WO2024068740A1 - Novel cdk9 inhibitors - Google Patents
Novel cdk9 inhibitors Download PDFInfo
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- WO2024068740A1 WO2024068740A1 PCT/EP2023/076719 EP2023076719W WO2024068740A1 WO 2024068740 A1 WO2024068740 A1 WO 2024068740A1 EP 2023076719 W EP2023076719 W EP 2023076719W WO 2024068740 A1 WO2024068740 A1 WO 2024068740A1
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- WIPO (PCT)
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- optionally substituted
- pyridazin
- imidazo
- difluorophenyl
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the field of biomedicine, and specifically includes a series of novel CDK9 inhibitors with imidazopyridazine structure and their uses. It includes compounds as CDK9 inhibitors, pharmaceutically acceptable salts, solvates of the above compounds or prodrugs, and the use of pharmaceutical compositions of the above-mentioned compounds.
- Cyclin-dependent kinases are a member of the serine/threonine kinase family and form a heterodimer with the regulatory subunit cyclin to perform its catalytic function.
- the members of the CDKs family can be divided into periodic CDKs and transcriptional CDKs according to their functional differences.
- the former mainly includes CDK1/2/4/6, which control the cell cycle process; the latter mainly includes CDK7/8/9, which regulate the transcription of mRNA and processing (Malumbres M. et al. Genome Biol., 2014, 15:122).
- CDK9 is related to the occurrence of a variety of tumors, inflammation, and virus replication, such as acute myeloid leukemia, breast cancer, colon cancer, and prostate cancer, as well as human immunodeficiency virus and adenovirus (Franco L.C. et al. J. Cell Biochem.,2017,119:1273-1284).
- First generation pan-CDK inhibitors that have entered the clinic include Flavopiridol, Dinaciclib, SNS-032 and CYC065, but showed clinical side-effects due to their lack of selectivity over a range of CDKs.
- pharmaceutical research is focusing on the identification and development of mainly selective CDK9 inhibitors. These are currently in preclinical and early clinical research such as BAY- 1143572, KB-0742, and AZD4573.
- the present invention provides CDK9 small molecule inhibitors containing imidazopyridazine structures.
- the present invention provides one or more compounds of formula (I): wherein
- R1 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group; all of which groups may optionally be 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.
- R4 is H or C1.
- R4 is H.
- R3 is C1
- R2 is a phenyl group that is substituted by 1, 2 or 3 substituents that are independently selected from F, C1, Br and Me.
- R2 is a phenyl group that is substituted in the 2 and 6 position (i.e., a phenyl group carrying two ortho substituents).
- R2 is a 2,6-difluorophenyl group.
- R1 is an optionally substituted C 3-7 cycloalkyl group, an optionally substituted heterocycloalkyl group containing from 3 to 9 ring atoms that are 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 that are independently selected from C, N, O and S, or a group of formula -CH 2 -Het, wherein Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms that are independently selected from C, N, O and S.
- R1 is an optionally substituted C 3-7 cycloalkyl group, an optionally substituted heterocycloalkyl group containing from 3 to 9 ring atoms that are independently selected from C, N and O, or a group of formula -CH 2 -Het, wherein Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms that are independently selected from C, N, O and S.
- R1 is selected from the following groups: wherein R 5 is NH 2 , a C 1-8 heteroalkyl group, or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O; and R 5a is hydrogen, a C 1-6 alkyl group, a C 1-8 heteroalkyl group, an optionally substituted C 5-6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
- R1 is selected from the following groups: wherein R 5 is NH 2 , a Cw heteroalkyl group, or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O; and R 5a is hydrogen, a C 1-6 alkyl group, an optionally substituted C 5-6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
- R 5a is hydrogen, a C 1-6 alkyl group, or a group of formula -SO 2 -C 1-6 alkyl, - -CONH- C 1-6 alkyl, or -COO-C 1-6 alkyl; or an optionally substituted C 5-6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
- R 5 is a group of formula -N(CH 2 CH 2 ) 2 NMe, NH 2 , -N(CH 2 CH 2 ) 2 O, or -NMe 2 .
- R 5a is a group of formula -Me, -SO 2 Me, or -COO t Bu.
- R1 is a group of formula -CH 2 -Het wherein Het is an optionally substituted pyridyl group.
- the optional substituents at group R1 are independently selected from -N(CH 2 CH 2 ) 2 NMe, -N(CH 2 CH 2 ) 2 O, NH 2 , -NMe 2 , -Me, -SO 2 Me, and -COO t Bu.
- R1 an optionally substituted heteroalkyl group containing from 1 to 12 carbon atoms and from 1 to 6 heteroatoms selected from N, O and S. Further preferably, R1 is an optionally substituted C 4-6 cycloalkyl group, an optionally substituted heterocycloalkyl group containing from 5 to 8 ring atoms that are independently selected from C, N and O, an optionally substituted phenyl group or an optionally substituted pyrazol-4-yl group.
- R1 is selected from the following groups: wherein R 5 is a -NH 2 group, a C 1-6 heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
- R 5 is selected from the following groups: -NH 2 , -NMe 2 , pyrrolidinyl, piperidinyl, morpholinyl, -NH(CH 2 ) 2 F, -NH(CH 2 ) 3 F, -NH(CH 2 ) 2 OH, -NH(CH 2 ) 3 OH, -NH(CH 2 ) 2 OMe, - NH(CH 2 ) 3 OMe, -N(Me)(CH 2 ) 2 F, -N(Me)(CH 2 ) 3 F, -N(Me)(CH 2 ) 2 OH, -N(Me)(CH 2 ) 3 OH, - N(Me)(CH 2 ) 2 OMe, and -N(Me)(CH 2 ) 3 OMe.
- R1 is selected from the following groups: wherein R 5a is hydrogen, a C 1-6 alkyl group, a C 1-8 heteroalkyl group, an optionally substituted C 5- 6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
- R1 has the following structure: wherein R 6a is hydrogen, halogen or a C 1-4 heteroalkyl group (especially a -O-C 1-4 alkyl group); R 6b is hydrogen, halogen or a C 1-4 heteroalkyl group (especially a -O-C 1-4 alkyl group) and R 6 is a C 1-6 alkyl group, a C 1-6 heteroalkyl group, an optionally substituted C 3-7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N and O.
- R 6a is hydrogen, C1 or OMe.
- R 6b is hydrogen.
- 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.
- R 6 is a group of formula -Cy-L-R 6c , wherein Cy is an optionally substituted C 3-7 cycloalkylene group or an optionally substituted heterocycloalkylene group containing from 3 to 7 ring atoms that are independently selected from C, N and O; L is a bond or a CH 2 group and R 6C is an optionally substituted C 3-7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N and O.
- Cy is a cyclohexylene group or a piperidinylene group.
- R 6c is a cyclopropyl group or an optionally substituted heterocycloalkyl group containing from 4 to 6 ring atoms that are independently selected from C, N and O.
- R1 has the following structure: wherein R 7a is hydrogen, halogen, CN or an -O- C 1-4 alkyl group; R 7b is hydrogen, halogen, CN or an -O-C 1-4 alkyl group and R 7 is a C 1-6 heteroalkyl group, an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N and O or an optionally substituted heteroalkylcycloalkyl group containing from 4 to 12 atoms that are independently selected from C, N and O.
- R 7b is hydrogen or a methoxy group; preferably hydrogen.
- R 7a is hydrogen, fluorine, CN or an -O-C 1-4 alkyl group; preferably hydrogen.
- R 7 is an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, an optionally substituted morpholinyl group or an optionally substituted tetrahydropyridinyl group.
- R 7 is a group of formula -Cy'-L'-R 7c , wherein Cy' is an optionally substituted C 3-7 cycloalkylene group or an optionally substituted heterocycloalkylene group containing from 3 to 7 ring atoms that are independently selected from C, N and O; L' is a bond or a CH 2 group and R 7C is an optionally substituted C 3-7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N and O.
- R 7 is a group of formula -CO-R 7d or -CO-NH-R 7d , wherein R 7d is a C 1-4 alkyl group or an optionally substituted heterocycloalkylene group containing from 3 to 7 ring atoms that are independently selected from C, N and O.
- R1 is a group of formula -CH 2 -R 1a or -CH 2 -CH 2 -R 1a , wherein R 1a is an optionally substituted heterocycloalkyl group having 5 or 6 ring atoms that are independently selected from C, N and O (Preferably, the optional substituent at R 1a is a C 1-4 alkyl group).
- the most preferred compounds of the present invention are the compounds disclosed in the examples, or a salt thereof.
- alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, especially from 1 to 6 (e.g.
- C 1-6 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 6 carbon atoms.
- C 1-4 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms. Examples are a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl group.
- alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, especially from 2 to 10 (e.g., 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethynyl (acetylenyl), propynyl (e.g., propargyl), butynyl, isoprenyl or hex-2-enyl group.
- alkenyl groups have one or two (especially preferably one) double bond(s)
- alkynyl groups have one or two (especially preferably one) triple bond(s).
- alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or C1) such as, for example, a 2,2,2- trichloroethyl or a trifluoromethyl group.
- a halogen atom preferably F or C1
- heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more (preferably 1 to 8; especially preferably 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or by a SO or a SO 2 group.
- the expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxy alkyl, carboxy alkylamide or alkoxy carbonyloxy.
- heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or C1).
- a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 8 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen).
- a heteroalkyl group contains from 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).
- C 1-8 heteroalkyl refers to a heteroalkyl group containing from 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).
- C 1-6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from 0, S and/or N (especially O and/or N).
- C 1-4 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).
- heteroalkyl groups are groups of formulae: R a -O-Y a -, R a -S-Y a -, R a -SO-Y a -, R a -SO 2 -Y a -, R a -N(R b )-SO 2 -Y a -, R a -SO 2 -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-O-Y a -, R a -CO-N(R b )-Y a -, R
- heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, iso- propyloxy, n-butoxy, tert-butyloxy, methoxymethyl, -CH 2 CH 2 OH, -CH 2 OH, -SO 2 Me, -NHAc, - C(CH 3 ) 2 CN, -COO t Bu, methoxyethyl, ethoxymethyl, 1 -methoxyethyl, 1 -ethoxyethyl, 2- methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, eth
- cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.
- cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbomyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.
- cycloalkyl refers to a saturated cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.
- heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO 2 group.
- a heterocycloalkyl group has preferably 1 or 2 ring(s) and 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S).
- examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g.
- alkylcycloalkyl refers to groups that contain both cycloalkyl and alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups.
- An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings and from 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.
- heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1 , 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO 2 group.
- a heteroalkylcycloalkyl group preferably contains 1 or 2 rings having from 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) having from 1 or 2 to 6 carbon atoms.
- Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.
- aryl refers to an aromatic group that contains one or more rings and from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms.
- the expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH 2 , N 3 or NO 2 groups. Examples are the phenyl (Ph), naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3 -nitrophenyl or 4-hydroxyphenyl group.
- heteroaryl refers to an aromatic group that contains one or more rings and from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, comprising one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N).
- heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N 3 , NH 2 or NO 2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g.
- thiazolyl isothiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, oxadiazo lyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4-hydroxypyridyl (4-pyridonyl), 3,4- hydroxypyridyl (3, 4-pyridonyl), oxazolyl, isoxazolyl, triazo lyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl,
- aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups.
- aralkyls are phenylcyclopentyl, cyclohexylphenyl as well as groups derived from toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetraline, dihydronaphthalene, indanone, cumene, fluorene and indane.
- An aralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or one or two cycloalkyl group containing 3, 4, 5, 6 or 7 ring carbon atoms.
- heteroaralkyl refers to groups containing both aryl and/or heteroaryl groups and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions.
- a heteroaralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 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 comprising 1, 2, 3 or 4 oxygen, sulfur or nitrogen atoms.
- Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroaryl-heterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl-alkylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl-alkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, hetero
- all alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl groups described herein may optionally be substituted.
- halogen refers to F, C1, Br or I.
- aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated or fused or bridged.
- optionally substituted refers to a group which is unsubstituted or substituted by one or more (especially by one, two or three; preferably by one or two) substituents.
- a group comprises more than one substituent, these substituents are independently selected, i.e. they may be the same or different.
- a group is substituted by a cyclic group, such as e.g. a cycloalkyl group or a heterocycloalkyl group, this cyclic group may be bonded to said group via a single or double bond or this cyclic group may be annulated or fused to said group.
- a cyclic group such as e.g. a cycloalkyl group or a heterocycloalkyl group
- substituents are fluorine, chlorine, bromine and iodine and OH, SH, NH 2 , - SO 3 H, -SO 2 NH 2 , -CO0H, -COOMe, -COMe (Ac), -NHSO 2 Me, -SO 2 NMe 2 , -CH 2 NH 2 , -NHAc, - SO 2 Me, -COO t Bu, NMe 2 , Me, -N(CH 2 CH 2 ) 2 NMe, -N(CH 2 CH 2 ) 2 O, -CONH 2 , -CN, -NHCONH 2 , -NHC(NH)NH 2 , -NOHCH 3 , -N 3 and -NO 2 groups.
- substituents are C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 heteroalkyl, C 3 -C 18 cycloalkyl, C 1 -C 17 heterocycloalkyl, C 4 -C 20 alkylcycloalkyl, C 1 -C 19 heteroalkylcycloalkyl, C 6 -C 18 aryl, C 1 -C 17 heteroaryl, C7-C 2 o aralkyl and C 1 -C 19 heteroaralkyl groups; especially C 1-6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1-6 heteroalkyl, C 3 -C 10 cycloalkyl, C 1 -C 9 heterocycloalkyl, C 4 -C 12 alkylcycloalkyl, C 1 -C 11 heteroalkylcycloalkyl, C 6 -C
- Preferred substituents are halogen atoms (e.g., F, C1, Br) and -OH, -NH 2 , -CN, C 1-6 alkyl, C 2 -C 6 alkenyl, C 1-6 heteroalkyl, cyclopropyl and -CH 2 -cyclopropyl groups.
- substituents are halogen atoms (e.g. F, C1, Br) and -OH, -NH 2 , -CN, -C 1-4 alkyl (e.g. -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu, -CH 2 CH 2 F, CH 2 CHF 2 , -CH 2 CF 3 and -CF3), -O-C 1-4 alkyl (e.g.
- the present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) or a salt thereof as defined herein or a pharmaceutically acceptable ester, prodrug, hydrate or solvate thereof, optionally in combination with a pharmaceutically acceptable carrier and/or adjuvant. It is a further object of the present invention to provide a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment of one or more diseases specified herein.
- the compounds of the present invention may be used for the treatment and/or prevention of the following conditions:
- CDK cytokine-induced inflammatory, and autoimmune diseases
- local or systemic viral infection diseases 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
- various non-solid and solid malignancies, cancers or hyperproliferative diseases such as acute myelogenous leukemia, chronic lymphocytic leukemia, relapsed multiple myeloma, nonHodgkin’s lymphoma, acute lymphoblastic leukemia, acute biphenotypic leukemia, aggressive MYC-driven B-Cell lymphoma, primary peritoneal carcinoma, Kaposi 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,
- the compounds may be used to treat a hematologic malignancy, or a solid tumor caused by aberrant expression of MYC- or MCL-1.
- the compounds may be used as modulator of the immune response and for the treatment and/or prevention of mechanical/inj ury-induced inflammation such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory disease, including gastrointestinal or urinary tracts inflammatory diseases inflammatory diseases and inflammatory diseases of the eye, such as Sjogren’s disease and glaucoma, bacteria-induced inflammatory disease, such as gingivitis, periodontitis, and for the treatment and/or prevention of cardiovascular diseases such as cardiac hypertrophy, dilated cardiomyopathy, atherosclerosis, and cardio- metabolic diseases such as obesity and diabetes.
- PTOA post-traumatic osteoarthritis
- inflammatory diseases inflammatory diseases and inflammatory diseases of the eye, such as Sjogren’s disease and glaucoma
- bacteria-induced inflammatory disease such as gingivitis, periodon
- 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 a disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
- the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered, the route of administration, the condition being treated, as well as the patient being treated.
- the salt of a compound of formula (I) is preferably a pharmacologically acceptable salt.
- pharmacologically acceptable salts of sufficiently basic compounds of formula (I) are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid.
- a sufficiently acidic compound of formula (I) may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of formula (I).
- alkali or earth alkali metal salts for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine
- Compounds of formula (I) may be solvated, especially hydrated.
- the hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula (I).
- the solvates and/or hydrates may e.g. be present in solid or liquid form.
- certain compounds of formula (I) may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis/trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R/S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention.
- the compounds of formula (I) may contain asymmetric C- atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.
- the present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.
- one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium.
- Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology.
- Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and/or increases the formation of desired active metabolites.
- the present invention also encompasses the partially and fully deuterated compounds of formula (I).
- the term hydrogen also encompasses deuterium.
- the present invention also relates to pro-drugs which are composed of a compound of formula (I) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g.
- a compound of formula (I) carrying a hydroxy group (-OH): a sulfate, a phosphate (-OPO3 or - OCH2OPO3) or an ester of an amino acid.
- a hydroxy group a sulfate, a phosphate (-OPO3 or - OCH2OPO3) or an ester of an amino acid.
- ester especially refers to esters which hydrolyze in vivo and include those that break down readily 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, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
- esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
- the present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers, chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds of formula (I).
- a prodrug a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diaste
- therapeutically useful agents that contain compounds of formula (I), their solvates, salts or formulations are also comprised in the scope of the present invention.
- compounds of formula (I) will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent.
- such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g.
- liquid aerosol transdermal
- TDS transdermal delivery system
- the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
- pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
- excipients are e.g.
- excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils.
- lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 run) preferred in phosphate buffered saline (pH 7 to 8, preferred 7.4).
- excipients as are e.g.
- the pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
- stabilization e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
- a daily dosage in general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 20 mg to about 1 ,000 mg, should be appropriate, although the upper limit may be exceeded when indicated.
- the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.
- the present invention provides a method for treating one or more diseases specified herein which comprises 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.
- the present invention provides a method for treating one or more diseases specified herein which comprises administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.
- Flash chromatography was performed on a Biotage Isolera(R) or Selekt® system using SNAP or SFAR silica cartridges and ethyl acetate/cyclohexane/methanol or dichloromethane/methanol gradients as eluent.
- Microwave conditions Reactions under micro wave conditions are performed in a Biotage initiator(R) microwave system.
- SEMIprep reversed phase chromatography The following instrumentation was used for SEMIprep reversed phase chromatography: 2x Varian PrepStar SD-1, lx Dionex P580 Pump 1 Channel(MakeUP I), lx Dionex AXP-MS (MakeUP II), lx Dionex MSQ, lx Dionex UVD 340V - Prep Flow Cell, Gilson 215 Liquid Handler, SunFire Prep C18 OBD 5 pm, 19x50 mm column, lx G7159B 1290 Infinity II Preparative Open-Bed Sampler/Collector, lx G7161B 1290 Infinity II Preparative Binary Pump, lx G711 IB 1260 Infinity II Quaternary Pump (Modifier), lx G711 IB 1260 Infinity II Quaternary Pump (Analyltic I MakeUp), lx G7165A 1260 Infinity II Multiple Wavelength Detector incl.
- Typical Analytical Modifier Column flow was 1 mL/min, Solvent A was acetonitrile, Solvent B was water, and Solvent C was 5% acetic Acid in acetonitrile/water 1 :1.
- a Mass Spectrometer Detector (API-ES, positive) at UV 220 nm, 254 nm, or 310 nm was used for detection.
- Step 1 6,8-dibromo-3 -chloroimidazo [ 1 ,2-b]pyridazine;
- 6,8-dibromoimidazo[l,2-b]pyridazine (leq.) was dissolved in 1,2-dichloroathan and acetonitrile ia (1/1 v/v 16 mL/mmol), followed by the portion wise addition of NCS (1.3eq.). The mixture was stirred at r.t. for 3h. The mixture was quenched with sodium thiosulphate solution (5M in water), extracted with DCM, dried filtered and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.
- the product from the step before was dissolve in dioxane (0.5M). Water (10%v/v) was added. The corresponding boronic acid (1.3 eq.) , Pd2(dba)3 (0.2eq.), X-Phos (0.8eq) and K2CO3 (3eq.) were added. The mixture was degassed with N2 and heated for one night at 80°C. Additional boronic acid, Pd2(dba)3 and X-Phos (same amounts than before) were added, followed by heating at 80°C. This was repeated until completion of the reaction (HPLC). The mixture was filtered through a plug of celite, washed with MeOH and water, concentrated, re-diluted 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 reversed phase HPLC.
- Example #14, #15 were synthesized using these protocols with modifications.
- the compound of example #15 was in DCM (dry), methane sulfonyl chloride (5eq.) and triethylamine (5 eq.) were added. The mixture was stirred o.n. at r.t.. The mixture was dilute 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 purified by reversed phase HPLC.
- the compounds of examples #14, #15, #16, #18 are racemic mixtures.
- the product from the step before was dissolve in dioxane (0.5M). Water (10%v/v) was added. The corresponding boronic acid (1.3 eq.) , Pd2(dba)3 (0.2eq.), X-Phos (0.8eq) and K2CO3 (3eq.) were added. The mixture was degassed with N2 and heated for one night at 80°C. Additional boronic acid, Pd2(dba)3 and X-Phos (same amounts than before) were added, followed by heating at 80°C. This was repeated until completion of the reaction (HPLC). The mixture was filtered through a plug of celite, washed with MeOH and water, concentrated, re-diluted 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 reversed phase HPLC to separate the products from the mixture.
- the product from the step before was dissolve in dioxane (0.5M). Water (10%v/v) was added. 2,6- Di fluorophenyl boronic acid (1.3 eq.), Pd(dppf)DCM (0.2eq.) and Na2CO3aq. (IM) (3eq.) were added. The mixture was degassed with N2 and heated for 3h at 80°C. Additional boronic acid and Pd(dppf)DCM were added, followed by heating at 80°C. This was repeated until completion of the reaction (HPLC). The mixture was filtered through a plug of celite, washed with MeOH and water, concentrated, re-diluted with water and extracted with DCM. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude material was purified by gradient flash chromatography.
- Step 1 The boc-protected diamine was dissolved in acetonitrile. Dibromo pentane (2eq.) and DIPEA (5eq.) were added and the mixture stirred at r.t. o.n.. The mixture was diluted with EtOAc and washed with ammonium chloride (aq. sat.) and water. The organic layer was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by reversed phased HPLC.
- Step 2 The product from step 1 was dissolved in MeOH and treated with HC1 (4M in dioxane, excess) o.n.. The mixture was concentrated and used without further purifications as HC1 salt.
- Example#1 3-chloro-6-(2,6-difluorophenyl)-N-((1r,4r)-4-(4-methylpiperazin-l- yl)cyclohexyl)imidazo[l,2-b]pyridazin-8-amine; "HPLC-MS C"; 3.653 min; 461.2;
- Example# 10 3 -chloro-6-(2,6-difluorophenyl)-N-(l -methylpiperidin-4-yl)imidazo [1 ,2- b]pyridazin-8-amine; "HPLC-MS C "; 3.480min; 378.2;
- Example#12 (lr,4r)-Nl-(3-chloro-6-(2,6-di
- Example# 14 3 -chloro-6-(2,6-difluorophenyl)-N-(3 -methyl- 1 -(methylsulfonyl)piperidin-4- yl)imidazo[l,2-b]pyridazin-8-amine"HPLC-MS C"; 4.021min; 456.2.
- Example#! 5 3-chloro-6-(2,6-difluorophenyl)-N-(3-methylpiperidin-4-yl)imidazo[l ,2- b]pyridazin-8-amine;"HPLC-MS C"; 3.562 min; 378.2.
- Example# 16 tert-butyl-4-((3-chloro-6-(2,6-difluorophenyl)imidazo [ 1 ,2-b]pyridazin-8- yl)amino)-3-methylpiperidine-l-carboxylate;"HPLC-MS C"; 4.698 min; 478.2.
- Example#17 3-chloro-6-(2,6-difluorophenyl)-N-(l-(methylsulfonyl)piperidin-4-yl)imidazo[l,2- b]pyridazin-8-amine;" HPLC-MS C"; 3.889 min; 442.2.
- Example#! 8 3-chloro-6-(2,6-difluorophenyl)-N-(l-methylpyrrolidin-3-yl)imidazo[l,2- b]pyridazin-8-amine; "HPLC-MS C"; 3.416 min; 364.2.
- the testing compound was evaluated in 12 concentrations in a 1:3 dilution series, starting from 5microM as the highest concentration.
- ADP Gio reagent ready to use, ADP Gio Kinase assay, Promega GmbH, Germany # V9102
- ADP Gio Kinase assay Promega GmbH, Germany # V9102
- ADP Gio Detection reagent (ready to use, ADP Gio Kinase assay, Promega GmbH, Germany # V9102) were added, mixed and incubated for 30 min at RT.
- the inhibitor concentration was plotted against the luminescence to determine the IC50 using XLFit 5.5 (IDBS, Guildford) to fit to a sigmoidal dose response curve with a variable slope.
- Example#3 Example#4, Example#10, Example#11, Example#17, Example#18.
- Example#1 IC50 ⁇ 200nM: Example#1, Example#8, Example#9, Example#12, Example#14, Example#15, Example# 16.
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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 infectious diseases, and cardiovascular diseases.
Description
NOVEL CDK9 INHIBITORS
The present invention relates to the field of biomedicine, and specifically includes a series of novel CDK9 inhibitors with imidazopyridazine structure and their uses. It includes compounds as CDK9 inhibitors, pharmaceutically acceptable salts, solvates of the above compounds or prodrugs, and the use of pharmaceutical compositions of the above-mentioned compounds.
Cyclin-dependent kinases (CDKs) are a member of the serine/threonine kinase family and form a heterodimer with the regulatory subunit cyclin to perform its catalytic function. The members of the CDKs family can be divided into periodic CDKs and transcriptional CDKs according to their functional differences. The former mainly includes CDK1/2/4/6, which control the cell cycle process; the latter mainly includes CDK7/8/9, which regulate the transcription of mRNA and processing (Malumbres M. et al. Genome Biol., 2014, 15:122). Overexpression or functional enhancement of transcriptional CDKs will cause a significant increase in the expression of specific downstream genes, especially the anti-apoptotic protein Mcl-1, which will cause tumors (Morales F. et al. Cell Cycle, 2016, 15:519) -27). In recent years, it has been discovered that non-selective CDK inhibitors can achieve anti-tumor effects by inhibiting the function of CDK9. Therefore, the research on CDK inhibitors has attracted people's attention (Krystof V. et al. Target, Curr. Pharm. Des. ,2012,18:2883-2890). Studies have revealed that the overexpression of CDK9 is related to the occurrence of a variety of tumors, inflammation, and virus replication, such as acute myeloid leukemia, breast cancer, colon cancer, and prostate cancer, as well as human immunodeficiency virus and adenovirus (Franco L.C. et al. J. Cell Biochem.,2017,119:1273-1284). These findings indicate that CDK9 is an effective target for cancer treatment. First generation pan-CDK inhibitors that have entered the clinic include Flavopiridol, Dinaciclib, SNS-032 and CYC065, but showed clinical side-effects due to their lack of selectivity over a range of CDKs. In recent years pharmaceutical research is focusing on the identification and development of mainly selective CDK9 inhibitors. These are currently in preclinical and early clinical research such as BAY- 1143572, KB-0742, and AZD4573.
It has been an object of the present invention to provide for novel inhibitors of CDK9 which overcome the drawbacks of the compounds of the prior art. It was especially an object to increase selectivity to CDK9 and improve druggability. The main object of the present invention was to
provide for a class of CDK9 small molecule inhibitors which show high efficiency, low toxicity, and excellent drug metabolism properties, and which can be used for disease prevention and/or treatment. This object has been solved by the compounds of the present invention. The present invention provides CDK9 small molecule inhibitors containing imidazopyridazine structures.
R1 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group; all of which groups may optionally be 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.
Preferably, R4 is H or C1.
Moreover preferably, R4 is H.
Further preferably, R3 is C1
Further preferably, R2 is a phenyl group that is substituted by 1, 2 or 3 substituents that are independently selected from F, C1, Br and Me.
Moreover preferably, R2 is a phenyl group that is substituted in the 2 and 6 position (i.e., a phenyl group carrying two ortho substituents).
Most preferably, R2 is a 2,6-difluorophenyl group.
Preferably, R1 is an optionally substituted C3-7 cycloalkyl group, an optionally substituted heterocycloalkyl group containing from 3 to 9 ring atoms that are 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 that are independently selected from C, N, O and S, or a group of formula -CH2-Het, wherein Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms that are independently selected from C, N, O and S.
Further preferably, R1 is an optionally substituted C3-7 cycloalkyl group, an optionally substituted heterocycloalkyl group containing from 3 to 9 ring atoms that are independently selected from C, N and O, or a group of formula -CH2-Het, wherein Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms that are independently selected from C, N, O and S.
Moreover preferably, R1 is selected from the following groups:
wherein R5 is NH2, a C1-8 heteroalkyl group, or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O; and R5a is hydrogen, a C1-6 alkyl group, a C1-8 heteroalkyl group, an optionally substituted C5-6 cycloalkyl group or an
optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
Further preferably, R1 is selected from the following groups:
wherein R5 is NH2, a Cw heteroalkyl group, or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O; and R5a is hydrogen, a C1-6 alkyl group, an optionally substituted C5-6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
Moreover preferably, R5a is hydrogen, a C1-6 alkyl group, or a group of formula -SO2-C1-6 alkyl, - -CONH- C1-6 alkyl, or -COO-C1-6 alkyl; or an optionally substituted C5-6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
Further preferably, R5 is a group of formula -N(CH2CH2)2NMe, NH2, -N(CH2CH2)2O, or -NMe2.
Further preferably, R5a is a group of formula -Me, -SO2Me, or -COOtBu.
Moreover preferably, R1 is a group of formula -CH2-Het wherein Het is an optionally substituted pyridyl group.
Further preferably, the optional substituents at group R1 are independently selected from -N(CH2CH2)2NMe, -N(CH2CH2)2O, NH2, -NMe2, -Me, -SO2Me, and -COOtBu.
Further preferably, R1 an optionally substituted heteroalkyl group containing from 1 to 12 carbon atoms and from 1 to 6 heteroatoms selected from N, O and S.
Further preferably, R1 is an optionally substituted C4-6 cycloalkyl group, an optionally substituted heterocycloalkyl group containing from 5 to 8 ring atoms that are independently selected from C, N and O, an optionally substituted phenyl group or an optionally substituted pyrazol-4-yl group.
Moreover preferably, R1 is selected from the following groups:
wherein R5 is a -NH2 group, a C1-6 heteroalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
Preferably, R5 is selected from the following groups: -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.
Moreover preferably, R1 is selected from the following groups:
wherein R5a is hydrogen, a C1-6 alkyl group, a C1-8 heteroalkyl group, an optionally substituted C5- 6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
Further preferably, R1 has the following structure:
wherein R6a is hydrogen, halogen or a C1-4 heteroalkyl group (especially a -O-C1-4 alkyl group); R6b is hydrogen, halogen or a C1-4 heteroalkyl group (especially a -O-C1-4 alkyl group) and R6 is a
C1-6 alkyl group, a C1-6 heteroalkyl group, an optionally substituted C3-7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N and O.
Preferably, R6a is hydrogen, C1 or OMe.
Moreover preferably, R6b is hydrogen.
Further preferably, R6 is a methyl group, a group of formula -C(CH3)2CN, an optionally substituted cyclohexyl group, an optionally substituted piperidinyl group or a tetrahydropyranyl group.
Moreover preferably, R6 is a group of formula -Cy-L-R6c, wherein Cy is an optionally substituted C3-7 cycloalkylene group or an optionally substituted heterocycloalkylene group containing from 3 to 7 ring atoms that are independently selected from C, N and O; L is a bond or a CH2 group and R6C is an optionally substituted C3-7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N and O.
Further preferably, Cy is a cyclohexylene group or a piperidinylene group.
Moreover preferably, R6c is a cyclopropyl group or an optionally substituted heterocycloalkyl group containing from 4 to 6 ring atoms that are independently selected from C, N and O.
Further preferably, R1 has the following structure:
wherein R7a is hydrogen, halogen, CN or an -O- C1-4 alkyl group; R7b is hydrogen, halogen, CN or an -O-C1-4 alkyl group and R7 is a C1-6 heteroalkyl group, an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C,
N and O or an optionally substituted heteroalkylcycloalkyl group containing from 4 to 12 atoms that are independently selected from C, N and O.
Preferably, R7b is hydrogen or a methoxy group; preferably hydrogen.
Further preferably, R7a is hydrogen, fluorine, CN or an -O-C1-4 alkyl group; preferably hydrogen.
Moreover preferably, R7 is an optionally substituted piperazinyl group, an optionally substituted piperidinyl group, an optionally substituted morpholinyl group or an optionally substituted tetrahydropyridinyl group.
Further preferably, R7 is a group of formula -Cy'-L'-R7c, wherein Cy' is an optionally substituted C3-7 cycloalkylene group or an optionally substituted heterocycloalkylene group containing from 3 to 7 ring atoms that are independently selected from C, N and O; L' is a bond or a CH2 group and R7C is an optionally substituted C3-7 cycloalkyl group or an optionally substituted heterocycloalkyl group containing from 3 to 7 ring atoms that are independently selected from C, N and O.
Moreover preferably, R7 is a group of formula -CO-R7d or -CO-NH-R7d, wherein R7d is a C1-4 alkyl group or an optionally substituted heterocycloalkylene group containing from 3 to 7 ring atoms that are independently selected from C, N and O.
Further preferably, R1 is a group of formula -CH2-R1a or -CH2-CH2-R1a, wherein R1a is an optionally substituted heterocycloalkyl group having 5 or 6 ring atoms that are independently selected from C, N and O (Preferably, the optional substituent at R1a is a C1-4 alkyl group).
The most preferred compounds of the present invention are the compounds disclosed in the examples, or a salt thereof.
It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., any embodiment for R1 may be combined with any embodiment of R2).
The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, especially from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms, for example a methyl (Me, CH3), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), fro-butyl (iBu), sec-butyl (sBu), tert-butyl (tBu), n-pentyl, iso-pentyl, n-hexyl, 2,2-dimethylbutyl or o-octyl group.
The expression C1-6 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 6 carbon atoms. The expression C1-4 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms. Examples are a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl group.
The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, especially from 2 to 10 (e.g., 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethynyl (acetylenyl), propynyl (e.g., propargyl), butynyl, isoprenyl or hex-2-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s), and alkynyl groups have one or two (especially preferably one) triple bond(s).
Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or C1) such as, for example, a 2,2,2- trichloroethyl or a trifluoromethyl group.
The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more (preferably 1 to 8; especially preferably 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or by a SO or a SO2 group. The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxy alkyl, carboxy alkylamide or alkoxy carbonyloxy. Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or C1).
Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 8 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Especially preferably, a heteroalkyl group contains from 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). The term C1-8 heteroalkyl refers to a heteroalkyl group containing from 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). The term C1-6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from 0, S and/or N (especially O and/or N). The term C1-4 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).
Examples of heteroalkyl groups are groups of formulae: Ra-O-Ya-, Ra-S-Ya-, Ra-SO-Ya-, Ra-SO2-Ya-, Ra-N(Rb)-SO2-Ya-, Ra-SO2-N(Rb)-Ya-, Ra-N(Rb)-Ya-, Ra-CO-Ya-, Ra-O-CO-Ya-, Ra-CO-O-Ya-, Ra-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya-, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-O-Ya-, - Ya-CN, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-O-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-O-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-O-CS-O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, Ra-S-CO-O-Ya-, Ra-O-CO-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-S-Ya-, Ra-S-CS-O-Ya-, Ra-O-CS-S-Ya-, wherein Ra being a hydrogen atom, a C1-6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rb being a hydrogen atom, a C1-6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rc being a hydrogen atom, a C1-6 alkyl, a C2-C6 alkenyl or a C2-C6 alkynyl group; Rd being a hydrogen atom, a C1-6 alkyl, a C2.C6 alkenyl or a C2-C6 alkynyl group and Ya being a bond, a Ci-C6 alkylene, a C2-C6 alkenylene or a C2-C6 alkynylene group, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms.
Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, iso- propyloxy, n-butoxy, tert-butyloxy, methoxymethyl, -CH2CH2OH, -CH2OH, -SO2Me, -NHAc, - C(CH3)2CN, -COOtBu, methoxyethyl, ethoxymethyl, 1 -methoxyethyl, 1 -ethoxyethyl, 2- methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl,
diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N- ethyl-N -methylcarbamoyl or N -methyl carbamoyl. Further examples of heteroalkyl groups are nitrile (-CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.
The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbomyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group. Preferably, the expression cycloalkyl refers to a saturated cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.
The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1, 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heterocycloalkyl group has preferably 1 or 2 ring(s) and 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). The expression heterocycloalkyl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups. Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g. -N(CH2CH2)2O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.
The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl,
cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings and from 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.
The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1 , 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heteroalkylcycloalkyl group preferably contains 1 or 2 rings having from 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) having from 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.
The expression aryl refers to an aromatic group that contains one or more rings and from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. The expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are the phenyl (Ph), naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3 -nitrophenyl or 4-hydroxyphenyl group.
The expression heteroaryl refers to an aromatic group that contains one or more rings and from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, comprising one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). The expression heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N3, NH2 or NO2 groups. Examples are 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, oxadiazo lyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4-hydroxypyridyl (4-pyridonyl), 3,4- hydroxypyridyl (3, 4-pyridonyl), oxazolyl, isoxazolyl, triazo lyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl,
isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3 '-bifuryl, pyrazolyl (e.g. 3- pyrazolyl) and isoquinolinyl groups.
The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are phenylcyclopentyl, cyclohexylphenyl as well as groups derived from toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetraline, dihydronaphthalene, indanone, cumene, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or one or two cycloalkyl group containing 3, 4, 5, 6 or 7 ring carbon atoms.
The expression heteroaralkyl refers to groups containing both aryl and/or heteroaryl groups and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 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 comprising 1, 2, 3 or 4 oxygen, sulfur or nitrogen atoms.
Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroaryl-heterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl-alkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkyl-cycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, phthalidyl, 2- or 3-
ethylindo lyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group.
As already stated above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =0, SH, =S, NH2, =NH, N3 or NO2 groups.
According to a preferred embodiment, all alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl groups described herein may optionally be substituted.
The term halogen refers to F, C1, Br or I.
When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated or fused or bridged.
The suffix "-ene" like e.g. in "phenylene" refers to the corresponding divalent group.
The term "optionally substituted" refers to a group which is unsubstituted or substituted by one or more (especially by one, two or three; preferably by one or two) substituents.
If a group comprises more than one substituent, these substituents are independently selected, i.e. they may be the same or different.
If a group is substituted by a cyclic group, such as e.g. a cycloalkyl group or a heterocycloalkyl group, this cyclic group may be bonded to said group via a single or double bond or this cyclic group may be annulated or fused to said group.
Specific examples for substituents are fluorine, chlorine, bromine and iodine and OH, SH, NH2, - SO3H, -SO2NH2, -CO0H, -COOMe, -COMe (Ac), -NHSO2Me, -SO2NMe2, -CH2NH2, -NHAc, -
SO2Me, -COOtBu, NMe2, Me, -N(CH2CH2)2NMe, -N(CH2CH2)2O, -CONH2, -CN, -NHCONH2, -NHC(NH)NH2, -NOHCH3, -N3 and -NO2 groups.
Further examples of substituents are C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 heteroalkyl, C3-C18 cycloalkyl, C1-C17 heterocycloalkyl, C4-C20 alkylcycloalkyl, C1-C19 heteroalkylcycloalkyl, C6-C18 aryl, C1-C17 heteroaryl, C7-C2o aralkyl and C1-C19 heteroaralkyl groups; especially C1-6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-6 heteroalkyl, C3-C10 cycloalkyl, C1-C9 heterocycloalkyl, C4-C12 alkylcycloalkyl, C1-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 aralkyl and C1-C11 heteroaralkyl groups, further preferably C1-6 alkyl and C1-6 heteroalkyl groups.
Preferred substituents are halogen atoms (e.g., F, C1, Br) and -OH, -NH2, -CN, C1-6 alkyl, C2-C6 alkenyl, C1-6 heteroalkyl, cyclopropyl and -CH2-cyclopropyl groups.
Further preferred substituents are halogen atoms (e.g. F, C1, Br) and -OH, -NH2, -CN, -C1-4 alkyl (e.g. -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu, -CH2CH2F, CH2CHF2, -CH2CF3 and -CF3), -O-C1-4 alkyl (e.g. -OMe, -OEt, -O-nPr, -O-iPr, -O-nBu, -O-iBu and -O-tBu), -NHC1-4 alkyl (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(CI-6 alkyl)2, - C(CH3)2CN, -CONH-C1-4 alkyl (e.g. -CONHCH2CF3, -CONHEt, -CONHtBu), -COOH, -COOMe, -COMe, -CH2CH2CH=CH2, cyclopropyl and -CH2-cyclopropyl groups.
The therapeutic use of compounds according to formula (I), their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) or a salt thereof as defined herein or a pharmaceutically acceptable ester, prodrug, hydrate or solvate thereof, optionally in combination with a pharmaceutically acceptable carrier and/or adjuvant.
It is a further object of the present invention to provide a compound of formula (I) as defined herein or a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment of one or more diseases specified herein.
Preferably the compounds of the present invention may be used for the treatment and/or prevention of the following conditions:
Diseases in which abnormal CDK (especially CDK9 and/or CDK2) regulation is observed, including broad number of cytokine-induced inflammatory, and autoimmune diseases, local or systemic viral infection diseases, 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 such as acute myelogenous leukemia, chronic lymphocytic leukemia, relapsed multiple myeloma, nonHodgkin’s lymphoma, acute lymphoblastic leukemia, acute biphenotypic leukemia, aggressive MYC-driven B-Cell lymphoma, primary peritoneal carcinoma, Kaposi 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 haematological/solid malignancies. In particular, the compounds may be used to treat a hematologic malignancy, or a solid tumor caused by aberrant expression of MYC- or MCL-1. Furthermore, the compounds may be used as modulator of the immune response and for the treatment and/or prevention of mechanical/inj ury-induced inflammation such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory disease, including gastrointestinal or urinary tracts inflammatory diseases inflammatory diseases and inflammatory diseases of the eye, such as Sjogren’s disease and glaucoma, bacteria-induced inflammatory disease, such as gingivitis, periodontitis, and for the treatment and/or prevention of cardiovascular diseases such as cardiac hypertrophy, dilated cardiomyopathy, atherosclerosis, and cardio- metabolic diseases such as obesity and diabetes.
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 a disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered, the route of administration, the condition being treated, as well as the patient being treated.
The salt of a compound of formula (I) is preferably a pharmacologically acceptable salt. Examples of pharmacologically acceptable salts of sufficiently basic compounds of formula (I) are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound of formula (I) may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of formula (I).
Compounds of formula (I) may be solvated, especially hydrated. The hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of formula (I). The solvates and/or hydrates may e.g. be present in solid or liquid form.
It should be appreciated that certain compounds of formula (I) may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis/trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R/S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds of formula (I) may contain asymmetric C- atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of
enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.
According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and/or increases the formation of desired active metabolites. Accordingly, the present invention also encompasses the partially and fully deuterated compounds of formula (I). The term hydrogen also encompasses deuterium.
The present invention also relates to pro-drugs which are composed of a compound of formula (I) and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, 2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkylidene ethyl group or an acyloxy group as defined herein, e.g. ethoxy, benzyloxy, acetyl or acetyloxy or, especially for a compound of formula (I), carrying a hydroxy group (-OH): a sulfate, a phosphate (-OPO3 or - OCH2OPO3) or an ester of an amino acid. Especially preferred are pro-drugs of the hydroxy group of a compound of formula (I).
As used herein, the term pharmaceutically acceptable ester especially refers to esters which hydrolyze in vivo and include those that break down readily 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, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
Preferably, the present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers,
chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds of formula (I).
As mentioned above, therapeutically useful agents that contain compounds of formula (I), their solvates, salts or formulations are also comprised in the scope of the present invention. In general, compounds of formula (I) will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent.
For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules, one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 run) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 20 mg to about 1 ,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.
According to a moreover preferred embodiment, the present invention provides a method for treating one or more diseases specified herein which comprises 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.
According to a further preferred embodiment, the present invention provides a method for treating one or more diseases specified herein which comprises administering to a subject in need of such treatment a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.
EXAMPLES
General Synthesis methods
The following methods were used in synthesis of the compounds described herein.
Flash chromatography: Flash chromatography was performed on a Biotage Isolera(R) or Selekt® system using SNAP or SFAR silica cartridges and ethyl acetate/cyclohexane/methanol or dichloromethane/methanol gradients as eluent.
Microwave conditions: Reactions under micro wave conditions are performed in a Biotage initiator(R) microwave system.
SEMIprep reversed phase chromatography: The following instrumentation was used for SEMIprep reversed phase chromatography: 2x Varian PrepStar SD-1, lx Dionex P580 Pump 1 Channel(MakeUP I), lx Dionex AXP-MS (MakeUP II), lx Dionex MSQ, lx Dionex UVD 340V - Prep Flow Cell, Gilson 215 Liquid Handler, SunFire Prep C18 OBD 5 pm, 19x50 mm column, lx G7159B 1290 Infinity II Preparative Open-Bed Sampler/Collector, lx G7161B 1290 Infinity II Preparative Binary Pump, lx G711 IB 1260 Infinity II Quaternary Pump (Modifier), lx G711 IB
1260 Infinity II Quaternary Pump (Analyltic I MakeUp), lx G7165A 1260 Infinity II Multiple Wavelength Detector incl. Flow C6ll (Product# G1315-60022, Serial# DE185H6157, Path Length 10.00 mm, Volume 13.00 pl), lx G7170B 1290 Infinity II MS Flow Modulator, lx G6125B MSD 6100 Series Single Quadrupole inch G1948B Electrospray Interface, and 3x G1170A 1290 Infinity Valve Drive (14 Ports, 6 Positions Valve Head for Analytic Column Selection; 14 Ports, 6 Positions Valve Head for Preparative Column Selection; 14 Ports, 2 Positions Valve Head for Analytic / Preparative Mode Selection).
Preparative columns: Waters SunFire Prep C18 5 pm OBD 30x100 mm, #186002572, Waters Atlantis T3 Prep 5pm OBD 30x100 mm, #186003702, and Waters XSelect CSH Prep C18 5 pm OBD 30x100 mm, #186005425.
Analytical columns: Waters SunFire C18 2.5 pm 3.0x75mm, #186005636, Waters Atlantis T3 3pm 3.0 x75 mm, #186005653, and Waters XSelect CSH C18 2.5 pm 3.0 x 75mm, #186006106. Typical chromatography conditions are as follows:
Column flow was 30 mL/min, Solvent A was methanol containing 0.3% acetic acid, and Solvent B was water containing 0.3% acetic acid.
Typical times and relative volumes of Solvent and Solvent B are shown in Table 1.
Typical preparative method: Column flow was 60 mL/min, Solvent A was acetonitrile, and Solvent B was water. Preparation included Modifier Flow: 1.8 mL/min Modifier Flow containing 10% Acetic Acid in Acetonirile/Water 1:1 => resulting 0.3% Acetic Acid in Flow; and 0.5M NH4Ac/NH4OH-Buffer (pH 9.2) in Acetonitrile/Water 1:9 => resulting 15 mM Buffer Concentration in Flow.
MS MakeUp: 0.9 mL/min 0.05% Acetic Acid in Acetonirile/Water 1 :1.
Typical Analytical Modifier: Column flow was 1 mL/min, Solvent A was acetonitrile, Solvent B was water, and Solvent C was 5% acetic Acid in acetonitrile/water 1 :1.
Typical times and relative volumes of Solvent, Solvent B, Solvent C are shown in Table 3.
A Mass Spectrometer Detector (API-ES, positive) at UV 220 nm, 254 nm, or 310 nm was used for detection.
Terms and abbreviations used in the Examples are provided in Table 4.
The analytical HPLC Methods used in preparation of the compounds are listed in Table 5.
Description of synthesis steps:
6,8-dibromoimidazo[l,2-b]pyridazine (leq.) was dissolved in 1,2-dichloroathan and acetonitrile ia (1/1 v/v 16 mL/mmol), followed by the portion wise addition of NCS (1.3eq.). The mixture was stirred at r.t. for 3h. The mixture was quenched with sodium thiosulphate solution (5M in water), extracted with DCM, dried filtered and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.
6,8-dibromo-3-chloroimidazo[l,2-b]pyridazine (leq.) and the corresponding amine (leq.) were dissolved in dioxane (3mL/mmol). DIPEA (2.0 eq.) was added and the mixture heated to 180°C for 30 min under microwave irritation. The mixture was diluted with NaHCO3aq. sat. 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.
Step 3: Arylation
The product from the step before was dissolve in dioxane (0.5M). Water (10%v/v) was added. The corresponding boronic acid (1.3 eq.) , Pd2(dba)3 (0.2eq.), X-Phos (0.8eq) and K2CO3 (3eq.) were added. The mixture was degassed with N2 and heated for one night at 80°C. Additional boronic acid, Pd2(dba)3 and X-Phos (same amounts than before) were added, followed by heating at 80°C. This was repeated until completion of the reaction (HPLC). The mixture was filtered through a plug of celite, washed with MeOH and water, concentrated, re-diluted 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 reversed phase HPLC.
The compounds of Examples #1, #3, #4, #10, #11, #12, #16, #17 #18 #19 were synthesized using these protocols.
The compounds of Example #14, #15 were synthesized using these protocols with modifications.
Example #15:
The compound of example #16 was dissolved in dry MeOH and treated with HC1 (4M in dioxane) for 24h. The mixture was concentrated under reduced pressure and the crude product purified by reversed phase HPLC.
Example #14:
The compound of example #15 was in DCM (dry), methane sulfonyl chloride (5eq.) and triethylamine (5 eq.) were added. The mixture was stirred o.n. at r.t.. The mixture was dilute 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 purified by reversed phase HPLC.
The compounds of examples #14, #15, #16, #18 are racemic mixtures.
Description of synthesis steps:
8-bromo-6-chloroimidazo[l,2-b]pyridazine (leq.) and the corresponding amine as HCL salt (1.2eq.) were mixed in dioxane (3mL/mmol). DIPEA (6.0 eq.) was added and the mixture heated to 180°C for 30 min under microwave irritation. The mixture was diluted with NaHCO3aq. sat. 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.
The product from the step before was dissolve in dioxane was dissolved in 1,2-dichloroethan and acetonitrile (1/1 v/v 16 mL/mmol), followed by the portion wise addition of NCS (1.3eq.). The mixture was stirred at r.t. for 6h, then at 40°C o.n.. The reaction showed no completion (HPLC). Additional NCS (leq.) was added. The mixture was heated for an additional night at 80°C. The
two chlorinated products were observed. The mixture was quenched with sodium thiosulphate solution (5M 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 separated.
The product from the step before was dissolve in dioxane (0.5M). Water (10%v/v) was added. The corresponding boronic acid (1.3 eq.) , Pd2(dba)3 (0.2eq.), X-Phos (0.8eq) and K2CO3 (3eq.) were added. The mixture was degassed with N2 and heated for one night at 80°C. Additional boronic acid, Pd2(dba)3 and X-Phos (same amounts than before) were added, followed by heating at 80°C. This was repeated until completion of the reaction (HPLC). The mixture was filtered through a plug of celite, washed with MeOH and water, concentrated, re-diluted 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 reversed phase HPLC to separate the products from the mixture.
6,8-dibromoimidazo[1,2-b]pyridazine (leq.) and [4-(6-Bromo-imidazo[l,2-b]pyridazin-8-ylamino)- cyclohexyl]-carbamic acid tert-butyl ester as HCL salt (1.2eq.) were mixed in dioxane (3mL/mmol). DIPEA (6.0 eq.) was added and the mixture heated to 180°C for 60 min under microwave irritation. The mixture was diluted withNaHCO3aq. sat. 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.
The product from the step before was dissolve in dioxane (0.5M). Water (10%v/v) was added. 2,6- Di fluorophenyl boronic acid (1.3 eq.), Pd(dppf)DCM (0.2eq.) and Na2CO3aq. (IM) (3eq.) were added. The mixture was degassed with N2 and heated for 3h at 80°C. Additional boronic acid and Pd(dppf)DCM were added, followed by heating at 80°C. This was repeated until completion of the reaction (HPLC). The mixture was filtered through a plug of celite, washed with MeOH and water, concentrated, re-diluted 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.
The product from the step before was dissolve in dioxane was dissolved in 1,2-dichloroethan and acetonitrile (1/1 v/v 10 mL/mmol), followed by the portion wise addition of NCS (1.3eq.). The mixture was stirred at for 5h at 80°C. The mixture was quenched with sodium thiosulphate solution (5M in water), extracted with DCM, dried filtered and concentrated under reduced pressure. The crude product was purified by gradient flash chromatography.
The product from the step before was dissolve in dioxane was dissolved in 1 ,2-dichloroethan and acetonitrile (1/1 v/v 10 mL/mmol), followed by the portion wise addition of NCS (1.3eq.). The mixture was stirred at for 5h at 60°C. The mixture was quenched with sodium thiosulphate solution (5M in water), extracted with DCM, dried filtered and concentrated under reduced pressure. The crude product mixture was used without purification.
Step 4: Deprotection:
The mixture from the step before was dissolved in MeOH (dry) and treated with an excess HC1 (4M in dioxane). The mixture was stirred at r.t., until completion, then concentrated to dryness and purified by reversed phase HPLC.
The compounds of Examples #8, and #9 were synthesized using this procedure.
The amines used were either commercially available, described in the literature, or made by one of the following procedures:
A: 4-(piperidin- 1-y1)cyclohexanamines:
Step 1: The boc-protected diamine was dissolved in acetonitrile. Dibromo pentane (2eq.) and DIPEA (5eq.) were added and the mixture stirred at r.t. o.n.. 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 reversed phased HPLC.
Step 2: The product from step 1 was dissolved in MeOH and treated with HC1 (4M in dioxane, excess) o.n.. The mixture was concentrated and used without further purifications as HC1 salt.
The following examples were prepared according to the procedures described above:
Example: name; HPLC method; r.t.; MH+; NMR
Example#1 + 3-chloro-6-(2,6-difluorophenyl)-N-((1r,4r)-4-(4-methylpiperazin-l- yl)cyclohexyl)imidazo[l,2-b]pyridazin-8-amine; "HPLC-MS C"; 3.653 min; 461.2;
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 "; 3.93min; 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)."
Example#4: 3-chloro-6-(2,6-difluorophenyl)-N-(pyridin-3-ylmethyl)imidazo[l,2-b]pyridazin-8- amine; "HPLC-MS C 3.67min; 372.0; "1H NMR (600 MHz, Chloroform-d) 5 8.64 (d, J = 2.4 Hz, 1H), 8.60-8.56 (m, 1H), 7.70 (dt, J = 7.9, 2.0 Hz, 1H), 7.50 (s, 1H), 7.39 (tt, J = 8.5, 6.3 Hz, 1H), 7.31 (dd, J = 7.9, 4.8 Hz, 1H), 7.04-6.97 (m, 2H), 6.34 (d, J = 6.0 Hz, 1H), 6.12 (s, 1H), 4.59 (d, J = 5.7 Hz, 2H).
Example#8: (lr,4r)-Nl-(3,7-dichloro-6-(2,6-difluorophenyl)imidazo[l,2-b]pyridazin-8- yl)cyclohexane-l,4-diamine; "HPLC-MS C "; 3.737nmin; 412.2; "1H NMR (600 MHz, Chloroform-d) 8 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 (broad s, 2H, NH2), 2.98 (d, J = 12.0 Hz, 1HH), 2.33 (d, J = 12.6 Hz, 2H), 2.15 (d, J = 12.7 Hz, 2H), 1.72-1.60 (m, 2H), 1.44-1.34 (m, 2H)."
Example#9: (lr,4r)-Nl-(3-chloro-6-(2,6-difluorophenyl)imidazo[l,2-b]pyridazin-8- yl)cyclohexane-l,4-diamine; "HPLC-MS C ": 3.358min; 378.2; “1H NMR (800 MHz, Chloroform-d) 3 7.84 (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 (broad 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)
Example# 10: 3 -chloro-6-(2,6-difluorophenyl)-N-(l -methylpiperidin-4-yl)imidazo [1 ,2- b]pyridazin-8-amine; "HPLC-MS C "; 3.480min; 378.2;
Example#1 1 : 3-chloro-6-(2,6-difluorophenyl)-N-((lr,4r)-4-morpholinocyclohexyl)imidazo[1,2- b]pyridazin-8-amine; "HPLC-MS C "; 3.763min; 448.2; "1H NMR (800 MHz, Chloroform-d) δ 7.49 (s, 1H), 7.43 (td, J = 8.7, 4.3 Hz, 1H), 7.05 (t, J = 7.8 Hz, 2H), 6.10 (s, 1H), 5.72 (d, J = 8.0 Hz, 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)."
Example#12: (lr,4r)-Nl-(3-chloro-6-(2,6-difluorophenyl)imidazo[l,2-b]pyridazin-8-yl)-N4,N4- dimethylcyclohexane-l,4-diamine; "HPLC-MS C 3.630min; 406.2;
Example# 14: 3 -chloro-6-(2,6-difluorophenyl)-N-(3 -methyl- 1 -(methylsulfonyl)piperidin-4- yl)imidazo[l,2-b]pyridazin-8-amine"HPLC-MS C"; 4.021min; 456.2.
Example#! 5 : 3-chloro-6-(2,6-difluorophenyl)-N-(3-methylpiperidin-4-yl)imidazo[l ,2- b]pyridazin-8-amine;"HPLC-MS C"; 3.562 min; 378.2.
Example# 16 : tert-butyl-4-((3-chloro-6-(2,6-difluorophenyl)imidazo [ 1 ,2-b]pyridazin-8- yl)amino)-3-methylpiperidine-l-carboxylate;"HPLC-MS C"; 4.698 min; 478.2.
Example#17: 3-chloro-6-(2,6-difluorophenyl)-N-(l-(methylsulfonyl)piperidin-4-yl)imidazo[l,2- b]pyridazin-8-amine;" HPLC-MS C"; 3.889 min; 442.2.
Example#! 8: 3-chloro-6-(2,6-difluorophenyl)-N-(l-methylpyrrolidin-3-yl)imidazo[l,2- b]pyridazin-8-amine; "HPLC-MS C"; 3.416 min; 364.2.
Example# 19 : 3-chloro-6-(2,6-difluorophenyI)-N-( 1 -methyIazetidin-3 -yl)imidazo [ 1 ,2- b]pyridazin-8-amine; "HPLC-MS C"; 4.453 min; 350.2; "1H NMR (400 MHz, Chloroform-d) 8 7.52 (s, 1H), 7.41 (tt, J = 8.2, 6.2 Hz, 1H), 7.08 - 6.99 (m, 2H), 6.03 (s, 1H), 4.50 (dd, J = 14.5, 7.0 Hz, 1H), 4.10 (dd, J = 14.2, 5.6 Hz, 1H), 3.26 (s, 3H), 3.22 (s, 2H), 3.14 (d, J = 11.9 Hz, 1H), 2.67 (t, J = 11.1 Hz, 1H)."
Biological Data
ASSAY PROTOCOL for determination of inhibitory activity
The testing compound was evaluated in 12 concentrations in a 1:3 dilution series, starting from 5microM as the highest concentration.
In a white 384 microplate (Greiner bio-one, Austria #784904,) with 2 microL of 3 -fold concentrated CDK9/CyclinTl (ProQinase/Reaction Biology, USA #0371-0345-1, LOT.: 012),
final concentration (f.c.) 6 nM, in 1 x kinase buffer, 2 microL of compound (3x fold concentrated in f.c. 1.66% DMSO/H2O) was added and incubated at Room Temperature (RT) for 10 min. Then 2 microL of Substrate/ ATP-Mix (3 x PDKtide f.c. 40 microM, SignalChem Biotech, Canada via Biozol, Eching, Germany # P10-58, LOT.: L2230-7 and 3 x UltraPure ATP f.c. 10 microM (ADP Gio Kinase assay, Promega GmbH, Germany # V9102)) were added, mixed and incubated for 120 min at RT.
After incubation time, 5 microL of ADP Gio reagent (ready to use, ADP Gio Kinase assay, Promega GmbH, Germany # V9102) were added, mixed and incubated for 40 min at RT.
In the last step, 10 microL of ADP Gio Detection reagent (ready to use, ADP Gio Kinase assay, Promega GmbH, Germany # V9102) were added, mixed and incubated for 30 min at RT.
GloMax Discover GM3000 Reader (Promega GmbH, Germany 9700000249) was used for the readout.
The inhibitor concentration was plotted against the luminescence to determine the IC50 using XLFit 5.5 (IDBS, Guildford) to fit to a sigmoidal dose response curve with a variable slope.
CDK9/T1 ADPGlo Activity of the compounds of the above-described examples:
IC50 < 20nM: Example#3, Example#4, Example#10, Example#11, Example#17, Example#18.
IC50 < 200nM: Example#1, Example#8, Example#9, Example#12, Example#14, Example#15, Example# 16.
Claims
R1 is an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group; all of which groups may optionally be 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. A compound according to claim 1, wherein R4 is H or C1. A compound according to claim 1, wherein R4 is H. A compound according to any one of the preceding claims, wherein R3 is C1 A compound according to any one of the preceding claims, wherein R2 is a phenyl group that is substituted by 1 , 2 or 3 substituents that are independently selected from F, C1, Br and Me.
A compound according to any one of the preceding claims, wherein R2 is a 2,6- difluorophenyl group. A compound according to any one of the preceding claims, wherein R1 is an optionally substituted C3-7 cycloalkyl group, an optionally substituted heterocycloalkyl group containing from 3 to 9 ring atoms that are 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 that are independently selected from C, N, O and S, or a group of formula -CH2-Het, wherein Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms that are independently selected from C, N, O and S. A compound according to any one of the preceding claims 1 to 6, wherein R1 is an optionally substituted C3-7 cycloalkyl group, an optionally substituted heterocycloalkyl group containing from 3 to 9 ring atoms that are independently selected from C, N and O, or a group of formula -CH2-Het, wherein Het is an optionally substituted heteroaryl group containing 5 or 6 ring atoms that are independently selected from C, N, 0 and S. A compound according to any one of the preceding claims 1 to 6, wherein R1 is selected from the following groups:
wherein R5 is NH2, a C1-8 heteroalkyl group, or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O; and R5a is hydrogen, a C1-6 alkyl group, a C1-8 heteroalkyl group, an optionally substituted C5-6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O.
A compound according to any one of the preceding claims 1 to 6, wherein R1 is selected from the following groups:
wherein R5 is NH2, a C1-6 heteroalkyl group, or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O; and R5a is hydrogen, a C1-6 alkyl group, an optionally substituted C5-6 cycloalkyl group or an optionally substituted heterocycloalkyl group containing 5 or 6 ring atoms that are independently selected from C, N and O. A compound according to any one of the preceding claims 1 to 6, wherein R1 is a group of formula -CH2-Het wherein Het is an optionally substituted pyridyl group. A compound according to claim 1 which is selected from the following compounds or a salt thereof:
3 -chloro-6-(2,6-difhuorophenyl)-N-(( 1 r,4r)-4-(4-methylpiperazin- 1 - yl)cyclohexyl)imidazo[l,2-b]pyridazin-8-amine;
3-chloro-6-(2,6-difluorophenyl)-N-((4,6-dimethylpyridin-3-yl)methyl)imidazo[l,2- b]pyridazin-8-amine;
3-chloro-6-(2,6-difluorophenyl)-N-(pyridin-3-ylmethyl)imidazo[l,2-b]pyridazin-8- amine;
( 1 r,4r)-N 1 -(3 ,7-dichloro-6-(2,6-difluorophenyl)imidazo [ 1 ,2-b]pyridazin-8- yl)cyclohexane- 1 ,4-diamine;
(lr,4r)-Nl-(3-chloro-6-(2,6-difluorophenyl)imidazo[l,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-(( 1 r,4r)-4-morpholinocyclohexyl)imidazo [ 1 ,2- b]pyridazin-8-amine;
(lr,4r)-Nl-(3-chloro-6-(2,6-difluorophenyl)imidazo[l,2-b]pyridazin-8-yl)-N4,N4- dimethylcyclohexane- 1 ,4-diamine;
3-chloro-6-(2,6-difluorophenyl)-N-(3-methyl-l-(methylsulfonyl)piperidin-4- yl)imidazo[l,2-b]pyridazin-8-amine;
3-chloro-6-(2,6-difluorophenyl)-N-(3-methylpiperidin-4-yl)imidazo[l,2-b]pyridazin-8- amine; tert-butyl-4-((3-chloro-6-(2,6-difluorophenyl)imidazo[l,2-b]pyridazin-8-yl)amino)-3- methy Ipiperidine- 1 -carboxylate;
3-chloro-6-(2,6-difluorophenyl)-N-(l-(methylsulfonyl)piperidin-4-yl)imidazo[l,2- b]pyridazin-8-amine;
3-chloro-6-(2,6-difluorophenyl)-N-(l-methylpyrrolidin-3-yl)imidazo[l,2-b]pyridazin-8- amine; and 3-chloro-6-(2,6-difhiorophenyl)-N-(l-methylazetidin-3-yl)imidazo[l,2-b]pyridazin-8- amine. A pharmaceutical composition comprising a compound according to anyone of the preceding claims and optionally one or more carrier substances and/or one or more adjuvants. 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 diseases in which abnormal CDK, especially CDK9 and/or CDK2 regulation is observed, including broad number of cytokine-induced inflammatory, and autoimmune diseases, local or systemic viral infection diseases, 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 such as acute myelogenous 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 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 haematological/solid malignancies (in particular, for use in the treatment of a
hematologic malignancy, or a solid tumor caused by aberrant expression of MYC- or MCL-1); or for use as modulator of the immune response and for use in the treatment and/or prevention of mechanical/inj ury-induced inflammation such as post-traumatic osteoarthritis (PTOA), systemic and local cytokine-induced inflammatory disease, including gastrointestinal or urinary tracts inflammatory diseases inflammatory diseases and inflammatory diseases of the eye, such as Sjogren’s disease and glaucoma, bacteria- induced inflammatory disease, such as gingivitis, periodontitis, and for the treatment and/or prevention of cardiovascular diseases such as cardiac hypertrophy, dilated cardiomyopathy, atherosclerosis, and cardio-metabolic diseases such as obesity and diabetes.
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Citations (2)
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WO2004026867A2 (en) * | 2002-09-19 | 2004-04-01 | Schering Corporation | Imidazopyridines as cyclin dependent kinase inhibitors |
US20130109661A1 (en) * | 2011-11-01 | 2013-05-02 | Hoffmann-La Roche Inc. | Imidazopyridazine compounds |
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WO2004026867A2 (en) * | 2002-09-19 | 2004-04-01 | Schering Corporation | Imidazopyridines as cyclin dependent kinase inhibitors |
US20130109661A1 (en) * | 2011-11-01 | 2013-05-02 | Hoffmann-La Roche Inc. | Imidazopyridazine compounds |
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FRANCO L.C. ET AL., J. CELL BIOCHEM., vol. 119, 2017, pages 1273 - 1284 |
KRYSTOF V ET AL., TARGET, CURR. PHARM. DES., vol. 18, 2012, pages 2883 - 2890 |
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