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 various diseases, including hyperproliferative diseases, virally induced infectious diseases, and cardiovascular diseases. # imgabs0 #

Description

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

[0002] Cyclin-dependent kinases (CDKs) are members of the serine / threonine kinase family, forming heterodimers with regulatory subunit cyclins to perform catalytic functions. Based on functional differences, CDK family members can be divided into cyclic CDKs and transcriptional CDKs. 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 functional enhancement of transcriptional CDKs can significantly increase the expression of specific downstream genes, especially the anti-apoptotic protein Mcl-1, leading to tumorigenesis (Morales F. et al., Cell Cycle, 2016, 15:519–27). In recent years, it has been found that non-selective CDK inhibitors can achieve anti-tumor effects by inhibiting the function of CDK9. Therefore, the study of CDK inhibitors has attracted people's attention (Krystof V. et al., Target, Curr. Pharm. Des., 2012, 18: 2883-2890). Studies have shown that overexpression of CDK9 is associated with the occurrence, inflammation and viral replication of various tumors, 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). These findings show that CDK9 is an effective target for cancer treatment. The first generation of pan-CDK inhibitors that have entered the clinic include Flavopiridol, Dinaciclib, SNS-032 and CYC065, but due to a series of CDK lack of selectivity, clinical side effects are shown. In recent years, the focus of drug research has been on identifying and developing CDK9 inhibitors that are mainly selective. These drugs are currently in preclinical and early clinical research stages, such as BAY-1143572, KB-0742 and AZD4573.

[0003] The object of the present invention is to provide a novel CDK9 inhibitor that overcomes the shortcomings of the compounds in the prior art. A particular object of the present invention is to increase the selectivity for CDK9 and improve drugability. The main object of the present invention is to provide a class of CDK9 small molecule inhibitors that show high efficiency, low toxicity and excellent drug metabolism properties and can be used for disease prevention and / or treatment. The compounds of the present invention have solved this purpose. The present invention provides a CDK9 small molecule inhibitor containing an imidazopyridazine structure.

[0004] The present invention provides one or more compounds represented by formula (I):

[0005]

[0006] in

[0007] R1 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group; all of which may be optionally substituted;

[0008] R2 is an optionally substituted phenyl group;

[0009] R3 is a halogen atom;

[0010] R4 is a hydrogen atom or a halogen atom;

[0011] or a salt thereof.

[0012] Preferably, R4 is H or Cl.

[0013] More preferably, R4 is H.

[0014] More preferably, R3 is Cl.

[0015] Further preferably, R2 is phenyl substituted by 1, 2 or 3 substituents independently selected from F, Cl, Br and Me.

[0016] More preferably, R2 is phenyl substituted at the 2 and 6 positions (ie, phenyl with two ortho substituents).

[0017] Most preferably, R2 is 2,6-difluorophenyl.

[0018] Preferably, R1 is an optionally substituted C 3-7 Cycloalkyl, optionally substituted heterocycloalkyl containing 3 to 9 ring atoms independently selected from C, N and O, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl containing 5 or 6 ring atoms independently selected from C, N, O and S, or a group represented by the formula -CH2-Het, wherein Het is an optionally substituted heteroaryl containing 5 or 6 ring atoms independently selected from C, N, O and S.

[0019] More preferably, R1 is an optionally substituted C 3-7 Cycloalkyl, optionally substituted heterocycloalkyl containing 3 to 9 ring atoms independently selected from C, N and O, or a group represented by the formula -CH2-Het, wherein Het is optionally substituted heteroaryl containing 5 or 6 ring atoms independently selected from C, N, O and S.

[0020] More preferably, R1 is selected from the following group:

[0021]

[0022] Where R 5 NH2, C 1-8 heteroalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O; R 5a For hydrogen, C 1-6 Alkyl, C 1-8 Heteroalkyl, optionally substituted C 5-6 Cycloalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O.

[0023] Further preferably, R1 is selected from the following group:

[0024]

[0025] Where R 5 NH2, C 1-6 heteroalkyl, or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O; R 5a For hydrogen, C 1-6 Alkyl, optionally substituted C 5-6 Cycloalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O.

[0026] More preferably, R 5a For hydrogen, C 1-6 Alkyl, or -SO2-C 1-6 Alkyl, -CONH-C 1-6 Alkyl or -COO-C 1-6 or an optionally substituted C 5-6 Cycloalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O.

[0027] More preferably, R 5 It is a group represented by the formula -N(CH2CH2)2NMe, NH2, -N(CH2CH2)2O or -NMe2.

[0028] More preferably, R 5aFormula -Me, -SO2Me or -COO t The group shown in Bu.

[0029] More preferably, R1 is a group represented by the formula -CH2-Het, wherein Het is an optionally substituted pyridyl group.

[0030] Further preferably, the optional substituents on the group R1 are independently selected from -N(CH2CH2)2NMe, -N(CH2CH2)2O, NH2, -NMe2, -Me, -SO2Me and -COO t Bu.

[0031] Further 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.

[0032] More preferably, R1 is an optionally substituted C 4-6 Cycloalkyl, optionally substituted heterocycloalkyl containing 5 to 8 ring atoms independently selected from C, N and O, optionally substituted phenyl or optionally substituted pyrazol-4-yl group.

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

[0034]

[0035] Where R 5 -NH2 group, C 1-6 Heteroalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O.

[0036] Preferably, R 5 Selected from the following group: -NH2, -NMe2, pyrrolidinyl, piperidinyl, 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.

[0037] More preferably, R1 is selected from the following group:

[0038]

[0039] Where R 5a For hydrogen, C 1-6 Alkyl, C 1-8 Cycloalkyl, optionally substituted C 5-6Cycloalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O.

[0040] Further preferably, R1 has the following structure:

[0041]

[0042] Where R 6a is hydrogen, halogen or C 1-4 Heteroalkyl (especially -OC 1-4 Alkyl); R 6b is hydrogen, halogen or C 1-4 Heteroalkyl (especially -OC 1-4 Alkyl) and R 6 C 1-6 Alkyl, C 1-6 Heteroalkyl, optionally substituted C 3-7 Cycloalkyl or optionally substituted heterocycloalkyl containing 3 to 7 ring atoms independently selected from C, N and O.

[0043] Preferably, R 6a is hydrogen, Cl or OMe.

[0044] More preferably, R 6b For hydrogen.

[0045] More preferably, R 6 It is methyl, a group represented by the formula -C(CH3)2CN, an optionally substituted cyclohexyl, an optionally substituted piperidinyl or a tetrahydropyranyl.

[0046] More preferably, R 6 Formula: -Cy-LR 6c The group shown, wherein Cy is an optionally substituted C 3-7 Cycloalkylene or optionally substituted heterocycloalkylene containing 3 to 7 ring atoms independently selected from C, N and O; L is a bond or a CH2 group and R 6c is an optionally substituted C 3-7 Cycloalkyl or optionally substituted heterocycloalkyl containing 3 to 7 ring atoms independently selected from C, N and O.

[0047] More preferably, Cy is cyclohexylene or piperidinylene.

[0048] More preferably, R 6c is cyclopropyl or optionally substituted heterocycloalkyl containing 4 to 6 ring atoms independently selected from C, N and O.

[0049] Further preferably, R1 has the following structure:

[0050]

[0051] Where R 7a is hydrogen, halogen, CN or -OC 1-4 Alkyl; R 7b is hydrogen, halogen, CN or -OC 1-4 Alkyl, R 7 C 1-6 heteroalkyl, optionally substituted heterocycloalkyl containing 3 to 7 ring atoms independently selected from C, N and O, or optionally substituted heteroalkylcycloalkyl containing 4 to 12 atoms independently selected from C, N and O.

[0052] Preferably, R 7b is hydrogen or methoxy; preferably hydrogen.

[0053] More preferably, R 7a is hydrogen, fluorine, CN or -OC 1-4 Alkyl; preferably hydrogen.

[0054] More preferably, R 7 is optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted morpholinyl or optionally substituted tetrahydropyridinyl.

[0055] More preferably, R 7 Formula: -Cy'-L'-R 7c The group shown, wherein Cy' is an optionally substituted C 3-7 Cycloalkylene or optionally substituted heterocycloalkylene containing 3 to 7 ring atoms independently selected from C, N and O; L' is a bond or a CH2 group, R 7c is an optionally substituted C 3-7 Cycloalkyl or optionally substituted heterocycloalkyl containing 3 to 7 ring atoms independently selected from C, N and O.

[0056] More preferably, R 7 Formula: -CO-R 7d or -CO-NH-R 7d The group shown, where R 7d C 1-4 Alkyl or optionally substituted heterocycloalkylene containing 3 to 7 ring atoms independently selected from C, N and O.

[0057] More preferably, R1 is of the formula -CH2-R 1a or -CH2-CH2-R 1a The group shown, where R 1a is an optionally substituted heterocycloalkyl group having 5 or 6 ring atoms independently selected from C, N and O (preferably, in R 1a The optional substituent on is C 1-4 alkyl).

[0058] The most preferred compounds of the present invention are the compounds disclosed in the Examples or their salts.

[0059] Furthermore, the preferred embodiments of the present invention may be combined in any desired manner (eg, R1 in any embodiment may be combined with R2 in any embodiment).

[0060] Alkyl refers to a saturated straight-chain or branched 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, for example 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, n-octyl.

[0061] C 1-6 Alkyl refers to a saturated straight or branched hydrocarbon group containing 1 to 6 carbon atoms. 1-4 Alkyl refers to a saturated straight or branched hydrocarbon group containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

[0062] Alkenyl and alkynyl are at least partially unsaturated straight-chain or branched hydrocarbon radicals 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, for example vinyl (vinyl), propenyl (allyl), isopropenyl, butenyl, ethynyl (ethynyl), propynyl (e.g. propargyl), butynyl, isopentenyl or hex-2-enyl. Preferably, alkenyl has one or two (particularly preferably one) double bonds and alkynyl has one or two (particularly preferably one) triple bonds.

[0063] Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms are replaced by halogen atoms, preferably F or Cl, such as, for example, 2,2,2-trichloroethyl or trifluoromethyl groups.

[0064] 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 SO2 groups. Heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as an acyl group, an acylalkyl group, an alkoxycarbonyl group, an acyloxy group, an acyloxyalkyl group, a carboxyalkylamide or an alkoxycarbonyloxy group. In addition, the term heteroalkyl refers to a group in which one or more hydrogen atoms are replaced by a halogen atom (preferably F or Cl).

[0065] 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 (such as 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). The term C 1-8 Heteroalkyl refers to heteroalkyl groups 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 Heteroalkyl refers to heteroalkyl groups 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 Heteroalkyl refers to heteroalkyl groups containing 1 to 4 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S and / or N (especially O and / or N).

[0066] Examples of heteroalkyl groups include groups of the formula: R a -OY a -、R a -SY 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-OY 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-OY a -、-Y a -CN、R a -N(Rb )-CO-N(R c )-Y a -、R a -O-WHAT-OY 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-OY 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-WHAT-Y a -、R a -WHAT-S-Y a -、R a -S-CO-N(R b )-Y a -、R a -N(R b )-WHAT-S-Y a -、R a -S-CO-OY a -、R a -O-WHAT-S-Y a -、R a -S-WHAT-S-Y 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, a C2-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, Y a For key, C 1- C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, wherein each heteroalkyl group includes at least one carbon atom and one or more hydrogen atoms which may be substituted by fluorine or chlorine atoms.

[0067] Specific examples of heteroalkyl are methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, methoxymethyl, -CH2CH2OH, -CH2OH, -SO2Me, -NHAc, -C(CH3)2CN, -COO t In some embodiments, the alkyl radicals of the present invention include alkyl radicals of the present invention, such as alkyl radicals of the present invention, ...

[0068] Cycloalkyl refers to a saturated or partially unsaturated (e.g. cycloalkenyl) cyclic group containing one or more rings (preferably 1 or 2) and 3 to 14 cyclic carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) cyclic carbon atoms. Cycloalkyl also refers to a group 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, thus, for example, cyclic ketones such as cyclohexanone, 2-cyclohexanone or cyclopentanone. More specific examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetrahydronaphthyl, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl. Preferably, cycloalkyl refers to a saturated cyclic group containing one or more rings (preferably 1 or 2) and containing 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.

[0069] Heterocycloalkyl refers to a cycloalkyl group as defined above, wherein one or more (preferably 1, 2 or 3) ring carbon atoms are substituted by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably oxygen, sulfur or nitrogen atoms) or SO groups or SO2 groups. Heterocycloalkyl preferably has 1 or 2 rings and 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). Heterocycloalkyl also refers to a group substituted by a fluorine, chlorine, bromine or iodine atom or an OH, =O, SH, =S, NH2, =NH, N3 or NO2 group. For example, piperidinyl, proline, imidazolidinyl, piperazinyl, morpholinyl (such as -N(CH2CH2)2O), urotropine, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrofuranyl or 2-pyrazolinyl, as well as lactam, lactone, cyclic imine and cyclic anhydride groups.

[0070] Alkylcycloalkyl refers to a group containing both a cycloalkyl group and an alkyl, alkenyl or alkynyl group as defined above, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl. Alkylcycloalkyl preferably comprises 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.

[0071] Assorted alkylcycloalkyl refers to alkylcycloalkyl as defined above, wherein one or more (preferably 1,2 or 3) carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulphur atom (preferably oxygen, sulphur or nitrogen atom) or SO group or SO2 group.Assorted alkylcycloalkyl preferably comprises 1 or 2 rings with 3 to 10 (particularly 3,4,5,6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or assorted alkyl groups (particularly alkyl or assorted alkyl groups) with 1 or 2 to 6 carbon atoms.The example of this group is alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, assorted alkylcycloalkyl, assorted alkylheterocycloalkyl and assorted alkylheterocycloalkenyl, and the cyclic group is saturated or single, double or tri-unsaturated.

[0072] 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. Aryl also refers to a group substituted by a fluorine, chlorine, bromine or iodine atom or an OH, SH, NH2, N3 or NO2 group. For example, a phenyl (Ph), naphthyl, biphenyl, 2-fluorophenyl, anilino, 3-nitrophenyl or 4-hydroxyphenyl group.

[0073] 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, which contains one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). Heteroaryl also refers to groups substituted by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH2, N3 or NO2 groups. For example, pyridyl (e.g., 4-pyridyl), imidazolyl (e.g., 2-imidazolyl), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazole, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4-hydroxypyridinyl (4-pyridonyl), 3,4-hydroxypyridinyl (3,4-pyridonyl), oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, pyridazinyl, quinolyl, isoquinolyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3′-difuranyl, pyrazolyl (3-pyrazole) and isoquinolyl groups.

[0074] Aralkyl refers to a group containing an aryl group as defined above and an alkyl, alkenyl, alkynyl and / or cycloalkyl group, such as, for example, an aralkyl, an alkenyl, an aralkynyl, an arylcycloalkyl, an arylcycloalkenyl, an alkylarylcycloalkyl and an alkylarylcycloalkenyl group. Specific examples of aralkyl are phenylcyclopentyl, cyclohexylphenyl and groups derived from toluene, xylene, m-xylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, isopropylbenzene, fluorene and indene. Aralkyl preferably comprises one or two aromatic ring systems (particularly 1 or 2 rings), each ring 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.

[0075] Heteroaralkyl refers to a group containing both aryl and / or heteroaryl as defined above and alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl. Heteroaralkyl preferably comprises one or two aromatic ring systems (especially 1 or 2 rings), each ring 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 cycloalkyl group comprising 3, 4, 5, 6 or 7 ring carbon atoms, and / or one or two heterocycloalkyl groups, each heterocycloalkyl group comprising 3, 4, 5, 6 or 7 ring atoms containing 1, 2, 3 or 4 oxygen, sulfur or nitrogen atoms.

[0076] For example, arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, aralkylheterocycloalkyl, aralkenylheterocycloalkyl, aralkynylheterocycloalkyl, aralkylheterocycloalkenyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heteroarheteroalkyl, heteroarcycloalkyl, heteroarcycloalkenyl, heteroarheterocycloalkyl, heteroarheterocycloalkenyl, heteroaralkylcycloalkyl, heteroaralkylheterocycloalkenyl, heteroaralkylcycloalkyl, heteroaralkylheterocycloalkenyl, heteroaralkylcycloalkyl, heteroaralkylheterocycloalkenyl, heteroaralkylcycloalkyl, heteroaralkylheterocycloalkenyl and heteroaralkylheterocycloalkyl groups, the cyclic group is saturated or mono-, di- or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, phthalidyl, 2- or 3-ethylindolyl, 4-methylpyridyl, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl groups.

[0077] As mentioned above, 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, NH2, =NH, N3 or NO2 groups.

[0078] According to a preferred embodiment, all alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl groups described herein may be optionally substituted.

[0079] The term halogen refers to F, Cl, Br or I.

[0080] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, the rings may be joined to each other by single or double bonds, or the rings may be cyclic or fused or bridged.

[0081] The suffix "ene" (eg, "phenylene") refers to the corresponding divalent radical.

[0082] The term "optionally substituted" means that the group is unsubstituted or substituted with one or more (particularly one, two or three; preferably one or two) substituents.

[0083] If a group contains more than one substituent, these substituents may be independently selected, ie they may be the same or different.

[0084] If a group is substituted by a cyclic group, such as a cycloalkyl group or a heterocycloalkyl group, the cyclic group may be linked to the group via a single bond or a double bond, or the cyclic group may be cyclic or fused to the group.

[0085] Specific examples of substituents are: fluorine, chlorine, bromine and iodine and OH, SH, NH2, -SO3H, -SO2NH2, -COOH, -COOMe, -COMe(Ac), -NHSO2Me, -SO2NMe2, -CH2NH2, -NHAc, -SO2Me, -COO t Bu, NMe2, Me, -N(CH2CH2)2NMe, -N(CH2CH2)2O, -CONH2, -CN, -NHCONH2, –NHC(NH)NH2, -NOHCH3, -N3 and -NO2 groups.

[0086] Further examples of substituents are C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Heteroalkyl, C3-C 18 Cycloalkyl, C1-C 17 Heterocycloalkyl, C4-C 20 Alkylcycloalkyl, C1-C 19 Heteroalkylcycloalkyl, C6-C 18 Aryl, C1-C17 Heteroaryl, C7-C 20 Arylalkyl and C1-C 19 Heteroaralkyl groups; in particular C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, C1-C9 heterocycloalkyl, C4-C 12 Alkylcycloalkyl, C1-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Arylalkyl and C1-C 11 Heteroaralkyl group; further preferably C1-C6 alkyl, C1-C6 heteroalkyl group.

[0087] Preferred substituents are halogen atoms (eg F, Cl, Br) and -OH, -NH2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, cyclopropyl and -CH2-cyclopropyl groups.

[0088] Further preferred substituents are halogen atoms (such as F, Cl, Br) and -OH, -NH2, -CN, -C 1-4 Alkyl (such as -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu, -CH2CH2F, CH2CHF2, -CH2CF3 and -CF3), -OC 1-4 Alkyl (-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 (such as -CONHCH2CF3, -CONHEt, -CONH t Bu), -COOH, -COOMe, -COMe, -CH2CH2CH=CH2, cyclopropyl and -CH2-cyclopropyl groups.

[0089] The therapeutic use of the compounds according to formula (I), their pharmacologically acceptable salts, solvates and hydrates, as well as formulations and pharmaceutical compositions also fall within the scope of the present invention.

[0090] The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) or salts thereof as defined herein, or pharmaceutically acceptable esters, prodrugs, hydrates or solvates thereof, optionally in combination with a pharmaceutically acceptable carrier and / or adjuvant.

[0091] Another object of the present invention is to provide a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein for use in the preparation of a medicament for the treatment of one or more diseases as described herein.

[0092] Preferably, the compounds of the present invention can be used to treat and / or prevent the following conditions:

[0093] Diseases in which CDKs (particularly CDK9 and / or CDK2) are abnormally regulated include a large number of cytokine-induced inflammatory and autoimmune diseases, local or systemic viral infections, ocular viral infections, viral respiratory tract infections, 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, such as acute myeloid leukemia, chronic lymphocytic leukemia, relapsed multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia, acute bi-type leukemia, aggressive MYC-driven B-cell lymphomas, primary peritoneal cancer, 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, including advanced and / or metastatic hematological / solid malignancies. In particular, these compounds can be used to treat hematological malignancies or solid tumors caused by abnormal expression of MYC- or MCL-1. In addition, the compounds can be used as immune response modifiers, and for the treatment and / or prevention of mechanical / injury-induced inflammation, such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory diseases, including gastrointestinal or urinary tract inflammatory diseases, inflammatory diseases 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 myocardial hypertrophy, dilated cardiomyopathy, atherosclerosis, and cardiovascular metabolic diseases, such as obesity and diabetes.

[0094] According to the present invention, the therapeutically effective amount of a compound refers to the amount of the compound that effectively prevents, alleviates or improves disease symptoms or prolongs the survival time of the treated subject. The determination of the therapeutically effective amount belongs to the technical scope of the art.

[0095] The therapeutically effective amount or dosage of the compound according to the present invention can vary over a wide range and can be determined in a manner known in the art. Such dosage can be adjusted according to the individual requirements of each particular case, including the specific compound administered, the route of administration, the condition to be treated, and the patient to be treated.

[0096] The salts of the compounds of formula (I) are preferred pharmacologically acceptable salts. Examples of pharmacologically acceptable salts of sufficiently alkaline compounds of formula (I) are physiologically acceptable mineral acid salts, such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; or organic acid salts, 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, sufficiently acidic compounds of formula (I) can form alkali metal or earth alkali 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, triethanolamine salts, lysine salts or arginine salts; all of which are also further examples of salts of formula (I).

[0097] The compound of formula (I) may be a solvate, in particular a hydrate. Hydration may occur during the production process or may be the result of the hygroscopicity of the initially water-free compound of formula (I). Solvates and / or hydrates may exist in the form of solid or liquid.

[0098] It should be understood that some compounds of formula (I) may have isomeric forms, only one of which may be specifically mentioned or described in the following description, different geometric isomers (usually represented as cis / trans isomers, or more generally as (E) and (Z) isomers), or different optical isomers due to one or more chiral carbon atoms (usually named using the Cahn-Ingold-Prelog or R / S system). The present invention includes all such isomers, geometric or optical isomers (as well as racemates and diastereomers) and polymorphic forms. Since the compounds of formula (I) may contain asymmetric C atoms, they may be achiral compounds, diastereomeric mixtures, enantiomeric mixtures, or optically pure compounds. The present invention includes all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any mixing ratio.

[0099] According to another embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention can be replaced by deuterium. Deuterium modification can improve the metabolic characteristics of the drug, while having little or no effect on its intrinsic pharmacological effects. Deuteration at specific molecular positions can improve metabolic stability, reduce the formation of toxic metabolites and / or increase the formation of required active metabolites. Therefore, the present invention also includes partially and completely deuterated compounds of formula (I). The term hydrogen also includes deuterium.

[0100] The present invention also relates to a prodrug consisting of a compound of formula (I) and at least one pharmacologically acceptable protecting group which is cleaved off under physiological conditions, such as an alkoxy-, aralkyloxy-, acyl-, formyloxy group (e.g. pivaloyloxymethyl), 2-alkyl-, 2-acyl- or 2-acylalkyl-oxycarbonyl-2-alkyleneethyl group or an acyloxy group as defined herein, such as ethoxy, benzyloxy, acetyl or acetoxy, or, in particular for compounds of formula (I), with a hydroxyl group (-OH): sulfuric acid, phosphoric acid (-OPO3 or -OCH2OPO3) or an amino acid ester. Particularly preferred are prodrugs of the hydroxyl group of the compound of formula (I).

[0101] As used herein, pharmaceutically acceptable esters refer in particular to esters that are hydrolyzable in vivo, including esters that are readily decomposed in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids, wherein the number of carbon atoms in each alkyl or alkenyl moiety preferably does not exceed 6. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0102] Preferably, the present invention also relates to prodrugs, biohydrolyzable esters, biohydrolyzable amides, polymorphs, isomers, stereoisomers, metabolites, N-oxides, biohydrolyzable carbamates, biohydrolyzable ethers, physiologically functional derivatives, atropisomers or in vivo hydrolyzable precursors, diastereomers or diastereomeric mixtures, chemically protected forms, affinity reagents, complexes, chelates and stereoisomers of compounds of formula (I).

[0103] As mentioned above, therapeutic agents containing compounds of formula (I), their solvates, salts or preparations are also within the scope of the present invention. Generally speaking, compounds of formula (I) can be administered alone or in combination with any other therapeutic agent in an acceptable manner known in the art.

[0104] In terms of oral administration, such therapeutic agents may be administered by one of the following routes: oral administration, such as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, such as soft or hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups; parenteral injection, including intravenous injection, intramuscular injection and subcutaneous injection, such as injection solutions or suspensions; rectal administration, such as suppositories; inhalation or insufflation, such as powder preparations, microcrystals or sprays (such as liquid sprays); transdermal administration, such as through a transdermal drug delivery system (TDS), such as a plaster containing an active ingredient or intranasal administration. In the production of such tablets, pills, semisolids, coated tablets, dragees and hard capsules (such as gelatin capsules), the therapeutic product may 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, skimmed milk powder, etc. For the production of soft capsules, excipients such as vegetable oil, petroleum, animal oil or synthetic oil, wax, fat, polyol, etc. can be used. For the production of liquid solutions, emulsions, suspensions or syrups, water, alcohols, physiological saline, glucose aqueous solution, polyols, glycerol, lipids, phospholipids, cyclodextrins, vegetable oil, petroleum, animal oil or synthetic oil can be used as excipients. Particularly preferred are lipids, more preferably phospholipids (preferably natural sources; particularly preferably particle size between 300 and 350nm), preferably phosphate buffered saline (pH = 7 to 8, preferably 7.4). For suppositories, excipients such as vegetable oil, petroleum, animal oil or synthetic oil, wax, fat and polyol can be used. For aerosol formulations, compressed gases suitable for this purpose, such as oxygen, nitrogen and carbon dioxide, can be used. Pharmaceutically useful agents may also contain additives for preservation and stabilization, such as UV stabilizers, emulsifiers, sweeteners, fragrances, salts that change osmotic pressure, buffers, coating additives and antioxidants.

[0105] Generally speaking, for an adult weighing about 80 kg, the daily dose for oral or parenteral administration should be about 10 mg to about 10,000 mg, preferably about 20 mg to about 1,000 mg, but the upper limit may be exceeded when indicated. The daily dose may be administered in a single or divided dose, and parenteral administration may be continuous infusion or subcutaneous injection.

[0106] According to another preferred embodiment, the present invention provides a method for treating one or more diseases described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0107] According to another preferred embodiment, the present invention provides a method for treating one or more diseases described herein, which comprises administering to a subject in need of treatment a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. Example

[0108] General Synthesis Methods

[0109] The following methods were used for the synthesis of the compounds described herein.

[0110] Flash chromatography: using SNAP or Silica gel column and ethyl acetate / cyclohexane / methanol or dichloromethane / methanol gradient as eluent, in Biotage Isolera(R) or Rapid chromatography was performed on the system.

[0111] Microwave conditions: Reactions under microwave conditions were performed in a Biotage initiator(R) microwave system.

[0112] SEMIprep Reverse Phase Chromatography: The following instruments were used for SEMIprep reverse phase chromatography: 2x Varian PrepStarSD-1, 1x Dionex P580 pump 1 channel (supplement I), 1x Dionex AXP-MS (supplement 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 Quad Pump (modified), 1x G7111B 1260 Infinity II Quad Pump (analytical / supplement), 1x G7165A 1260 Infinity II Multi-Wavelength Detection including flow cell (Cat. #G1315-60022, Serial #DE185H6157, path length 10.00 mm, volume 13.00 μl), 1x G7170B 1290 Infinity II MS Flow Conditioner, 1x G6125B MSD 6100 Series Single Quadrupole including G1948B Electrospray Interface and 3x G1170A 1290 Infinity Valve Drive (14-port, 6-position analytical column selection valve; 14-port, 6-position preparative column selection valve; 14-port, 2-position analytical / preparative mode selection valve).

[0113] Preparative columns: Waters SunFire Prep C18 5 μm OBD 30x100 mm, #186002572, Waters Atlantis T3 Prep 5 μm OBD 30x100 mm, #186003702, and Waters XSelect CSH Prep C18 5 μm OBD 30x100 mm, #186005425.

[0114] Analytical columns: Waters SunFire C18 2.5 μm 3.0x75 mm, #186005636, Waters Atlantis T3 3 μm 3.0x75 mm, #186005653 and Waters XSelect CSH C18 2.5 μm 3.0x 75 mm, #186006106.

[0115] Typical chromatographic conditions are as follows:

[0116] 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.

[0117] Typical usage times and associated volumes of Solvent A and Solvent B are shown in Table 1.

[0118] Table 1

[0119]

[0120]

[0121] Typical preparation method: chromatographic column flow rate is 60mL / min, solvent A is acetonitrile, and solvent B is water. The preparation process includes modifier flow: modifier flow rate is 1.8mL / min, containing 10% acetic acid in acetonitrile / water 1:1=> so that the acetic acid concentration in the mobile phase is 0.3%; 0.5M NH4Ac / NH4OH-buffer (pH 9.2) in acetonitrile / water 1:9=> so that the buffer concentration in the mobile phase is 15mM.

[0122] MS supplement: 0.9 mL / min of 0.05% acetic acid in acetonitrile / water 1:1.

[0123] A typical focused gradient schedule, such as the 59.7% elution point, is shown in Table 2.

[0124] Table 2

[0125] Time (minutes) Solvent A Solvent B -2.37 18.6 84.4 0.00 18.6 84.4 1.15 18.6 84.4 1.16 43.5 56.5 8.46 63.5 36.5 8.47 100 0 10.77 100 0 10.78 18.6 84.4

[0126] Typical analytical modification: column flow rate 1 mL / min, solvent A is acetonitrile, solvent B is water, and solvent C is 5% acetic acid in acetonitrile / water 1:1.

[0127] Typical times and associated volumes for Solvent, Solvent B, and Solvent C are shown in Table 3.

[0128] Table 3

[0129] Time (minutes) Solvent A Solvent B Solvent C 0 2 96 2 0.5 2 96 2 5.5 96 2 2 5.6 98 0 2 6.9 98 0 2 7.0 2 2 2

[0130] The mass spectrometer was used for detection at a UV wavelength of 220 nm, 254 nm or 310 nm.

[0131] The terms and abbreviations used in the examples are shown in Table 4.

[0132] Table 4

[0133]

[0134] Table 5 lists the HPLC analytical methods used to prepare the compounds.

[0135] Table 5

[0136]

[0137] General route of imidazopyridazines A:

[0138]

[0139] Overview of the synthesis steps:

[0140] Step 1: 6,8-Dibromo-3-chloroimidazo[1,2-b]pyridazine ：

[0141]

[0142] 6,8-dibromo-3-chloroimidazo[1,2-b]pyridazine (1 eq.) was dissolved in 1,2-dichloroethane and acetonitrile ia (1 / 1 v / v 16 mL / mmol), and NCS (1.3 eq.) was added in portions. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with sodium thiosulfate solution (5 M in water), extracted with DCM, dried and filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0143] Step 2: Amination:

[0144]

[0145] 6,8-Dibromo-3-chloroimidazo[1,2-b]pyridazine (1 eq.) and the corresponding amine (1 eq.) were dissolved in dioxane (3 mL / mmol). DIPEA (2.0 eq.) was added and the mixture was heated to 180°C for 30 minutes under microwave stimulation. The mixture was diluted with NaHCO3 aq.sat. and extracted with DCM. The organic layer was dried (Na2SO4) and filtered and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0146] Step 3: Arylation

[0147]

[0148] The product of the previous step was dissolved in dioxane (0.5M). Water (10% v / v) was added. The corresponding boronic acid (1.3 eq.), Pd2(dba)3 (0.2 eq.), X-Phos (0.8 eq.) and K2CO3 (3 eq.) were added. The mixture was degassed with N2 and heated at 80°C overnight. Boric acid, Pd2(dba)3 and X-Phos (same amount as before) were added and then heated at 80°C. This was repeated until the reaction was complete (HPLC). The mixture was filtered through a celite plug, washed with MeOH and water, concentrated, diluted again with water, and then extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography and then by preparative reverse phase HPLC.

[0149] These protocols were used to synthesize the compounds in Examples #1, #3, #4, #10, #11, #12, #16, #17, #18, and #19.

[0150] The compounds in Examples #14 and #15 were synthesized using modifications of these protocols.

[0151] Example #15:

[0152] The compound of Example #16 was dissolved in dry MeOH and treated with hydrochloric acid (4M in dioxane) for 24 hours. The mixture was concentrated under reduced pressure and the crude product was purified by reverse phase HPLC.

[0153] Example #14:

[0154] To Example #15 compound 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 then extracted with EtOAc. The combined organic layer was dried, filtered and concentrated under reduced pressure. The mixture was concentrated under reduced pressure and the crude product was purified by reverse phase HPLC.

[0155] The compounds of Examples #14, #15, #16, and #18 are racemic mixtures.

[0156] General route B for imidazopyridazines:

[0157]

[0158] Overview of the synthesis steps:

[0159] Step 1: Amination

[0160]

[0161] 8-Bromo-6-chloroimidazo[1,2-b]pyridazine (1 eq.) and the HCL salt of the corresponding amine (1.2 eq.) were mixed in dioxane (3 mL / mmol). DIPEA (6.0 eq.) was added and the mixture was heated to 180°C for 30 minutes under microwave stimulation. The mixture was diluted with NaHCO3 aq.sat. and extracted with DCM. The organic layer was dried (Na2SO4) and filtered and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0162] Step 2: Chlorination

[0163]

[0164] The product of the previous step was dissolved in 1,2-dichloroethane and acetonitrile (1 / 1 v / v 16 mL / mmol), and NCS (1.3 eq.) was added in portions. The mixture was stirred at room temperature for 6 hours and then at 40°C overnight. The reaction was not completed (HPLC). NCS (1 eq.) was added again. 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 chloro intermediates were not isolated.

[0165] Step 3: Arylation

[0166]

[0167] The product of the previous step was dissolved in dioxane (0.5M). Water (10% v / v) was added. The corresponding boronic acid (1.3 eq.), Pd2(dba)3 (0.2 eq.), X-Phos (0.8 eq.) and K2CO3 (3 eq.) were added. The mixture was degassed with N2 and heated at 80°C overnight. Boric acid, Pd2(dba)3 and X-Phos (same amount as before) were added and then heated at 80°C. This was repeated until the reaction was complete (HPLC). The mixture was filtered through a celite plug, washed with MeOH and water, concentrated, diluted again with water, and then extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography and then the product was separated from the mixture by preparative reverse phase HPLC.

[0168] General pathway D of imidazopyridazines:

[0169]

[0170] Step 1: Amination

[0171]

[0172] 6,8-Dibromo-3-chloroimidazo[1,2-b]pyridazine (1 eq.) and [4-(6-bromo-imidazo[1,2-b]pyridazine-8-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester HCL salt were mixed in dioxane (3 mL / mmol). DIPEA (6.0 eq.) was added and the mixture was heated to 180°C under microwave stimulation for 60 minutes. The mixture was diluted with NaHCO3 aq.sat. and extracted with DCM. The organic layer was dried (Na2SO4) and filtered and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0173] Step 2: Suzuki Reaction

[0174]

[0175] The product from the previous step was dissolved in dioxane (0.5 M). Water (10% v / v) was added. 2,6-difluorophenylboronic acid (1.3 eq.), Pd(dppf)DCM (0.2 eq.) and Na2CO3 aq. (1 M) (3 eq.) were added. The mixture was degassed with N2 and heated at 80°C for 3 hours. Boric acid and Pd(dppf)DCM were added and then heated at 80°C. This was repeated until the reaction was complete (HPLC). The mixture was filtered through a celite plug, washed with MeOH and water, concentrated, diluted again with water, and then extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0176] The product of the previous step was dissolved in 1,2-dichloroethane and acetonitrile (1 / 1 v / v 10 mL / mmol), and then NCS (1.3 eq.) was added in portions. The mixture was stirred at 80 ° C for 5 hours. The mixture was quenched with sodium thiosulfate solution (5 M in water), extracted with DCM, dried and filtered, and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.

[0177] Step 3: Chlorination

[0178]

[0179] The product from the previous step was dissolved in 1,2-dichloroethane and acetonitrile (1 / 1 v / v 10 mL / mmol), and NCS (1.3 eq.) was added in portions. The mixture was stirred at 60°C for 5 hours. The mixture was quenched with sodium thiosulfate solution (5 M in water), extracted with DCM, dried and filtered, and concentrated under reduced pressure. The crude product mixture was used directly without purification.

[0180] Step 4: Deprotect:

[0181]

[0182] 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.

[0183] The compounds in Examples #8 and #9 were synthesized using this protocol.

[0184] The amines used were commercially available, described in the literature, or prepared by the following process:

[0185] A: 4-(Piperidin-1-yl)cyclohexylamine:

[0186]

[0187] Step 1 : The boc protected diamine was dissolved in acetonitrile. Dibromopentane (2 eq.) and DIPEA (5 eq.) were added and the mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc and washed with ammonium chloride (aq.sat.) and water. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC.

[0188] 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.

[0189] The following intermediates were synthesized according to the following scheme.

[0190]

[0191] The following examples were prepared according to the above process:

[0192] Example: Name; HPLC method; Room temperature; MH+; NMR

[0193] 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;

[0194] 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)."

[0195] 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 (600MHz, chloroform-d) δ8.64 (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, 1H), 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).

[0196] 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 nmin; 412.2; "1H NMR (600MHz, chloroform-d) δ7.54 (s, 1H), 7.44 (tt, J = 8.5, 6.3Hz, 1H), 7.05-6.99 (m, 2H), 5.17 (m, 2H, CH and NH), 4.94 (roughly 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). "

[0197] 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; "1H NMR (800MHz, chloroform-d) δ7.84 (d, J = 1.1 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.46 (tt, J = 8.3, 6.2 Hz, 1H), 7.09-7.02 (m, 2H), 5.23 (t, J = 10.9 Hz, 1H), 5.18 (d, J = 9.0 Hz, 1H, NH), 3.86-3.61 (approximately m, 2H, NH2), 2.93 (s, 1H), 2.34 (d, J = 12.4 Hz, 2H), 2.11 (d, J = 16.1 Hz, 2H), 1.59 (q, J = 12.7, 11.9 Hz, 2H), 1.45-1.38 (m, 2H). "

[0198] 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;

[0199] 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 minutes; 448.2; "1H NMR (800MHz, chloroform-d) δ7.49 (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). "

[0200] 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;

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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 minutes; 350.2; "1H NMR (400MHz, chloroform-d) δ7.52 (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). "

[0207] Biological data

[0208] Assay protocol for determination of inhibitory activity

[0209] Twelve concentrations of the test compounds were evaluated in a 1:3 dilution series starting with a maximum concentration of 5 μmol / L.

[0210] In a white 384-well microplate (Greinerbio-one, Austria #784904,) add 2 μl of 3x concentrated CDK9 / Cyclin T1 (ProQinase / Reaction Biology, USA #0371-0345-1, LOT.: 012) at a final concentration (fc) of 6 nM in 1x kinase buffer, add 2 μl of compound (3x concentrated in a final concentration of 1.66% DMSO / H2O) and incubate for 10 min at room temperature (RT). Then 2 μl of substrate / ATP-mix (3xPDKtide, final concentration 40 μmol / l, SignalChem Biotech, Canada, via Biozol, Eching, Germany #P10-58, LOT: L2230-7 and 3x UltraPure ATP, final concentration 10 μmol / l (ADP Glo Kinase Assay, Promega GmbH, Germany #V9102)) were added, mixed and incubated for 120 min at room temperature.

[0211] After the incubation time, 5 μl 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.

[0212] In the last step, 10 μl of ADP Glo detection reagent (Ready to use, ADP Glo Kinase Assay, Promega GmbH, Germany #V9102) was added, mixed and incubated at room temperature for 30 minutes.

[0213] The readings were performed using a GloMax Discover GM3000 reader (Promega GmbH, Germany 9700000249).

[0214] Sigmoidal dose-response curves with variable slopes were fitted using XLFit 5.5 (IDBS, Guilford), and inhibitor concentration was plotted against luminescence to determine IC50.

[0215] CDK9 / T1 ADPGlo activity of the compounds in the above examples:

[0216] IC50<20nM: Example #3, Example #4, Example #10, Example #11, Example #17, Example #18.

[0217] IC50<200nM: Example #1, Example #8, Example #9, Example #12, Example #14, Example #15, Example #16.

Claims

1. A compound represented by formula (I): It is characterized in that R1 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group; all of which 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; or a salt thereof.

2. The compound according to claim 1, characterized in that R4 is H or Cl.

3. The compound according to claim 1, characterized in that R4 is H.

4. A compound according to any one of the preceding claims, characterized in that R3 is Cl.

5. A compound according to any one of the preceding claims, characterized in that R2 is phenyl substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br and Me.

6. A compound according to any one of the preceding claims, characterized in that R2 is 2,6-difluorophenyl.

7. A compound according to any one of the preceding claims, characterized in that R1 is an optionally substituted C 3-7 Cycloalkyl, optionally substituted heterocycloalkyl containing 3 to 9 ring atoms independently selected from C, N and O, optionally substituted phenyl, optionally substituted benzyl, optionally substituted heteroaryl containing 5 or 6 ring atoms independently selected from C, N, O and S, or a group represented by the formula -CH2-Het, wherein Het is an optionally substituted heteroaryl containing 5 or 6 ring atoms independently selected from C, N, O and S.

8. The compound according to any one of claims 1 to 6, characterized in that R1 is an optionally substituted C 3-7 Cycloalkyl, optionally substituted heterocycloalkyl containing 3 to 9 ring atoms independently selected from C, N and O, or a group represented by the formula -CH2-Het, wherein Het is optionally substituted heteroaryl 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, characterized in that R1 is selected from the following group: Where R 5 NH2, C 1-8 heteroalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O; R 5a For hydrogen, C 1-6 Alkyl, C 1-8 Heteroalkyl, optionally substituted C 5-6 Cycloalkyl or optionally substituted heterocycloalkyl 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, characterized in that R1 is selected from the following group: Where R 5 NH2, C 1-6 heteroalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O; R 5a For hydrogen, C 1-6 Alkyl, optionally substituted C 5-6 Cycloalkyl or optionally substituted heterocycloalkyl containing 5 or 6 ring atoms independently selected from C, N and O.

11. The compound according to any one of claims 1 to 6, characterized in that R1 is a group represented by the formula -CH2-Het, wherein Het is an optionally substituted pyridyl group.

12. The compound according to 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. A pharmaceutical composition comprising a compound as claimed in any preceding claim and optionally one or more carrier substances and / or one or more adjuvants.

14. Use of the compound according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 13 for treating diseases in which CDK, in particular CDK9 and / or CDK2, is dysregulated, including inflammatory and autoimmune diseases induced by a large number of cytokines, local or systemic viral infections, ocular viral infections, viral respiratory infections, viral infections of the central and / or peripheral nervous systems caused by DNA and / or RNA viruses, and 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 lymphocytic leukemia, acute bi-type leukemia, aggressive MYC-driven B-cell lymphoma, primary peritoneal cancer, 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, including advanced and / or metastatic blood / solid malignancies (in particular, these compounds can be used to treat blood system malignancies or solid tumors caused by abnormal expression of MYC- or MCL-1); or the compounds can be used as immune response regulators, as well as for the treatment and / or prevention of mechanical / injury-induced inflammation, such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory diseases, including gastrointestinal or urinary tract inflammatory diseases, inflammatory diseases 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 myocardial hypertrophy, dilated cardiomyopathy, atherosclerosis and cardiovascular metabolic diseases, such as obesity and diabetes.

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