Novel CDK9 inhibitors

Abstract

The present invention relates to novel compounds of formula (I). These compounds 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] TIFF2025532289000032.tif45170

Description

[Technical Field]

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

[0002] Cyclin-dependent kinases (CDKs) are members of the serine / threonine kinase family and exert their catalytic function by forming heterodimers with regulatory subunits, cyclins. CDK family members can be classified into cyclic CDKs and transcriptional CDKs according to their functions. The former include CDK1 / 2 / 4 / 6, which primarily control cell cycle processes; the latter include CDK7 / 8 / 9, which primarily regulate mRNA transcription and processing (Malumbres M. et al., Genome Biol., 2014, 15:122). Overexpression or enhanced function of transcriptional CDKs leads to a significant increase in the expression of certain downstream genes, particularly the anti-apoptotic protein Mcl-1, which leads to tumorigenesis (Morales F. et al., Cell Cycle, 2016, 15:519-27). Recently, 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 considerable attention (Krystof V. et al., Target, Curr. Pharm. Des., 2012, 18:2883-2890). Studies have shown that overexpression of CDK9 is associated with the development of various tumors, inflammation, and viral replication, including acute myeloid leukemia, breast cancer, colorectal cancer, and prostate cancer, as well as human immunodeficiency virus and adenovirus (Franco LC et al., J. Cell Biochem., 2017, 119:1273-1284). These findings suggest that CDK9 is an effective target for cancer treatment. First-generation pan-CDK inhibitors introduced into clinical practice include flavopiridol, dinaciclib, SNS-032, and CYC065, but all exhibited clinical side effects due to their lack of selectivity for a broad range of CDKs. In recent years, pharmaceutical research has focused primarily on identifying and developing selective CDK9 inhibitors. These are currently in preclinical and early clinical studies, such as BAY-1143572, KB-0742 and AZD4573. [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 [Non-patent document 3] Krystof V. et al., Target, Curr. Pharm. Des., 2012, 18:2883~2890 [Non-patent document 4] Franco LC et al., J. Cell Biochem., 2017, 119:1273-1284 Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention is to provide novel inhibitors of CDK9 that overcome the drawbacks of prior art compounds. In particular, the object was to increase selectivity for CDK9 and improve drug discoverability. 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. This object has been achieved by the compounds of the present invention. The present invention provides CDK9 small molecule inhibitors containing an imidazopyridazine structure. [Means for solving the problem]

[0005] The present invention provides one or more compounds of formula (I) or salts thereof:

[0006] [ka]

[0007] (In the formula, R1 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; all of these groups may be optionally substituted; R2 is an optionally substituted phenyl group; R3 is a halogen atom; R4 is a hydrogen atom or a halogen atom).

[0008] Preferably, R4 is H or Cl.

[0009] More preferably, R4 is H.

[0010] More preferably, R3 is Cl.

[0011] More preferably, R2 is a phenyl group substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br and Me.

[0012] More preferably, R2 is a phenyl group substituted at the 2- and 6-positions (ie, a phenyl group having two ortho substituents).

[0013] Most preferably, R2 is a 2,6-difluorophenyl group.

[0014] Preferably, R1 is an optionally substituted C 3~7a 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 a group of the formula -CH2-Het, where Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms independently selected from C, N, O, and S.

[0015] More preferably, R1 is an optionally substituted C 3~7 a cycloalkyl group, an optionally substituted heterocycloalkyl group containing 3 to 9 ring atoms independently selected from C, N, and O, or a group of the formula -CH2-Het, where Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms selected from C, N, O, and S.

[0016] Even more preferably, R1 is selected from the following groups:

[0017] [ka]

[0018] (In the formula, R 5 is NH2, C 1~8 a heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N, and O; and R 5a is hydrogen, C 1~6 Alkyl group, C 1~8 Heteroalkyl 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).

[0019] More preferably, R1 is selected from the following groups:

[0020] [ka]

[0021] (In the formula, R 5 is NH2, 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; and R 5a is hydrogen, C ~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).

[0022] Even more preferably, R 5a is hydrogen, C 1~6 Alkyl groups or groups of the formula -SO 2- C 1~6 Alkyl, -CONH-C l~6 Alkyl or -COO-C l~6 alkyl groups; or 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.

[0023] More preferably, R 5 is a group of formula -N(CH2CH2)2NMe, NH2, -N(CH2CH2)2O or -NMe2.

[0024] More preferably, R 5a is a group of formula -Me, -SO2Me or -COOtBu.

[0025] Even more preferably, R1 is a group of formula -CH2-Het, where Het is an optionally substituted pyridyl group.

[0026] More preferably, the optional substituents on the R1 group are independently selected from -N(CH2CH2)2NMe, -N(CH2CH2)2O, NH2, -NMe2, -Me, -SO2Me, and -COOtBu.

[0027] More preferably, R1 is an optionally substituted heteroalkyl group containing 1 to 12 carbon atoms and 1 to 6 heteroatoms selected from N, O and S.

[0028] More preferably, R1 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.

[0029] More preferably, R1 is selected from the following group:

[0030] [ka]

[0031] (In the formula, R 5 is the -NH2 group, C 1~6 heteroalkyl or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N and O).

[0032] Preferably, R 5is selected from the following groups: -NH, -NMe, pyrrolidinyl, piperidinyl, morpholinyl, -NH(CH)F, -NH(CH)F, -NH(CH)OH, -NH(CH)OH, -NH(CH)OMe, -NH(CH)OMe, -N(Me)(CH)F, -N(Me)(CH)F, -N(Me)(CH)OH, -N(Me)(CH)OH, -N(Me)(CH)OMe, and -N(Me)(CH)OMe.

[0033] More preferably, R1 is selected from the following group: [ka]

[0034] (In the formula, R 5a is hydrogen, C 1~6 Alkyl group, C 1~8 Heteroalkyl 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, R1 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 3~7a 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] More preferably, R 6b is hydrogen.

[0040] More preferably, R 6 is a methyl group, a group of formula —C(CH 3 ) 2 CN, an optionally substituted cyclohexyl group, an optionally substituted piperidinyl group, or a tetrahydropyranyl group.

[0041] More preferably, R 6 is the formula -Cy-LR 6c 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 6c is optionally replaced by C 3~7 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] Even more 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, R1 has the following structure:

[0045] [ka]

[0046] (In the formula, R 7a is hydrogen, halogen, CN or -OC 1~4 is an alkyl group; R 7b is hydrogen, halogen, CN or -OC 1~4 is an alkyl group, and R 7 is C 1~6 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] Further R 7a is hydrogen, fluorine, CN or -OC 1~4 It is an alkyl group; preferably it is hydrogen.

[0049] Even more 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 optionally replaced by C 3~7A cycloalkyl group or an optionally substituted heterocycloalkyl group containing 3 to 7 ring atoms independently selected from C, N, and O.

[0051] More preferably, R 7 is the formula -CO-R 7d or -CO-NH-R 7d where R 7d is C 1~4 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, R1 is of the formula -CH2-R 1a or -CH2-CH2-R 1a (wherein R 1a is an optionally substituted heterocycloalkyl group having 5 or 6 ring atoms independently selected from C, N, and O) (preferably R 1a Any substituent of C 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 (eg, any embodiment of R1 can be combined with any embodiment of R2). DETAILED DESCRIPTION OF THE INVENTION

[0055] The term alkyl refers to a saturated straight-chain or saturated 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, a methyl (Me, CH3), 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 group.

[0056] C 1~6 The term alkyl refers to a saturated straight-chain or branched-chain hydrocarbon group containing 1 to 6 carbon atoms. 1~4 The term alkyl refers to saturated straight-chain or branched-chain hydrocarbon groups containing 1 to 4 carbon atoms. Examples are methyl, 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, straight-chain 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 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 group or a trifluoromethyl group.

[0059] The term heteroalkyl refers to an alkyl, alkenyl, or alkynyl group 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 SO groups. The term heteroalkyl also 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). 1~8 The term heteroalkyl refers to a heteroalkyl group containing 1 to 8 carbon atoms and 1, 2, 3, 4 or 5 heteroatoms selected from O, S and / or N (especially O and / or N). 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 groups of the formula: R a -OY a -, R a -SY a -, Ra -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-Y a -、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 -, where R a is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; R b is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; R c is a hydrogen atom, a C1-C6 alkyl group, C 2~ a C6 alkenyl group or a C2-C6 alkynyl group; R d is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group; and Ya is a bond, a C1-C6 alkylene group, a C2-C6 alkenylene group, or a C2-C6 alkynylene group, where each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by a fluorine or chlorine atom.

[0062] Specific examples of heteroalkyl groups include methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, n-butoxy, tert-butyloxy, methoxymethyl, -CH2CH2OH, -CH2OH, -SO2Me, -NHAc, -C(CH3)2CN, and -COO t Bu, 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 (especially 3, 4, 5, 6, or 7) ring carbon atoms. Furthermore, the term cycloalkyl refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine, or iodine atoms, or by OH, ═O, SH, ═S, NH, ═NH, N, or NO groups, and thus refers to cyclic ketones such as, for example, 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) and containing 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 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 an SO or SO group. Heterocycloalkyl groups preferably have one or two rings and 3 to 10 (in particular 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). Furthermore, the term heterocycloalkyl refers to groups substituted by fluorine, chlorine, bromine or iodine atoms or by OH, ═O, SH, ═S, NH, ═NH, N or NO groups. Examples are piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g., —N(CHCH)O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl groups, and also lactams, lactones, cyclic imides and cyclic anhydrides.

[0065] The term alkylcycloalkyl refers to groups containing both a cycloalkyl group and an alkyl, alkenyl or alkynyl group as defined above, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. The alkylcycloalkyl group preferably contains 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 term "heteroalkylcycloalkyl" refers to an alkylcycloalkyl group as defined above, in which one or more (preferably one, two, or three) carbon atoms have been replaced by oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms (preferably by oxygen, sulfur, or nitrogen atoms) or by an SO or SO 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, where the cyclic groups are saturated or mono-, di-, or tri-unsaturated.

[0067] The term aryl refers to an aromatic group 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, NH, N or NO 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 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, N, NH or NO 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 group), oxazolyl group, isoxazolyl group, triazolyl group, tetrazolyl group, isoxazolyl group, indazolyl group, indolyl group, benzimidazolyl group, benzoxazolyl group, benzisoxazolyl group, benzthiazolyl group, pyridazinyl group, quinolinyl group, isoquinolinyl group, pyrrolyl group, purinyl group, carbazolyl group, acridinyl group, pyrimidyl group, 2,3'-bifuryl group, pyrazolyl group (e.g., 3-pyrazolyl group), and isoquinolinyl group.

[0069] The term "aralkyl" refers to groups containing both an aryl group as defined above and an alkyl, alkenyl, alkynyl and / or cycloalkyl group as defined above, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyl groups are phenylcyclopentyl, cyclohexylphenyl, and groups derived from toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, cumene, fluorene and indane. The aralkyl group preferably comprises one or two aromatic ring systems (especially one or two rings) 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 and alkyl, alkenyl, alkynyl and / or heteroalkyl groups, and / or cycloalkyl and / or heterocycloalkyl groups, in accordance with the above definitions. Heteroaralkyl groups preferably contain one or two aromatic ring systems (especially one or two rings), 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 and 1, 2, 3 or 4 oxygen, sulphur or nitrogen atoms.

[0071] Examples of heteroaralkyl groups include 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, heteroarylheteroalkyl-cycloalkenyl groups, and heteroarylheteroalkylheterocycloalkyl groups, where the cyclic group is saturated or mono-, di-, or tri-unsaturated. Specific examples include tetrahydroisoquinolinyl groups, benzoyl groups, phthalidyl groups, 2- or 3-ethylindolyl groups, 4-methylpyridino groups, 2-, 3-, or 4-methoxyphenyl groups, 4-ethoxyphenyl groups, and 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.

[0073] According to preferred embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl groups described herein may be optionally 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 may be joined to each other through single or double bonds, or the rings may be annulated, fused, or bridged.

[0076] For example, the suffix "-ene," as 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 includes multiple substituents, the substituents are independently selected, i.e., they can be the same or different.

[0079] When a group is 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 substituents include fluorine, chlorine, bromine, and iodine, as well as OH, SH, NH, -SOH, -SONH, -COOH, -COOMe, -COMe(Ac), -NHSOMe, -SONMe, -CHNH, -NHAc, -SOMe, -COO t Bu group, NM e2 -Me group, -N(CH2CH2)2NMe group, -N(CH2CH2)2O 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, C1-C 11 Heteroaralkyl groups are more preferred, and C1-C6 alkyl groups and C1-C6 heteroalkyl groups are more preferred.

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

[0083] Further preferred substituents are halogen atoms (e.g., F, Cl, Br) and -OH groups, -NH groups, -CN groups, -C groups. 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 pharmaceutically acceptable ester, prodrug, hydrate or solvate thereof, optionally in combination with a pharmaceutically 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 of the diseases identified herein.

[0087] Preferably, the compounds of the present invention can be used in the treatment and / or prevention of the following conditions: Diseases in which aberrant CDK (particularly CDK9 and / or CDK2) 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, and various non-solid and solid malignancies, cancers, or hyperproliferative diseases, e.g., 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 hepatocellular carcinoma such as hepatocellular carcinoma, cervical intraepithelial neoplasia, prostate cancer, melanoma, glioma, glioblastoma, neuroblastoma, astrocytoma, anaplastic astrocytoma, or glioblastoma, for example, advanced and / or metastatic hematologic / solid malignancies. In particular, the compounds can be used to treat hematologic malignancies or solid tumors caused by aberrant expression of MYC or MCL-1. Furthermore, the compounds can be used as modulators of immune responses, 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 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 in accordance with 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 being treated. Determination of a therapeutically effective amount is within the skill of those in the art.

[0089] The therapeutically effective amount or dosage of a compound according to the invention may 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 particular compound administered, the route of administration, the condition being treated, and the patient being treated.

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

[0091] The compounds of formula (I) may be solvated, in particular hydrated. Hydration may occur during the production process or as a result of the hygroscopic nature of the compounds of formula (I), which 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 designated as cis / trans isomers or more commonly as (E) and (Z) isomers), only one of which may be specifically mentioned or depicted in the following description, or different optical isomers (usually designated 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. Because compounds of formula (I) may contain asymmetric C atoms, they may exist as either 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 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 without significantly or completely changing 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. Therefore, 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 that is cleaved under physiological conditions, such as an alkoxy, arylalkyloxy, acyl, acyloxymethyl group (e.g., pivaloyloxymethyl), a 2-alkyl, 2-aryl, or 2-arylalkyl-oxycarbonyl-2-alkylideneethyl group, or an acyloxy group, such as ethoxy, benzyloxy, acetyl, or acetyloxy, or, in particular, in the case of a compound of formula (I) bearing a hydroxy group (-OH): sulfate, phosphate (-OPO or -OCHOPO) or an ester of an amino acid, as defined herein. Particularly preferred are prodrugs of the hydroxy group of the compound of formula (I).

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

[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 compounds of formula (I), their solvates, salts, or formulations are also included within the scope of the present invention. Generally, compounds of formula (I), alone or in combination with any other therapeutic agent, are administered by using known and art-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, e.g., soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups; parenterally, for example, by intravenous, intramuscular and subcutaneous injection, e.g., as injectable solutions or suspensions; rectally as suppositories; by inhalation or insufflation, for example, as a powder formulation, as microcrystals or as a spray (e.g., liquid aerosol); transdermally, for example, via a transdermal delivery system (TDS) such as a plaster containing the active ingredient; or intranasally. For the preparation of tablets, pills, semisolids, coated tablets, sugar-coated tablets, and hard (e.g., gelatin) capsules, therapeutically useful products can be mixed with pharmaceutically inert inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salts, and skim milk powder. For the preparation of soft capsules, excipients such as vegetable oils, petroleum oils, animal oils, or synthetic oils, waxes, fats, and polyols can be used. For the preparation of solutions, emulsions, 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. Lipids are particularly preferred, and more preferred are phospholipids (naturally derived, preferably with a particle size of 300-350 nm) in phosphate-buffered saline (pH 7-8, preferably 7.4). For suppositories, excipients can be, for example, vegetable oil, petroleum, animal or synthetic oil, wax, fat, and polyol.For aerosol preparations, suitable compressed gases for this purpose can be used, for example, oxygen, nitrogen, and carbon dioxide.The pharmaceutically useful agent can also contain additives for preservation and stabilization, such as UV stabilizers, emulsifiers, sweeteners, flavorings, salts for changing osmotic pressure, buffers, coating additives, and antioxidants.

[0099] Generally, for oral or parenteral administration to an adult weighing approximately 80 kg, a daily dose of about 10 mg to about 10,000 mg, preferably about 20 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded if indicated. The daily dose can be administered as a single dose or in divided doses, and for parenteral administration, it may be given as continuous infusion or subcutaneous injection.

[0100] According to an even 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 pharmaceutically acceptable salt 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 therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. [Example]

[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.

[0103] Microwave conditions: Reactions under microwave conditions are carried out in a Biotage initiator® microwave system.

[0104] 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, Gilson 215 liquid handler, SunFire Prep C18 OBD 5 μm, 19x50 mm 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 One G7170B 1290 Infinity II MS flow modulator, one G6125B MSD 6100 Series single quadrupole, G1948B electrospray interface, and three G1170A 1290 Infinity valve drives (a 14-port, 6-position valve head for analytical column selection; a 14-port, 6-position valve head for preparative column selection; and a 14-port, 2-position valve head for analytical / preparative mode selection), including a multi-wavelength detector and flow cell (product number G1315-60022, serial number DE185H6157, 10.00 mm path length, 13.00 μl volume).

[0105] 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.

[0106] 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.

[0107] 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.

[0108] Typical times and relative amounts of solvent B and solvent B are shown in Table 1.

[0109] [Table 1]

[0110] Typical preparative method: column flow rate was 60 mL / min, solvent A was acetonitrile, and solvent B was water. The preparation included modifier flows: 10% acetic acid in 1:1 acetonitrile / water, 1.8 mL / min modifier flow rate => acetic acid in flow rate is 0.3%; 0.5 M NH4Ac / NH4OH buffer (pH 9.2) in 1:9 acetonitrile / water => buffer concentration in flow rate is 15 mM.

[0111] MS makeup: 0.9 mL / min 0.05% acetic acid in acetonitrile / water 1:1.

[0112] For example, a typical focusing gradient timetable for a 59.7% elution point is shown in Table 2.

[0113] [Table 2]

[0114] Typical analytical modifiers: column flow rate 1 mL / min, solvent A was acetonitrile, solvent B was water, solvent C was 5% acetic acid in acetonitrile / water 1:1.

[0115] Typical times and relative amounts of solvent A, solvent B, and solvent C are shown in Table 3.

[0116] [Table 3]

[0117] For detection, a mass spectrometer detector (API-ES, positive) at UV 220 nm, 254 nm, or 310 nm was used.

[0118] Terms and abbreviations used in the examples are shown in Table 4.

[0119] [Table 4]

[0120] The analytical HPLC methods used for the preparation of the compounds are shown in Table 5.

[0121] [Table 5]

[0122] General Route A to Imidazopyridazines:

[0123] [ka]

[0124] Description of synthesis steps: Step 1: 6,8-dibromo-3-chloroimidazo[1,2-b]pyridazine;

[0125] [ka]

[0126] 6,8-Dibromoimidazo[1,2-b]pyridazine (1 equiv.) was dissolved in 1,2-dichloroethane and acetonitrile (1 / 1 v / v 16 mL / mmol), followed by the portionwise addition of NCS (1.3 equiv.). The mixture was stirred at room temperature for 3 h. The mixture was quenched with sodium thiosulfate solution (5 M in water), extracted with DCM, dried, filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0127] Step 2: Amination

[0128] [ka] 6,8-Dibromo-3-chloroimidazo[1,2-b]pyridazine (1 equiv.) and the corresponding amine (1 equiv.) were dissolved in dioxane (3 mL / mmol). DIPEA (2.0 equiv.) was added, and the mixture was heated at 180 °C for 30 min under microwave conditions. The mixture was diluted with NaHCO (saturated aqueous solution) and extracted with DCM. The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography. Step 3: Arylation [ka]

[0129] The product from the previous step was dissolved in dioxane (0.5 M). Water (10% v / v) was added. The corresponding boronic acid (1.3 equiv), Pd2(dba)3 (0.2 equiv), X-Phos (0.8 equiv), and K2CO3 (3 equiv) were added. The mixture was degassed with N2 and heated at 80 °C overnight. Additional boronic acid, Pd2(dba)3, and X-Phos (same amount as before) were added and heated at 80 °C. This was repeated until the reaction was complete (HPLC). The mixture was filtered through a plug of Celite, washed with MeOH and water, concentrated, diluted again with water, and extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by gradient flash chromatography followed by preparative reverse-phase HPLC.

[0130] Compounds in Examples #1, #3, #4, #10, #11, #12, #16, #17, #18, and #19 were synthesized using these protocols.

[0131] The compounds of Examples #14 and #15 were synthesized using modifications of these protocols.

[0132] Working Example #15: The compound of Example #16 was dissolved in dry MeOH and treated with HCl (4M in dioxane) for 24 h. The mixture was concentrated under reduced pressure and the crude product was purified by reverse phase HPLC.

[0133] Working Example #14: To the compound of Example #15 in DCM (dry) was added methanesulfonyl chloride (5 eq.) and triethylamine (5 eq.). The mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated under reduced pressure. The mixture was concentrated under reduced pressure, and the crude product was purified by reverse-phase HPLC.

[0134] The compounds of Examples #14, #15, #16, and #18 are racemic mixtures.

[0135] General Route B to Imidazopyridazines:

[0136] [ka]

[0137] Description of synthesis steps: Step 1: Amination

[0138] [ka]

[0139] 8-Bromo-6-chloroimidazo[1,2-b]pyridazine (1 equiv.) and the HCl salt of the corresponding amine (1.2 equiv.) were mixed in dioxane (3 mL / mmol). DIPEA (6.0 equiv.) was added, and the mixture was heated at 180 °C for 30 min under microwave conditions. The mixture was diluted with NaHCO (saturated aqueous solution) and extracted with DCM. The organic layer was dried (NaSO), filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0140] Step 2: Chlorination

[0141] [ka]

[0142] The product of the previous step, dissolved in dioxane, was dissolved in 1,2-dichloroethane and acetonitrile (1 / 1 v / v 16 mL / mmol), followed by the portionwise addition of NCS (1.3 equiv). The mixture was stirred at room temperature for 6 hours and then at 40°C overnight. The reaction was not complete (HPLC). Additional NCS (1 equiv) was added. The mixture was heated at 80°C overnight. Two chlorinated products were observed. The mixture was quenched with sodium thiosulfate solution (5 M in water), extracted with DCM, dried, filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography. The two chlorinated intermediates were not separated.

[0143] Step 3: Arylation

[0144] [ka]

[0145] The product from the previous step was dissolved in dioxane (0.5 M). Water (10% v / v) was added. The corresponding boronic acid (1.3 equiv.), Pd2(dba)3 (0.2 equiv.), X-Phos (0.8 equiv.), and K2CO3 (3 equiv.) were added. The mixture was degassed with N2 and heated at 80 °C overnight. Additional boronic acid, Pd2(dba)3, and X-Phos (same amount as before) were added, followed by heating at 80 °C. This was repeated until the reaction was complete (HPLC). The mixture was filtered through a plug of Celite, washed with MeOH and water, concentrated, diluted again with water, and extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by gradient flash chromatography, followed by preparative reverse-phase HPLC to separate the product from the mixture.

[0146] General Route D to Imidazopyridazines:

[0147] [ka]

[0148] Step 1: Amination

[0149] [ka]

[0150] 6,8-Dibromoimidazo[1,2-b]pyridazine (1 equivalent) and [4-(6-bromo-imidazo[1,2-b]pyridazin-8-ylamino)cyclohexyl]carbamic acid tert-butyl ester HCl salt (1.2 equivalents) were mixed in dioxane (3 mL / mmol). DIPEA (6.0 equivalents) was added, and the mixture was heated at 180 °C for 60 min under microwave conditions. The mixture was diluted with NaHCO3 aq and extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0151] Step 2: Suzuki

[0152] [ka]

[0153] The product of the previous step was dissolved in dioxane (0.5 M). Water (10% v / v) was added. 2,6-Difluorophenylboronic acid (1.3 equiv), Pd(dppf)DCM (0.2 equiv), and aqueous Na2CO3 (1 M) (3 equiv) were added. The mixture was degassed with N2 and heated at 80 °C for 3 h. Additional boronic acid and Pd(dppf)DCM were added, followed by heating at 80 °C. This was repeated until the reaction was complete (HPLC). The mixture was filtered through a plug of Celite, washed with MeOH and water, concentrated, diluted again with water, and extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by gradient flash chromatography.

[0154] The product of the previous step, dissolved in dioxane, was dissolved in 1,2-dichloroethane and acetonitrile (1 / 1 v / v 10 mL / mmol), followed by the portionwise addition of NCS (1.3 equiv.). The mixture was stirred at 80 °C for 5 h. The mixture was quenched with sodium thiosulfate solution (5 M in water), extracted with DCM, dried, filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0155] Step 3: Chlorination

[0156] [ka]

[0157] The product of the previous step, dissolved in dioxane, was dissolved in 1,2-dichloroethane and acetonitrile (1 / 1 v / v 10 mL / mmol), followed by the portionwise addition of NCS (1.3 equiv.). The mixture was stirred at 60 °C for 5 h. The mixture was quenched with sodium thiosulfate solution (5 M in water), extracted with DCM, dried, filtered, and concentrated under reduced pressure. The crude product mixture was used without further purification.

[0158] Step 4: Deprotection

[0159] [ka]

[0160] The mixture from the previous step was dissolved in MeOH (dry) and treated with excess HCl (4M in dioxane). The mixture was stirred at room temperature until completion, then concentrated to dryness and purified by reverse phase HPLC.

[0161] The compounds of Examples #8 and #9 were synthesized using this procedure.

[0162] The amines used were either commercially available, described in the literature, or prepared by one of the following procedures.

[0163] A: 4-(piperidin-1-yl)cyclohexanamine:

[0164] [ka]

[0165] Step 1: The boc-protected diamine was dissolved in acetonitrile. Dibromopentane (2 equiv.) and DIPEA (5 equiv.) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with ammonium chloride (saturated aqueous solution) and water. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC.

[0166] Step 2: The product from Step 1 was dissolved in MeOH and treated with HCl (4 M in dioxane, excess) overnight. The mixture was concentrated and used as the HCl salt without further purification.

[0167] The following intermediates were synthesized according to these protocols:

[0168] [ka]

[0169] The following examples were prepared according to the procedures above.

[0170] Example: Name; HPLC Method; Room Temperature; MH+; NMR

[0171] Example #1: 3-chloro-6-(2,6-difluorophenyl)-N-((1r,4r)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,2-b]pyridazin-8-amine; "HPLC-MS C"; 3.653 min; 461.2;

[0172] Example #3: 3-chloro-6-(2,6-difluorophenyl)-N-((4,6-dimethylpyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-8-amine; HPLC-MS C; 3.93 min; 400.2; 1H NMR (600 MHz, chloroform-d) δ 8.39 (s, 1H), 7.46 (s, 1H), 7.41 (tt, J = 8.4, 6.2 Hz, 1H), 7.07-6.99 (m, 3H), 6.21 (s, 1H), 5.91 (t, J = 5.2 Hz, 1H), 4.46 (d, J = 5.1 Hz, 22H), 2.53 (s, 3H), 2.35 (s, 3H).

[0173] Example #4: 3-chloro-6-(2,6-difluorophenyl)-N-(pyridin-3-ylmethyl)imidazo[1,2-b]pyridazin-8-amine; HPLC-MS C; 3.67 min; 372.0; 1H NMR (600 MHz, chloroform-d) δ 8.64(d,J=2.4Hz,1H),8.60-8.56(m,1H),7.70(dt,J=7.9,2.0Hz,1H),7.50(s,1H),7.39(tt,J=8.5,6.3Hz,1 H),7.31(dd,J=7.9,4.8Hz,1H),7.04-6.97(m,2H),6.34(d,J=6.0Hz,1H),6.12(s,1H),4.59(d,J=5.7Hz,2H).

[0174] Example #8: (1r,4r)-N1-(3,7-dichloro-6-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-yl)cyclohexane-1,4-diamine; "HPLC-MS C"; 3.737 n min; 412.2; "1H NMR (600 MHz, chloroform-d) δ 7.54 (s, 1H), 7.44 (tt, J=8.5, 6.3 Hz, 1H), 7.05-6.99 (m, 2H), 5.17 (m, 2H, CH and NH),4.94(wide width s,2H,NH2),2.98(d,J=12.0Hz,1HH),2.33(d,J=12.6Hz,2H),2.15(d,J=12.7Hz,2H),1.72-1.60(m,2H),1.44-1.34(m,2H).”

[0175] Example #9: (1r,4r)-N1-(3-chloro-6-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-yl)cyclohexane-1,4-diamine; HPLC-MS C: 3.358 min; 378.2; H NMR (800 MHz, chloroform-d) δ 7.84(d,J=1.1Hz,1H),7.62(d,J=1.2Hz,1H),7.46(tt,J=8.3,6.2Hz,1H),7.09-7.02(m,2H),5.23(t,J=10.9Hz,1H),5.18(d,J=9.0Hz,1H,N "

[0176] Example #10: 3-chloro-6-(2,6-difluorophenyl)-N-(1-methylpiperidin-4-yl)imidazo[1,2-b]pyridazin-8-amine; "HPLC-MS C"; 3.480 min; 378.2;

[0177] Example #11: 3-chloro-6-(2,6-difluorophenyl)-N-((1r,4r)-4-morpholinocyclohexyl)imidazo[1,2-b]pyridazin-8-amine; HPLC-MS C; 3.763 min; 448.2; HPLC-MS C; 3.763 min; 448.2; 1H NMR (800 MHz, chloroform-d) δ 7.49(s,1H),7.43(td,J=8.7,4.3Hz,1H),7.05(t,J=7.8Hz,2H),6.10(s,1H),5.72(d,J=8.0Hz,1H) ,3.76-3.73(m,4H),3.44(s,11H),2.59(s,4H),2.29(s,3H),2.07-2.04(m,2H),1.43-1.38(m,4H).”

[0178] Example #12: (1r,4r)-N1-(3-chloro-6-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-yl)-N4,N4-dimethylcyclohexane-1,4-diamine; "HPLC-MS C"; 3.630 min; 406.2;

[0179] Example #14: 3-chloro-6-(2,6-difluorophenyl)-N-(3-methyl-1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-8-amine "HPLC-MS C"; 4.021 min; 456.2.

[0180] Example #15: 3-chloro-6-(2,6-difluorophenyl)-N-(3-methylpiperidin-4-yl)imidazo[1,2-b]pyridazin-8-amine; "HPLC-MS C"; 3.562 min; 378.2.

[0181] Example #16: tert-Butyl-4-((3-chloro-6-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-yl)amino)-3-methylpiperidine-1-carboxylate; "HPLC-MS C"; 4.698 min; 478.2.

[0182] Example #17: 3-chloro-6-(2,6-difluorophenyl)-N-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-8-amine; "HPLC-MS C"; 3.889 min; 442.2.

[0183] Example #18: 3-chloro-6-(2,6-difluorophenyl)-N-(1-methylpyrrolidin-3-yl)imidazo[1,2-b]pyridazin-8-amine; "HPLC-MS C"; 3.416 min; 364.2.

[0184] Example #19: 3-chloro-6-(2,6-difluorophenyl)-N-(1-methylazetidin-3-yl)imidazo[1,2-b]pyridazin-8-amine; "HPLC-MS C"; 4.453 min; 350.2; 1H NMR (400 MHz, chloroform-d) δ 7.52(s,1H),7.41(tt,J=8.2,6.2Hz,1H),7.08-6.99(m,2H),6.03(s,1H),4.50(dd,J=14.5,7.0Hz,1H), 4.10(dd,J=14.2,5.6Hz,1H),3.26(s,3H),3.22(s,2H),3.14(d,J=11.9Hz,1H),2.67(t,J=11.1Hz,1H).”

[0185] Biological data Assay protocol for measuring inhibitory activity Test compounds were evaluated at 12 concentrations in a 1:3 dilution series, starting at a top concentration of 5 μM. Two microliters of 3x concentrated CDK9 / cyclin T1 (ProQinase / Reaction Biology, USA #0371-0345-1, LOT.:012) was added to a white 384 microplate (Greiner bio-one, Austria #784904) at a final concentration (fc) of 6 nM in 1x kinase buffer, followed by 2 microliters of compound (fc 3x concentrated in 1.66% 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, Promega GmbH, Germany #V9102)) was added, mixed and incubated for 120 minutes 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 at room temperature for 40 minutes. In the final 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 minutes 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, Guildford) and fitted to sigmoidal dose-response curves with variable slope.

[0186] CDK9 / T1 ADPGlo activity of the compounds in the above examples:

[0187] IC50<20nM: Example #3, Example #4, Example #10, Example #11, Example #17, Example #18.

[0188] IC50<200nM: Example #1, Example #8, Example #9, Example #12, Example #14, Example #15, Example #16.

Claims

1. A compound of formula (I), or a salt of said compound: 【Chemical 1】 (In the formula, R1 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; all of these groups may be optionally substituted; R2 is an optionally substituted phenyl group; R3 is a halogen atom; R4 is a hydrogen atom or a halogen atom).

2. 2. The compound of claim 1, wherein R4 is H or Cl.

3. The compound of claim 1, wherein R4 is H.

4. 4. The compound of claim 1, wherein R3 is Cl.

5. 5. The compound of claim 1, wherein R2 is a phenyl group substituted with 1, 2, or 3 substituents independently selected from F, Cl, Br, and Me.

6. The compound according to any one of claims 1 to 5, wherein R2 is a 2,6-difluorophenyl group.

7. R1 is an optionally substituted C ３～７ 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 a group of the formula -CH ２ 7. The compound of any one of claims 1 to 6, wherein the group is -Het, where Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms independently selected from C, N, O and S.

8. R1 is an optionally substituted C ３～７ a cycloalkyl group, an optionally substituted heterocycloalkyl group containing 3 to 9 ring atoms independently selected from C, N, and O, or a group of the formula -CH ２ 7. The compound of any one of claims 1 to 6, wherein the group is -Het, where Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms independently selected from C, N, O and S.

9. The compound according to any one of claims 1 to 6, wherein R1 is selected from the following groups: 【Chemistry 2】 (In the formula, R ５ is NH ２ , C １～８ a heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms independently selected from C, N, and O; and R ５ａ is hydrogen, C １～６ Alkyl group, C １～８ Heteroalkyl groups, optionally substituted C ５～６ cycloalkyl groups, or optionally substituted heterocycloalkyl groups containing 5 or 6 ring atoms independently selected from C, N, and O).

10. The compound according to any one of claims 1 to 6, wherein R1 is selected from the following groups: 【Chemistry 3】 (In the formula, R ５ is NH ２ , 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; and R ５ａ is hydrogen, C １～６ alkyl group, optionally substituted C ５～６ cycloalkyl groups, or optionally substituted heterocycloalkyl groups containing 5 or 6 ring atoms independently selected from C, N and O).

11. R1 is a group of the formula -CH ２ 7. The compound of any one of claims 1 to 6, wherein the group is -Het, wherein Het is an optionally substituted pyridyl group.

12. 10. The compound of claim 1 selected from the following compounds or salts thereof: 3-chloro-6-(2,6-difluorophenyl)-N-((1r,4r)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,2-b]pyridazin-8-amine; 3-chloro-6-(2,6-difluorophenyl)-N-((4,6-dimethylpyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-8-amine; 3-chloro-6-(2,6-difluorophenyl)-N-(pyridin-3-ylmethyl)imidazo[1,2-b]pyridazin-8-amine; (1r,4r)-N1-(3,7-dichloro-6-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-yl)cyclohexane-1,4-diamine; (1r,4r)-N1-(3-chloro-6-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-yl)cyclohexane-1,4-diamine; 3-chloro-6-(2,6-difluorophenyl)-N-(1-methylpiperidin-4-yl)imidazo[1,2-b]pyridazin-8-amine; 3-chloro-6-(2,6-difluorophenyl)-N-((1r,4r)-4-morpholinocyclohexyl)imidazo[1,2-b]pyridazin-8-amine; (1r,4r)-N1-(3-chloro-6-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-yl)-N4,N4-dimethylcyclohexane-1,4-diamine; 3-chloro-6-(2,6-difluorophenyl)-N-(3-methyl-1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-8-amine; 3-chloro-6-(2,6-difluorophenyl)-N-(3-methylpiperidin-4-yl)imidazo[1,2-b]pyridazin-8-amine; tert-butyl-4-((3-chloro-6-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-yl)amino)-3-methylpiperidine-1-carboxylate; 3-chloro-6-(2,6-difluorophenyl)-N-(1-(methylsulfonyl)piperidin-4-yl)imidazo[1,2-b]pyridazin-8-amine; 3-chloro-6-(2,6-difluorophenyl)-N-(1-methylpyrrolidin-3-yl)imidazo[1,2-b]pyridazin-8-amine; and 3-chloro-6-(2,6-difluorophenyl)-N-(1-methylazetidin-3-yl)imidazo[1,2-b]pyridazin-8-amine.

13. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, and optionally one or more carrier substances and / or one or more adjuvants.

14. Diseases in which aberrant CDK, particularly CDK9 and / or CDK2, 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 14. A compound according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13, for use in the treatment of glioblastoma, for example an advanced and / or metastatic hematological / solid malignancy (in particular for use in the treatment of a hematological malignancy or solid tumor caused by aberrant expression of MYC- or MCL-1); or 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, for example 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.

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