CDK9 inhibitors

Abstract

The present invention relates to novel compounds of formula (I), which are inhibitors of CDK9 and are useful in the treatment of a variety of diseases, including hyperproliferative diseases, virally induced infections and cardiovascular diseases. [Formula 1] JPEG2025503030000029.jpg63170

Description

[Technical field]

[0001] The present invention relates to the field of biomedicine, specifically includes a series of novel CDK9 inhibitors with imidazotriazine structure and their uses.The present invention includes the use of compounds as CDK9 inhibitors, pharmaceutically acceptable salts and solvates of said compounds, and pharmaceutical compositions of said compounds. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are members of the serine / threonine kinase family that exert their catalytic function by forming heterodimers with regulatory subunits, cyclins. Members of the CDK family can be classified into cyclic CDKs and transcriptional CDKs according to their different functions. The former mainly include CDK1 / 2 / 4 / 6, which control the cell cycle process; the latter mainly include CDK7 / 8 / 9, which regulate the transcription and processing of mRNA (Malumbres M. et al., Genome Biol., 2014, 15:122). Overexpression or enhanced function of transcriptional CDKs causes a significant increase in the expression of certain downstream genes, especially the anti-apoptotic protein Mcl-1, which results in tumors (Morales F. et al., Cell Cycle, 2016, 15:519)-27). In recent years, it has been discovered that nonselective CDK inhibitors can achieve antitumor effects by inhibiting the function of CDK9. Therefore, research on CDK inhibitors has attracted people's attention (Krystof V. et al., Target, Curr. Pharm. Des., 2012, 18:2883-2890). Research has revealed that overexpression of CDK9 is associated with the development of various tumors, inflammation and viral replication, such as acute myeloid leukemia, breast cancer, colon cancer and prostate cancer, as well as human immunodeficiency virus and adenovirus (Franco LC. et al., J. Cell Biochem., 2017, 119:1273-1284). CDK9 inhibitors introduced into clinical practice include flavopiridol, dinaciclib, SNS-032 and CYC065, all of which lack selectivity for CDK9. Some CDK9 selective inhibitors are currently in preclinical studies, such as LY2857785, LDC000067, while others are in clinical stage, such as KB-0742 in phase I / II, enitsilib (VIP152 or BAY-1251152) in phase I / II, and atubeciclib (BAY-1143572) in phase I. Fadracilib (CMY065) is a clinical stage CDK9 inhibitor for anticancer applications (Frame S. et al., PLos ONE, 2020, 15(7):e0234103). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Malumbres M. et al., Genome Biol., 2014, 15:122 [Non-Patent Document 2] Morales F. et al., Cell Cycle, 2016, 15:519)-27 [Non-Patent Document 3] Krystof V. et al., Target, Curr. Pharm. Des., 2012, 18:2883-2890 [Non-Patent Document 4] Franco L.C. et al., J. Cell Biochem., 2017, 119:1273-1284 [Non-Patent Document 5] Frame S. et al., PLos ONE, 2020, 15(7):e0234103 Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention was to provide novel inhibitors of CDK9 that overcome the shortcomings of the prior art compounds. In particular, it was an object to increase selectivity for CDK9 and improve druggability. The main object of the present invention was to provide a class of CDK9 small molecule inhibitors that exhibit high efficiency, low toxicity, and excellent drug metabolism properties and can be used for the prevention and / or treatment of diseases. [Means for solving the problem]

[0005] This object has been achieved by the compounds of the present invention. The present invention provides CDK9 small molecule inhibitors that contain an imidazotriazine structure.

[0006] The present invention provides one or more compounds of formula (I), or a salt or solvate thereof:

[0007] [ka]

[0008] In the formula, R 1 is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group; any of these groups may be optionally substituted; R 2 is a phenyl group substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br and Me; R 3 is a halogen atom, CN, C 1-4 Alkyl group or C 1-4 It is a heteroalkyl group.

[0009] Preferably, R 3 is Cl, Br, CN, CF3, a methyl group, an ethyl group, or an isopropyl group.

[0010] More preferably, R 3 is Cl, Br, CN, CF3 or a methyl group.

[0011] Most preferably, R 3 is Cl.

[0012] Preferably, R 2 is a 2- and 6-substituted phenyl group (ie, a phenyl group having two ortho substituents relative to the point of attachment).

[0013] Also preferably, R 2 is a 2,6-difluorophenyl group, a 2,6-dichlorophenyl group or a 2-chloro-6-fluorophenyl group.

[0014] Most preferably, R 2is a 2,6-difluorophenyl group.

[0015] Preferably, R 1 is an optionally substituted C 3-7 a cycloalkyl group, an optionally substituted heterocycloalkyl group having 3 to 9 ring atoms independently selected from C, N, and O, an optionally substituted phenyl group, an optionally substituted benzyl group, an optionally substituted heteroaryl group having 5 or 6 ring atoms independently selected from C, N, O, and S, or an optionally substituted heteroalkyl group having 1 to 12 carbon atoms and 1 to 6 heteroatoms independently selected from N, O, and S.

[0016] More preferably, R 1 is an optionally substituted C 4-6 A cycloalkyl group, an optionally substituted heterocycloalkyl group containing 5 to 8 ring atoms independently selected from C, N and O, an optionally substituted phenyl group or an optionally substituted pyrazol-4-yl group.

[0017] Also preferably, R 1 is selected from the following group:

[0018] [ka]

[0019] In the formula, R 5 is an NH2 group, C 1-6 A heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O.

[0020] More preferably, R 1 is selected from the following group:

[0021] [ka]

[0022] In the formula, R 5 is an NH2 group, C 1-6 A heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O.

[0023] Also preferably, R 1 has the following structure:

[0024] [ka]

[0025] In the formula, R 5 is an NH2 group, C 1-6 A heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O.

[0026] Preferably, R 5 is selected from the following groups: -NH2, -NMe2, pyrrolidinyl, piperidinyl, N-methylpiperazinyl, morpholinyl, -NH(CH2)2F, -NH(CH2)3F, -NH(CH2)2OH, -NH(CH2)3OH, -NH(CH2)2OMe, -NH(CH2)3OMe, -N(Me)(CH2)2F, -N(Me)(CH2)3F, -N(Me)(CH2)2OH, -N(Me)(CH2)3OH, -N(Me)(CH2)2OMe, and -N(Me)(CH2)3OMe.

[0027] More preferably, R 1 is selected from the following group:

[0028] [ka]

[0029] In the formula, R 5a is hydrogen, C 1-6Alkyl groups, optionally substituted C 5-6 A cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O.

[0030] Also preferably, R 1 is the formula -CH2-R 1a or -CH2-CH2-R 1a where R 1a is an optionally substituted heterocycloalkyl group having 5 or 6 ring atoms independently selected from C, N, and O; or an optionally substituted heteroaryl group having 5 or 6 ring atoms independently selected from C, N, S, and O.

[0031] Preferably, R 1a , R 5 and R 5a The optional substituents in 1-4 Alkyl and C 1-4 heteroalkyl.

[0032] Also preferably, R 1 has the following structure:

[0033] [ka]

[0034] In the formula, R 5a is hydrogen, C 1-6 Alkyl groups, optionally substituted C 5-6 A cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O.

[0035] More preferably, R 1 has the following structure:

[0036] [ka]

[0037] In the formula, R 6a is hydrogen, halogen or C 1-4 Heteroalkyl groups (especially -OC 1-4 alkyl group); R 6b is hydrogen, halogen or C 1-4 Heteroalkyl groups (especially -OC 1-4 alkyl group), and R 6 is C 1-6 Alkyl group, C 1-6 Heteroalkyl groups, optionally substituted C 3-7 It is a cycloalkyl group or an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms independently selected from C, N and O.

[0038] Preferably, R 6a is hydrogen, Cl or OMe.

[0039] Also preferably, R 6b is hydrogen.

[0040] More preferably, R 6 is a methyl group, a group of the formula -C(CH3)2CN, an optionally substituted cyclohexyl group, an optionally substituted piperidinyl group, or a tetrahydropyranyl group.

[0041] Also preferably, R 6 is the formula -Cy-LR 6c In the formula, Cy is an optionally substituted C 3-7 is a cycloalkylene group, or an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms independently selected from C, N, and O; L is a bond or a CH group, and R 6c is an optionally substituted C 3-7 It is a cycloalkyl group or an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms independently selected from C, N and O.

[0042] More preferably, Cy is a cyclohexylene group or a piperidinylene group.

[0043] Also preferably, R 6c is a cyclopropyl group or an optionally substituted heterocycloalkyl group containing 4 to 6 ring atoms independently selected from C, N and O.

[0044] More preferably, R 1 has the following structure:

[0045] [ka]

[0046] In the formula, R 7a is hydrogen, halogen, CN or -OC 1-4 R is an alkyl group; 7b is hydrogen, halogen, CN or -OC 1-4 is an alkyl group, R 7 is C 1-6 a heteroalkyl group, an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms independently selected from C, N, and O, or an optionally substituted heteroalkylcycloalkyl group containing 4 to 12 atoms independently selected from C, N, and O.

[0047] Preferably, R 7b is hydrogen or a methoxy group; preferably hydrogen.

[0048] More preferably, R 7a is hydrogen, fluorine, CN or -OC 1-4 It is an alkyl group; preferably it is hydrogen.

[0049] Also preferably, R 7 is an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, an optionally substituted morpholinyl group, or an optionally substituted tetrahydropyridinyl group.

[0050] More preferably, R 7 is of the formula -Cy'-L'-R 7c wherein Cy′ is an optionally substituted C 3-7 is a cycloalkylene group, or an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms independently selected from C, N, and O; L' is a bond or a CH group, and R 7c is an optionally substituted C 3-7 It is a cycloalkyl group or an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms independently selected from C, N and O.

[0051] Also preferably, R 7 is represented by the formula -CO-R 7d or -CO-NH-R 7d where R 7d is C 1-4 It is an alkyl group or an optionally substituted heterocycloalkylene group containing 3 to 7 ring atoms independently selected from C, N and O.

[0052] More preferably, R 1 is the formula -CH2-R 1a or -CH2-CH2-R 1a where R 1a is an optionally substituted heterocycloalkyl group having 5 or 6 ring atoms independently selected from C, N and O (preferably, R 1a The optional substituents in 1-4 is an alkyl group).

[0053] The most preferred compounds of the present invention are the compounds disclosed in the Examples or salts thereof.

[0054] It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., 1 Any of the embodiments relating to R 2 (This may be combined with any of the embodiments relating to the above.) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] The term alkyl refers to a saturated, straight or branched chain hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, in particular 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms, such as, for example, methyl (Me, CH3), CF3, CD3, ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), isobutyl (iBu), sec-butyl (sBu), tert-butyl (tBu), n-pentyl, isopentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl groups.

[0056] C 1~6 The term alkyl refers to a saturated straight or branched chain hydrocarbon group containing 1 to 6 carbon atoms. 1~4 The term alkyl refers to a saturated, straight or branched chain hydrocarbon group containing 1 to 4 carbon atoms. Examples are methyl, CF3, CD3, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl groups.

[0057] The terms alkenyl and alkynyl refer to at least partially unsaturated linear or branched hydrocarbon groups containing 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, in particular 2 to 10 (e.g. 2, 3 or 4) carbon atoms, such as the ethenyl (vinyl), propenyl (allyl), isopropenyl, butenyl, ethynyl (acetylenyl), propynyl (e.g. propargyl), butynyl, isoprenyl or hex-2-enyl groups. Preferably, alkenyl groups have one or two (particularly preferably one) double bonds and alkynyl groups have one or two (particularly preferably one) triple bonds.

[0058] Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced with a halogen atom (preferably F or Cl), such as a 2,2,2-trichloroethyl or trifluoromethyl group.

[0059] The expression heteroalkyl refers to alkyl, alkenyl or alkynyl groups in which one or more (preferably 1 to 8; particularly preferably 1, 2, 3 or 4) carbon atoms are replaced by oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atoms (preferably oxygen, sulfur or nitrogen atoms) or by SO or SO2 groups. The expression heteroalkyl further refers to carboxylic acids or groups derived from carboxylic acids, such as acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy. Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms are replaced by halogen atoms (preferably F or Cl).

[0060] Preferably, the heteroalkyl group contains 1 to 12 carbon atoms and 1 to 8 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Particularly preferably, the heteroalkyl group contains 1 to 6 (e.g., 1, 2, 3 or 4) carbon atoms and 1, 2, 3 or 4 (especially 1, 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). 1-6 The term heteroalkyl refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and / or N (especially O and / or N). 1-4 The term heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and / or N (especially O and / or N).

[0061] Examples of heteroalkyl groups include those of the formula: R a -OYa -、R a -S-Y a -、R a -SO-Y a -、R a -SO2-Y a -、R a -N(R b )-SO2-Y a -、R a -SO2-N(R b )-Y a -、R a -N(R b )-Y a -、R a -CO-Y a -、R a -O-CO-Y a -、R a -CO-O-Y a -、R a -CO-N(R b )-Y a -、R a -N(R b )-CO-Y a -、R a -O-CO-N(R b )-Y a -、R a -N(R b )-CO-O-Y a -、-Y a -CN、R a -N(R b )-CO-N(R c )-Y a -、R a -O-CO-O-Y a -、R a -N(R b )-C(=NR d )-N(R c )-Y a -、R a -CS-Y a -、R a -O-CS-Y a -、R a -CS-O-Y a -、R a -CS-N(R b )-Y a -、R a -N(R b )-CS-Ya -, R a -O-CS-N(R b )-Y a -, R a -N(R b )-CS-OY a -, R a -N(R b )-CS-N(R c )-Y a -, R a -O-CS-OY a -, R a -S-CO-Y a -, R a -CO-SY a -, R a -S-CO-N(R b )-Y a -, R a -N(R b )-CO-SY a -, R a -S-CO-OY a -, R a -O-CO-SY a -, R a -S-CO-SY a -, R a -S-CS-Y a -, R a -CS-SY a -, R a -S-CS-N(R b )-Y a -, R a -N(R b )-CS-SY a -, R a -S-CS-OY a -, R a -O-CS-SY a - group, where R a is a hydrogen atom, C 1- C6 alkyl group, C 2- C6 alkenyl group or C 2- C6 alkynyl group; R b is a hydrogen atom, C 1- C6 alkyl group, C 2- C6 alkenyl group or C 2- C6 alkynyl group; R c is a hydrogen atom, C1- C6 alkyl group, C 2- C6 alkenyl group or C 2- C6 alkynyl group; R d is a hydrogen atom, C 1- C6 alkyl group, C 2- C6 alkenyl group or C 2- Y is a C6 alkynyl group; a is a bond, C 1- C6 alkylene group, C 2- C6 alkenylene group or C 2- C6 alkynylene group, where each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms.

[0062] Illustrative examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, tert-butyloxy, methoxymethyl, -CHCHOH, -CHOH, -SOMe, -NHAc, -OCD, -C(CH)CN, methoxyethyl, ethoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N-ethyl-N-methyl-carbamoyl or N-methyl-carbamoyl. Further examples of heteroalkyl groups are nitrile (-CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate, and alkylnitrile groups.

[0063] The term cycloalkyl refers to saturated or partially unsaturated cyclic groups (e.g. cycloalkenyl groups) containing one or more rings (preferably one or two) and containing 3 to 14 ring carbon atoms, preferably 3 to 10 (in particular 3, 4, 5, 6 or 7) ring carbon atoms. Furthermore, the term cycloalkyl refers to groups in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups, and thus, for example, cyclic ketones such as cyclohexanone, 2-cyclohexenone or cyclopentanone. Further particular examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl. Preferably, the term cycloalkyl refers to saturated cyclic groups containing one or more rings (preferably one or two, particularly preferably one) and containing 3 to 14 ring carbon atoms, preferably 3 to 10 (in particular 3, 4, 5, 6 or 7) ring carbon atoms.

[0064] The term heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably by oxygen, sulfur or nitrogen atoms) or by a SO or SO2 group. Heterocycloalkyl groups preferably have one or two (particularly preferably one) rings and 3 to 10 (particularly 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). Furthermore, the term heterocycloalkyl refers to groups which are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups. Examples are piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g., -N(CHCH)O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl groups, as well as lactams, lactones, cyclic imides and cyclic anhydrides.

[0065] The expression alkylcycloalkyl refers to groups which contain both a cycloalkyl group and an alkyl, alkenyl or alkynyl group as defined above, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. Alkylcycloalkyl groups preferably contain a cycloalkyl group containing one or two rings and 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having 1 or 2 to 6 carbon atoms.

[0066] The expression heteroalkylcycloalkyl refers to an alkylcycloalkyl group as defined above, in which one or more (preferably 1, 2 or 3) carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably by oxygen, sulfur or nitrogen atoms) or by a SO or SO2 group. Heteroalkylcycloalkyl groups preferably contain one or two rings with 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups) with 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, in which the cyclic groups are saturated or mono-, di- or tri-unsaturated.

[0067] The term aryl refers to aromatic groups containing one or more rings and 6 to 14 ring carbon atoms, preferably 6 to 10 (especially 6) ring carbon atoms. Furthermore, the term aryl refers to groups substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are phenyl (Ph), naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl groups.

[0068] The term heteroaryl refers to an aromatic group containing one or more rings and 5 to 14 ring atoms, preferably 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, including one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). Furthermore, the term heteroaryl refers to groups substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N3, NH2 or NO2 groups. Examples include pyridyl groups (e.g., 4-pyridyl groups), imidazolyl groups (e.g., 2-imidazolyl groups), phenylpyrrolyl groups (e.g., 3-phenylpyrrolyl groups), thiazolyl groups, isothiazolyl groups, 1,2,3-triazolyl groups, 1,2,4-triazolyl groups, oxadiazolyl groups, thiadiazolyl groups, indolyl groups, indazolyl groups, tetrazolyl groups, pyrazinyl groups, pyrimidinyl groups, pyridazinyl groups, 4-hydroxypyridyl groups (4-pyridonyl groups), 3,4-hydroxypyridyl groups (3 ,4-pyridonyl groups), oxazolyl groups, isoxazolyl groups, triazolyl groups, tetrazolyl groups, isoxazolyl groups, indazolyl groups, indolyl groups, benzimidazolyl groups, benzoxazolyl groups, benzisoxazolyl groups, benzthiazolyl groups, pyridazinyl groups, quinolinyl groups, isoquinolinyl groups, pyrrolyl groups, purinyl groups, carbazolyl groups, acridinyl groups, pyrimidyl groups, 2,3'-bifuryl groups, pyrazolyl groups (e.g., 3-pyrazolyl groups), and isoquinolinyl groups.

[0069] The term aralkyl refers to groups containing both an aryl group according to the above definition and an alkyl, alkenyl, alkynyl and / or cycloalkyl group, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyl are phenylcyclopentyl, cyclohexylphenyl and groups derived from toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, cumene, fluorene and indane. An aralkyl group preferably comprises one or two aromatic ring systems (especially one or two rings, particularly preferably one ring) each containing 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or one or two cycloalkyl groups containing 3, 4, 5, 6 or 7 ring carbon atoms.

[0070] The term heteroaralkyl refers to groups containing both aryl and / or heteroaryl groups according to the above definitions, which contain at least one heteroatom, preferably selected from N, O and S, and alkyl, alkenyl, alkynyl and / or heteroalkyl groups and / or cycloalkyl and / or heterocycloalkyl groups. Heteroaralkyl groups preferably contain one or two aromatic ring systems (especially one or two rings, particularly preferably one ring) each containing 5 or 6 to 9 or 10 ring atoms (preferably selected from C, N, O and S) and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or one or two heteroalkyl groups containing 1 to 6 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and N and / or one or two cycloalkyl groups each containing 3, 4, 5, 6 or 7 ring carbon atoms and / or one or two heterocycloalkyl groups each containing 3, 4, 5, 6 or 7 ring atoms including 1, 2, 3 or 4 oxygen, sulphur or nitrogen atoms.

[0071] Examples are arylheteroalkyl groups, arylheterocycloalkyl groups, arylheterocycloalkenyl groups, arylalkylheterocycloalkyl groups, arylalkenylheterocycloalkyl groups, arylalkynylheterocycloalkyl groups, arylalkylheterocycloalkenyl groups, heteroarylalkyl groups, heteroarylalkenyl groups, heteroarylalkynyl groups, heteroarylheteroalkyl groups, heteroarylcycloalkyl groups, heteroarylcycloalkenyl groups, heteroarylheterocycloalkyl groups, heteroarylheterocycloalkenyl groups, heteroarylalkylcycloalkyl groups, heteroarylalkylheterocycloalkenyl groups, heteroarylheteroalkylcycloalkyl groups, heteroarylheteroalkylcycloalkenyl groups and heteroarylheteroalkylheterocycloalkyl groups, where the cyclic groups are saturated or mono-, di- or tri-unsaturated.Specific examples are tetrahydroisoquinolinyl groups, benzoyl groups, phthalidyl groups, 2- or 3-ethylindolyl groups, 4-methylpyridino groups, 2-, 3- or 4-methoxyphenyl groups, 4-ethoxyphenyl groups, 2-, 3- or 4-carboxyphenylalkyl groups.

[0072] As already mentioned above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups substituted by fluorine, chlorine, bromine or iodine atoms, or by OH, ═O, SH, ═S, NH, ═NH, N or NO groups, unless otherwise specified.

[0073] According to preferred embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl groups described herein may be substituted.

[0074] The term halogen refers to F, Cl, Br or I.

[0075] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, or heteroaralkyl group contains multiple rings, the rings can be joined to each other through single or double bonds or the rings can be cyclized, fused, or bridged.

[0076] The suffix "-ene", for example in "phenylene", refers to the corresponding divalent radical.

[0077] The term "optionally substituted" refers to a group that is unsubstituted or substituted with one or more (especially 1, 2 or 3, preferably 1 or 2) substituents.

[0078] When a group contains multiple substituents, the substituents are independently selected, i.e., they can be the same or different.

[0079] When a group is substituted with a cyclic group, such as a cycloalkyl group or a heterocycloalkyl group, the cyclic group may be attached to the group through a single or double bond, or the cyclic group may be cyclized or fused to the group.

[0080] Specific examples of the substituents are fluorine, chlorine, bromine and iodine, as well as an OH group, an SH group, an NH2 group, a -SO3H group, a -SO2NH2 group, a C 1-4 Alkyl, C 1-4 Heteroalkyl, -COOH group, -COOMe group, -COMe(Ac) group, -NHSO2Me group, -SO2NMe2 group, -CH2NH2 group, -NHAc group, -SO2Me group, -CONH2 group, -CN group, -NHCONH2 group, -NHC(NH)NH2 group, -NOHCH3 group, -N3, and -NO2 group.

[0081] Further examples of substituents include C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl groups, C1-C 10 Heteroalkyl groups, C3-C 18 Cycloalkyl groups, C1-C 17 Heterocycloalkyl groups, C4-C 20 Alkylcycloalkyl groups, C1-C 19 Heteroalkylcycloalkyl groups, C6-C 18 Aryl groups, C1-C 17 Heteroaryl groups, C7-C 20 Aralkyl groups and C1-C 19 Heteroaralkyl groups; in particular, C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C1-C6 heteroalkyl groups, C3-C 10 Cycloalkyl groups, C1-C9 heterocycloalkyl groups, C4-C 12 Alkylcycloalkyl groups, C1-C 11 Heteroalkylcycloalkyl groups, C6-C 10 Aryl groups, C1-C9 heteroaryl groups, C7-C 12 Aralkyl groups and C1-C 11 Heteroaralkyl groups, more preferably C1-C6 alkyl groups and C1-C6 heteroalkyl groups.

[0082] Preferred substituents are halogen atoms (e.g., F, Cl, Br), as well as -OH, -NH2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, cyclopropyl and -CH2-cyclopropyl groups.

[0083] Further preferred substituents are halogen atoms (e.g., F, Cl, Br), as well as -OH, -NH, -CN, -C 1-4 Alkyl groups (e.g., -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu, -CH2CH2F, CH2CHF2, -CH2CF3, and -CF3), -OC 1-4Alkyl groups (e.g., -OMe, -OEt, -O-nPr, -O-iPr, -O-nBu, -O-iBu and -O-tBu), -NHC 1-6 Alkyl groups (e.g., -NH(CH2)2F and -NH(CH2)3F), -NH(CH2)2OH, -NH(CH2)3OH, -NH(CH2)2OMe, -NH(CH2)3OMe, -N(Me)(CH2)2OH, -N(Me)(CH2)3OH, -N(Me)(CH2)2OMe, -N(Me)(CH2)3OMe, -N(C 1-6 alkyl)2, -C(CH3)2CN, -CONH-C 1-4 Alkyl (e.g., -CONHCH2CF3, -CONHEt, -CONH t Bu), -COOH, -COOMe, -COMe, -CH2CH2CH=CH2, a cyclopropyl group, and a -CH2-cyclopropyl group.

[0084] Therapeutic uses, as well as formulations and pharmaceutical compositions, of the compounds of formula (I), their pharmacologically acceptable salts, solvates and hydrates, respectively, are also within the scope of the present invention.

[0085] The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) as defined herein, or a salt thereof, or a pharma- ceutically acceptable ester, prodrug, hydrate or solvate thereof, optionally in combination with a pharma- ceutically acceptable carrier and / or adjuvant.

[0086] It is a further object of the present invention to provide a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment of one or more diseases as identified herein.

[0087] Preferably, the compounds of the invention can be used in the treatment and / or prevention of the following conditions: Diseases in which aberrant CDK (particularly CDK9) regulation is observed, such as a wide range of cytokine-induced inflammatory diseases and autoimmune diseases, local or systemic viral infections, viral infections of the eye, viral respiratory infections, or viral infections of the central and / or peripheral nervous system caused by DNA and / or RNA viruses, as well as various non-solid and solid malignancies, cancers, or hyperproliferative diseases, such as acute myeloid leukemia, acute myeloid leukemia, and acute myeloid leukemia. In particular, the compounds may be used to treat hematological / solid malignancies, such as advanced and / or metastatic hematological malignancies or solid tumors, including, for example, myeloma, chronic lymphocytic leukemia, relapsed multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, acute biphenotypic leukemia, aggressive MYC-driven B-cell lymphoma, primary peritoneal carcinoma, Kaposi's sarcoma, advanced breast cancer, non-small cell lung cancer, colorectal cancer, or liver cancer, such as hepatocellular carcinoma, cervical intraepithelial neoplasia, prostate cancer, melanoma, glioma, glioblastoma, neuroblastoma, astrocytoma, anaplastic astrocytoma, or glioblastoma. In particular, the compounds may be used to treat hematological malignancies or solid tumors, such as those caused by aberrant expression of MYC- or MCL-1. Furthermore, the compounds can be used as modulators of the immune response and for the treatment and / or prevention of mechanical / trauma-induced inflammation, such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory diseases, such as inflammatory diseases of the gastrointestinal or urinary tract, and ocular inflammatory diseases, such as Sjogren's disease and glaucoma, bacterial-induced inflammatory diseases, such as gingivitis, periodontitis, and for the treatment and / or prevention of cardiovascular diseases, such as cardiac hypertrophy, dilated cardiomyopathy, atherosclerosis, and cardiometabolic diseases, such as obesity and diabetes.

[0088] A therapeutically effective amount of a compound according to this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject receiving treatment. Determination of a therapeutically effective amount is within the skill of one in the art.

[0089] The therapeutically effective amount or dosage of the compounds according to the invention can vary within a wide range and can be determined in a manner known in the art. Such dosage can be adjusted to the individual requirements in each particular case, including the specific compound administered, the route of administration, the condition being treated, and the patient receiving the treatment.

[0090] The salt of the compound of formula (I) is preferably a pharmacologically acceptable salt.The examples of the pharmacologically acceptable salt of the sufficiently basic compound of formula (I) are the salts of physiologically acceptable mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; or the salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.Furthermore, the sufficiently acidic compound of formula (I) can form alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, lithium salts, calcium salts or magnesium salts; ammonium salts; or organic base salts, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylenediamine salts, ethanolamine salts, choline hydroxide salts, meglumine salts, piperidine salts, morpholine salts, tris-(2-hydroxyethyl)amine salts, lysine salts or arginine salts; all of these are also further examples of the salt of formula (I). The salts of the compounds of formula (I) may be, for example, disalts or mixed salts.

[0091] The compounds of formula (I) may be solvated, in particular hydrated. Hydration / hydration may occur during the preparation process or as a result of the hygroscopic nature of the compounds of formula (I) that do not initially contain water. Solvates and / or hydrates may exist, for example, in solid or liquid form.

[0092] It should be understood that certain compounds of formula (I) may have tautomers, different geometric isomers (usually represented as cis / trans isomers or more commonly as (E) and (Z) isomers), of which only one may be specifically mentioned or depicted in the following description, or different optical isomers (usually named according to the Cahn-Ingold-Prelog or R / S system) resulting from one or more chiral carbon atoms. All these tautomers, geometric or optical isomers (as well as racemates and diastereomers) and polymorphs are included in the present invention. Compounds of formula (I) may contain asymmetric C atoms and therefore may exist either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or optically pure compounds. The present invention includes both all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any mixture ratio.

[0093] According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention can be replaced with deuterium. Deuterium modification improves the metabolic properties of a drug with little or no change in its inherent pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces the formation of toxic metabolites, and / or increases the formation of desired active metabolites. Thus, the present invention also encompasses partially and fully deuterated compounds of formula (I). The term hydrogen also encompasses deuterium.

[0094] The present invention also relates to prodrugs consisting of a compound of formula (I) and at least one pharmacologically acceptable protecting group which is cleaved under physiological conditions, examples of which include alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl groups (e.g. pivaloyloxymethyl), 2-alkyl-, 2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkylideneethyl groups, or acyloxy groups as defined herein, such as ethoxy, benzyloxy, acetyl or acetyloxy, or, in particular in the case of compounds of formula (I) bearing a hydroxy group (-OH), sulfates, phosphates (-OPO3 or -OCHOPO3) or esters of amino acids.

[0095] As used herein, the term pharma- ceutically acceptable ester refers specifically to esters that hydrolyze in vivo, including esters that decompose easily in the human body to leave the parent compound or its salt.Suitable ester groups include, for example, those derived from pharma-ceutically acceptable aliphatic carboxylic acids, particularly alkanoic acid, alkenoic acid, cycloalkanoic acid and alkanedioic acid, each alkyl or alkenyl moiety advantageously having 6 or less carbon atoms.Specific examples of esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate and succinate ethyl ester.

[0096] Preferably, the present invention also relates to prodrugs, biohydrolyzable esters, biohydrolyzable amides, polymorphs, tautomers, stereoisomers, metabolites, N-oxides, biohydrolyzable carbamates, biohydrolyzable ethers, physiologically functional derivatives, atropisomers, or in vivo hydrolyzable precursors, diastereomers or mixtures of diastereomers, chemically protected forms, affinity reagents, complexes, chelates and stereoisomers of the compounds of formula (I).

[0097] As mentioned above, therapeutically useful agents containing the compounds of formula (I), their solvates, salts or formulations are also included in the scope of the present invention. In general, the compounds of formula (I) are administered alone or in combination with any other therapeutic agent by using known and acceptable modes known in the art.

[0098] For oral administration, such therapeutically useful agents can be administered by one of the following routes: orally, for example as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, such as soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups; parenterally, for example as intravenous, intramuscular and subcutaneous injections, for example as injectable solutions or suspensions; rectally as suppositories; by inhalation or insufflation, for example as powder formulations, microcrystals or sprays (for example liquid aerosols); transdermally, for example via transdermal delivery systems (TDS), such as plasters containing the active ingredient; or intranasally. For the production of such tablets, pills, semisolids, coated tablets, sugar-coated tablets, and hard capsules, such as gelatin capsules, the therapeutically useful products can be mixed with pharma- ceutically inert inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salts, skimmed milk powder, etc. For the production of soft capsules, excipients such as vegetable oils, petroleum oils, animal oils or synthetic oils, waxes, fats, polyols, etc. can be used. For the production of solutions, emulsions or suspensions or syrups, excipients such as water, alcohol, saline, aqueous glucose solutions, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable oils, petroleum oils, animal oils or synthetic oils can be used. Particularly preferred are lipids, more preferred are phospholipids (preferably of natural origin, particularly preferably with a particle size between 300 and 350 nm), preferably in phosphate-buffered saline (pH=7-8, preferably 7.4). For suppositories, excipients can be, for example, vegetable oils, petroleum oils, animal oils or synthetic oils, waxes, fats and polyols.For aerosol preparations, compressed gases suitable for this purpose can be used, for example, oxygen, nitrogen and carbon dioxide.The pharma-ceutical useful agent can also contain additives for preservation and stabilization, for example, UV stabilizers, emulsifiers, sweeteners, flavorings, salts for changing osmotic pressure, buffers, coating additives and antioxidants.

[0099] In general, when administered orally or parenterally to an adult weighing approximately 80 kg, the daily dose is about 10 mg to about 10,000 mg, preferably about 20 mg to about 1,000 mg, but may exceed the upper limit if necessary. The daily dose may be administered in a single dose or in divided doses, and when administered parenterally, it may be given as continuous infusion or subcutaneous injection.

[0100] According to a further preferred embodiment, the present invention provides a method for treating one or more of the diseases identified herein, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof.

[0101] According to a further preferred embodiment, the present invention provides a method for treating one or more of the diseases identified herein, comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof. EXAMPLES

[0102] General synthesis method The following methods were used in the synthesis of the compounds described herein. Flash Chromatography: Flash chromatography was performed on a Biotage Isolera® or Selekt® system using SNAP or SFAR silica cartridges and gradients of ethyl acetate / cyclohexane / methanol or dichloromethane / methanol as eluents. Microwave conditions: Reactions under microwave conditions are carried out in a Biotage initiator® microwave system.

[0103] Semi-preparative reversed-phase chromatography: For semi-preparative reversed-phase chromatography, the following equipment was used: 2x Varian PrepStar SD-1, 1x Dionex P580 pump 1 channel (MakeUP I), 1x Dionex AXP-MS (MakeUP II), 1x Dionex MSQ, 1x Dionex UVD 340V-preparative flow cell, Gilson215 liquid handler, SunFire Prep C18 OBD 5μm, 19x50mm column, 1x G7159B 1290 Infinity II preparative open-bed sampler / collector, 1x G7161B 1290 Infinity II preparative binary pump, 1x G7111B 1260 Infinity II quaternary pump (modifier), 1x G7111B 1260 Infinity II quaternary pump (analytical / makeup), 1x G7165A 1260 Infinity II 1x G7170B 1290 Infinity II MS Flow Modulator including Multi-Wavelength Detector, Flow Cell (product no. G1315-60022, serial no. DE185H6157, path length 10.00 mm, volume 13.00 μl), 1x G6125B MSD 6100 Series Single Quadrupole including G1948B Electrospray Interface, and 3x G1170A 1290 Infinity Valve Drives (14-port, 6-position valve head for analytical column selection; 14-port, 6-position valve head for preparative column selection; 14-port, 2-position valve head for analytical / preparative mode selection). Preparative columns: Waters SunFire preparative C18 5μm OBD 30x100mm, #186002572, Waters AtlantisT3 preparative 5μm OBD 30x100mm, #186003702, and Waters XSelect CSH preparative C18 5μm OBD 30x100mm, #186005425. Analytical columns: Waters SunFire C18 2.5μm 3.0x75mm, #186005636, Waters Atlantis T3 3μm 3.0x75mm, #186005653, and Waters XSelect CSH C18 2.5μm 3.0x75mm, #186006106.

[0104] Typical chromatographic conditions are as follows: The column flow rate was 30 mL / min, solvent A was methanol containing 0.3% acetic acid, and solvent B was water containing 0.3% acetic acid. Typical times and relative amounts of solvent B and solvent B are shown in Table 1.

[0105] [Table 1]

[0106] Typical preparative method: column flow rate was 60 mL / min, solvent A was acetonitrile and solvent B was water. Preparations included modifier flows: 1.8 mL / min modifier flow rate containing 10% acetic acid in acetonitrile / water 1:1 => acetic acid in the flow rate is 0.3%; 0.5 M NH4Ac / NH4OH buffer (pH 9.2) in acetonitrile / water 1:9 => buffer concentration in the flow rate is 15 mM. MS make-up: 0.05% acetic acid in acetonitrile / water 1:1 at 0.9 mL / min. For example, a typical focused gradient timetable for an elution point of 59.7% is shown in Table 2.

[0107] [Table 2]

[0108] Typical analytical modifiers: column flow rate 1 mL / min, solvent A was acetonitrile, solvent B was water, and solvent C was 5% acetic acid in acetonitrile / water 1:1. Typical times and relative amounts of Solvent A, Solvent B, and Solvent C are shown in Table 3.

[0109] [Table 3]

[0110] For detection, a mass spectrometer detector (API-ES, positive) with UV 220 nm, 254 nm or 310 nm was used.

[0111] Terms and abbreviations used in the examples are shown in Table 4.

[0112] [Table 4]

[0113] The analytical HPLC methods used in the preparation of the compounds are shown in Table 5.

[0114] [Table 5]

[0115] General Route to Imidazotriazines:

[0116] [ka]

[0117] Description of synthesis steps: Step 1: Amide formation: [ka]

[0118] 1-Amino-1H-imidazole-2-carboxylic acid ethyl ester (1 eq.) was dissolved in ammonia (7M in MeOH, 3 mL / mmol) followed by the addition of NH4Cl (10 eq.). The mixture was heated at 100° C. under microwave irradiation for 2 h. The solid was collected by filtration, washed with MeOH and dried. The crude product was used without further purification.

[0119] Step 2: Cyclization [ka]

[0120] 1-Amino-1H-imidazole-2-carboxylic acid amide (1 eq.) and the corresponding aldehyde were dissolved in HOAc (3 mL / mmol). The mixture was stirred at room temperature for 1 h, diluted with THF (9 mL / mmol), and then NIS (2 eq.) was added. The mixture was stirred at room temperature overnight. To complete the reaction, additional NIS (2 eq.) was added, followed by stirring at room temperature for another night. This was repeated twice. The mixture was quenched by addition of aqueous Na2S2C3, diluted with water, and extracted with DCM. The organic layer was dried, filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0121] Step 3: Chlorination [ka]

[0122] The product of the previous step was treated with DIPEA (1.25 mL / mmol) followed by slow addition of POCL3 (6 mL / mmol). The mixture was stirred at room temperature overnight. The volume was reduced under reduced pressure. The residue was added slowly to ice / water, stirred for 1 h and extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was used without further purification.

[0123] Step 4: Amination [ka]

[0124] The corresponding amine (2 equiv.) was dissolved in iPrOH (5 mL / mmol) and chloride (1 equiv.) dissolved in DIPEA (40% v / v) and iPrOH (10 mL / mmol) was added. The mixture was stirred at room temperature until the chloride was consumed. The mixture was diluted with water and extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was used without further purification.

[0125] Step 5: Chlorination [ka]

[0126] The product of the previous step (1 equiv.) was dissolved in dry DCM. NCS (1 equiv.) was added and the mixture was stirred at room temperature until nearly complete conversion was observed. The reaction mixture was quenched with aqueous Na2S2O3, extracted with DCM, and the organic layer was dried, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC / MS, concentrated, and lyophilized.

[0127] Compounds of Examples #1-#3, #5-#20, #27, #28, #36, #37 and #38 were synthesized using these protocols.

[0128] Compounds of examples #4, #21, #22 and #24 were synthesized using these protocols using the corresponding Boc-protected amines followed by a deprotection step.

[0129] Boc-deprotection The protected compound was dissolved in DCM (approximately 0.25 M). TFA (20% v / v) was added and the mixture was stirred at room temperature for 30 min. MeOH was added followed by concentration under reduced pressure. This was repeated three times. The crude product was purified by reverse phase HPLC / MS.

[0130] Special cases: Example #32: The product of Example #4 was dissolved in MeOH (dry). 2-Hydroxyacetaldehyde (1 eq.), AcOH (1 eq.), and sodium cyanoborohydride (2 eq.) were added. The mixture was stirred at room temperature overnight. The mixture was quenched with water and saturated aqueous NaHCO3, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC / MS.

[0131] The amines used were either commercially available, described in the literature, or prepared by one of the following procedures.

[0132] A: 4-(piperidin-1-yl)cyclohexanamine: [ka]

[0133] Step 1: The BOC-protected diamine was dissolved in acetonitrile. Dibromopentane (2 eq.) and DIPEA (5 eq.) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with ammonium chloride (sat. aq.) and water. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC.

[0134] Step 2: The product of Step 1 was dissolved in MeOH and treated with HCl (4M in dioxane, excess) overnight. The mixture was concentrated and used as the HCl salt without further purification.

[0135] The following intermediates were synthesized according to these protocols:

[0136] [ka]

[0137] B: Alkylcyclohexaneamine: [ka]

[0138] Step 1: The boc-protected cyclohexanediamine was dissolved in acetonitrile and an alkyl bromide (1 equiv.) and K2CO3 (2.5 equiv.) were added. The mixture was heated at 80° C. overnight. The mixture was filtered through Celite, concentrated under reduced pressure, and used without further purification.

[0139] Step 2: The mixture from step 1 was dissolved in DCM / TFA (2 / 1), stirred at room temperature for 1 h, and concentrated under reduced pressure. The product was used without further purification.

[0140] The following intermediates were synthesized using these methods:

[0141] [ka]

[0142] The following examples were prepared according to the procedures described above. Example No.: Name; HPLC-MS-Method; Retention time (min); m+H Observed; NMR

[0143] Example #1: 7-Chloro-2-(2,6-difluorophenyl)-N-((1r,4r)-4-morpholinocyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.75 min; 449.2; 1H NMR (600MHz, methanol-d4) δ=7.58(s, 1H), 7.53(tt, J=8.6, 6.3Hz, 1H), 7.13-7.07(m, 2H), 4.13(tt, J=11.4, 4.1Hz, 1H), 3.71(t, J=4.7Hz, 4H), 2.68(dd, J=5.9, 3.5Hz, 4H), 2.42(td, J=9.4, 8.0, 5.3Hz, 1H), 2.24-2.18(m, 2H), 2.06(dt, J=12.6, 2.7Hz, 2H), 1.56-1.40(m, 4H).

[0144] Example #3: (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine; HPLC-MS B; 2.76 min; 407.2; 1H NMR (400MHz, methanol-d4) δ=7.60(s, 1H), 7.54(tt, J=8.5, 6.4Hz, 1H), 7.11(dd, J=8.5, 7.6Hz, 2H), 4.19(dt, J=11. 2, 5.7Hz, 1H), 3.01(s, 1H), 2.69(s, 6H), 2.28(d, J=10.8Hz, 2H), 2.11(d, J=10.3Hz, 2H), 1.60(q, J=11.8Hz, 4H).

[0145] Example #4: (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,lf][1,2,4]triazin-4-yl)cyclohexane-1,4-diamine; HPLC-MS B; 2.68 min; 379.2; 1H NMR (600 MHz, methanol-d4) δ = 7.60 (s, 1H), 7.54 (tt, J = 8.5, 6.3 Hz, 1H), 7.12 (t, J = 8.0 Hz, 2H), 4.18 (tt, J = 11.4, 4.1 Hz, 1H), 3.17-3.10 (m, 1H), 2.28-2.19 (m, 2H), 2.10 (d, J = 11.8 Hz, 2H), 1.66-1.47 (m, 4H).

[0146] Example #5: 7-Chloro-2-(2,6-difluorophenyl)-N-((1r,4r)-4-(piperidin-1-yl)cyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.89 min; 447.2.

[0147] Example #6: 7-Chloro-2-(2,6-difluorophenyl)-N-((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.81 min; 433.2; 1H NMR (600MHz, methanol-d4) δ=7.60(s, 1H), 7.54(tt, J=8.5, 6.3Hz, 1H), 7.11(t, J=8.0Hz, 2H), 4.25-4.17(m, 1 H), 3.34(s, 5H), 3.14(d, J=11.9Hz, 1H), 2.33-2.22(m, 4H), 2.06(q, J=5.6, 4.6Hz, 4H), 1.70-1.53(m, 4H).

[0148] Example #7: (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)-N4-(2-methoxyethyl)cyclohexane-1,4-diamine; HPLC-MS B; 2.79 min; 437.2; 1H NMR (400MHz, methanol-d4) δ=7.60(s,1H),7.54(tt,J=8.5,6.4Hz,1H),7.15-7.07(m,2H),4.18(td,J=11.2,4.0Hz,1H),3.61(t,J =4.9Hz,2H),3.40(s,3H),3.18-3.09(m,2H),3.03(s,1H),2.21(dd,J=26.6,11.8Hz,4H),1.55(td,J=23.3,21.4,12.4Hz,4H).

[0149] Example #8: (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)-N4-(2-fluoroethyl)cyclohexane-1,4-diamine; HPLC-MS B; 2.75 min; 425.2; 1H NMR (400 MHz, methanol-d4) δ = 7.59 (s, 1H), 7.54 (tt, J = 8.4, 6.3 Hz, 1H), 7.15-7.07 (m, 2H), 4.97 (dd, J = 8.7, 5.2 Hz, 1H), 4.79-4.48 (m, 1H), 4.20 (s, 1H), 3.77-3.40 (m, 2H), 3.08 (s, 1H), 2.24 (s, 4H), 1.56 (s, 4H).

[0150] Example #9: (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)-N4-(3-fluoropropyl)cyclohexane-1,4-diamine; HPLC-MS B; 2.85 min; 439.2; 1H NMR (400MHz, methanol-d4) δ=7.60(s, 1H), 7.54(tt, J=8.4, 6.3Hz, 1H), 7.12(dd, J=8.5, 7.6Hz, 2H), 4.56(d, J=46.9Hz, 2H), 4.26-4.13(m, 1H) , 4.03-3.96(m, 1H), 3.80-3.62(m, 2H), 3.11(s, 2H), 2.23(dd, J=21.5, 10.5Hz, 2H), 2.05(d, J=24.8Hz, 2H), 1.54(dt, J=22.9, 12.2Hz, 4H).

[0151] Example #10: 7-Chloro-2-(2,6-difluorophenyl)-N-(1-isopropylpiperidin-4-yl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.77 min; 407.2.

[0152] Example #11: 7-Chloro-2-(2,6-difluorophenyl)-N-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.72 min; 449.2; 1H NMR (400MHz, methanol-d4)δ=7.60(s,1H),7.53(tt,J=8.5,6.3Hz,1H),7.15-7.06(m,2H),4.50-4.38(m,1H),4.09-3.97(m,2H),3.55 -3.37(m,4H),3.26(d,J=12.0Hz,1H),3.09-2.98(m,2H),2.30(d,J=13.4Hz,2H),2.20-1.99(m,4H),1.77(qd,J=11.7,4.2Hz,2H).

[0153] Example #12: 7-Chloro-N-(1-cyclopentylpiperidom-4-yl)-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.89 min; 433.2; 1H NMR (400MHz, methanol-d4)δ=7.61(s,1H),7.53(tt,J=8.5,6.3Hz,1H),7.16-7.06(m,2H),4.31(dq,J=10.6,5.3,4.3Hz,1H ),3.02-2.91(m,1H),2.63(d,J=12.5Hz,2H),2.25-2.14(m,2H),2.01(d,J=9.4Hz,2H),1.89(s,2H),1.81-1.50(m,6H).

[0154] Example #13: 7-Chloro-2-(2,6-difluorophenyl)-N-(1-methylpiperidin-4-yl)imidazo[2,1-f][l,2,4]triazin-4-amine; HPLC-MS B; 2.63 min; 379.2.

[0155] Example #14: [7-Chloro-2-(2,6-difluoro-phenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-(1-methyl-piperidin-2-ylmethyl)-amine; HPLC-MS B; 2.72 min; 393.2; 1H NMR (400 MHz, methanol-d4)δ=7.64(s, 1H), 7.54(tt, J=8.5, 6.3Hz, 1H), 7.16~7.08(m, 2H), 3.92(d, J=4.9Hz, 2H) , 3.20(d, J=12.0Hz, 1H), 2.97(s, 1H), 2.75(s, 3H), 2.68(dd, J=12.1, 3.3Hz, 1H), 1.90-1.41(m, 6H).

[0156] Example #15: 7-Chloro-2-(2,6-difluorophenyl)-N-((1-ethylpyrrolidin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.67 min; 393.2; 1H NMR (400MHz, methanol-d4) δ = 7.66 (s, 1H), 7.57 (tt, J = 8.5, 6.4 Hz, 1H), 7.20-7.10 (m, 2H), 3.95 (qd, J = 14.6, 5.0 Hz, 2H), 3.67-3.44 (m, 3H), 2.96 (dt, J = 19.7, 7.8 Hz, 2H), 2.29-1.98 (m, 4H), 1.14 (t, J = 7.3 Hz, 3H).

[0157] Example #16: [7-Chloro-2-(2,6-difluoro-phenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-piperidin-4-yl-amine; HPLC-MS A; 2.93 min; 365.2.

[0158] Example #17: [7-Chloro-2-(2,6-difluoro-phenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-(1-methyl-piperidin-4-ylmethyl)-amine; HPLC-MS B; 2.65 min; 393.2.

[0159] Example #18: (1-Aza-bicyclo[2.2.2]oct-3-yl)-[7-chloro-2-(2,6-difluoro-phenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-amine; HPLC-MS B; 2.69 min; 391.2.

[0160] Example #19: [7-Chloro-2-(2,6-difluoro-phenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-(2-morpholin-4-yl-ethyl)-amine; HPLC-MS A; 2.89 min; 395.2.

[0161] Example #20: tert-butyl 3-(((7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)amino)methyl)piperidine-1-carboxylate; HPLC-MS B; 4.55 min; 479.2.

[0162] Example #21: 7-Chloro-2-(2,6-difluorophenyl)-N-(piperidin-4-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.63 min; 379.2; 1H NMR (400MHz, methanol-d4) δ = 7.60 (s, 1H), 7.54 (tt, J = 8.5, 6.3 Hz, 1H), 7.15-7.07 (m, 2H), 3.62 (d, J = 6.7 Hz, 2H), 3.38 (d, J = 12.6 Hz, 2H), 2.95 (td, J = 12.7, 3.0 Hz, 2H), 2.17-2.05 (m, 1H), 2.00 (d, J = 14.4 Hz, 2H), 1.60-1.44 (m, 2H).

[0163] Example #22: 7-Chloro-2-(2,6-difluorophenyl)-N-(piperidin-3-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.63 min; 379.2; 1H NMR (400MHz, methanol-d4)δ=7.63(s,1H),7.56(tt,J=8.5,6.3Hz,1H),7.18-7.09(m,2H),3.65(dd,J=6.6,3.3Hz,2H),3.42(d,J=12.3Hz, 1H),3.30(s,1H),2.96-2.84(m,1H),2.78(t,J=12.1Hz,1H),2.23(s,1H),1.97(d,J=10.8Hz,2H),1.81-1.64(m,1H),1.47-1.33(m,1H).

[0164] Example #24: N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)cyclopentane-1,3-diamine; HPLC-MS B; 2.65 min; 365.2; 1H NMR (400MHz, methanol-d4) δ=7.62(s, 1H), 7.54(tt, J=8.5, 6.3Hz, 1H), 7.17-7.05(m, 2H), 4.62(q, J=7.7Hz, 1H), 3.65(p, J=7.5Hz, 1H), 2.71( dt, J=14.2, 7.4Hz, 1H), 2.20(ddt, J=21.2, 14.7, 7.1Hz, 2H), 2.00(dt, J=15.0, 7.4Hz, 1H), 1.91-1.82(m, 1H), 1.74(dt, J=13.3, 8.2Hz, 1H).

[0165] Example #27: 7-Chloro-2-(2-chloro-6-fluorophenyl)-N-((1r,4r)-4-morpholinocyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS A; 3.073; 465.2; 1H NMR(400MHz,cd3od)δ=7.58(s,1H),7.49(td,J=8.3,5.9Hz,1H),7.36(d,J=8.1Hz,1H),7.25-7.18(m,1H) ,4.14(s,1H),3.79(s,4H),2.97(s,4H),2.81(s,1H),2.19(d,J=46.0Hz,5H),1.56(q,J=11.7,9.9Hz,4H).

[0166] Example #28: 7-Chloro-2-(2,6-dichlorophenyl)-N-((1r,4r)-4-morpholinocyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS C; 3.916; 481.2; 1H NMR (400MHz, cd3od) δ = 7.58 (s, 1H), 7.52-7.41 (m, 3H), 4.18-4.05 (m, 1H), 3.74 (t, J = 4.7Hz, 4H), 2.84 (s, 4H), 2.62 (s, 1H), 2.15 (d, J = 52.1Hz, 4H), 1.62-1.38 (m, 4H).

[0167] Example #32: 2-(((1r,4r)-4-((7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)amino)cyclohexyl)amino)ethan-1-ol; HPLC-MS B; 2.70 min; 423.2; 1H NMR (400 MHz, methanol-d4) δ = 7.60 (s, 1H), 7.54 (tt, J = 8.5, 6.3 Hz, 1H), 7.16-7.08 (m, 2H), 4.19 (td, J = 11.2, 4.4 Hz, 1H), 3.83-3.71 (m, 2H), 3.12-2.97 (m, 3H), 2.22 (dd, J = 24.7, 11.6 Hz, 4H), 1.66-1.43 (m, 4H).

[0168] Example #36: 7-Chloro-2-(2,6-difluorophenyl)-N-(pyridin-3-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.86 min; 373; 1H NMR (600MHz, methanol-d4) δ = 8.64-8.58 (m, 1H), 8.44 (dd, J = 5.0, 1.6Hz, 1H), 7.93 (dt, J = 7.9, 1.9Hz, 1H), 7.61 (s, 1H), 7.53 (tt, J = 8.5, 6.3Hz, 1H), 7.41 (ddd, J = 7.9, 5.0, 0.9Hz, 1H), 7.15-7.08 (m, 2H), 4.85 (s, 2H).

[0169] Example #37: 7-Chloro-2-(2,6-difluorophenyl)-N-((4,6-dimethylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.76 min; 401; 1H NMR (600 MHz, methanol-d4) δ = 8.40 (s, 1H), 7.62 (s, 1H), 7.54 (tt, J = 8.4, 6.3 Hz, 1H), 7.30 (s, 1H), 7.17-7.07 (m, 2H), 4.84 (s, 2H), 2.52 (s, 3H), 2.47 (s, 3H).

[0170] Example #38: 7-Chloro-2-(2,6-difluorophenyl)-N-((1r,4r)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; HPLC-MS B; 2.46 min; 462.2; 1H NMR (400MHz, methanol-d4) δ=7.58(s,1H),7.57-7.49(m,1H),7.14-7.07(m,2H),4.14(s,1H),2.81(d,J=24.5 Hz,8H),2.60(s,1H),2.48(s,3H),2.22(s,2H),2.05(s,2H),1.51(q,J=9.9Hz,4H),1.25(d,J=6.2Hz,4H).

[0171] Biological Data Assay protocol for measuring inhibitory activity Test compounds were evaluated at 12 concentrations in a 1:3 dilution series starting at a highest concentration of 5 μM.

[0172] In a white 384 microplate (Greiner bio-one, Austria, #784904), 2 microL of 3x concentrated, final concentration (fc) 6 nM, CDK9 / cyclin T1 (ProQinase / Reaction Biology, USA, #0371-0345-1, LOT.:012) in 1x kinase buffer was added, followed by 2 microL of compounds (3x concentrated, fc 1.66%, in DMSO / H2O) and incubated for 10 min at room temperature (RT). Then, 2 microL of substrate / ATP mix (3xPDKtide fc40 microM; SignalChem Biotech, Canada; via Biozol, Eching, Germany; #P10-58, LOT.:L2230-7, and 3xUltraPure ATP fc10 microM (ADP Glo Kinase Assay, PromegaGmbH, Germany, #V9102)) was added, mixed, and incubated for 120 min at room temperature. After the incubation period, 5 microL of ADP Glo reagent (Ready-to-use, ADP Glo Kinase Assay, Promega GmbH, Germany, #V9102) was added, mixed and incubated for 40 min at room temperature. In the last step, 10 microL of ADP Glo detection reagent (ready-to-use, ADP Glo Kinase Assay, Promega GmbH, Germany, #V9102) was added, mixed and incubated for 30 min at room temperature. For readout, a GloMax Discover GM3000 Reader (Promega GmbH, Germany, 9700000249) was used. Inhibitor concentrations were plotted against luminescence and IC50s were determined using XLFit5.5 (IDBS, Guilford) and fitted to variable gradient sigmoidal dose-response curves.

[0173] CDK9 / T1 ADPGlo activity of the compounds in the above examples: IC50<20nM: Example #1, Example #3, Example #4, Example #5, Example #6, Example #7, Example #8, Example #9, Example #13, Example #16, Example #17, Example #24, Example #27, Example #28, Example #32, Example #38 IC50<200nM: Example #10, Example #11, Example #12, Example #14, Example #15, Example #18, Example #19, Example #20, Example #21, Example #22, Example #36, Example #37

Claims

1. A compound represented by the following formula (I), or a salt or solvate thereof: 【Chemistry 1】 (In the formula, R １ is an alkyl group, an alkenyl group, an alkynyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkylcycloalkyl group, a heteroalkylcycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, or a heteroaralkyl group, any of which may be substituted; R ２ is a phenyl group substituted by 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br and Me; R ３ is a halogen atom, CN, C １－４ Alkyl group or C １－４ is a heteroalkyl group.

2. R ３ But Cl, Br, CN, CF ３ , a methyl group, an ethyl group, or an isopropyl group.

3. R ３ The compound of claim 1 , wherein is Cl.

4. R ２ The compound according to any one of claims 1 to 3, wherein is a phenyl group substituted at the 2- and 6-positions.

5. R ２ The compound according to any one of claims 1 to 3, wherein is a 2,6-difluorophenyl group, a 2,6-dichlorophenyl group, or a 2-chloro-6-fluorophenyl group.

6. R ２ The compound according to any one of claims 1 to 3, wherein is a 2,6-difluorophenyl group.

7. R １ is optionally substituted C ３－７ The compound according to any one of claims 1 to 6, which is a cycloalkyl group; an optionally substituted heterocycloalkyl group containing 3 to 9 ring atoms independently selected from C, N and O; an optionally substituted phenyl group; an optionally substituted benzyl group; an optionally substituted heteroaryl group containing 5 or 6 ring atoms independently selected from C, N, O and S; or an optionally substituted heteroalkyl group containing 1 to 12 carbon atoms and 1 to 6 heteroatoms selected from N, O and S.

8. R １ The compound according to any one of claims 1 to 6, wherein is selected from the following group: 【Chemistry 2】 (In the formula, R ５ is -NH ２ Group, C １－６ A heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O.

9. R １ The compound of any one of claims 1 to 6, wherein: 【Chemistry 3】 (In the formula, R ５ is -NH ２ Group, C １－６ A heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O.

10. R ５ but, -NH ２ , -NMe ２ , pyrrolidinyl, piperidinyl, N-methylpiperazinyl, morpholinyl, -NH(CH ２ ) ２ F, -NH(CH ２ ) ３ F, -NH(CH ２ ) ２ OH, -NH(CH ２ ) ３ OH, -NH(CH ２ ) ２ OMe, -NH(CH ２ ) ３ OMe, -N(Me)(CH ２ ) ２ F, -N(Me)(CH ２ ) ３ F, -N(Me)(CH ２ ) ２ OH, -N(Me)(CH ２ ) ３ OH, -N(Me)(CH ２ ) ２ -OMe, and -N(Me)(CH ２ ) ３ 10. The compound according to claim 8 or 9, selected from OMe.

11. R １ The compound according to any one of claims 1 to 6, wherein is selected from the following group: 【Chemistry 4】 (In the formula, R ５ａ is hydrogen, C １－６ Alkyl group, optionally substituted C ５－６ A cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O.

12. R １ is of the formula -CH ２ -R １ａ or -CH ２ -CH ２ -R １ａ (In the formula, R １ａ is an optionally substituted heterocycloalkyl group having 5 or 6 ring atoms independently selected from C, N, and O; or an optionally substituted heteroaryl group having 5 or 6 ring atoms independently selected from C, N, S, and O.

13. The optional substituents are １－４ Alkyl and C １－４ 13. The compound of claim 8, 9, 11 or 12, independently selected from heteroalkyl.

14. The compound according to claim 1, selected from the following compounds or salts or solvates thereof: 7-chloro-2-(2,6-difluorophenyl)-N-((1r,4r)-4-morpholinocyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)-N4,N4-dimethylcyclohexane-1,4-diamine; (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)cyclohexane-1,4-diamine; 7-chloro-2-(2,6-difluorophenyl)-N-((1r,4r)-4-(piperidin-1-yl)cyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; 7-chloro-2-(2,6-difluorophenyl)-N-((1r,4r)-4-(pyrrolidin-1-yl)cyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)-N4-(2-methoxyethyl)cyclohexane-1,4-diamine; (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)-N4-(2-fluoroethyl)cyclohexane-1,4-diamine; (1r,4r)-N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)-N4-(3-fluoropropyl)cyclohexane-1,4-diamine; 7-chloro-2-(2,6-difluorophenyl)-N-(1-isopropylpiperidin-4-yl)imidazo[2,1-f][1,2,4]triazin-4-amine; 7-chloro-2-(2,6-difluorophenyl)-N-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)imidazo[2,1-f][1,2,4]triazin-4-amine; 7-chloro-N-(1-cyclopentylpiperidin-4-yl)-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-amine; 7-chloro-2-(2,6-difluorophenyl)-N-(1-methylpiperidin-4-yl)imidazo[2,1-f][1,2,4]triazin-4-amine; [7-chloro-2-(2,6-difluoro-phenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-(1-methyl-piperidin-2-ylmethyl)-amine; 7-chloro-2-(2,6-difluorophenyl)-N-((1-ethylpyrrolidin-2-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; [7-chloro-2-(2,6-difluorophenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-piperidin-4-yl-amine; [7-chloro-2-(2,6-difluorophenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-(1-methyl-piperidin-4-ylmethyl)-amine; (1-Aza-bicyclo[2.2.2]oct-3-yl)-[7-chloro-2-(2,6-difluoro-phenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-amine; [7-chloro-2-(2,6-difluoro-phenyl)-imidazo[2,1-f][1,2,4]triazin-4-yl]-(2-morpholin-4-yl-ethyl)-amine; tert-butyl 3-(((7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)amino)methyl)piperidine-1-carboxylate; 7-chloro-2-(2,6-difluorophenyl)-N-(piperidin-4-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-amine; 7-chloro-2-(2,6-difluorophenyl)-N-(piperidin-3-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-amine; N1-(7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)cyclopentane-1,3-diamine; 7-chloro-2-(2-chloro-6-fluorophenyl)-N-((1r,4r)-4-morpholinocyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; 7-chloro-2-(2,6-dichlorophenyl)-N-((1r,4r)-4-morpholinocyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine; 2-(((1r,4r)-4-((7-chloro-2-(2,6-difluorophenyl)imidazo[2,1-f][1,2,4]triazin-4-yl)amino)cyclohexyl)amino)ethan-1-ol; 7-chloro-2-(2,6-difluorophenyl)-N-(pyridin-3-ylmethyl)imidazo[2,1-f][1,2,4]triazin-4-amine; 7-chloro-2-(2,6-difluorophenyl)-N-((4,6-dimethylpyridin-3-yl)methyl)imidazo[2,1-f][1,2,4]triazin-4-amine; and 7-Chloro-2-(2,6-difluorophenyl)-N-((1r,4r)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[2,1-f][1,2,4]triazin-4-amine.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and optionally containing one or more carrier substances and / or one or more adjuvants.

16. One or more diseases in which aberrant CDK9 regulation is observed, such as a wide range of cytokine-induced inflammatory diseases, and autoimmune diseases, local or systemic viral infections, viral infections of the eye, viral respiratory infections, or viral infections of the central and / or peripheral nervous system caused by DNA and / or RNA viruses, as well as various non-solid and solid malignancies, cancers, or hyperproliferative diseases, such as acute myeloid leukemia, chronic lymphocytic leukemia, relapsed multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, acute biphenotypic leukemia, intermediate-grade MYC-driven B-cell lymphoma, primary peritoneal carcinoma, Kaposi's sarcoma, advanced breast cancer, non-small cell lung cancer, colorectal cancer, or liver cancer, such as hepatocellular carcinoma, cervical intraepithelial neoplasia, prostate cancer, melanoma, glioma, glioblastoma, neuroblastoma, astrocytoma, anaplastic astrocytoma, or glioblastoma, such as 16. A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15, for example for use in the treatment of progressive and / or metastatic hematological / solid malignancies, in particular for use in the treatment of hematological malignancies or solid tumours caused by aberrant expression of MYC- or MCL-1; or for use as a modulator of the immune response, as well as for the treatment and / or prevention of mechanical / trauma-induced inflammation, such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory diseases, such as inflammatory diseases of the gastrointestinal or urinary tract, and ocular inflammatory diseases, such as Sjogren's disease and glaucoma, bacterial-induced inflammatory diseases, such as gingivitis, periodontitis, and for the treatment and / or prevention of cardiovascular diseases, such as cardiac hypertrophy, dilated cardiomyopathy, atherosclerosis, and cardiometabolic diseases, such as obesity and diabetes.

17. A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for use in the treatment of local or systemic viral infections, ocular viral infections, viral respiratory infections or viral infections of the central and / or peripheral nervous system caused by DNA and / or RNA viruses.

18. A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for use in the treatment of various non-solid and solid malignancies, cancers or hyperproliferative diseases, such as acute myeloid leukemia, chronic lymphocytic leukemia, relapsed multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, acute biphenotypic leukemia, aggressive MYC-driven B-cell lymphoma, primary peritoneal carcinoma, Kaposi's sarcoma, advanced breast cancer, non-small cell lung cancer, colorectal cancer or liver cancer such as hepatocellular carcinoma, cervical intraepithelial neoplasia, prostate cancer, melanoma, glioma, glioblastoma, neuroblastoma, astrocytoma, anaplastic astrocytoma or glioblastoma, for example progressive and / or metastatic hematological / solid malignancies, in particular for use in the treatment of hematological malignancies or solid tumors caused by aberrant expression of MYC- or MCL-1.

19. A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for use in the treatment of inflammation-related diseases, including a wide range of cytokine-induced inflammatory diseases and autoimmune diseases, or for use as a modulator of the immune response, and for the treatment and / or prevention of mechanical / trauma-induced inflammation, such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory diseases, such as inflammatory diseases of the gastrointestinal or urinary tract, and inflammatory diseases of the eye, such as Sjogren's disease and glaucoma, bacterial-induced inflammatory diseases, such as gingivitis, periodontitis, and for the treatment and / or prevention of cardiovascular diseases, such as dilated cardiomyopathy, atherosclerosis, cardiac hypertrophy, and cardiometabolic diseases, such as obesity and diabetes.

20. A compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for use in the treatment of a combination of two or more diseases according to any one of claims 17 to 19.

21. One or more diseases in which aberrant CDK9 regulation is observed, such as a wide range of cytokine-induced inflammatory diseases, and autoimmune diseases, local or systemic viral infections, viral infections of the eye, viral respiratory infections, or viral infections of the central and / or peripheral nervous system caused by DNA and / or RNA viruses, as well as various non-solid and solid malignancies, cancers, or hyperproliferative diseases, such as acute myeloid leukemia, chronic lymphocytic leukemia, relapsed multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, acute biphenotypic leukemia, intermediate-grade MYC-driven B-cell lymphoma, primary peritoneal carcinoma, Kaposi's sarcoma, advanced breast cancer, non-small cell lung cancer, colorectal cancer, or liver cancer, such as hepatocellular carcinoma, cervical intraepithelial neoplasia, prostate cancer, melanoma, glioma, glioblastoma, neuroblastoma, astrocytoma, anaplastic astrocytoma, or glioblastoma, such as advanced and / or metastatic hematological / solid malignancies, in particular for use in the treatment of hematological malignancies or solid tumors caused by aberrant expression of MYC- or MCL-1; or for use as a modulator of the immune response, as well as for the treatment and / or prevention of mechanical / trauma-induced inflammation, such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory diseases, such as inflammatory diseases of the gastrointestinal or urinary tract, and ocular inflammatory diseases, such as Sjogren's disease and glaucoma, bacterial-induced inflammatory diseases, such as gingivitis, periodontitis, and for the treatment and / or prevention of cardiovascular diseases, such as cardiac hypertrophy, dilated cardiomyopathy, atherosclerosis, and cardiometabolic diseases, such as obesity and diabetes.

22. Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment of a local or systemic viral infection, an ocular viral infection, a viral respiratory infection or a viral infection of the central nervous system and / or peripheral nervous system caused by a DNA virus and / or an RNA virus.

23. Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment of various non-solid and solid malignancies, cancers or hyperproliferative diseases, such as acute myeloid leukemia, chronic lymphocytic leukemia, relapsed multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, acute biphenotypic leukemia, aggressive MYC-driven B-cell lymphoma, primary peritoneal carcinoma, Kaposi's sarcoma, advanced breast cancer, non-small cell lung cancer, colorectal cancer or liver cancer such as hepatocellular carcinoma, cervical intraepithelial neoplasia, prostate cancer, melanoma, glioma, glioblastoma, neuroblastoma, astrocytoma, anaplastic astrocytoma or glioblastoma, for example progressive and / or metastatic hematological / solid malignancies, in particular for use in the treatment of hematological malignancies or solid tumors caused by aberrant expression of MYC- or MCL-1.

24. 16. Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment of inflammation-related diseases, including a wide range of cytokine-induced inflammatory diseases and autoimmune diseases, or for use as a modulator of the immune response, and for use in the treatment and / or prevention of mechanical / trauma-induced inflammation, such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory diseases, such as inflammatory diseases of the gastrointestinal or urinary tract, and inflammatory diseases of the eye, such as Sjogren's disease and glaucoma, bacterial-induced inflammatory diseases, such as gingivitis, periodontitis, and for the treatment and / or prevention of cardiovascular diseases, such as dilated cardiomyopathy, atherosclerosis, cardiac hypertrophy, and cardiometabolic diseases, such as obesity and diabetes.

25. Use of a compound according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment of a combination of two or more diseases according to any one of claims 22 to 24.

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