[M+H] +

[0658] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.331(1.94),2.518(13.23),2.523(8.62),2.673(1.93),3.546(6.18),3.668(10.32),4.829(5.6 4),7.825(5.47),7.845(5.97),8.170(10.26),8.190(8.84),8.252(16.00),9.321(1.98),14.158(0.49).

[0659] Example 7 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0660] 2-(Methanesulfonyl)-4-(methylsulfanyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazine ((Intermediate 33), 50.0 mg, 160 μmol) and 1-{5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methanamine ((Intermediate 36), 42.5 mg, 176 μmol) were dissolved in acetonitrile (3 mL). N,N-Diisopropylethylamine (112 μL, 640 μmol; CAS-RN: [7087-68-5]) was added, and the mixture was stirred at 150° C. in a microwave for 2 hours. Morpholine (9.5 mg, 109 μmol; CAS-RN: [110-91-8]) was added to the crude reaction mixture, and the mixture was stirred at 70° C. for 1 hour and at 60° C. overnight. The reaction mixture was concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane / ethyl acetate / ethanol gradient) to give the crude product. The crude product was purified by flash chromatography (silica gel, dichloromethane / ethanol gradient) to give 5.0 mg (9% yield) of the title compound.

[0661] LC-MS (Method 2):R t =1.32min;MS(ESIpos):m / z=513[M+H] +

[0662] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.851(0.83),1.230(4.70),1.256(1.35),1.295(0.49),1.352(0.45),1.906(0.59),2.326(3.56),2.332(2.48),2. 335(1.12),2.518(16.00),2.522(10.40),2.668(3.58),2.673(2.51),2.678(1.15),3.499(5.56),3.510(5.16),3.572(5. 44), 3.584(5.57), 4.742(3.76), 4.756(3.64), 7.656(3.21), 7.676(3.81), 7.720(3.05), 7.725(3.02), 7.819(0.53), 7.841(0.84), 7.926(5.84), 7.933(3.80), 7.953(2.99), 8.195(0.44), 9.318(0.87), 9.332(1.66), 9.346(0.78), 12.079(1.38).

[0663] Example 8 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0664] 2-(Methanesulfonyl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 39), 32.0 mg, 61.4 μmol) was dissolved in acetonitrile (1.0 mL). Morpholine (7.0 μL, 80 μmol) and N,N-diisopropylethylamine (32 μL, 180 μmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70° C. for 23 hours. Morpholine (100 μL, 562.5 μmol) was added, and the reaction mixture was stirred at 70° C. for an additional 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were concentrated and the residue was purified by preparative HPLC (HT basic) to give 8.0 mg (23% yield) of the title compound.

[0665] LC-MS (Method 2):R t =1.38min;MS(ESIpos):m / z=529[M+H] +

[0666] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.833(0.58),0.850(0.94),1.232(5.94),2.540(16.00),3.500(12.25),3.512(10.9 0),3.575(11.56),3.587(11.98),4.730(7.91),4.744(7.47),7.297(6.77),7.317(7.50),7. 383 (0.55), 7.403 (0.55), 7.584 (6.84), 7.588 (6.76), 7.706 (0.58), 7.727 (0.54), 7.827 (10.52), 7.849 (9.55), 7.923 (10.19), 9.303 (1.84), 9.317 (3.56), 9.331 (1.70), 11.972 (3.15).

[0667] Example 9 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0668] 2-(Methanesulfonyl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 46), 100 mg, 60% purity, 119 μmol) was dissolved in acetonitrile (2.0 mL). Morpholine (13 μL, 150 μmol) and N,N-diisopropylethylamine (62 μL, 360 μmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70° C. for 72 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified by preparative HPLC (HT basic) to give 19.6 mg (32% yield) of the title compound.

[0669] LC-MS (Method 2):R t =1.33min;MS(ESIpos):m / z=513[M+H] +

[0670] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.845(0.47),1.227(2.65),2.518(4.44),2.535(1.40),3.561(7.54),3.681(11.16),3.692(13.17),4.733(8.43),7.6 55(6.47),7.676(7.54),7.734(8.15),7.931(7.29),7.951(6.13),8.229(16.00),8.473(0.41),9.180(2.09),12.128(2.08).

[0671] Example 10 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0672] 2-(Methanesulfonyl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 50), 80.0 mg, 66% purity, 101 μmol) was dissolved in acetonitrile (2.0 mL). Morpholine (12 μL, 130 μmol) and N,N-diisopropylethylamine (53 μL, 300 μmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70 °C for 20 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was concentrated, and the residue was purified by preparative HPLC (HT basic) to give 16.5 mg (30% yield) of the title compound.

[0673] LC-MS (Method 2):R t =1.33min;MS(ESIpos):m / z=529[M+H] +

[0674] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.850(0.51),0.940(0.59),0.957(0.58),1.232(2.65),2.332(1.63),2.336(0.72),2.518(8.13), 2.523(5.17),2.673(1.65),3.567(6.91),3.686(10.74),3.698(12.18),3.708(7.00),4.722(7.07),7.30 0(6.81), 7.321(7.50), 7.388(0.48), 7.405(0.44), 7.599(6.88), 7.602(6.71), 7.706(0.48), 7.725(0.44), 7.828(11.73), 7.833(4.12), 7.845(3.84), 7.850(10.35), 8.229(16.00), 9.165(1.85), 12.025(2.88).

[0675] Example 11 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0676] 2-(Methanesulfonyl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 55), 60.0 mg, 118 μmol) was dissolved in acetonitrile (2.2 mL). Morpholine (41 μL, 470 μmol; CAS-RN: [110-91-8]) and N,N-diisopropylethylamine (100 μL, 590 μmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70 °C for 6 hours. Morpholine (3 mL, 34.4 mmol; CAS-RN: [110-91-8]) was added, and the mixture was stirred at 100 °C for 3 hours and at room temperature for 5 days. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane / ethyl acetate gradient) to give 29.0 mg (43% yield) of the title compound.

[0677] LC-MS (Method 2):R t =0.99min;MS(ESIpos):m / z=514[M+H] +

[0678] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:0.851(0.86),1.232(2.44),1.983(0.99),2.005(0.46),2.337( 1.16),2.518(16.00),2.523(11.15),2.571(0.46),2.635(1.02),2.64 7(1.22),2.678(1.21),3.357(1.07),3.371(2.95),3.381(0.99),3.39 2(0.72),3.416(0.66),3.454(6.26),3.465(10.96),3.477(10.18),3. 499 (0.99), 3.506 (1.08), 3.519 (1.06), 3.530 (1.17), 3.549 (11.18), 3.561 (12.39), 3.572 (7.74), 3.659 (0.97), 3.672 (0.96), 4.829 (5.25), 4.840 (5.24), 7.822 (6.57), 7.843 (7.15), 7.885 (0.51), 7.942 (9.05), 7.943 (9.25), 8.166 (8.88), 8.186 (7.65), 9.470 (2.23), 14.150 (0.48).

[0679] Example 12 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0680] 2-(Methanesulfonyl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 59), 62.0 mg, 20% purity, 24.5 μmol) was dissolved in acetonitrile (1.0 mL). Morpholine (2.8 μL, 32 μmol) and N,N-diisopropylethylamine (13 μL, 73 μmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70° C. for 23 hours. Morpholine (4.3 μL, 49.1 μmol) was added, and the mixture was stirred at 70° C. for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was concentrated, and the residue was purified by preparative HPLC [Waters Autopurification system; column: Kinetex Evo C18 150*30mm*5μm; eluent A: water (0.2% aqueous ammonia (32%)), eluent B: acetonitrile; gradient: 0-0.5 min 35% B (35-70 mL / min), 0.5-5.5 min 35-65% B; flow rate: 70 mL / min; temperature: 25°C; detector: DAD scan 210-400 nm; analytical method: instrument: Waters Acquity UPLCMS SingleQuad; column: Kinetex Evo C18 2.0μ, 100 × 2.1 mm; eluent A: water + 0.2% (v / v) aqueous ammonia (32%); eluent B: acetonitrile; gradient: 0–4.0 min 1–99% B, 4.0–5.0 min 99% B; flow rate: 0.8 ml / min; temperature: 40°C; DAD scan: 210–400 nm] to give 3.6 mg (27% yield) of the title compound.

[0681] LC-MS:R t =3.06min;MS(ESIpos):m / z=514[M+H] +

[0682] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.232(1.72),1.351(0.52),2.074(0.42),2.336(1.21),2.518(16.00),2.52 3(10.72),3.387(1.17),3.495(4.10),3.507(3.72),3.571(3.90),3.583(4.16),4. 758 (2.21), 4.771 (2.12), 7.841 (1.72), 7.862 (1.89), 7.877 (2.80), 7.930 (3.35), 8.307 (1.05), 8.331 (0.95), 8.509 (0.51), 9.118 (1.92), 9.366 (0.82), 12.225 (0.87).

[0683] Alternatively, 2-(methylsulfanyl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 58), 450 mg, 949 μmol) was prepared in dichloromethane (25 mL) at 0 °C, mCPBA (818 mg, 4.74 mmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature for 4 h. Morpholine (4.0 mL, 45.9 mmol) was added, and dichloromethane was removed at 60 °C and a reduced pressure of 700 mbar. The remaining mixture was stirred at 70 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried on a hydrophobic filter, and concentrated. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient). The product was stirred in dichloromethane. The precipitate was collected by filtration and dried to give 133 mg of the title compound.

[0684] LC-MS (Method 2):R t =1.22 min;MS(ESIpos):m / z=514[M+H] +

[0685] Example 13 N-{[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0686] 2-(Methanesulfinyl)-N-{[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methyl}-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 63), 47.2 mg, 88% purity, 92.0 μmol) was dissolved in acetonitrile (1.0 mL). Morpholine (10 μL, 120 μmol) and N,N-diisopropylethylamine (48 μL, 280 μmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred at 70 °C for 22 h. Morpholine (38 μL, 456 μmol) was added, and the mixture was stirred at 70 °C for an additional 48 h. Morpholine (38 μL, 456 μmol) and N,N-diisopropylethylamine (80 μL, 466 μmol; CAS-RN: [7087-68-5]) were added, and the mixture was stirred in a microwave at 70° C. for 72 hours and at 140° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified by preparative HPLC (HT basic) to give 24.5 mg (51% yield) of the title compound.

[0687] LC-MS (Method 2):R t =1.18 min;MS(ESIpos):m / z=475[M+H] +

[0688] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.231(1.23),2.332(0.80),2.336(0.50),2.518(3.88),2.522(2.51),2.673(0.68),3.508(6. 32),3.519(5.12),3.582(5.57),3.594(5.68),3.668(0.43),3.743(16.00),4.714(3.16),4.727(2.7 3), 6.878(3.51), 6.900(3.70), 6.933(0.44), 6.948(0.47), 6.970(0.46), 7.371(2.56), 7.375(2.50), 7.512(0.44), 7.530(0.44), 7.637(3.73), 7.658(3.44), 7.918(5.21), 9.288(1.08), 11.782(1.34).

[0689] Example 14 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0690] To 2-(methanesulfonyl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine ((Intermediate 68), 90.0 mg, 172 μmol), morpholine (1.0 mL, 11.5 mmol; CAS-RN: [110-91-8]) was added, and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (HT acid) to give 33.0 mg (36% yield) of the title compound.

[0691] LC-MS (Method 2):R t =1.12 min;MS(ESIpos):m / z=530[M+H]+

[0692] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.232(0.85),1.353(0.43),2.327(3.27),2.331(2.23),2.337(0.99),2.518(12.81),2.523(8.92),2.669 (3.32),2.674(2.30),2.678(1.01),3.457(6.86),3.468(11.89),3.480(10.70),3.502(0.81),3.552(11.86),3.5 64(12.77), 3.575(7.07), 4.806(5.18), 4.816(5.06), 7.452(5.45), 7.473(5.68), 7.937(9.67), 7.939(9.67), 8.057(2.16), 8.064(16.00), 8.070(4.85), 8.082(4.85), 8.087(14.29), 8.094(1.53), 9.449(2.36), 14.042(0.56).

[0693] Example 15 N-{[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0694] 2-{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide ((Intermediate 24), 100 mg, 278 μmol) and 6-methoxypyridine-3-carboximidamide hydrochloride (1 / 1) (62.5 mg, 333 μmol) were dissolved in N,N-dimethylformamide (3.0 mL). Sodium ethylate (37.8 mg, 555 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 45 min. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT acid) to give 38.4 mg (28% yield) of the title compound.

[0695] LC-MS (Method 1):R t =1.10min;MS(ESIpos):m / z=477[M+H] +

[0696] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]:2.074(2.19),2.327(1.02),2.331(0.72),2.518(4.40),2.523(2.92 ),2.669(1.01),2.673(0.72),3.554(1.97),3.677(3.10),3.896(16.00),4. 788(1.20),6.915(0.89),6.936(0.90),8.182(1.76),8.187(1.85),8.203(1 .66),8.209(1.78),8.245(4.39),8.732(2.46),8.736(2.44),9.287(0.52).

[0697] Example 16 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0698] 2-{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide ((Intermediate 24), 100 mg, 278 μmol) and 6-(trifluoromethyl)pyridine-3-carboximidamide hydrogen chloride (1 / 1) (75.1 mg, 333 μmol) were dissolved in N,N-dimethylformamide (3.0 mL). Sodium ethylate (37.8 mg, 555 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 45 minutes. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT acid) to give 78.2 mg (55% yield) of the title compound.

[0699] LC-MS (Method 1):R t =1.21 min;MS(ESIpos):m / z=515[M+H] +

[0700] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]:2.074(1.00),2.331(2.52),2.336(1.16),2.518(16.00),2.523(10.8 3),2.669(3.52),2.673(2.47),3.549(5.79),3.663(9.01),4.858(6.94),7.9 99(5.86),8.019(6.30),8.258(15.79),8.550(4.08),8.554(3.85),8.571(3 .55),8.574(3.64),9.302(7.08),9.307(7.00),9.355(2.10),14.336(0.63).

[0701] Example 17 2-(morpholin-4-yl)-N-({5-[6-(trifluoromethoxy)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0702] 2-{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide ((Intermediate 24), 100 mg, 278 μmol) and 6-(trifluoromethoxy)pyridine-3-carboximidamide hydrogen chloride (1 / 1) (80.5 mg, 333 μmol) were dissolved in N,N-dimethylformamide (3.0 mL). Sodium ethylate (37.8 mg, 555 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave oven for 1 h and 45 min. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT acid) to give 29.9 mg (20% yield) of the title compound.

[0703] LC-MS (Method 1):R t =1.26min;MS(ESIpos):m / z=531[M+H] +

[0704] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]:2.331(2.73),2.336(1.20),2.428(1.04),2.518(16.00),2.523(11.1 2),2.673(2.75),2.678(1.27),3.551(6.26),3.663(7.94),4.842(3.51),7.3 78(1.70),7.398(1.86),8.253(11.89),8.477(5.75),8.483(6.18),8.498(5 .51),8.505(5.71),8.891(8.86),8.895(8.84),9.346(2.00),14.147(1.70).

[0705] Example 18 N-{[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0706] 2-{[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]amino}acetohydrazide ((Intermediate 73), 100 mg, 278 μmol) and 6-methoxypyridine-3-carboximidamide hydrochloride (1 / 1) (62.5 mg, 333 μmol) were dissolved in N,N-dimethylformamide (2.5 mL). Sodium ethylate (37.8 mg, 555 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 45 minutes. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT acid) to give a first batch of 32.4 mg (25% yield) and a second batch of 20.4 mg (14% yield) of the title compound.

[0707] LC-MS (Method 2):R t =0.82min;MS(ESIpos):m / z=477[M+H] +

[0708] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.327(0.60),2.332(0.43),2.518(2.75),2.523(1.88),2.673(0.43),3.47 6(3.01),3.488(2.71),3.559(3.15),3.572(3.43),3.582(1.91),3.894(16.00),4. 801(1.14), 6.911(0.89), 6.933(0.92), 7.934(2.53), 8.177(1.72), 8.184(1.80), 8.200(1.53), 8.205(1.72), 8.728(2.18), 8.732(2.21), 8.734(1.99), 9.436(0.55).

[0709] LC-MS (Method 2):R t =0.82min;MS(ESIpos):m / z=477[M+H] +

[0710] H-NMR (400 MHz, DMSO-d6) δ [ppm]:2.518(2.88),2.523(2.15),3.466(1.67),3.476(2.88),3.488(2.57 ),3.559(2.93),3.572(3.16),3.582(1.76),3.894(16.00),4.801(1.16),6. 912(1.06),6.934(1.09),7.935(2.40),8.177(1.62),8.184(1.79),8.200(1 .52),8.205(1.72),8.726(1.95),8.728(2.10),8.732(2.03),9.436(0.49).

[0711] Example 19 2-(morpholin-4-yl)-N-({5-[6-(trifluoromethoxy)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0712] 2-{[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]amino}acetohydrazide ((Intermediate 73), 65.0 mg, 180 μmol) and 6-(trifluoromethoxy)pyridine-3-carboximidamide hydrogen chloride (1 / 1) (52.3 mg, 216 μmol) were dissolved in N,N-dimethylformamide (1.6 mL). Sodium ethylate (24.6 mg, 361 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 2 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT acid) to give 21.4 mg (22% yield) of the title compound.

[0713] LC-MS (Method 1):R t =1.26min;MS(ESIpos):m / z=531[M+H] +

[0714] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.332(2.97),2.336(1.27),2.518(16.00),2.523(11.43),2.678(1.28),3.150(1.33),3.451(7 .68),3.462(13.58),3.475(12.50),3.504(0.77),3.554(12.87),3.566(14.30),3.577(8.25),4.832(6 .98), 4.844(7.00), 7.385(7.34), 7.406(7.67), 7.941(11.19), 7.943(11.81), 8.472(8.66), 8.478(8.51), 8.494(7.69), 8.499(7.81), 8.884(9.40), 8.890(9.27), 8.892(9.19), 9.476(3.08), 14.167(0.65).

[0715] Example 20 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0716] 2-{[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]amino}acetohydrazide ((Intermediate 73), 100 mg, 278 μmol) and 6-(trifluoromethyl)pyridine-3-carboximidamide hydrogen chloride (1 / 1) (75.1 mg, 333 μmol) were dissolved in N,N-dimethylformamide (1.6 mL). Sodium ethylate (37.8 mg, 555 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 2 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT acid). The crude product was stirred in dichloromethane, and the precipitate was filtered off and dried under reduced pressure at 60 °C to give 67.3 mg (47% yield) of the title compound.

[0717] LC-MS (Method 1):R t =1.21 min;MS(ESIpos):m / z=515[M+H] +

[0718] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:2.074(2.34),2.331(1.28),2.518(6.59),2.523(4.38),3.448(8.78),3.459(15.36),3.471 (13.85),3.500(0.70),3.550(14.31),3.563(16.00),3.573(9.14),4.859(8.58),4.873(8.46),7. 946(12.28), 7.948(12.70), 7.995(6.53), 8.016(6.94), 8.545(4.92), 8.549(4.64), 8.565(4.27), 8.569(4.34), 9.297(8.46), 9.302(8.30), 9.489(2.15), 9.503(4.38), 9.516(2.05), 14.296(0.84).

[0719] Example 21 N-{[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0720] N-{[5-(6-Methoxypyridin-3-yl)-1H-imidazol-2-yl]methyl}-2-(methylsulfanyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine ((Intermediate 77), 53.0 mg, 121 μmol) was dissolved in dichloromethane (5 mL) at 0 °C, 3-chlorobenzene-1-carboperoxoic acid (83.8 mg, 486 μmol; CAS-RN: [937-14-4]) was added, and the mixture was stirred at room temperature for 1 h. Morpholine (1.1 mL, 12 mmol; CAS-RN: [110-91-8]) was added, and the solvent was evaporated under reduced pressure at 60 °C. The residue was purified by column chromatography (silica gel, dichloromethane / ethanol gradient) to give 17.0 mg (29% yield) of the title compound.

[0721] LC-MS (Method 1):R t =0.94min;MS(ESIpos):m / z=m / z=476[M+H] +

[0722] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.232(0.80),2.327(2.04),2.332(1.46),2.336(0.65),2.518(7.38),2.523(5.63),2.669(2.03),2.673(1.40),2. 678(0.58),3.573(2.03),3.691(2.86),3.703(3.22),3.714(1.87),3.843(16.00),4.714(1.97),4.727(1.82),5.759(0.9 5), 6.788(1.85), 6.807(1.83), 6.809(1.95), 7.502(2.19), 7.507(2.08), 7.989(1.54), 7.995(1.55), 8.010(1.30), 8.016(1.52), 8.228(4.00), 8.515(1.75), 8.517(1.89), 8.522(1.88), 9.149(0.43), 9.164(0.88), 9.178(0.41), 11.950(0.81).

[0723] Example 22 N-{[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0724] 2-{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}acetohydrazide ((Intermediate 24), 100 mg, 278 μmol) and 6-methylpyridine-3-carboximidamide hydrogen chloride (1 / 1) (57.2 mg, 333 μmol) were dissolved in N,N-dimethylformamide (2.5 mL). Sodium ethylate (37.8 mg, 555 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 2 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT basic) to give 23.9 mg (18% yield) of the title compound.

[0725] LC-MS (Method 2):R t =0.75min;MS(ESIpos):m / z=461[M+H] +

[0726] 1 H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.229(0.45),2.327(2.61),2.331(1.91),2.336(1.07),2.518(11.32),2.523(7.48),2.669(2.60),2 .673(1.85),2.678(0.86),2.775(0.43),3.559(7.59),3.629(1.45),3.642(1.34),3.674(10.04),3.687(11. 71), 3.697 (7.13), 3.986 (0.55), 4.783 (16.00), 5.758 (9.06), 7.318 (5.54), 7.338 (5.73), 8.143 (4.78), 8.149 (4.93), 8.163 (4.46), 8.169 (4.63), 8.208 (0.41), 8.234 (13.51), 8.538 (1.66), 8.998 (6.48), 9.002 (6.61).

[0727] Example 23 N-{[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine [ka]

[0728] 2-{[2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-yl]amino}acetohydrazide ((Intermediate 73), 62.0 mg, 172 μmol) and 6-methylpyridine-3-carboximidamide hydrogen chloride (1 / 1) (35.4 mg, 206 μmol) were dissolved in N,N-dimethylformamide (2.5 mL). Sodium ethylate (23.4 mg, 344 μmol; CAS-RN: [141-52-6]) was added, and the mixture was stirred at 180 °C in a microwave for 2 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HT basic) to give 22.2 mg (25% yield) of the title compound.

[0729] LC-MS (Method 2):R t =0.77min;MS(ESIpos):m / z=461[M+H] +

[0730] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.035(0.47),1.052(0.91),1.070(0.44),1.229(0.51),2.327(3.11),2.331(2.23),2.518(16.00),2.523(10 .14),2.669(3.11),2.673(2.24),3.466(8.15),3.476(13.94),3.489(13.10),3.539(1.82),3.558(13.19),3.570(14 .30), 3.581(8.21), 3.643(0.75), 3.655(0.82), 4.807(14.63), 5.759(3.44), 7.333(6.39), 7.353(6.73), 7.934(10.61), 8.147(5.47), 8.153(5.46), 8.167(5.03), 8.173(5.22), 8.536(1.99), 8.999(7.59), 9.003(7.57), 9.423(0.72).

[0731] Example 24 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine [ka]

[0732] N-Hydroxy{[2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl]amino}ethanimidamide ((Intermediate 82), 50.0 mg, 145 μmol) and sodium bicarbonate (67.1 mg, 799 μmol; CAS-RN: [144-55-8]) were dissolved in tetrahydrofuran (2 mL) and water (0.75 mL) and stirred at 70 °C. 2-Bromo-1-[6-(trifluoromethyl)pyridin-3-yl]ethan-1-one (38.9 mg, 145 μmol) was dissolved in tetrahydrofuran (1 mL) and added dropwise to the mixture. The reaction mixture was stirred at 70 °C overnight. The mixture was concentrated, and the residue was diluted with ethyl acetate and water. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried on a hydrophobic filter and concentrated to give a residue, which was purified by preparative HPLC [Waters Autopurification system; column: Waters XBridge C18 100*30 mm*5 μm; eluent A: water (0.1% formic acid), eluent B: acetonitrile; gradient: 0.0-0.5 min 32% B (25-70 mL / min), 0.51-5.5 min 32-52% B; flow rate 70 mL / min; detector: DAD scan 210-400 nm] to give 1.3 mg (2% yield) of the title compound.

[0733] LC-MS (Method 1):R t =1.17min;MS(ESIpos):m / z=514[M+H] +

[0734] 1H-NMR(400 MHz,DMSO-d6)δ [ppm]:1.233(0.78),2.327(3.73),2.331(2.68),2.336(1.20),2.518(16.00),2.523(1 0.68),2.669(3.76),2.673(2.63),2.678(1.19),3.566(2.76),3.682(4.11),3.694(4. 90), 4.748(2.61), 4.759(2.57), 7.845(1.82), 7.866(2.05), 7.891(2.28), 8.177(2.37), 8.237(6.32), 8.311(1.22), 8.331(1.11), 9.121(2.30), 9.216(0.97), 12.265(1.10).

[0735] Experimental Section - Biological Assays For selected biological assays, the Examples were tested one or more times. When tested multiple times, the data are reported as either the mean or median. The mean value, also known as the arithmetic mean, is the sum of the values ​​obtained divided by the number of tests performed. The median represents the middle number in a group of values ​​when ranked in ascending or descending order. If the number of values ​​in a data set is odd, the median is the middle value. If the number of values ​​in a data set is even, the median is the arithmetic mean of the two middle values.

[0736] The Examples were synthesized one or more times, and when synthesized multiple times, the data from the biological assays represent the mean or median calculated using data sets obtained from testing one or more synthesis batches.

[0737] A blank column in any of the tables below means that the respective compound has not been tested in that assay.

[0738] 1. Expression and purification of CDK12 / CycK and CDK13 / CycK used in CDK12 and CDK13 kinase activity assays 1.1 Cloning of CDK 12 / 13, CycK, and CAK1 in insect destination vectors cDNAs encoding the following protein sequences were codon-optimized for expression in Sf9 / Hi-5 insect cells and synthesized by GeneArt Technology at Thermo Fischer Scientific.

[0739] The full-length sequences of human CDK12 wt / DN (Acc. Q9NYV4), CDK13 (Q14004), CycK (O75909), and Saccharomyces cerevisiae CAK1 (P43568) were used for cloning. These cDNAs also encoded att site sequences at the 5' and 3' ends for subcloning into the following destination vectors using Gateway Technology:

[0740] Using a baculovirus vector with a strong polyhedrin promoter, we fused a His-tag with a Tobacco Edge virus cleavage site to the N-terminal of the integrated gene of interest. The Saccharomyces cerevisiae CAK1 (P43568) full-length sequence alone was cloned into an insect vector, delivering the gene of interest without a tag.

[0741] 1.2 Arrays His-CDK12(aa Q696-S1082) MTSHHHHHHS SMGSRTSLYK KAGSDYDIPT TENLYFQGQP YKKRPKICCP RYGERRQTES DWGKRCVDKF DIIGIIGEGT YGQVYKAKDK DTGELVALKK VRLDNEKEGF PITAIREIKI LRQLIHRSVV NMKEIVTDKQ DALDFKKDKG AFYLVFEYMD HDLMGLLESG LVHFSEDHIK SFMKQLMEGL EYCHKKNFLH RDIKCSNILL NNSGQIKLAD FGLARLYNSE ESRPYTNKVI TLWYRPPELL LGEERYTPAI DVWSCGCILG ELFTKKPIFQ ANLELAQLEL ISRLCGSPCP AVWPDVIKLP YFNTMKPKKQ YRRRLREEFS FIPSAALDLL DHMLTLDPSK RCTAEQTLQS DFLKDVELSK MAPPDLPHWQ DCHELWSKKR RRQRQSGVVV EEPPPSKTSR KETTSGTSTE PVKNS

[0742] His-CDK12-DN(aa Q696-S1082;K756A;D877N) MTSHHHHHHS SMGSRTSLYK KAGSDYDIPT TENLYFQGQP YKKRPKICCP SMOKERRQTES DWGKRCVDKF DIIGIIGEGT YGQVYKAKDK DTGELVALAK VRLDNEKEGF PITAIREIKI LRQLIHRSVV NMKEIVTDKQ DALDFKKDKG AFYLVFEYMD HDLMGLLESG LVHFSEDHIK SFMKQLMEGL EYCHKKNFLH RDIKCSNILL NNSGQIKLAN FGLARLYNSE ESRPYTNKVI TLWYRPPELL LGEERYTPAI DVWSCGCILG ELFTKKPIFQ ANLELAQLEL ISRLCGSPCP AVWPDVIKLP YFNTMKPKKQ YRRRLREEFS FIPSAALDLL DHMLTLDPSK RCTAEQTLQS DFLKDVELSK MAPPDLPHWQ DCHELWSKKR RRQRQSGVVV EEPPPSKTSR KETTSGTSTE PVKNS

[0743] His-CDK13(aa Q673-P1059) MTSHHHHHHS SMGSRTSLYK KAGSDYDIPT TENLYFQGQL HSKRRPKICG PRYGETKEKD IDWGKRCVDK FDIIGIIGEG TYGQVYKARD KDTGEMVALK KVRLDNEKEG FPITAIREIK ILRQLTHQSI INMKEIVTDK EDALDFKKDK GAFYLVFEYM DHDLMGLLES GLVHFNENHI KSFMRQLMEG LDYCHKKNFL HRDIKCSNIL LNNRGQIKLA DFGLARLYSS EESRPYTNKV ITLWYRPPEL LLGEERYTPA IDVWSCGCIL GELFTKKPIF QANQELAQLE LISRICGSPC PAVWPDVIKL PYFNTMKPKK QYRRKLREEF VFIPAAALDL FDYMLALDPS KRCTAEQALQ CEFLRDVEPS KMPPPDLPLW QDCHELWSKK RRRQKQMGMT DDVSTIKAPR KDLSLGLDDS RTNTP

[0744] His-CDK13-DN(aa Q673-P1059;K734A;D855N) MTSHHHHHHS SMGSRTSLYK KAGSDYDIPT TENLYFQGQL HSKRRPKICG PRYGETKEKD IDWGKRCVDK FDIIGIIGEG TYGQVYKARD KDTGEMVALA KVRLDNEKEG FPITAIREIK ILRQLTHQSI INMKEIVKEDKDKDVYKDVYKDKDKDK DHDLMGLLES GLVHFNENHI KSFMRQLMEG LDYCHKKNFL HRDIKCSNIL LNNRGQIKLA NFGLARLYSS EESRPYTNKV ITLWYRPPEL LLGEERYTPA IDVWSCGCIL GELFTKKPIF QANQELAQLE LISRICGSPC PAVKLAWKLAWKLFKLFKWRPKYTPA IDVWSCGCIL VFIPAAALDL FDYMLALDPS KRCTAEQALQ CEFLRDVEPS KMPPPDLPLW QDCHELWSKK RRRQKQMGMT DDVSTIKAPR KDLSLGLDDS RTNTP

[0745] His-CycK(aa M1-S300) MTSHHHHHHS SMGSRTSLYK KAGSDYDIPT TENLYFQGMK ENKENSSPSV TSANLDHTKP CWYWDKKDLA HTPSQLEGLD PATEARYRRE GARFIFDVGT RLGLHYDTLA TGIIYFHRFY MFHSFKQFPR YVTGAG FLAG CLCKVKKKKVKKKK LLNDVQFGQF GDDPKEEVMV LERILLQTIK FDLQVEHPYQ FLLKYAKQLK GDKNKIQKLV QMAWTFVNDS LCTTLSLQWE PEIIAVAVMY LAGRLCKFEI QEWTSKPMYR RWWEQFVQDV PVDVLEDICH QILQDLQQQSLQQSQLQHPT L PQVPQVQQSQ PSQSSEPS

[0746] CAK1(aa M1-P368) MKLDSIDITH CQLVKSTRTA RIYRSDTYAI KCLALDFDIP PHNAKFEVSI LNKLGNKCKH ILPLLESKAT DNNDLLLLFP FEEMNLYEFM QMHYKRDRRK KNPYYDLLNP SIPIVADPPV QKYTNQLDVN RYSLSFFRQM VEGIAFLHEN KIIHRDIKPQ NIMLTNNTST VSPKLYIIDF GISYDMANNS QTSAEPMDSK VTDISTGIYK APEVLFGVKC YDGGVDVWSL LIIISQWFQR ETSRMGHVPA MIDDGSDDMN SDGSDFRLIC SIFEKLGIPS IQKWEEVAQH GSVDAFVGMF GADGDGKYVL DQEKDVQISI VERNMPRLDE IADVKVKQKF INCILGMVSF SPNERWSCQR ILQELEKP

[0747] 1.3 Expression of CDK12-CycK and CDK13-CycK complexes Hi-5 insect cells were cultured in Insect Xpress Medium (Lonza # BE12-730Q) and for co-infection the following baculoviruses with multiplicities of infection (MOI) were used for expression of the complexes: CDK12 and CDK13 with an MOI of 1.0; CycK and CAK1 with an MOI of 0.5.

[0748] 2 × 10 Hi-5 cells grown in suspension in an 8 L waver for 72 hours 6 Complex formation was performed by coinfection to a density of 1000 cells / mL. Cells were harvested by centrifugation (10 min, 170 g, 4°C) and cell pellets were stored at -80°C.

[0749] 1.4 Purification of CDK12 and CDK13 complexes Purification of the His-CDK12 / His-CycK / CAK1 or His-CDK13 / His-CycK / CAK1 complexes was achieved by affinity chromatography using Ni-Sepharose High Performance (GE Healthcare #17-5268-02) or HisTrap™ HP (GE Healthcare #17-5247-01 / 05).

[0750] The cell pellet was resuspended in lysis buffer (50 mmol / L Hepes pH 7.5, 500 mmol / L NaCl, 40 mmol / L imidazole, 10% glycerol; 0.5% NP40, benzonase (150 U / 10 g cell pellet), 1 mmol / L DTT, and 1× Complete EDTA-free protease inhibitor cocktail (Roche #1873580)).

[0751] Lysates were incubated on ice for 30 min and clarified by centrifugation (1 h, 4°C, 27,500 × g). Proteins were captured overnight at 4°C using Ni-Sepharose or HisTrap HP material, washed with CDK12 / 13 wash buffer (50 mmol / L Hepes pH 7.5, 500 mmol / L NaCl, 40 mmol / L imidazole, 10% glycerol, 1 mmol / L DTT), and eluted with wash buffer using an imidazole gradient (40-500 mmol / L).

[0752] To remove imidazole, the eluted protein complex was desalted using Zeba™ Desalt Spin Columns (Pierce #89893) against CDK12 / 13 DS buffer (50 mmol / L Hepes pH 7.5, 500 mmol / L NaCl, 10% glycerol, 1 mmol / L DTT).

[0753] Final concentrations were calculated densitometrically using BSA as a standard in Coomassie-stained gels. Elution fractions were aliquoted and shock-frozen using liquid nitrogen.

[0754] The following assays may demonstrate the in vitro activity of the compounds of the invention.

[0755] 2. Biochemical Kinase Assay 2.1 CDK12 / CycK low ATP kinase assay The CDK12 / CycK inhibitory activity of the compounds of the present invention at 10 micromol / L adenosine triphosphate (ATP) was quantified using a TR-FRET (TR-FRET = time-resolved fluorescence energy transfer) based CDK12 / CycK activity inhibition assay, described in the following paragraphs.

[0756] The enzymes used were human recombinant CDK12 and human recombinant CycK (both N-terminally His-tagged, expressed, and purified as described above).The biotinylated peptide biotin-Ahx-KFELLPTPPLSPSRRSGL (C-terminus amide), available from Biosyntan (Berlin-Buch, Germany), was used as a substrate for the kinase reaction.

[0757] For the assay, 50 nanoliters of a 100x concentrated solution of test compound in DMSO was pipetted into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), and 2 microliters of a CDK12 / CycK solution in aqueous assay buffer [25 mmol / L HEPES pH 7.5, 20 mmol / L MgCl2, 5 mmol / L β-glycerophosphate, 2 mmol / L EGTA, 1.0 mmol / L dithiothreitol, 0.01% (v / v) Nonidet-P40 (Sigma), 0.01% (w / v) bovine serum albumin] was added, and the mixture was incubated at 22°C for 15 minutes to allow prebinding of the test compound to the enzyme before initiation of the kinase reaction. The kinase reaction was then initiated by adding 3 microliters of solution ATP (16.7 micromol / L = 10 micromol / L final concentration in a 5 microliter assay volume) and substrate (1.67 micromol / L = 1 micromol / L final concentration in a 5 microliter assay volume) in assay buffer, and the resulting mixture was incubated for a reaction time of 60 minutes at 22° C. The concentration of CDK12 / CycK was adjusted depending on the activity of the enzyme lot and was appropriately selected to have an assay in the linear range, with a typical concentration being approximately 2 nanomol / L. The reaction was stopped by adding 3 microliters of a solution of TR-FRET detection reagents (125 nmol / L streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 0.67 nmol / L anti-phospho-c-Myc (Ser 62) (E1J4K) antibody from Cell Signaling [# 13748] and 2 nmol / L LANCE EU-W1024-labeled anti-rabbit IgG antibody [Perkin-Elmer, product no. 0083]) in EDTA water solution (133 mmol / L EDTA in 66.7 mmol / L HEPES pH 7.5, 0.27% (w / v) bovine serum albumin).

[0758] The resulting mixture was incubated at 22°C for 1 hour to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate was then assessed by measuring resonance energy transfer from the Eu chelate to streptavidin-XL. To this end, fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in a TR-FRET reader, e.g., Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components without enzyme = 100% inhibition). Test compounds were typically tested at 11 different concentrations ranging from 20 μmol / L to 0.07 nmol / L (20 μmol / L, 5.7 μmol / L, 1.6 μmol / L, 0.47 μmol / L, 0.13 μmol / L, 38 nmol / L, 11 nmol / L, 3.1 nmol / L, 0.9 nmol / L, 0.25 nmol / L, and 0.07 nmol / L, a dilution series prepared separately prior to the assay at the level of a 100x concentrated solution in DMSO by serial dilution; the exact concentrations may vary depending on the pipettor used) on the same microtiter plate with duplicate values ​​for each concentration, and IC values ​​were calculated using Genedata Screener™ software. 50 values ​​were calculated.

[0759] 2.2 CDK12 / CycK high ATP kinase assay In the context of the present invention, the term "IC50 CDK12 hATP" refers to the IC obtained according to the assay described in this section (2.2) herein below. 50 value, i.e., IC for inhibition of CDK12 at high (2 mM) ATP 50 Points to a value.

[0760] The CDK12 / CycK inhibitory activity of the compounds of the present invention at 2 mmol / L adenosine triphosphate (ATP) was quantified using a TR-FRET (TR-FRET = time-resolved fluorescence energy transfer) based CDK12 / CycK activity inhibition assay, described in the following paragraphs.

[0761] The enzymes used were human recombinant CDK12 and human recombinant CycK (both N-terminally His-tagged, expressed, and purified as described above).The biotinylated peptide biotin-Ahx-KFELLPTPPLSPSRRSGL (C-terminus amide), available from Biosyntan (Berlin-Buch, Germany), was used as a substrate for the kinase reaction.

[0762] For the assay, 50 nanoliters of a 100x concentrated solution of test compound in DMSO was pipetted into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), and 2 microliters of a CDK12 / CycK solution in aqueous assay buffer [25 mmol / L HEPES pH 7.5, 20 mmol / L MgCl2, 5 mmol / L β-glycerophosphate, 2 mmol / L EGTA, 1.0 mmol / L dithiothreitol, 0.01% (v / v) Nonidet-P40 (Sigma), 0.01% (w / v) bovine serum albumin] was added, and the mixture was incubated at 22°C for 15 minutes to allow prebinding of the test compound to the enzyme before initiation of the kinase reaction. The kinase reaction was then initiated by adding 3 microliters of solution ATP (3.33 mmol / L = 2 mmol / L final concentration in a 5 microliter assay volume) and substrate (1.67 micromol / L = 1 micromol / L final concentration in a 5 microliter assay volume) in assay buffer, and the resulting mixture was incubated for a reaction time of 60 minutes at 22° C. The concentration of CDK12 / CycK was adjusted depending on the activity of the enzyme lot and chosen appropriately to have an assay in the linear range, with a typical concentration being approximately 0.75 nanomol / L. The reaction was stopped by adding 3 microliters of a solution of TR-FRET detection reagents (125 nmol / L streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 0.67 nmol / L anti-phospho-c-Myc (Ser 62) (E1J4K) antibody from Cell Signaling [# 13748] and 2 nmol / L LANCE EU-W1024-labeled anti-rabbit IgG antibody [Perkin-Elmer, product no. 0083]) in EDTA water solution (133 mmol / L EDTA in 66.7 mmol / L HEPES pH 7.5, 0.27% (w / v) bovine serum albumin).

[0763] The resulting mixture was incubated at 22°C for 1 hour to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate was then assessed by measuring resonance energy transfer from the Eu chelate to streptavidin-XL. To this end, fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in a TR-FRET reader, e.g., Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components without enzyme = 100% inhibition). Test compounds were typically tested at 11 different concentrations ranging from 20 μmol / L to 0.07 nmol / L (20 μmol / L, 5.7 μmol / L, 1.6 μmol / L, 0.47 μmol / L, 0.13 μmol / L, 38 nmol / L, 11 nmol / L, 3.1 nmol / L, 0.9 nmol / L, 0.25 nmol / L, and 0.07 nmol / L, a dilution series prepared separately prior to the assay at the level of a 100x concentrated solution in DMSO by serial dilution; the exact concentrations may vary depending on the pipettor used) on the same microtiter plate with duplicate values ​​for each concentration, and IC values ​​were calculated using Genedata Screener™ software. 50 values ​​were calculated.

[0764] [Table 2]

[0765] 2.3 CDK13 / CycK low ATP kinase assay The CDK13 / CycK inhibitory activity of the compounds of the present invention at 10 micromol / L adenosine triphosphate (ATP) was quantified using a TR-FRET (TR-FRET = time-resolved fluorescence energy transfer) based CDK13 / CycK activity inhibition assay, described in the following paragraphs.

[0766] The enzyme used was a complex of human recombinant CDK13 and human recombinant CycK (both N-terminally His-tagged, expressed, and purified as described above). The biotinylated peptide biotin-Ahx-KFELLPTPPLSPSRRSGL (C-terminus amide), available from Biosyntan (Berlin-Buch, Germany), was used as a substrate for the kinase reaction.

[0767] For the assay, 50 nanoliters of a 100x concentrated solution of test compound in DMSO was pipetted into either a black low-volume 384-well microtiter plate or a black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), and 2 microliters of a CDK13 / CycK solution in aqueous assay buffer [25 mmol / L HEPES pH 7.5, 20 mmol / L MgCl2, 5 mmol / L β-glycerophosphate, 2 mmol / L EGTA, 1.0 mmol / L dithiothreitol, 0.01% (v / v) Nonidet-P40 (Sigma), 0.01% (w / v) bovine serum albumin] was added, and the mixture was incubated at 22°C for 15 minutes to allow prebinding of the test compound to the enzyme before initiation of the kinase reaction. The kinase reaction was then initiated by adding 3 microliters of solution ATP (16.7 micromol / L = 10 micromol / L final concentration in a 5 microliter assay volume) and substrate (1.67 micromol / L = 1 micromol / L final concentration in a 5 microliter assay volume) in assay buffer, and the resulting mixture was incubated for a reaction time of 60 minutes at 22° C. The concentration of CDK13 / CycK was adjusted depending on the activity of the enzyme lot and was appropriately selected to have an assay in the linear range, with a typical concentration being approximately 5 nanomol / L. The reaction was stopped by adding 3 microliters of a solution of TR-FRET detection reagents (125 nmol / L streptavidin-XL665 [Cisbio Bioassays, Codolet, France] and 0.67 nmol / L anti-phospho-c-Myc (Ser 62) (E1J4K) antibody from Cell Signaling [# 13748] and 2 nmol / L LANCE EU-W1024-labeled anti-rabbit IgG antibody [Perkin-Elmer, product no. 0083]) in EDTA water solution (133 mmol / L EDTA in 66.7 mmol / L HEPES pH 7.5, 0.27% (w / v) bovine serum albumin).

[0768] The resulting mixture was incubated at 22°C for 1 hour to allow the formation of a complex between the phosphorylated biotinylated peptide and the detection reagent. The amount of phosphorylated substrate was then assessed by measuring resonance energy transfer from the Eu chelate to streptavidin-XL. To this end, fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured in a TR-FRET reader, e.g., Pherastar FS (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The ratio of emissions at 665 nm and 622 nm was used as a measure of the amount of phosphorylated substrate. Data were normalized (enzyme reaction without inhibitor = 0% inhibition, all other assay components without enzyme = 100% inhibition). Test compounds were typically tested at 11 different concentrations ranging from 20 μmol / L to 0.07 nmol / L (20 μmol / L, 5.7 μmol / L, 1.6 μmol / L, 0.47 μmol / L, 0.13 μmol / L, 38 nmol / L, 11 nmol / L, 3.1 nmol / L, 0.9 nmol / L, 0.25 nmol / L, and 0.07 nmol / L, a dilution series prepared separately prior to the assay at the level of a 100x concentrated solution in DMSO by serial dilution; the exact concentrations may vary depending on the pipettor used) on the same microtiter plate with duplicate values ​​for each concentration, and IC values ​​were calculated using Genedata Screener™ software. 50 values ​​were calculated.

[0769] 2.4 CDK2 / CycE kinase assay The CDK2 / CycE inhibitory activity of the compounds of the present invention was determined using the CDK2 / CycE TR-FRET assay described in the following paragraphs.

[0770] Recombinant fusion proteins of GST and human CDK2 and GST and human CycE, expressed in insect cells (Sf9) and purified by glutathione-Sepharose affinity chromatography, were purchased from ProQinase GmbH (Freiburg, Germany). For example, the biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus amide), available from JERINI peptide technologies GmbH (Berlin, Germany), was used as a substrate for the kinase reaction.

[0771] For the assay, 50 nanoliters of a 100x concentrated solution of test compound in DMSO was pipetted into a black low-volume 384-well or black 1536-well microtiter plate (both Greiner Bio-One, Frickenhausen, Germany), and 2 microliters of a CDK2 / CycE solution in aqueous assay buffer [50 mmol / L Tris / HCl pH 8.0, 10 mmol / L MgCl2, 1.0 mmol / L dithiothreitol, 0.1 mmol / L sodium orthovanadate, 0.01% (v / v) Nonidet-P40 (Sigma)] was added. The mixture was incubated at 22°C for 15 minutes to allow prebinding of the test compound to the enzyme before initiation of the kinase reaction. The kinase reaction was then initiated by adding 3 microliters of adenosine triphosphate solution (ATP, 3.33 mmol / L = 2 mmol / L final concentration in a 5 microliter assay volume) and substrate...

Claims

1. A compound of formula (I), 【Chemistry 1】 (In the formula, A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R １ is a halogen atom and C １ ~C ３ - haloalkyl groups, R ２ is C １ ~C ３ - alkyl group, C １ ~C ３ -alkoxy group, C １ ~C ３ -haloalkyl group and C １ ~C ３ -haloalkoxy groups, X is a nitrogen atom and CR ３ is selected from the group R ３ is a hydrogen atom, C １ ~C ３ -Alkyl group and C １ ~C ３ - haloalkyl groups, Y is selected from a nitrogen atom or a carbon atom. or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

2. A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R １ is a halogen atom, R ２ is C １ ~C ３ - alkyl group, C １ ~C ３ -alkoxy group, C １ ~C ３ -haloalkyl group and C １ ~C ３ -haloalkoxy groups, X is a nitrogen atom and CR ３ is selected from the group R ３ is a hydrogen atom, C １ ~C ３ -Alkyl group and C １ ~C ３ - haloalkyl groups, 2. The compound of claim 1, wherein Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

3. A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R １ is C １ ~C ３ -haloalkyl group, R ２ is C １ ~C ３ - alkyl group, C １ ~C ３ -alkoxy group, C １ ~C ３ -haloalkyl group and C １ ~C ３ -haloalkoxy groups, X is a nitrogen atom and CR ３ is selected from the group R ３ is a hydrogen atom, C １ ~C ３ -Alkyl group and C １ ~C ３ - haloalkyl groups, 2. The compound of claim 1, wherein Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

4. A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R １ is a halogen atom, R ２ is C １ ~C ３ -haloalkyl group and C １ ~C ３ -haloalkoxy groups, X is a nitrogen atom and CR ３ is selected from the group R ３ is a hydrogen atom, C １ ~C ３ -Alkyl group and C １ ~C ３ - haloalkyl groups, 3. The compound of claim 1, wherein Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

5. A and B are each independently selected from a nitrogen atom or a carbon atom, and when A is a nitrogen atom, B is a carbon atom, and when A is a carbon atom, B is a nitrogen atom; R １ is C １ ~C ３ -haloalkyl group, R ２ is C １ ~C ３ -haloalkyl group and C １ ~C ３ -haloalkoxy groups, X is a nitrogen atom and CR ３ is selected from the group R ３ is a hydrogen atom, C １ ~C ３ -Alkyl group and C １ ~C ３ - haloalkyl groups, 4. The compound of claim 1, wherein Y is selected from a nitrogen atom or a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

6. A is a nitrogen atom, 3. The compound of claim 1 or claim 2, wherein B is a carbon atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

7. A is a carbon atom, 3. The compound according to claim 1 or claim 2, wherein B is a nitrogen atom, or a tautomer, or an N-oxide, or a salt, or a salt of the tautomer, or a salt of the N-oxide, or a mixture thereof.

8. A compound of formula (I) according to claim 1 or claim 2 selected from the group consisting of: 8-bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 8-bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 8-bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 8-bromo-2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine, 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine, 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-1H-imidazol-2-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine, 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine, N-{[5-(4-methoxyphenyl)-1H-imidazol-2-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine, 2-(morpholin-4-yl)-N-({5-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine, N-{[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, 2-(morpholin-4-yl)-N-({5-[6-(trifluoromethoxy)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, N-{[5-(6-methoxypyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine, 2-(morpholin-4-yl)-N-({5-[6-(trifluoromethoxy)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine, 2-(morpholin-4-yl)-7-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-4H-1,2,4-triazol-3-yl}methyl)imidazo[2,1-f][1,2,4]triazin-4-amine, N-{[5-(6-methoxypyridin-3-yl)-1H-imidazol-2-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, N-{[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine, N-{[5-(6-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl]methyl}-2-(morpholin-4-yl)-7-(trifluoromethyl)imidazo[2,1-f][1,2,4]triazin-4-amine, and 2-(morpholin-4-yl)-8-(trifluoromethyl)-N-({5-[6-(trifluoromethyl)pyridin-3-yl]-1H-imidazol-2-yl}methyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine.

9. A compound of formula (I) according to claim 1 or claim 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for use as a pharmaceutical.

10. A compound of formula (I) according to claim 1 or claim 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for use in the treatment and / or prevention of a disease, which disease is preferably a hyperproliferative disorder.

11. 10. A compound of formula (I) as claimed in claim 1 or claim 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture thereof, for use in the treatment of breast cancer, liver cancer, lung cancer, ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, gastric cancer, esophageal cancer, bladder cancer, prostate cancer, Ewing's sarcoma, glioblastoma and acute myeloid leukemia.

12. 10. A compound of formula (I) as defined in claim 1 or claim 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for use in the treatment of lung cancer, breast cancer, liver cancer, colorectal cancer, gastric cancer, prostate cancer and leukemia.

13. 10. Use of a compound of formula (I) according to claim 1 or claim 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for the manufacture of a medicament for the treatment and / or prevention of a hyperproliferative disease, which disease is preferably cancer.

14. 10. Use of a compound of formula (I) according to claim 1 or claim 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for treating and / or preventing a hyperproliferative disease, which disease is preferably cancer.

15. 14. The use according to claim 13, wherein the hyperproliferative disease is selected from lung cancer, breast cancer, liver cancer, colorectal cancer, gastric cancer, prostate cancer and leukemia.

16. 10. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or claim 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, and a pharmaceutically acceptable carrier.

17. 17. The pharmaceutical composition according to claim 16 for the treatment and / or prevention of a hyperproliferative disease, which disease is preferably cancer.

18. One or more first active ingredients selected from the compounds of general formula (I) according to claim 1 or claim 2; one or more second active ingredients selected from chemotherapeutic anti-cancer agents; 10. A pharmaceutical combination comprising:

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