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HK1188990A - IMIDAZO[5, 1-ƒ][1,2-4]TRIAZINES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS - Google Patents

IMIDAZO[5, 1-ƒ][1,2-4]TRIAZINES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS Download PDF

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Publication number
HK1188990A
HK1188990A HK14101979.7A HK14101979A HK1188990A HK 1188990 A HK1188990 A HK 1188990A HK 14101979 A HK14101979 A HK 14101979A HK 1188990 A HK1188990 A HK 1188990A
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Hong Kong
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methyl
alkyl
pyrazol
formula
compound
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HK14101979.7A
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Chinese (zh)
Inventor
T．A．查比
J.M.汉姆弗利
P．R．维尔霍斯特
E.扬
C.J.赫拉尔
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辉瑞大药厂
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Description

Imidazo [5,1-f ] [1,2,4] triazines for the treatment of neurological disorders
Technical Field
The present invention relates to imidazo [5,1-f ] [1,2,4] triazines which are selective inhibitors of PDE 2. The invention further relates to intermediates useful in the preparation of said compounds; pharmaceutical compositions comprising said compounds; and the use of such compounds in methods of treating certain Central Nervous System (CNS) or other disorders. The invention also relates to methods for treating neurodegenerative diseases or psychiatric disorders including psychosis, impaired cognitive function, schizophrenia, depression, dementia, and other conditions in a mammal.
Background
Phosphodiesters (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) to their respective nucleotide monophosphates. These cyclic nucleotides act as second messengers in several cellular pathways, regulating intracellular processes within neurons of the cascade of the central nervous system, including activation of cAMP-and cGMP-dependent protein kinases, which produce subsequent phosphorylation of proteins involved in the regulation of synaptic transmission, synaptic plasticity, neuronal cell differentiation and survival.
To date, only a single gene for PDE2 (PDE2A) has been identified; however, several alternatively spliced isoforms (isoforms) of PDE2A have been reported, including PDE2a1, PDE2a2, and PDE2 A3. PDE2A was identified as a unique family based on its primary amino acid sequence and different enzymatic activities. The human PDE2A3 sequence was isolated in 1997 (Rosman et al, Isolation and characterization of human cDNAs encoding a cGMP-stimulated3',5' -cyclic nucleotide phosphodiesteraze, Gene, 191(1):89-95, 1997).
Inhibition of PDE2A demonstrates enhancement of cognitive function across multiple preclinical models reflecting improved cognitive abilities to recognize memory, social, and working memory, all of which are lacking in schizophrenia (Boess et al, Inhibition of cognitive 2 acquired cGMP, synthetic pathology and memory performance, Neuropharmacology, 47 (7): 1081-92, 2004). PDE2A inhibition also ameliorates The cognitive deficits manifested by aging and Alzheimer's disease (Domek-Lopatinska and Strossznajder, The effect of selective inhibition of cyclic GMP hydrolysis phosphorus reactions 2 and 5 on learning and methylation and nitrile oxide synthesis activity in branched driving, Brain Research, 1216:68-77, 2008). Bayer (Bayer) has published biochemical and behavioral traits of BAY60-7550 (behavial profile), suggesting a role for PDE2 inhibition in cognitive disorders (Brandon et al, Potential CNS Applications for phosphorus metabolism enzymes Inhibitors, Annual Reports in medicinal chemistry 42: 4-5, 2007). However, this compound showed significant efficacy in other PDE isoforms, and had high clearance and limited brain penetration and was not considered to progress to the clinic.
PDE 2inhibitors have also been shown: therapeutic efficacy is shown in preclinical models of anxiety and depression (Masood et al, anaerobic effects of phosphorus-2 inhibited aerobic with secreted cGMP signaling, JPET331 (2): 690-.
The PDE2A Protein, which is expressed in The dorsal horn and dorsal root ganglion of The spinal cord, enables PDE2A to modulate cyclic nucleotide content in these regions during The management of Neuropathic pain and Inflammatory pain (Schmidtko et al, cGMP Produced by NO-Sensitive Guanylyl cycle diseases receptors to inflammation and Neuropathic pain Using Targets from cGMP-Dependent Protein kinase I, The Journal of Neuroscience, 28(34):8568-8576, 2008).
Peripherally, the expression of PDE2A in endothelial cells has been shown to play a key role in regulating endothelial barrier function. PDE2A is expressed in increased amounts in endothelial cells to react with inflammatory cytokines such as TNF-alpha in conditions of sepsis and acute respiratory distress syndrome and to cause disruption of endothelial barrier function. Inhibition of PDE2A has been demonstrated: reversal of permeability defects and increased survival in sepsis in animal models of sepsis and intrinsic poisoning (Seybold et al, Tumor neocross factor- { alpha } -dependent expression of phosphorus estimators 2: role in endovenous hyperresponsiveness, Blood, 105:3569-3576, 2005; Kayhan et al, The adenosine deaminase inhibitor inhibition-erythro-9- [ 2-hydroxy-3-nonyl ] -adenosine decreasewise ] and protective additive theory: a promoter, random modified laboratory infection, Critical E, 12(5): R125, 2008).
Certain imidazotriazines have been disclosed as kinase inhibitors such as: international patent publication WO2011005909 entitled "Process for the preparation of substistidine [5,1-f ] [1,2,4] triazine derivatives"; U.S. patent publication: US20090286768 entitled "suspended Imidazopyrazines and amidizotriazines as ACK1 inhibitors and the preparation"; international patent publication WO200911748 entitled "Preparation of mTOR inhibitors saltformers"; international patent publication: WO2009008992 entitled "Preparation of imidazole [1,5-a ] pyrazin-8-amine for use in combining therapeutics of cameras and cancer methodologies"; U.S. patent publication No. US20080139582 entitled "Preparation of sulfated pyrazolopyrimidines inhibitors of Bruton's tyrosine kinase"; international patent publication: WO2007106503 entitled "Imidazo [1,5-a ] pyrazin-8-amine in combined treatment with an EGFR kinase inhibitor and an agent primers molecules to the effects of EGFR kinase inhibitors"; international patent publication No. WO2007087395, entitled "Preparation of ethyl-acetyl-imidazole azines and imidazole azines as a monoclonal target of rapamycin (mTOR) inhibitors for the treatment of cancer and diseases"; U.S. patent publication No. US20070112005 entitled "preparation of substentified Imidazopyrazines and related compounds as mTORinhitobits"; U.S. patent publication No. US20060019957 entitled "Preparation of imidazole derivatives as protein kinases inhibitors"; and International patent publication WO2005097800 entitled "Preparation of6,6-bicyclic ring subunit protein kinase inhibitors".
Summary of The Invention
The present invention relates to novel compounds of formula I
Or a pharmaceutically acceptable salt thereof, wherein
“-A-R5"is:
R1is hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C15) Cycloalkyl, - (C)1-C6) alkyl-OH, - (C)1-C6) alkyl-CN, -SF5、-CF3、-CHF2or-CH2F；
R2Is- (C)1-C6) alkyl-R9、-NHR3、-N(R3)2、-O-(C1-C6) alkyl-R9、-OR8、(C3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl or (C)1-C14) A heteroaryl group; wherein (C) is3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups; and wherein the- (C)1-C6) alkyl-R9、-O-(C1-C6) alkyl-R9、(C3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl or (C)1-C14) Heteroaryl moieties may optionally be substituted by 1-3 substituents independently selected from (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halogen and-CF3Substituted with the substituent(s);
each R3Is independently selected from: - (C)1-C6) alkyl-R9、-(C2-C6) alkenyl-R9、-(C2-C6) alkynyl-R9And- (C)3-C15) cycloalkyl-R9Or when R is2is-N (R)3)2When two R are present3Can form together with the nitrogen atom to which they are attached an optionally oxo-group (O =) optionally containing 1 or 2 and optionally being independently selected from hydrogen, fluoro, -CN, -CF3、-CHF2、-CH2F、-OH、-O-(C1-C6) Alkyl, NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, - (C = O) -R8、-(C=O)-OR8、-(C=O)-N(R8)2、-O-(C=O)-R8、-OR8、-O-(C=O)-OR8、-SR8、-S(O)R8、-S(O)2R8、-S(O)2N(R8)2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-O-(C=O)-N(R8)2、-NH-(C=O)-N(R8)2、-N[(C1-C6) Alkyl radical](C=O)-R8、-N[(C1-C6) Alkyl radical](C=O)-OR8、-N[(C1-C6) Alkyl radical](C=O)-N(R8)2、(C3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl and (C)1-C14) A 4-6 membered heterocycle substituted with a substituent for heteroaryl; wherein (C) is3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups;
each R4Is independently selected from: hydrogen, halogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, -CF3、-CHF2、-CH2F or (C)3-C15) A cycloalkyl group;
R4ais hydrogen, (C)1-C6) Alkyl, (C)3-C4) Alkenyl, (C)3-C4) Alkynyl, -CF3、-CHF2、-CH2F or (C)3-C15) A cycloalkyl group;
R5comprises the following steps:
wherein n is 0, 1,2,3 or 4;
each R6Independently selected from: hydrogen, halogeno, (C)1-C6) Alkyl, -CF3、-CHF2、-CH2F、-CF2-(C1-C6) Alkyl, -SF5、-CN、-(C1-C6) alkyl-CN, -NO2、-(C=O)-R8、-(C=O)-OR8、-OR8、-O-(C=O)-N(R8)2、-SR8、-S(O)R8、-S(O)2R8、NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-N[(C1-C6) Alkyl radical](C=O)-R8、-N[(C1-C6) Alkyl radical](C=O)-OR8、(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C15) Cycloalkyl group, (C)1-C14) Heterocyclic group, (C)6-C10) Aryl and (C)1-C14) A heteroaryl group; wherein (C) is3-C15) Cycloalkyl group, (C)1-C14) Heterocyclyl and (C)1-C14) Heteroaryl groups may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups;
each R7Independently selected from: hydrogen, halogen, (C)1-C6) Alkyl, (C)2-C4) Alkenyl, (C)2-C6) Alkynyl, -CN, -CF3、-CHF2、-CH2F、-O-(C1-C6) Alkyl and (C)3-C15) A cycloalkyl group;
each R8Independently selected from wherever it appears: hydrogen, (C)1-C6) Alkyl, (C)3-C15) Cycloalkyl, -CF3and-CHF2(ii) a And is
Each R9Independently selected from: hydrogen, halogen, -CF3、-CHF2、-CH2F、-CF2-(C1-C6) Alkyl, -CN, - (C)1-C6) alkyl-CN, -NO2、-(C=O)-R8、-(C=O)-OR8、-OR8、-O-(C=O)-N(R8)2、-SR8、-S(O)R8、-S(O)2R8、NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-N[(C1-C6) Alkyl radical](C=O)-R8、-N[(C1-C6) Alkyl radical](C=O)-OR8、(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C15) Cycloalkyl group, (C)1-C14) Heterocyclic group, (C)6-C10) Aryl and (C)1-C14) Heteroaryl group of which (C)3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups; and, wherein each of (C)3-C15) Cycloalkyl group, (C)1-C14) Heterocyclic group, (C)6-C10) Aryl and (C)1-C14) Heteroaryl moieties may optionally be substituted by 1-3 substituents independently selected from (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halo and-CF3Is substituted with the substituent(s).
As used herein, the term "alkyl" is defined to include saturated aliphatic hydrocarbons, which include straight and branched chains. Preferably, the alkyl group has 1 to 6 carbon atoms. For example, as used herein, the term "(C)1-C6) Alkyl "and other groups referred to herein (e.g., (C)1-C6) Alkoxy) refers to straight and branched chain groups of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl), which are optionally substituted with 1 to 5 suitable substituents.
Whenever a range of values is used herein, for example when 1-6 is used in the definition of "alkyl", it is meant that the alkyl group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and the like, up to and including 6 carbon atoms.
The term "alkenyl" as used herein is defined as a packageIncluding aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. Preferably, the alkenyl group has 2 to 6 carbon atoms. More preferably, the alkenyl group has 2 to 4 carbon atoms. For example, as used herein, the term "(C)2-C6) Alkenyl "represents a straight or branched chain unsaturated group of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like, optionally substituted with 1 to 5 suitable substituents. When the compound of formula I contains an alkenyl group, the alkenyl group may be present in pure E (ipsilateral (entgegen)) form, pure Z (ipsilateral (zusammen)) form, or any mixture thereof.
As used herein, the term "alkynyl" is defined to include aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. Preferably, the alkynyl group has 2 to 6 carbon atoms. For example, as used herein, the term "(C)2-C6) Alkynyl "is used herein to denote straight and branched hydrocarbon alkynyl groups as defined above having 2 to 6 carbon atoms and 1 triple bond, optionally substituted with 1 to 5 appropriate substituents.
As used herein, "cycloalkyl" is defined to include saturated or unsaturated (non-aromatic) monocyclic or bicyclic hydrocarbon rings (e.g., monocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or bicyclic rings including bridged or fused systems such as bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, or bicyclo [5.2.0] nonyl, and the like), which are optionally substituted with 1-5 suitable substituents. Cycloalkyl groups have 3 to 15 carbon atoms. In one embodiment, the cycloalkyl group may optionally contain 1,2 or more non-cumulative (non-cumulative) non-aromatic double or triple bonds and 1-3 oxo groups. Preferably, the bicycloalkyl group has 6 to 15 carbon atoms. Bicycloalkyl is optionally substituted with 1-5 suitable substituents. In one embodiment, the bicycloalkyl group may optionally contain one, two or more non-cumulative non-aromatic double or triple bonds.
As used herein, the term "aryl" is defined to include monocyclic or fused ring polycyclic groups of all carbons having a conjugated pi-electron system. Aryl groups have 6, 8, or 10 carbon atoms in the ring. More commonly, aryl groups have 6 or 10 carbon atoms in the ring. Most commonly, aryl groups have 6 carbon atoms in the ring. For example, as used herein, the term "(C)6-C10) Aryl "means an aryl group having 6 to 10 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and the like. Aryl is optionally substituted with 1-5 suitable substituents.
As used herein, the term "heteroaryl" is defined to include monocyclic or fused ring polycyclic aromatic heterocyclic groups having one or more heteroatoms selected from O, S and N in at least one ring. Heteroaryl has 5 to 14 ring atoms, including 1 to 13 carbon atoms and 1 to 5 heteroatoms selected from O, S and N. Preferably, heteroaryl groups have 5-10 ring atoms including 1-4 heteroatoms. Heteroaryl groups also contain 1-3 oxo groups. More preferably, heteroaryl has 5 to 8 ring atoms including 1,2 or 3 heteroatoms. Monocyclic heteroaryl groups of particular interest include those having 5 ring atoms including 1-3 heteroatoms or those having 6 ring atoms including 1 or 2 nitrogen heteroatoms. Fused bicyclic heteroaryls of particular interest include 2 fused 5 and/or 6 membered monocyclic rings having 1-4 heteroatoms.
Suitable heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1, 3-oxazolyl, 1, 2-oxazolyl), thiazolyl (e.g., 1, 2-thiazolyl, 1, 3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2, 3-triazolyl, 1,2, 4-triazolyl), oxadiazolyl (e.g., 1,2, 3-oxadiazolyl), thiadiazolyl (e.g., 1,3, 4-thiadiazolyl), quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, indolyl, pyridone, pyrimidinone (pyrimidinone), pyrazinone, pyrimidinone (pyrimidinone), and the like. Heteroaryl is optionally substituted with 1-5 suitable substituents.
As used herein, the term "heterocycle" is defined to include monocyclic, bridged polycyclic or fused polycyclic, saturated or unsaturated, non-aromatic, 3 to 14 membered ring systems, 1 to 13 carbon atoms and including 1 to 5 heteroatoms selected from O, S and N. Heterocyclyl also includes 1-3 oxo groups. Examples of heterocycloalkyl rings include azetidinyl, tetrahydrofuryl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, 2-azabicyclo [2.2.1] heptanone, 3-azabicyclo [3.1.0] hexane, 3-azabicyclo [4.1.0] heptane, and the like. Other examples of such heterocycloalkyl rings include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1, 3-oxazolidin-3-yl, isothiazolidine, 1, 3-thiazolidin-3-yl, 1, 2-pyrazolidin-2-yl, 1, 2-tetrahydrothiazin-2-yl, 1, 3-tetrahydrothiazin-3-yl, 1, 2-tetrahydrodiazin-2-yl, 1, 3-tetrahydrodiazin-1-yl, 1, 4-oxazin-2-yl, oxazolidinone, and the like. The heterocycloalkyl ring is optionally substituted with 1 to 5 suitable substituents. Preferred heterocycles include 5 and 6 membered monocyclic rings or 9 and 10 membered fused bicyclic rings.
As used herein, the term "halo" or "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.
As noted above, the compounds of formula I may be present in the form of pharmaceutically acceptable salts (such as, for example, acid addition salts and base addition salts of the compounds of formula I). The phrase "pharmaceutically acceptable salt(s)", as used herein, unless otherwise indicated, includes acid addition or base salts which may be present in the compounds of formula I.
Pharmaceutically acceptable salts of the compounds of formula (I) include their acid addition and base salts.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include ethylhydrochloric acid, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, salicylate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, sucrose salts, and mixtures thereof, Stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates and xinafoates.
Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts (benzathine), calcium salts, choline salts, diethylamine salts, dialcohol salts, glycine salts, lysine salts, magnesium salts, meglumine salts, alkanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.
Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.
For reviews of suitable Salts, see Stahl and Wermuth, Handbook of pharmaceutical Salts: properties, Selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of compounds of formula I are known to those skilled in the art.
The terms "formula I" and "formula I or a pharmaceutically acceptable salt thereof" as used herein are defined to include all forms of the compound of formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, polymorphs, metabolites and prodrugs thereof.
The compounds of formula I or pharmaceutically acceptable salts thereof may exist in unsolvated as well as solvated forms. When the solvent or water is intimately bound, the complex will have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound (as in channel solvates and hygroscopic compounds), the water/solvent content will depend on the humidity and drying conditions. In such a case, the non-stoichiometry would become normal.
The compounds of formula I may exist as cage compounds or other complexes. Included within the scope of the invention are complexes such as clathrate compounds (drug-host inclusion complexes) wherein the drug and host are present in stoichiometric or non-stoichiometric amounts as compared to the aforementioned solvates. Also included are complexes of formula I containing two or more organic and/or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of the complexes, see j.pharm.sci., 1975, 64, 1269-.
Also included within the scope of the invention are metabolites of the compounds of formula I, i.e. compounds which form in vivo upon administration of a drug. Metabolites of formula I include wherein R1A compound that is hydroxy-alkyl.
The compounds of formula I may have asymmetric carbon atoms. The carbon-carbon bond of the compound of formula I may be described herein as a solid (—), solid wedgeOr virtual wedge shapeA description is given. The use of a solid line to depict a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) are included on that carbon. The use of solid or dashed wedges to describe the bond to an asymmetric carbon atom is meant to indicate that only the stereoisomers shown are intended to be included. The compounds of formula I may contain more than one asymmetric carbon atom.In the compounds, the use of a solid line to describe the bond to the asymmetric carbon atom is meant to indicate all possible stereoisomers to be included. For example, unless otherwise indicated, it is intended that the compounds of formula I may exist as enantiomers and diastereomers, or racemates and mixtures thereof. The use of a solid line to describe the bond to one or more asymmetric carbon atoms in a compound of formula I and a solid or dotted wedge to describe the bond to other asymmetric carbon atoms in the same compound is meant to indicate the presence of a mixture of diastereomers.
Stereoisomers of formula I include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, geometric isomers, rotamers, configurational isomers and tautomers of compounds of formula I (including compounds exhibiting more than one type of isomerization); and mixtures thereof (such as racemates and diastereomer pairs). Also included are acid addition or base addition salts in which the counterion is optically active (e.g., D-lactate or L-lysine), or racemic (e.g., DL-tartrate or DL-arginine).
When any racemate crystallizes, it is possible to have two different types of crystals. The first type is the racemic compound referred to above (true racemate), in which a homogeneous form of crystals containing equimolar amounts of the two enantiomers is produced. The second type is a racemic mixture or a crystal mass (a consortium) in which two crystal forms, each containing a single enantiomer, are produced in equimolar amounts.
The compounds of formula I may exist in the form of tautomerism and structural isomerism. For example, the compounds of formula I may exist in several tautomeric forms (including enol and imine forms, and keto and enamine forms), and geometric isomers, and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of formula I. Tautomers exist as mixtures of tautomeric groups in solution. In solid forms, often predominate as one tautomer. Although one tautomer may be illustrated, the present invention includes all tautomers of the compounds of formula I.
The invention also includes isotopically-labeled compounds, which are identical to those recited in formula I above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of formula I include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to2H、3H、13C、14C、15N、17O、18O、32P、35S、18F and36and (4) Cl. Certain isotopically-labeled compounds of formula I (e.g., those incorporating moieties such as3H and14a compound that is a radioisotope of C) may be used in drug and/or substrate tissue distribution assays. Tritiated isotopes (i.e.3H) And carbon-14 isotopes (i.e.14C) It is particularly preferred for its ease of preparation and detectability. In addition, with compounds such as deuterium (i.e. deuterium)2H) Substitution with heavier isotopes of (a) may afford certain therapeutic advantages due to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Isotopically labeled compounds of formula I can generally be prepared by carrying out the reaction schemes described below and/or the procedures disclosed in the examples and preparations to replace a non-isotopically labeled reagent with an isotopically labeled reagent.
A particular embodiment of the present invention relates to compounds of formula I
Or a pharmaceutically acceptable salt thereof, wherein:
“-A-R5"is:
R1is- (C)1-C6) Alkyl (more specifically methyl or ethyl; even more specifically methyl);
R2is-NHR3or-N (R)3)2；
Each R3Independently selected from: - (C)1-C6) alkyl-R9、-(C2-C6) alkenyl-R9、-(C2-C6) alkynyl-R9And- (C)3-C15) cycloalkyl-R9(more specifically, - (C)1-C6) alkyl-R9And even more specifically methyl); or when R is2is-N (R)3)2When two R are present3May form, together with the nitrogen atom to which they are attached, an optionally substituted 1-3 substituents independently selected from hydrogen, fluoro, -CN, -CF3、-CHF2、-CH2F、-OH、-O-(C1-C6) Alkyl, NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, - (C = O) -R8、-(C=O)-OR8、-(C=O)-N(R8)2、-O-(C=O)-R8、-OR8、-O-(C=O)-OR8、-SR8、-S(O)R8、-S(O)2R8、-S(O)2N(R8)2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-O-(C=O)-N(R8)2、-NH-(C=O)-N(R8)2、-N[(C1-C6) Alkyl radical](C=O)-R8、-N[(C1-C6) Alkyl radical](C=O)-OR8、-N[(C1-C6) Alkyl radical](C=O)-N(R8)2、(C3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl and (C)1-C14) Heteroaromatic compoundsA 4-6 membered heterocycle substituted with a substituent of group; (more specifically 1 or 2 substituents wherein said substituents are hydrogen, fluoro, -CF3、-CHF2、-CH2F、-OH、-O-(C1-C6) Alkyl, NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、(C1-C6) Alkyl OR-NH- (C = O) -OR8(ii) a Even more specifically wherein the substituents are hydrogen, fluoro, methoxy or methyl carbamate);
R4is hydrogen;
R4ais (C)1-C6) Alkyl (more specifically methyl or ethyl; even more specifically methyl);
R5comprises the following steps:
wherein n is 0, 1,2,3 or 4 (more specifically wherein n is 0, 1 or 2) (more specifically wherein R7Is hydrogen, chloro, fluoro, methyl, methoxy or cyano; and even more specifically wherein R6Is chlorine, bromine, methyl, ethyl, methoxy, -CF3、-CF2CH3、-OCF3、-OCHF2、NO2、-(C=O)-CH3、(C3-C15) Cycloalkyl or isopropyl.
A particular embodiment of the present invention relates to the so-called 5- (1H-pyrazol-4-yl) imidazo [1, 5-f) of the formula Ia][1,2,4]Triazine compounds in which formula I contains a group A1R5。
Another embodiment of the inventionThe so-called 5- (1H-imidazol-5-yl) imidazo [1, 5-f) of the formula Ib][1,2,4]Triazine compounds in which formula I contains a group A2R5。
Another particular embodiment of the invention relates to the so-called 5- (1H-pyrazol-5-yl) imidazo [1, 5-f) of the formula Ic][1,2,4]Triazine compounds in which formula I contains a group A3R5。
Another particular embodiment of the invention relates to the so-called 5- (5-phenyl-1H-pyrazol-4-yl) imidazo [1, 5-f) of formula Id][1,2,4]Triazine compound, wherein R5Are described as optionally substituted phenyl.
Another particular embodiment of the invention relates to the so-called 5- (1-phenyl-1H-imidazol-5-yl) imidazo [1, 5-f) of formula Ie][1,2,4]Triazine compound, wherein R5Are described as optionally substituted phenyl.
Another particular embodiment of the invention relates to the so-called 5- (4-phenyl-1H-pyrazol-5-yl) imidazo [1, 5-f) of formula If][1,2,4]Triazine compound, wherein R5Are described as optionally substituted phenyl.
Another particular embodiment of the invention relates to the so-called 5- [5- (pyridin-2-yl) -1H-pyrazol-4-yl radical of the formula Ig]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridin-2-yl.
Another particular embodiment of the invention relates to the so-called 5- [1- (pyridin-2-yl) -1H-imidazol-5-yl radical of the formula Ih]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridin-2-yl.
Another particular embodiment of the present invention relates to the so-called 5- [4- (pyridin-2-yl) -1H-pyrazol-5-yl radicals of the formula Ii]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridin-2-yl.
Another particular embodiment of the invention relates to the so-called 5- [5- (pyridin-3-yl) -1H-pyrazol-4-yl radical of the formula Ij]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridin-3-yl.
Another particular embodiment of the invention relates to the so-called 5- [1- (pyridin-3-yl) -1H-imidazol-5-yl radical of the formula Ik]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridin-3-yl.
Another particular embodiment of the invention relates to the so-called 5- [4- (pyridin-3-yl) -1H-pyrazol-5-yl radical of the formula II]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridin-3-yl.
Another particular embodiment of the invention relates to the so-called 5- [5- (pyrazin-2-yl) -1H-pyrazol-4-yl radical of the formula Im]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrazin-2-yl.
Another particular embodiment of the invention relates to the so-called 5- [1- (pyrazin-2-yl) -1H-imidazol-5-yl radical of the formula In]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrazin-2-yl.
Another particular embodiment of the invention relates to the so-called 5- [4- (pyrazin-2-yl) -1H-pyrazol-5-yl radical of the formula Io]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrazin-2-yl.
Another particular embodiment of the invention relates to the so-called 5- [5- (pyrimidin-2-yl) -1H-pyrazol-4-yl radical of the formula Ip]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrimidin-2-yl.
Another particular embodiment of the invention relates to the so-called 5- [1- (pyrimidin-2-yl) -1H-imidazol-5-yl radical of the formula Iq]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrimidin-2-yl.
Another particular embodiment of the invention relates to the so-called 5- [4- (pyrimidin-2-yl) -1H-pyrazol-5-yl radical of the formula Ir]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrimidin-2-yl.
Another particular embodiment of the invention relates to the so-called 5- [5- (pyridazin-3-yl) -1H-pyrazol-4-yl radicals of the formula Is]Imidazo[1,5-f][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridazin-3-yl.
Another particular embodiment of the invention relates to the so-called 5- [1- (pyridazin-3-yl) -1H-imidazol-5-yl radical of the formula It]Imidazo [5, 1-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridazin-3-yl.
Another particular embodiment of the invention relates to the so-called 5- [4- (pyridazin-3-yl) -1H-pyrazol-5-yl radical of the formula Iu]Imidazo [5, 1-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyridazin-3-yl.
Another particular embodiment of the invention relates to the so-called 5- [5- (pyrimidin-5-yl) -1H-pyrazol-4-yl radical of the formula Iv]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrimidin-5-yl.
Another particular embodiment of the invention relates to the so-called 5- [1- (pyrimidin-5-yl) -1H-imidazol-5-yl group of Iw]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrimidin-5-yl.
Another particular embodiment of the invention relates to the so-called 5- [4- (pyrimidin-5-yl) -1H-pyrazol-5-yl radical of the formula Ix]Imidazo [1, 5-f)][1,2,4]Triazine compound, wherein R5Are described as optionally substituted pyrimidin-5-yl.
Another embodiment of particular interest relates to compounds of formula I (and formulae Ia-Ix), wherein R2Is- (C)1-C6) alkyl-R9、-NHR3、-N(R3)2、-O-(C1-C6) alkyl-R9OR-OR8. Particular R of particular interest2The radical comprising-NHR3(especially wherein R3Is methyl, ethyl or propyl), and-N (R)3)2(especially wherein two R' s3Groups may form, together with the nitrogen atom to which they are attached, an optionally substituted azetidinyl group, particularly when the optionally substituted substituent is selected from hydrogen, fluoro, difluoro or methoxy). Other specific R2Comprises (C)1-C6) alkyl-R9and-O- (C)1-C6) alkyl-R9In particular wherein R9Is hydrogen, fluorine, -CF3、-CHF2、-CH2F or-CF2-(C1-C6) An alkyl group. In addition, the present invention also includes those wherein R2is-OR8(especially wherein R8Is hydrogen, -CF3、-CHF2Methyl or ethyl).
Another embodiment of particular interest relates to compounds of formula I (and formulae Ia-Ix), wherein R2Is (C)3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl or (C)1-C14) A heteroaryl group; wherein (C) is3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 or 2 double or triple bonds and 1-3 oxo (O =) groups; more specifically wherein (C)1-C14) Heterocyclyl or (C)1-C14) Heteroaryl contains 1 or 2 nitrogen atoms.
Another embodiment of particular interest relates to compounds of formula I (and formulae Ia-Ix), wherein R6Is halo, -CF3、-CHF2or-CH2F; more particularly wherein R6Is a halo group. Or compounds of particular interest include the fluoromethyl substituent-CF3、-CHF2or-CH2F。
Another embodiment of particular interest relates to compounds of formula I (and formulae Ia-Ix), wherein R6Is- (C = O) -R8、-(C=O)-OR8、-OR8、-O(C=O)-N(R8)2、-SR8、-S(O)R8、-S(O)2R8、NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-O-(C=O)-N(R8)2、-N[(C1-C6) Alkyl radical](C=O)-R8or-N [ (C)1-C6) Alkyl radical](C=O)-OR8(ii) a More particularly wherein R6Is- (C = O) -R8、-(C=O)-OR8、-OR8or-O (C = O) -N (R)8)2. In addition, the invention contemplates the so-called amino compound NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-O-(C=O)-N(R8)2、-N((C1-C6) Alkyl) - (C = O) -R8or-N ((C)1-C6) Alkyl) - (C = O) -OR8. In addition, the present invention contemplates the so-called thio compounds-SR8、-S(O)R8or-S (O)2R8。
Another embodiment of particular interest relates to compounds of formula I (and formulae Ia-Ix), wherein R6Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C15) Cycloalkyl group, (C)6-C10) Aryl or (C)1-C14) A heteroaryl group; more particularly wherein R6Is (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl. In addition, the present invention contemplates the ring compound (C)3-C15) Cycloalkyl group, (C)1-C14) Heterocyclic group, (C)6-C10) Aryl or (C)1-C14) A heteroaryl group.
Another embodiment of interest relates to compounds of formula I (and formulae Ia-Ix), wherein at least one substituent comprises SF5And (4) partial.
The foregoing embodiments are each intended to be construed as a single embodiment as well as embodiments in combination with the foregoing embodiments (e.g., each R6Together with R2And together with formulae Ia-Ix).
In another embodiment, the invention also relates to compounds as described in examples 1-86 in the examples section of this application and pharmaceutically acceptable salts thereof.
In another embodiment, the invention relates to a compound of formula I, wherein the compound is:
4- (azetidin-1-yl) -7-methyl-5- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] imidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -7-methyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [ [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -7-methyl-5- { 1-methyl-5- [6- (trifluoromethyl) pyridin-3-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- [5- (4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- [5- (5-chloropyridin-2-yl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine;
5- {5- [4- (difluoromethyl) phenyl ] -1-methyl-1H-pyrazol-4-yl } -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine;
7-methyl-N- (d)3) Methyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl]-1H-pyrazol-4-yl } imidazo [5,1-f][1,2,4]Triazin-4-amines;
n, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine;
4- (azetidin-1-yl) -5- {5- [ 3-fluoro-5- (trifluoromethyl) pyridin-2-yl ] -1-methyl-1H-pyrazol-4-yl } -7-methylimidazo [5,1-f ] [1,2,4] triazine;
n, 7-dimethyl-5- { 1-methyl-5- [6- (trifluoromethyl) pyridin-3-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine;
4- (azetidin-1-yl) -5- {5- [ 2-fluoro-6- (trifluoromethyl) pyridin-3-yl ] -1-methyl-1H-pyrazol-4-yl } -7-methylimidazo [5,1-f ] [1,2,4] triazine;
n, 7-dimethyl-5- { 1-methyl-5- [4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine;
4- (azetidin-1-yl) -5- {5- [4- (difluoromethyl) phenyl ] -1-methyl-1H-pyrazol-4-yl } -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (3-fluoroazetidin-1-yl) -7-methyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- [5- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- {5- [4- (difluoromethoxy) phenyl ] -1-methyl-1H-pyrazol-4-yl } -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4-azetidin-1-yl-7-methyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyrazin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine;
4-azetidin-1-yl-5- [5- (5-bromopyridin-2-yl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine; or
N, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyrazin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine; or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention relates to compounds of the formula I to be prepared which are selected from
5- (5- (3-fluoro-5- (trifluoromethyl) pyridin-2-yl) -1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine;
4- (azetidin-1-yl) -7-methyl-5- (1-methyl-5- (3-methyl-5- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -7-methyl-5- (1-methyl-5- (3-methyl-5- (trifluoromethyl) pyridin-2-yl) -1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazine;
n, 7-dimethyl-5- (1-methyl-5- (3-methyl-5- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine;
5- (5- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine;
5- (5- (5-bromo-3-fluoropyridin-2-yl) -1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine;
4- (azetidin-1-yl) -5- (5- (3-chloro-5- (trifluoromethyl) pyridin-2-yl) -1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazine;
n, 7-dimethyl-5- (1-methyl-5- (3-methyl-5- (trifluoromethyl) pyridin-2-yl) -1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine;
5- (5- (5-bromo-3-chloropyridin-2-yl) -1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine;
5- (5- (5-bromo-3-methylpyridin-2-yl) -1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine;
5- (1, 3-dimethyl-5- (5- (trifluoromethyl) pyridin-2-yl) -1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine;
4- (azetidin-1-yl) -5- (1, 3-dimethyl-5- (5- (trifluoromethyl) pyridin-2-yl) -1H-pyrazol-4-yl) -7-methylimidazo [1,5-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- (1, 3-dimethyl-5- (5- (trifluoromethyl) pyrazin-2-yl) -1H-pyrazol-4-yl) -7-methylimidazo [1,5-f ] [1,2,4] triazine;
3- (1-methyl-4- (7-methyl-4- (2,2, 2-trifluoroethyl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -1H-pyrazol-5-yl) aniline;
5- (5- (4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl) -7-methyl-4-phenylimidazo [5,1-f ] [1,2,4] triazine;
acetic acid 7-cyclopropyl-5- (5- (4-methoxyphenyl) -1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-yl ester;
4- (4- (4-methoxy-7-methylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -1-methyl-1H-pyrazol-5-yl) benzonitrile;
7-methyl-5- (1-methyl-5- (4- (methylsulfonyl) phenyl) -1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-yl hydrogen carbonate;
4- (1-methyl-4- (7-methyl-4- (2-methylcyclopentyl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -1H-pyrazol-5-yl) benzoic acid methyl ester;
4- (4- (4- (cyclopent-1, 3-dien-1-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -1-methyl-1H-pyrazol-5-yl) -N-methylaniline;
5- (5- (3-fluoro-4- (trifluoromethyl) phenyl) -1-methyl-1H-pyrazol-4-yl) -7-methyl-4- (pyrrolidin-3-yl) imidazo [5,1-f ] [1,2,4] triazine;
5- (5- (4-methoxy-3-methylphenyl) -1-methyl-1H-pyrazol-4-yl) -7-methyl-4- (1-methyl-1H-pyrazol-5-yl) imidazo [5,1-f ] [1,2,4] triazine;
acetic acid 2-methyl-4- (2-methyl-5- (4- (pyrrolidin-1-yl) -7- (trifluoromethyl) imidazo [5,1-f ] [1,2,4] triazin-5-yl) -1H-imidazol-1-yl) phenyl ester;
4- (5- (4- (azetidin-1-yl) -7-methylimidazo [ [5,1-f ] [1,2,4] triazin-5-yl) -3-methyl-1H-pyrazol-4-yl) benzonitrile;
4- (azetidin-1-yl) -5- (4- (5- (difluoromethyl) pyridin-2-yl) -3-methyl-1H-pyrazol-5-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazine;
1- (5- (5- (4- (azetidin-1-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazin-5-yl) -3-methyl-1H-pyrazol-4-yl) pyridin-2-yl) ethanone;
4- (azetidin-1-yl) -5- (4- (5-ethylpyrazin-2-yl) -3-methyl-1H-pyrazol-5-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- (4- (5-chloropyrimidin-2-yl) -3-methyl-1H-pyrazol-5-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- (4- (5, 6-dimethylpyridazin-3-yl) -3-methyl-1H-pyrazol-5-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- (4- (2, 4-bis (trifluoromethyl) pyrimidin-5-yl) -3-methyl-1H-pyrazol-5-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- (1- (4-fluoro-2-methylpyrimidin-5-yl) -2-methyl-1H-imidazol-5-yl) -7-methylimidazo [ [5,1-f ] [1,2,4] triazine;
or a pharmaceutically acceptable salt thereof.
The invention also relates to pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., pharmaceutical compositions). Thus, in one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula I, optionally comprising a pharmaceutically acceptable carrier, and optionally comprising at least one additional drug or agent. In one embodiment, the additional drug or agent is an anti-schizophrenia drug as described below.
The pharmaceutically acceptable carrier may include any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical composition may contain additional components such as flavoring agents, binders, excipients, and the like, if desired. Thus for oral administration, tablets containing various excipients, such as citric acid, may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used for tableting purposes. Solid compositions of a similar type may also be used in soft and hard gelatin filled capsules. Thus, non-limiting examples of materials include lactose or milk sugar (milk sugar) and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and if desired with the use of emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
The pharmaceutical composition may be, for example, in the form of: suitable for oral administration such as tablets, capsules, pills, powders, sustained release formulations, solutions or suspensions, for parenteral injection such as sterile solutions, suspensions or emulsions, for topical administration such as ointments or creams or for rectal administration such as suppositories.
Typical parenteral administration forms include solutions or suspensions of the active compounds in sterile aqueous solutions (e.g., aqueous propylene glycol or dextrose). The dosage form may be suitably buffered if desired.
The pharmaceutical compositions may be in unit dosage form suitable for single administration of precise dosages. One skilled in the art will appreciate that the compositions can be formulated as sub-therapeutic doses so that multiple doses are envisioned.
In a preferred embodiment the composition comprises a therapeutically effective amount of a compound of formula I and optionally a pharmaceutically acceptable carrier.
Another embodiment of the present invention encompasses a method of treating schizophrenia or psychosis in a mammal (preferably a human being) comprising administering to the mammal (preferably a human being) a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
Another embodiment of the invention encompasses a method of treating a PDE2 mediated disease, comprising administering to a mammal (preferably a human) in need of such treatment an amount of a compound of formula I effective to inhibit PDE 2; more preferably, the compound of formula I is administered in an amount effective to selectively inhibit PDE 2.
Another embodiment of the present invention provides a method of treating a mammal (preferably a human) for the following disorders: neurological disorders (such as migraine; epilepsy; Alzheimer's disease; Parkinson's disease; brain injury; stroke; cerebrovascular diseases (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage and cerebral hypoxia-ischemia), cognitive disorders (including amnesia, senile dementia, HIV-related dementia, dementia associated with Alzheimer's disease, dementia associated with Huntington's disease, dementia with Lewy bodies, vascular dementia, dementia associated with drugs, delirium and mild cognitive impairment), intellectual impairment (including Down's syndrome and fragile X syndrome), sleep disorders (including somnolence, circadian rhythm sleep disorders, insomnia, narcolepsy and sleep deprivation) and psychiatric disorders (such as anxiety disorders (including acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), synthetic disorders (including acute hallucinations), impulse control disorders (including compulsive gambling and stroke; and cerebral ischemia) Intermittent manic disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective state, major depression, chronic depression, seasonal depression, psychotic depression, and postpartum depression); psychomotor disorders; psychotic disorders (including schizophrenia, schizoaffective disorders, schizophreniform and delusional disorders); drug dependence (including narcotics dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, and drug withdrawal syndrome); eating disorders (including anorexia, bulimia, hyperphagia, and binge-eating); and childhood psychotic disorders (including attention deficit disorder, attention deficit/hyperactivity disorder, behavioral disorders, and autism), comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment of the invention encompasses a method of treating schizophrenia.
Another embodiment of the invention encompasses a method of treating cognitive impairment associated with schizophrenia.
The term "therapeutically effective amount" as used herein refers to an amount of a compound to be administered that reduces to some extent one or more of the symptoms of the condition to be treated. With respect to the treatment of schizophrenia, a therapeutically effective amount refers to an amount that reduces (or, preferably, eliminates) to some extent one or more symptoms associated with schizophrenia.
The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the development of, or preventing the disease or disorder to which the term applies or one or more symptoms of the disease or disorder. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" as just defined above. The term "treatment" also includes both adjuvant and neoadjuvant treatment of a subject.
Administration of the compounds of formula I may occur by any method capable of delivering the compound to the site of action. Such methods include oral, intranasal, inhalation, intraduodenal, parenteral (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.
In one embodiment of the invention, the compounds of formula I are preferably active via the oral route.
Dosage regimens may be adjusted to provide the optimum desired response. For example, it may be administered as a single bolus, may be administered in several doses over time or may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. The specification for the dosage unit forms of the invention depends on and directly depends on the following factors: (a) the unique characteristics of chemotherapeutic agents and the particular therapeutic or prophylactic effect to be achieved, and (b) the inherent limitations of the sensitivity of the therapeutically active compounds in the individual in a mixed technology. In one embodiment of the invention, the compounds of formula I are preferably useful for the treatment of humans.
It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It will be further appreciated that for any particular subject, the particular dosage regimen should be adjusted over time according to the individual need and the professional judgment of the person administering or managing the composition, and that the dosage ranges described herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. For example, the dosage may be adjusted according to pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or experimental values. Thus, the present invention encompasses dose escalation in patients as determined by one of skill in the art. Determining the appropriate dose and schedule for administration of the chemotherapeutic agent is routine for the relevant art and will be understood to be accomplished by one of skill in the art once the techniques disclosed herein are provided.
The amount of the compound of formula I administered will depend on the subject being treated, the severity of the disease or condition, the rate of administration, the configuration of the compound and the judgment of the prescribing physician. However, effective dosages in single or divided doses will generally range from about 0.01 to about 50mg per kg of body weight per day, preferably from about 0.01 to about 5 mg/kg/day. For a 70 kg human, an effective dose will be about 0.7 mg to about 3500 mg/g, preferably about 5mg to about 2000 mg/day. In some cases, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases, even larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several small doses for administration throughout the day.
As used herein, the term "combination therapy" relates to the sequential or simultaneous administration of a compound of formula I and at least one additional drug or agent (e.g., an anti-schizophrenia drug).
As mentioned above, the compounds of formula I may be used in combination with one or more of the following additional anti-schizophrenia drugs. When combination therapy is used, one or more additional anti-schizophrenia agents may be administered either sequentially or simultaneously with the compounds of the present invention. In one embodiment, the additional anti-schizophrenia agent is administered to the mammal (e.g., a human) prior to administration of the compound of the invention. In another embodiment, the additional anti-schizophrenia agent is administered to the mammal after administration of the compounds of the present invention. In another embodiment, the additional anti-schizophrenia agent is administered to the mammal (e.g., a human) concurrently with the administration of the compound of the invention.
The present invention also relates to a pharmaceutical composition for the treatment of schizophrenia in a mammal, including a human, comprising an amount of a compound of formula I as defined above, including hydrates, solvates and polymorphs of the compound or a pharmaceutically acceptable salt thereof, in combination with one or more, preferably one to three, anti-schizophrenia drugs such as ziprasidone, risperidone, olanzapine, quetiapine, aripiprazole, asenapine, blonanserin or iloperidone, wherein the amounts of the active agents and combination are generally therapeutically effective for the treatment of schizophrenia.
Detailed description of the invention
The compounds of formula I may be prepared according to the following reaction schemes and the accompanying discussion. Unless otherwise indicated, R in the following reaction schemes and discussions1-R8A, n and formula I are as defined above. In general, the compounds of the invention may be prepared by methods comprising methods analogous to those known in the chemical art, in particular in accordance with the description contained herein. Certain processes for preparing the compounds of the present invention are provided as further features of the invention and are illustrated in the following reaction schemes. Other methods can be described in the experimental section.
Reaction scheme 1
Reaction scheme 2
Reaction scheme 3
Reaction scheme 4
Reaction scheme 5
Reaction scheme 6
Reaction scheme 7
Reaction scheme 1 relates to the preparation of compounds of formula I. Referring to reaction scheme 1, compounds of formula I (wherein R5To the carbon atom in the group A) is derived from a compound of the formula II (wherein "A-X" is
And X is H, Cl, Br, I or trifluoromethanesulfonate) with a compound of the formula R5a-R5gPreparation of a palladium-catalyzed coupling reaction of the reagent of (1):
depending on the type of reaction employed, Z may represent Br, B (OH)2Or B (OR)2Or a trialkyltin moiety. For example, when X is halogen or triflate and R5When the reagent is boric acid or a borate ester, a Suzuki reaction [ A.Suzuki, J.Organomet.chem.1999, 576, 147-; n.miyaura and a.suzuki, chem.rev.1995, 95, 2457-; littke et al, J.Am.chem.Soc.2000, 122, 4020-]. More specifically, the heteroaromatic iodide, bromide or triflate of formula II is combined with 1 to 3 equivalents of an aryl or heteroaryl boronic acid or boronic ester and a suitable base, such as 2 to 5 equivalents of sodium carbonate, in a suitable organic solvent, such as ethanol. A palladium catalyst, such as 0.01 equivalents of tetrakis (triphenylphosphine) palladium (0), is added and the reaction mixture is heated to a temperature of 60-100 ℃ for 1-24 hours. In some cases it is advantageous to use 1 to 2 equivalents of copper (I) chloride and 1 to 2 equivalents of potassium bromide in the Suzuki reaction in 1, 2-dimethoxyethane as solvent. Alternatively, the coupling reaction may be carried out by reacting formula II (wherein X is H and Z is Br) with 1-3 equivalents of (R)5) The reaction of-Br reagent in the presence of 0.01-0.5 equivalents of allylpalladium chloride dimer and a suitable base, such as 2-4 equivalents of potassium carbonate, in a suitable organic solvent, such as 1, 4-dioxane. The reaction may be carried out at a temperature of 100 ℃ and 160 ℃ for 24-72 hours. Stille coupling [ V.Farina et al, organic reactions1997, 50, 1-652 ] can be used when X is halogen or triflate and Z is trialkyltin]. More specifically, a compound of formula II wherein X is bromide, iodide or triflate may be reacted with 1.5 to 3 equivalents of R in the presence of a palladium catalyst, such as 0.05 equivalents of dichlorobis (triphenylphosphine) palladium (II), in a suitable organic solvent, such as toluene5The stannanes are combined and the reaction can be heated to 100 deg.fA temperature of-130 ℃ for 12-36 hours. When X is Br, I or triflate and Z is Br or I, a Negishi coupling [ E.Erdik, Tetrahedron 1992, 48, 9577-]. More specifically, compounds of formula II (where X is bromide, iodide or triflate) can be transmetalated by treatment with a solution of 1-1.1 equivalents of an alkyllithium reagent followed by 1.2-1.4 equivalents of zinc chloride in a suitable solvent, such as tetrahydrofuran, at a temperature of-80 to-65 ℃. After heating to a temperature of 10-30 ℃, the reaction can use R5-Z reagent treatment and heating at 50-70 ℃ and addition of a catalyst such as tetrakis (triphenylphosphine) palladium (0). The reaction may be carried out for a period of 1-24 hours. These reactions are not limited to the use of solvents, bases or catalysts as described above, and many other conditions may be used.
Alternatively, referring to reaction scheme 1, AX1 or AX3 with any R5a-R5gThe polarity of the coupling reaction of (a) may be reversed. In this case, the X group of AX1 or AX3 is a boronic acid, boronic ester or trialkyltin moiety, and R5a-R5gThe Z group is Cl, Br, I or trifluoromethanesulfonate. The chemistry used to create the carbon-carbon bond is the same as described above.
Referring to reaction scheme 1, additional compounds of formula I (wherein R5The nitrogen atom bonded to the radical A) is reacted with a compound of the formula R by the method of P.Y.S.Lam et al (Tetrahedron Lett.1998, 39, 2941-2944) or of Z.xi et al (Tetrahedron2008, 64, 4254-4259)5a-R5gFrom a compound of formula II (wherein "A-X" is
And X is H).
Reaction scheme 2 relates to an alternative preparation of compounds of formula I. Referring to reaction scheme 2, compounds of formula I (wherein R2Is N (R)3)2Or HNR3) Can be used for dredgingWith 1.1 to 4 equivalents of a primary or secondary amine (H)2NR3Or HN (R)3)2) Prepared from a compound of formula III (wherein L is triazole or chlorine), optionally in the presence of a base such as cesium carbonate, in a suitable organic solvent such as dichloromethane or N, N-dimethylformamide. Suitable temperatures for the aforementioned reaction are between 0 ℃ and 100 ℃. Suitable reaction times are from 20 minutes to 48 hours. Alternatively, compounds of formula I (wherein R2Is aryl or heteroaryl) can be prepared from compounds of formula III by reaction with the appropriate aryl or heteroaryl iodide, bromide, trialkyltin derivatives, zinc derivatives, boronic acids or boronic esters as described in scheme 1 for the conversion of formula II to formula I to yield compounds of formula I. Alternatively, compounds of formula I (wherein R2Is alkyl) can be prepared from compounds of formula III (wherein L is chloro) by reaction with an appropriate zinc reagent in a Negishi reaction converting formula II to formula I in reaction scheme 1 above. (see also R.T.Hendricks et al, bioorg.Med.chem.Lett.2009, 19, 410-). Or a compound of formula I (wherein R2Being alkyl, cycloalkyl or heterocyclyl) can be prepared from compounds of formula III (wherein L is chloro) by reaction with a suitable grignard reagent in the presence of iron (III) acetylacetonate as described by l.k. ottesen et al (Organic lett.2006, 8, 1771-1773).
Referring to reaction scheme 2, compounds of formula I (wherein R2is-O- (C)1-C6) alkyl-R9OR-OR8) The compounds of formula IV can be prepared directly from the compounds of formula IV by alkylation with the corresponding halides or by Mitsunobu reaction with the desired alcohols. See s.b. bodendiek et al eur.j.med.chem.2009, 44, 1838-; khattab et al, Synth. Commun.2006, 36, 2751-; smith et al, j.med.chem.2008, 51, 8057-.
Compounds of formula III, wherein L is chloro or 1H-1,2, 4-triazol-1-yl, can be prepared from compounds of formula IV by treatment with phosphorus oxychloride, optionally in the presence of 1H-1,2, 4-triazole. More specifically, 2-4 equivalents of phosphorus oxychloride and 8-11 equivalents of 1H-1,2, 4-triazole are treated with 12-15 equivalents of triethylamine or N, N-diisopropylethylamine in a suitable organic solvent, such as acetonitrile or dichloromethane, at a temperature between-10 and 5 ℃. After addition of 1 equivalent of the imidazotriazinone of formula IV, the reaction mixture may be maintained at 25 ℃ to reflux temperature for 2-24 hours to provide the compound of formula III, wherein L is 1H-1,2, 4-triazole. If the 1H-1,2, 4-triazole is omitted from the reaction, in which case it may be carried out in toluene as solvent, the product being a compound of formula III in which L is chlorine. It is not necessary in all cases to isolate the intermediate of formula III, which can be reacted directly with an appropriate amine reagent. Compounds of formula III (wherein L is triflate) can be prepared from compounds of formula IV by standard methods; see b.t.shireman et al, bioorg.med.chem.lett.2008, 18, 2103-. These reactions are not limited to the use of the above-mentioned solvents or bases, and many other conditions may be used.
Reaction scheme 3 relates to compounds of formula II (wherein R2Is HNR3Or N (R)3)2) And (4) preparing. The compound of formula II can be converted to the compound of formula I according to the method of reaction scheme 1. Referring to scheme 3, compounds of formula II can be prepared from compounds of formula V by methods similar to those for the conversion of formula III to formula I in scheme 2. Compounds of formula V, wherein L is chloro or 1H-1,2, 4-triazol-1-yl, can be prepared from compounds of formula VI, wherein X is H, Cl, Br or I, by a process analogous to the conversion of compounds of formula IV to formula III in reaction scheme 2.
Reaction scheme 4 relates to a compound of formula II (wherein R2Is HNR3Or N (R)3)2And X is H or Cl). The compound of formula II can be converted to the compound of formula I according to the method of reaction scheme 1. Referring to reaction scheme 4, compounds of formula II can be prepared from bromine compounds of formula VII by palladium catalyzed coupling with appropriately substituted heteroaromatic compounds of formula ZAX:
the compounds of formula II (in compounds ZAX1 and ZAX3, X is H; in ZAX2,x may be H or a suitable protecting group for nitrogen, such as Boc, p-methoxybenzyl, allyl or 2- (trimethylsilyl) ethoxy, as is well known to those skilled in the art]Methyl group). When Z is B (OH)2Or B (OR)2When carbon-carbon bond coupling is performed under the conditions of the Suzuki reaction described above. One skilled in the art will recognize that if X is R5This chemistry would also be effective; in this case, the product will be a compound of formula I. A compound of formula VII (wherein R2Is HNR3Or N (R)3)2) Can be prepared from compounds of formula VIII by methods analogous to the conversion of compounds of formula III to formula I in reaction scheme 2. The compound of formula VIII can be prepared from the compound of formula IX by a method analogous to the conversion of the compound of formula IV to the compound of formula III in reaction scheme 2.
Reaction scheme 5 relates to the preparation of compounds of formula IV. The compound of formula IV can be converted to the compound of formula I according to the method of reaction scheme 2. Referring to scheme 5, compounds of formula IV can be prepared from compounds of formula VI (where X is H, Cl, Br, I, triflate, boronic acid, boronic ester, or trialkyltin) in the same manner as described for the conversion of compounds of formula II to compounds of formula I in scheme 1.
Reaction scheme 6 relates to the preparation of compounds of formula VI, wherein "A-X" is
And X is H, Cl, Br, I, triflate, boronic acid, boronic ester or trialkyltin. Compounds of formula VI can be converted to compounds of formula I using the methods described in reaction scheme 3 followed by reaction scheme 1 or reaction scheme 5 followed by reaction scheme 2. Referring to reaction scheme 6, compounds of formula VI can be generated from compounds of formula X by 1.1 to 3 equivalents of 1,1 '-carbonyldiimidazole or 1,1' -carbonylbis (1,2, 4-triazole) in a solvent such as 1, 4-dioxane or tetrahydrofuran, at a temperature of 40-70 ℃ for 1-4 hours.
A compound of formula X can be prepared by reactingFrom compounds of formula XI, they are prepared by treating with 2-5 equivalents of formamidine acetate in a solvent such as 2-butanol at a temperature of 60-100 deg.C for 1-12 hours. The compounds of the formula XI can be prepared by alkaline hydrolysis of amide or carbamate groups, or in which P is1In the case of (C = O) O-tert-butyl, by reaction with an excess of trifluoroacetic acid in dichloromethane solvent at a temperature of 15-35 ℃ by removal of the protecting group P1In which P is1Can be- (C = O) -aryl, - (C = O) -alkyl, - (C = O) O- (C = O)1-C4) Alkyl or another suitable protecting group known to those skilled in the art, from a compound of formula XII. The compound of formula XII may be protected by reaction with 1.1-2 equivalents of an N-protected R of the formula1-reaction of an iminohydrazide compound from a compound of formula XIII, wherein X is H, Cl, Br, I, triflate, boronic acid, boronic ester or trialkyltin and wherein LG is Cl, Br or I,
wherein P1 is- (C = O) -aryl, - (C = O) -alkyl, - (C = O) O- (C1-C4) Alkyl or another suitable protecting group known to those skilled in the art. This reaction can be carried out in a solvent such as 2-methyltetrahydrofuran and/or 1, 2-dimethoxyethane at a temperature of 60-90 ℃ in the presence of a base such as 2-4 equivalents of N, N-diisopropylethylamine. The imidohydrazide reagent XIX can be prepared by reacting the desired acylhydrazine with the appropriate imine ether according to the method of D.Hurtaud et al (Synthesis2001, 2435-2440).
Reaction scheme 7 relates to the preparation of compounds of formula VI (wherein X is H or Cl). Compounds of formula VI can be converted to compounds of formula I according to the methods described in reaction scheme 3 followed by reaction scheme 1 or reaction scheme 5 followed by reaction scheme 2. The compound of formula IX can be used to prepare compounds of formula I as described in scheme 4 followed by scheme 1. Referring to scheme 7, compounds of formula VI can be synthesized from compounds of formula IX by palladium catalyzed reaction with appropriately substituted heteroaromatic compounds of formula ZAX.
In this case, X is H or Cl in compounds ZAX1 and ZAX 3; in ZAX2, X may be H or a suitable protecting group for nitrogen well known to those skilled in the art, such as BOC, p-methoxybenzyl, allyl or 2- (trimethylsilyl) ethoxy]A methyl group; z is B (OH)2Or B (OR)2. The carbon-carbon coupling reaction can be carried out in a manner analogous to that described for the conversion of compound VII to the compound of formula II in scheme 4.
Compounds of formula IX can be prepared by reacting compounds of formula XIV (wherein P2Is (C)1-C4) Alkyl) with 1-30 equivalents of formamide at a temperature of 100-180 ℃ for 2-20 hours. The compounds of formula XIV can be prepared from compounds of formula XV by deprotonation with a base such as lithium bis (trimethylsilyl) amide and subsequent amination with a reagent such as O- (4-nitrobenzoyl) hydroxylamine or O- (diphenylphosphino) hydroxylamine. Care is taken that: o- (diphenylphosphino) hydroxylamine is a high energy substance that exhibits the ability to decompose explosively under ambient conditions. Its use should be carefully monitored. The compounds of formula XV may be prepared according to the method of T.L Grange et al (Tetrahedron Lett.2007, 48, 6301-6303) by bromination of the compound of formula XVI using bromine in a solvent such as N, N-dimethylformamide at a temperature of 60-90 ℃ under the influence of a base such as potassium bicarbonate. The compound of formula XVI may be produced by cyclisation of a compound of formula XVII, for example in a microwave reactor, by heating at 150 ℃ and 190 ℃ for 30 minutes to 3 hours, in a suitable inert solvent such as 1, 4-dioxane. The compound of formula XVII is obtained by reaction of propiolate with N-hydroxyimide of formula XVIII, which can be carried out at reflux temperature in a solvent such as methanol or ethanol for 2-24 hours. The compounds of formula XVIII are readily obtained from the corresponding nitriles as reported by x.yang et al (j.med. chem.2010, 53, 1015-.
The compounds of formula I having a chiral center may exist as stereoisomers (such as racemates, enantiomers or diastereomers). Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemates using, for example, chiral High Pressure Liquid Chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound (e.g., an alcohol, or an acid or base such as tartaric acid or 1-phenylethylamine in the case where the compound contains an acidic or basic moiety). The resulting mixture of diastereomers may be separated by chromatography and/or fractional crystallization and one or both of the diastereomers converted to the corresponding pure enantiomers in a manner well known to those skilled in the art. Chiral compounds of formula I (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography (typically HPLC) on asymmetric resins using a mobile phase consisting of a hydrocarbon (typically heptane or hexane) containing 0-50% (typically 2-20%) isopropanol and 0-5% alkylamine (typically 0.1% diethylamine). Concentration of the eluent provides an enriched mixture. Stereoisomeric crystal groups (comomerates) may be isolated by conventional techniques known to those skilled in the art. See, e.g., E.L. Eliel, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety. Suitable stereoselective techniques are well known to those skilled in the art.
In the case of compounds of formula I containing an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. The cis/trans isomers may be isolated by conventional techniques known to those skilled in the art (e.g., chromatography and fractional crystallization). The salts of the invention can be prepared according to methods known to those skilled in the art.
Those compounds of formula I which are basic in nature are capable of forming a wide variety of salts with a wide variety of inorganic and organic acids. Although such salts need to be pharmaceutically acceptable when administered to an animal, it is often desirable in practice to first isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then convert the latter to the free base compound by simple treatment with a basic agent, followed by conversion of the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of the present invention may be prepared by treatment with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Once the solvent was evaporated, the desired solid salt was obtained. The desired acidic salt may also be precipitated from a solution of the free base in an organic solvent by adding a suitable inorganic or organic acid to the solution.
If the compounds of the invention are bases, the desired pharmaceutically acceptable salts may be prepared by any suitable method available in the art, for example, with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, isonicotinic acid, acetic acid, lactic acid, pantothenic acid, ditartaric acid (bitartric acid), ascorbic acid, 2, 5-dihydroxybenzoic acid, fumaric acid, gluconic acid, glucaric acid, formic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and pamoic acid [ i.e. 1,1' -methylene-bis- (2-hydroxy-3-naphthoic acid) ], pyranosidyl acid (such as glucuronic acid or galacturonic acid ], An alpha-hydroxy acid (such as citric acid or tartaric acid), an amino acid (such as aspartic acid or glutamic acid), an aromatic acid (such as benzoic acid or cinnamic acid), a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), or the like.
Those compounds of formula I which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and in particular, sodium and potassium salts. These salts are all prepared by conventional techniques. Chemical bases useful as reagents for preparing the pharmaceutically acceptable base salts of the present invention are those that form non-toxic base salts with acidic compounds of formula I. Such salts may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. Such salts can also be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, those can also be prepared by mixing a lower alcohol solution of an acidic compound with a desired alkali metal alkoxide, and then evaporating the resultant solution to dryness in the same manner as described above. In either case, it is preferred to use stoichiometric amounts of reagents to ensure the integrity of the reaction and the highest yield of the desired end product.
The invention also includes isotopically-labeled compounds of formula I, in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Isotopically labeled compounds of formula I can generally be prepared by techniques known to those skilled in the art or by processes analogous to those described herein using an appropriate isotopically labeled reagent in place of a non-isotopically labeled reagent.
In the following examples and preparations, "DMSO" represents dimethyl sulfoxide, "N" represents an equivalent concentration, "M" represents a molar concentration, "mL" represents mL, "mmol" represents millimole, "μmol" represents micromole, "eq." represents an equivalent, "° c" represents degrees celsius, "Pa" represents pascal, "UV" represents ultraviolet light, and "MHz" represents megahertz.
Detailed description of the preferred embodiments
Experimental procedure
The experiments are generally carried out under an inert atmosphere (nitrogen or argon), in particular in the case of using reagents or intermediates in which oxygen or moisture is sensitive. Commercial solvents and reagents can generally be used without further purification, including, if appropriate, anhydrous solvents (generally Sure-Seal from Aldrich chemical Company, Milwaukee, Wisconsin)TMProduct). The product is typically dried under vacuum before being subjected to another product or biological assay. The mass spectrometry is performed from liquid chromatography-mass spectrometry (LCMS), atmospheric pressureChemical Ionization (APCI) or Gas Chromatography Mass Spectrometry (GCMS) instruments. Chemical shifts of Nuclear Magnetic Resonance (NMR) data are expressed in parts per million (ppm, δ) with reference to the residual peak of the deuterated solvent used.
For syntheses that refer to steps in other examples or methods, the reaction conditions (length and temperature of reaction) may vary. In general, the reaction is followed by thin-layer chromatography or mass spectrometry, and if appropriate by workup. The purification can vary between experiments: in general, the solvent and solvent ratio for the eluent/gradient are selected to provide the appropriate RfOr residence time.
Example 1
4- (azetidin-1-yl) -7-methyl-5- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] imidazo [5,1-f ] [1,2,4] triazine
Step 1.2 Synthesis of bromo-1- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] ethanone
Preparation of 1-methyl-5- (4-methylphenyl) -1H-pyrazole
(1-methyl-1H-pyrazol-5-yl) boronic acid (2.0g, 16mmol), 1-bromo-4-methylbenzene (1.96mL, 15.9mmol), sodium carbonate (5.05g, 47.6mmol), and dichlorobis (triphenylphosphine) palladium (II) (557mg, 0.794mmol) were combined in a mixture of water (20mL) and 1, 2-dimethoxyethane (100mL) and heated at 80 ℃ for 18 hours. After the reaction mixture had cooled, it was filtered through celite and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, and the aqueous layer was extracted with additional ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Silica gel chromatography (gradient: 0% to 50% ethyl acetate in heptane) afforded the product as a yellow oil. Yield: 1.15g, 6.68mmol, 42%. LCMS M/z173.1(M + 1).1H NMR(400MHz，CDCl3) δ 2.42(s, 3H), 3.89(s, 3H), 6.29(d, J =2.0Hz, 1H), 7.30(br AB quartet, J)AB=8Hz，ΔνAB=18Hz，4H)，7.51(d，J=1.9Hz，1H)。
Preparation of 4-iodo-1-methyl-5- (4-methylphenyl) -1H-pyrazole
N-iodosuccinimide (95%, 756mg, 3.19mmol) was added to a solution of 1-methyl-5- (4-methylphenyl) -1H-pyrazole (500mg, 2.90mmol) in acetonitrile (15mL) and the reaction was stirred at 85 ℃ for 1H. Removal of the solvent in vacuo provided a residue which was chromatographed on silica gel (gradient: 20% to 50% ethyl acetate in heptane) to provide the product as a brown oil. Yield: 630mg, 2.11mmol, 73%. LCMS M/z299.2(M + 1).1H NMR(400MHz，CDCl3)δ2.44(br s，3H)，3.83(s，3H)，7.26-7.33(m，4H)，7.57(s，1H)。
Preparation of 1- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] ethanone
Tributyl (1-ethoxyvinyl) stannane (95%, 1.39mL, 3.88mmol) was added to a mixture of 4-iodo-1-methyl-5- (4-methylphenyl) -1H-pyrazole (768mg, 2.58mmol), tetrakis (triphenylphosphine) palladium (0) (298mg, 0.258mmol) and lithium chloride (98%, 279mg, 6.45mmol) in N, N-dimethylformamide (20mL) and the reaction was stirred at 90 ℃ for 18H. After cooling, the mixture was filtered through celite and concentrated in vacuo; silica gel chromatography (gradient: 10% to 50% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 460mg, 2.15mmol, 83%. LCMS M/z215.3(M + 1).1H NMR(400MHz，CDCl3) Δ 2.17(s, 3H), 2.45(br s,3H), 3.69(s, 3H), 7.28(br AB quartet, J)AB=8Hz，ΔνAB=28Hz，4H)，7.99(s，1H)。
Synthesis of 2-bromo-1- [ 1-methyl-5- [ 4-methylphenyl ] -1H-pyrazol-4-yl ] ethanone
Bromine (97%, 0.104mL, 1.97mmol) was added to 1- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl]A solution of ethanone (420mg, 1.96mmol) in glacial acetic acid (10mL)And the reaction mixture was stirred vigorously at 80 ℃ for 2 hours. After removal of the solvent under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, washed with saturated sodium chloride solution and dried over sodium sulfate. The filtrate was filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography (gradient: 10% to 30% ethyl acetate in heptane) to afford the product as a colourless oil. Yield: 353mg, 1.20mmol, 61%. LCMS M/z293.1(M + 1).1H NMR(400MHz，CDCl3) Δ 2.46(s, 3H), 3.71(s, 3H), 3.97(s, 2H), 7.31(br AB quartet, J)AB=8Hz，ΔνAB=23Hz，4H)，8.05(s，1H)。
Step 2. Synthesis of N '-ethylideneimidoyl acethydrazide (N' -ethylidenehydrazide)
A mixture of sodium hydroxide (2.59g, 64.8mmol) in absolute ethanol (300mL) was stirred at 50 ℃ for 20 minutes to effect dissolution. The solution was cooled to 0 ℃ and ethyl acetamido ate hydrochloride (8.0g, 65mmol) was gradually added; the precipitated salt was removed by filtration and the filtrate was treated with acetohydrazide (4.80g, 64.8mmol) at room temperature. The mixture was heated to 80 ℃ for 10 minutes and then allowed to cool for 18 hours. The precipitate was collected by filtration and washed with diethyl ether to afford the product as a white solid. Yield: 4.4g, 38mmol, 59%.1H NMR(400MHz，DMSO-d6) And characteristic peak: δ 1.78(s, 3H), 1.95(s, 3H).
Step 3 Synthesis of N- { 2-methyl-4- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] -1H-imidazol-1-yl } acetamide
N' -Ethylimidoyl Acetylhydrazide (147mg, 1.28mmol) and sodium bicarbonate (99%, 181mg, 2.13mmol) were added to 2-bromo-1- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl]A solution of ethanone (250mg, 0.853mmol) in acetonitrile (9mL) and the mixture was heated at 80 ℃ for 3 hours. The reaction was cooled to room temperature and then diluted with dichloromethane and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel (eluent: in dichloromethane)10% methanol) to yield the product as a yellow oil. Yield: 236mg, 0.763mmol, 89%. LCMS M/z310.5(M + 1).1H NMR(400MHz，CDCl3) Assumed as a mixture of rotamers: δ 2.10 and 1.77(2s, 3H), 2.25 and 2.36(2s, 3H), 2.44 and 2.46(2s, 3H), 3.69 and 3.72(2s, 3H), 6.21(s, 1H), 7.22-7.33(4H, m, presumably; partially obscured by solvent peaks), 7.96(brs, 1H).
Step 4.2 Synthesis of methyl-4- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] -1H-imidazol-1-amine
Aqueous hydrochloric acid (1N, 7.0mL) was added to N- { 2-methyl-4- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl]A solution of-1H-imidazol-1-yl } acetamide (236mg, 0.763mmol) in methanol (1.0mL) and the mixture was heated at reflux for 30 min. Additional 1N aqueous hydrochloric acid (2.0mL) was added and heating continued for an additional 30 minutes. After cooling, the solution was basified with 1N aqueous sodium hydroxide solution, and the mixture was extracted twice with ethyl acetate containing 1% methanol. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow solid. Yield: 148.5mg, 0.5555mmol, 73%. LCMS M/z268.5(M + 1).1H NMR(400MHz，CDCl3) δ 2.39(s, 3H), 2.45(br s,3H), 3.70(s, 3H), 4.45(br s, 2H), 6.26(s, 1H), 7.24-7.32(m, 4H, hypothesis; partially obscured by solvent peaks), 7.97(s, 1H).
Step 5 Synthesis of N- { 2-methyl-4- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] -1H-imidazol-1-yl } iminocarboxamide
Ethyl Iminoformate hydrochloride (608mg, 5.55mmol) was added to 2-methyl-4- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl]-1H-imidazol-1-amine (148mg, 0.554mmol) in ethanol (5mL) and the reaction mixture was heated at 75 ℃ for 66 hours. Additional ethyl iminoformate hydrochloride (300mg, 2.74mmol) was added and heating continued for 8 hours. The final charge of ethyl iminoformate hydrochloride (300mg, 2.74mmol) was followed by maintaining the reaction at 75 ℃ for another 18 hours. Will be provided withThe reaction mixture was cooled, concentrated in vacuo and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. Filtration and concentration of the solvent under vacuum followed by purification using silica gel chromatography (eluent: 10% methanol in dichloromethane) gave the product as a yellow solid. Yield: 70mg, 0.24mmol, 43%. LCMS M/z295.5(M + 1).1H NMR(400MHz，CD3OD), assumed to be a rotamer or a mixture of tautomers: δ 2.20 and 2.25(2s, 3H), 2.43(br s,3H), 3.68(s, 3H), 6.14 and 6.30(2s, 1H), 7.26-7.30(m, 3H), 7.35(br d, J =8Hz, 2H), 7.84 and 7.81(2s, 1H).
Step 6.7 Synthesis of methyl-5- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one
Sodium hydride (60% dispersion in mineral oil, 24mg, 0.60mmol) was added to N- { 2-methyl-4- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl]-1H-imidazol-1-yl } iminocarboxamide (70mg, 0.24mmol) in 1, 4-dioxane (4.0mL) and the mixture was heated at 75 ℃ for 10 min. The reaction was cooled, treated with 1,1' -carbonyldiimidazole (135mg, 0.833mmol), allowed to stir at room temperature for 30 minutes, and then heated to 100 ℃ for 18 hours. After the reaction was cooled to room temperature, it was quenched with water and diluted with ethyl acetate. The organic layer was washed with water, then with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (gradient: 0% to 10% methanol in ethyl acetate) afforded the product as a white solid. Yield: 55mg, 0.17mmol, 71%. LCMS M/z321.5(M + 1).1H NMR(400MHz，DMSO-d6)δ2.34(br s，3H)，2.36(s，3H)，3.71(s，3H)，7.22(br d，J=8Hz，2H)，7.30(d，J=8.2Hz，2H)，7.79(s，1H)，7.95(s，1H)。
Step 7.7 Synthesis of 7-methyl-5- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] -4- (1H-1,2, 4-triazol-1-yl) imidazo [5,1-f ] [1,2,4] triazine
1H-1,2, 4-triazole (162mg, 2.34mmol) was triturated, mixed with dichloromethane (4.0mL) and cooled to 0 ℃. Phosphorus oxychloride (58.2 μ L, 0.624mmol) was added followed by dropwise addition of triethylamine (0.349mL, 2.50mmol) after 1 minute. After 10 minutes at 0 ℃, the ice bath was removed; after 5 minutes, 7-methyl-5- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl is added]Imidazo [5, 1-f)][1,2,4]Triazin-4 (3H) -one (50mg, 0.16 mmol). The reaction mixture was maintained at room temperature for 4 hours, then cooled to 0 ℃ and quenched with water, then treated with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. This crude material was used directly in the following step. LCMS M/z372.5(M + 1).1H NMR(400MHz，DMSO-d6)δ2.27(br s，3H)，2.70(s，3H)，3.73(s，3H)，6.86(br d，J=8.2Hz，2H)，7.06(br d，J=8.0Hz，2H)，7.37(s1H)，8.14(s，1H)，8.53(s，1H)，8.84(s，1H)。
Step 8.4- (azetidin-1-yl) -7-methyl-5- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] imidazo [5,1-f ] [1,2,4] triazine Synthesis
Azetidine (27.0. mu.L, 0.400mmol) and cesium carbonate (97%, 202mg, 0.601mmol) were added to 7-methyl-5- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl]-4- (1H-1,2, 4-triazol-1-yl) imidazo [5,1-f][1,2,4]A solution of triazine (material from the previous reaction,. ltoreq.0.16 mmol) in N, N-dimethylformamide (3.0mL) and the reaction mixture is stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate, washed with water, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (gradient: 0% to 5% methanol in dichloromethane) followed by azeotropy with heptane gave the product as a white solid. Yield: 35mg, 0.097mmol, 61% by 2 steps. LCMS M/z360.2(M + 1).1H NMR(400MHz，CDCl3) δ 2.20-2.28(m, 2H), 2.35(s, 3H), 2.64(s, 3H), 3.5-3.9(v br m, 2H), 3.90(s, 3H), 3.9-4.3(v br m, 2H), 7.21(AB quartet,JAB=8.1Hz，ΔνAB=32.1Hz，4H)，7.64(s，1H)，7.78(s，1H)。
example 2
4- (azetidin-1-yl) -7-methyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine
Step 1.2 Synthesis of Ethylimidoyl hydrazinecarboxylic acid tert-butyl ester
Sodium hydroxide (16.0g, 400mmol) was dissolved in absolute ethanol (1000mL) at 60 ℃. The solution was cooled to 0 ℃ and treated with ethyl acetimide hydrochloride (50g, 400mmol) in portions; after 10 minutes, tert-butyl hydrazinoformate (52.9g, 400mmol) was added in one portion. The reaction was heated to 70 ℃ and stirred at 70 ℃ for 2.5 hours. The mixture was then cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo and treated with tert-butyl methyl ether (500mL) and ethanol (20 mL). After seeding, the mixture was allowed to stir for 18 hours, after which the precipitated solid was collected by filtration and washed with ice-cold tert-butyl methyl ether (500 mL). The solid was dissolved in 2-methyltetrahydrofuran methanol (9:1 mixture, 300mL) and the solution was concentrated to dryness. The residue was washed with diethyl ether (3X 200mL) and dried to give the product as a very pale yellow solid. Yield: 50.2g, 290 mmol. 72 percent. LCMS M/z174.3(M + 1).1H NMR(500MHz，CD3OD)δ1.47(s，9H)，1.88(s，3H)。
Step 2.2 Synthesis of bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone
A.1- (1-methyl-1H-pyrazol-4-yl) ethanone Synthesis
4-bromo-1-methyl-1H-pyrazole (41.3mL, 400mmol) was dissolved in tetrahydrofuran (750mL) and cooled to-78 ℃. N-butyllithium (2.5M solution in hexane, 160mL, 400mmol) was added dropwise over 30 minutes, andthe resulting mixture was stirred at-78 ℃ for 1 hour. After a solution of N-methoxy-N-methylacetamide (40.9mL, 400mmol) in tetrahydrofuran (100mL) was added dropwise to the reaction mixture at-78 ℃, the cooling bath was heated to 0 ℃ over 4 hours. The reaction was then quenched with saturated aqueous sodium chloride (50mL) and the volatiles were removed in vacuo. The residue was diluted with ethyl acetate (1000mL), treated with magnesium sulfate, and stirred for 30 minutes before filtration and concentrated in vacuo. Purification was performed by silica gel chromatography (material loaded in a minimum amount of dichloromethane; gradient: 5% to 100% ethyl acetate in heptane) to give a light yellow oil which solidified on standing. Yield: 28.5g, 230mmol, 57%.1H NMR(500MHz，CDCl3)δ2.37(s，3H)，3.90(s，3H)，7.83(s，1H)，7.84(s，1H)。
B.Synthesis of 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone
A solution of 1- (1-methyl-1H-pyrazol-4-yl) ethanone (28.5g, 230mmol) in dichloromethane (400mL) was diluted with absolute ethanol (100mL) and treated portionwise with pyridinium tribromide (95%, 77.3g, 230 mmol). The reaction was stirred at room temperature for 3 hours, during which time it solidified; the mixture was diluted with dichloromethane (300mL) and water (400mL), treated with sodium sulfite (5g) and stirred for 10 min. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with water (200mL), collected by filtration, washed again with water, and dried to obtain the product as an off-white solid. Yield: 41.6g, 205mmol, 89%.1H NMR(500MHz，CDCl3)δ7.97-7.98(m，1H)，7.95(br s，1H)，4.17(s，2H)，3.95-3.96(m，3H)。
Step 3 Synthesis of tert-butyl [ 2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl ] carbamate
Tert-butyl 2-Iminoacylhydrazinecarboxylate (17.3g, 99.9mmol), 2-bromo-1- (1-methyl-1H-pyrazol-4-yl) ethanone (16.89g, 83.18mmol) and N, N-diisopropylethylamine (31.9mL, 183mmol) were combined in ice-cold 2-methyltetrahydrofuran (400mL) and 1, 2-dimethoxyethane (100mL), and the reaction was mixedThe compound was heated to reflux. After 2.5 hours, the reaction was cooled and washed with 50% saturated aqueous sodium chloride (75 mL). The aqueous layer was extracted with 2-methyltetrahydrofuran (100mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was dissolved in warm ethyl acetate (60mL), allowed to cool to room temperature, and then cooled to 5 ℃ over 30 minutes. The resulting solid was collected by filtration and washed with a small amount of cold ethyl acetate, then ether to give the product as a very pale yellow solid. Yield: 16.0g, 57.7mmol, 69%. LCMS M/z278.5(M + 1).1H NMR(500MHz，CDCl3)δ1.49(br s，9H)，2.23(s，3H)，3.84(s，3H)，6.87(s，1H)，7.51(s，1H)，7.60(s，1H)，8.67(br s，1H)。
Step 4.2 Synthesis of methyl-4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-amine, trifluoroacetate
Reacting [ 2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl]A solution of tert-butyl carbamate (8.0g, 29mmol) in dichloromethane (200mL) and trifluoroacetic acid (40mL) was stirred at room temperature for 2.5 hours. After removal of the solvent in vacuo, the residue was stirred in 1:1 ethyl acetate/heptane for 18 hours. The resulting solid was isolated by filtration to give the product as a white solid. Yield: 5.3g, 18mmol, 62%. The mother liquor was concentrated in vacuo and the residue was purified in ethyl acetate/heptane/ether (50mL) in 1: 1:1 stirring the mixture for 30 minutes; filtration provided additional product as a white solid. The combined yield was: 7.8g, 26.8mmol, 92%.1H NMR(400MHz，DMSO-d6)δ2.54(s，3H)，3.89(s，3H)，6.55(brs，2H)，7.65(s，1H)，7.85(d，J=0.7Hz，1H)，8.11(br s，1H)。
Step 5 Synthesis of N- [ 2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl ] iminocarboxamide
2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-amine, trifluoroacetate (103.0g, 353.7mmol) and formamidine acetate (98%, 131g, 1.23mol) were combined in 2-butanol (350 mL). The reaction was heated to 100 ℃ for 3 hours, at which time it was allowed to cool to room temperature anddiluted with a 2:1 mixture of 10N aqueous sodium hydroxide/saturated aqueous sodium chloride (300 mL). After vigorous stirring, the layers were separated and the aqueous layer was extracted with 2-butanol (4X 250 mL). The combined organic layers were concentrated in vacuo and the resulting solid was slurried with acetonitrile (550mL), stirred at room temperature for 2 hours and filtered. The collected solid was washed with anhydrous acetonitrile (3 × 100mL) and then dried in vacuo at 40 ℃ for 2 hours to give the product as an off-white solid. Yield: 61.5g, 301mmol, 85%. The mother liquor was concentrated to dryness, then dissolved in acetonitrile (200mL) and allowed to stand for 18 hours. The resulting solid was isolated by filtration to provide additional product as an off-white solid. The combined yield was: 64.8g, 317mmol, 90%.1H NMR(500MHz，CD3OD), assumed to be a rotamer or a mixture of tautomers: δ 2.25 and 2.29(2s, 3H), 3.88 and 3.88(2s, 3H), 7.03 and 7.19(2s, 1H), 7.39 and 7.94(2s, 1H), 7.69 and 7.67(2s, 1H), 7.77 and 7.75(2s, 1H).
Step 6.7 Synthesis of methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one (C1)
N- [ 2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl ] -was reacted at 63 ℃]Iminoformamide (58.3g, 285mmol) and 1,1' -carbonyldiimidazole (98%, 59.0g, 357mmol) were combined in tetrahydrofuran (1140mL), and the suspension was stirred at 65 ℃ for 2.5 h. The mixture was cooled and concentrated in vacuo; the resulting solid was slurried with methanol (400mL), heated to reflux for 20 minutes and cooled to 7 ℃. The solid was collected to give C1 as a pale yellow solid. Yield: 45.9g, 199mmol, 70%. LCMS M/z231.1(M + 1).1H NMR(500MHz，DMSO-d6)δ2.48(s，3H)，3.88(s，3H)，7.79(s，1H)，8.08(s，1H)，8.37(s，1H)，11.59(br s，1H)。
Step 7.4- (azetidin-1-yl) -7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazine (C2) synthesis
Finely ground 1H-1,2, 4-triazole (278g, 4.02mol) was mixed with acetonitrile (700mL), cooled to 0 deg.C, and treated with phosphorusThe acid chloride (62.4mL, 669mmol) was treated dropwise while maintaining the internal temperature below 15 ℃. The suspension was stirred for 10 minutes and then treated slowly dropwise with triethylamine (607mL, 4.35mol) under vigorous stirring, while maintaining the internal temperature below 48 ℃. When the reaction was cooled to 41 ℃, it was stirred for 15 minutes and then treated with 7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5, 1-f)][1,2,4]Triazin-4 (3H) -one (77.1g, 335mmol) was treated in portions. Upon completion of the addition, the reaction was heated to 73 ℃ for 1 hour and then cooled to room temperature, at which time thin layer chromatography (eluent: 10% methanol in ethyl acetate) indicated complete conversion to the triazole-substituted intermediate. The reaction slurry was treated with triethylamine (279mL, 2.00mol) followed by azetidine hydrochloride (94.0g, 1.00 mol); over 10 minutes, the internal temperature rose from 18 ℃ to 38 ℃. The mixture was stirred for 1 hour, cooled to 15-20 ℃ and filtered. The filter cake was washed with acetonitrile (600mL) and the filtrate was concentrated in vacuo. The resulting slurry was diluted with water (650mL) followed by aqueous sodium hydroxide (10N, 450 mL). The slurry was extracted with dichloromethane (3 × 350mL) and the combined organic layers were dried over sodium sulfate and filtered. The filtrate was passed through a column of silica gel (230-400 mesh, 150g) eluting with dichloromethane (1L) followed by 10% methanol in ethyl acetate (1L). The combined product-containing eluates were concentrated in vacuo and the residue was washed with tert-butyl methyl ether (350mL), collected by filtration and washed with diethyl ether. This solid was dissolved in water (200mL) and diluted more than once with aqueous sodium hydroxide (5N, 250 mL). The mixture was extracted with dichloromethane (3 × 250mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The solid was washed with tert-butyl methyl ether (350mL) and collected by filtration to give C2 as a pale tan solid. Yield: 82.15g, 305mmol, 91%.1H NMR(500MHz，CDCl3)δ2.23-2.30(m，2H)，2.65(s，3H)，3.96(s，3H)，3.98-4.07(m，4H)，7.61(br s，1H)，7.61(br s，1H)，7.85(s，1H)。
Step 8.4- (azetidin-1-yl) -7-methyl-5- { 1-methyl-5- [ 5-trifluoromethyl ] pyridin-2-yl } -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine Synthesis
Reacting 4- (azetidin-1-yl) -7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f][1,2,4]Triazine (10.0g, 37.1mmol), 2-bromo-5- (trifluoromethyl) pyridine (16.8g, 74.3mmol) and ground potassium carbonate (15.4g, 111mmol) were combined in a reaction flask, flushed with nitrogen, and treated with degassed 1, 4-dioxane (600 mL). Allyl palladium (II) chloride dimer (693mg, 1.86mmol) was added to this mixture and the system was again purged with nitrogen. The reaction was heated to 102 ℃ for 36 hours, then cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (400mL) and aqueous hydrochloric acid (1N, 200 mL). The aqueous phase was neutralized with solid sodium bicarbonate and extracted with ethyl acetate (4 × 50 mL). The combined organic layers were washed with 1N aqueous citric acid solution and then with saturated aqueous sodium bicarbonate solution. By usingAfter activated carbon treatment, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in a minimum amount of dichloromethane and concentrated under reduced pressure until it became a thick oil. Diethyl ether (100mL) was added and the solid began to precipitate as the mixture was stirred; stirring was continued for 1 hour at room temperature, and then a white solid was collected by filtration and washed with diethyl ether. The additional product in the mother liquor was isolated by concentrating the filtrate in vacuo and the residue was chromatographed on an alumina column (eluent: 70% ethyl acetate in heptane). The product from the column was recrystallized from warm 20% ethyl acetate in heptane to yield additional product as a white solid. The combined yield was: 5.3g, 12.8mmol, 35%. This material was combined with the product of a similar reaction (15.5 g total, 37.4mmol) and further purified as follows. The material was dissolved at room temperature in a mixture of ethyl acetate (100mL) and 2-methyltetrahydrofuran (150 mL). AddingThiol (SiliCycle, 1.35mmol/g, 15g) and the mixture was stirred for 20 hours and then filtered through celite. The filtrate is usedActivated carbon (500mg) and was stirred for 15 min before filtration and concentrated under reduced pressure. The resulting oil was azeotroped with a 1:1 mixture of heptane and ethyl acetate to give an off-white solid, which was mixed with heptane (100mL) and stirred at room temperature for 6 hours. Filtration afforded the product as a white solid. Purification yield: 14.4g, 34.7mmol, 93%. LCMS M/z415.0(M + 1).1H NMR(400MHz，CDCl3)δ2.17-2.26(m，2H)，2.70(s，3H)，3.3-3.8(v br m，2H)，3.8-4.3(v br m，2H)，4.18(s，3H)，7.63-7.66(m，1H)，7.66(s，1H)，7.79-7.83(m，2H)，8.95-8.96(m，1H)。
Example 3
N, 7-dimethyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine
Step 1.5 Synthesis of bromo-1-methyl-1H-pyrazole-4-carboxylic acid Ethyl ester
Copper (II) bromide (99%, 20.0g, 88.6mmol) and tert-butyl nitrite (90%, 14.1mL, 107mmol) were combined in acetonitrile (65mL) and heated to 65 ℃. Ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (10.0g, 59.1mmol) { caution: gas evolution! } and the reaction was maintained at 65 ℃ for 24 hours. The mixture was cooled to room temperature, poured into aqueous hydrochloric acid (3N, 600mL), diluted with ethyl acetate (300mL) and stirred for 10 min. The aqueous layer was extracted with ethyl acetate (150mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient: 5% to 100% ethyl acetate in heptane, and held at 32% for 5-min) to afford the product as a light yellow solid. Yield: 9.10g, 39.0mmol, 66%. LCMS M/z233.3(M + 1).1H NMR(500MHz，CDCl3)δ1.36(t，J=7.1Hz，3H)，3.92(s，3H)，4.32(q，J=7.1Hz，2H)，7.93(s，1H)。
Step 2.5 Synthesis of bromo-1-methyl-1H-pyrazole-4-carboxylic acid
A suspension of ethyl 5-bromo-1-methyl-1H-pyrazole-4-carboxylate (8.00g, 34.3mmol) in tetrahydrofuran (60mL), water (20mL) and ethanol (20mL) was treated with lithium hydroxide monohydrate (3.17g, 75.5mmol) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give a white solid residue, which was diluted with water (50mL), washed with diethyl ether (50mL) and adjusted to pH2.5 with 6N aqueous hydrochloric acid. The thick suspension was extracted with 2-methyltetrahydrofuran (2 × 125mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the product as an off-white solid. Yield: 6.49g, 31.7mmol, 92%. LCMS M/z205.2(M + 1).1H NMR(500MHz，DMSO-d6)δ3.86(s，3H)，7.91(s，1H)，12.64(br s，1H)。
Step 3.2 Synthesis of bromo-1- (5-bromo-1-methyl-1H-pyrazol-4-yl) ethanone
A solution of 5-bromo-1-methyl-1H-pyrazole-4-carboxylic acid (6.4g, 31mmol) in methanol (100mL) was placed in a water bath, treated as a single portion with sodium methoxide (95%, 1.86g, 32.7mmol) and stirred at room temperature for 30 min. After removal of volatiles in vacuo, the sodium salt was concentrated from heptane (100mL) twice. It was then suspended in dichloromethane (100mL) and treated with oxalyl chloride (3.15mL, 35.9mmol) followed by N, N-dimethylformamide (2 drops). The reaction was stirred at room temperature for 20 hours and then concentrated under reduced pressure. The solid residue was suspended in acetonitrile (100mL), treated dropwise with a solution of (trimethylsilyl) diazomethane in diethyl ether (2M, 39.0mL, 78.0mmol) and stirred for 3 hours. The mixture was cooled to 0 ℃ and hydrogen bromide (33% in acetic acid, 21.9mL, 125mmol) was added dropwise. After 1 hour at 0 ℃, the reaction mixture was concentrated, and the solid residue was mixed with heptane (250mL) and re-concentrated. The residue was diluted with ethyl acetate (100mL) and vigorously stirred with saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo; the crude product was purified by silica gel chromatography (gradient): 12% to 100% ethyl acetate in heptane) to give the product as an off-white solid, approximately 85% pure by LCMS analysis. Yield: 8.10g, about 78% (corrected for purity). LCMS M/z282.8(M + 1).1H NMR(500MHz，CDCl3)δ3.93(s，3H)，4.25(s，2H)，8.01(s，1H)。
Step 4 Synthesis of [4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -2-methyl-1H-imidazol-1-yl ] carbamic acid tert-butyl ester
Tert-butyl 2-ethanimidohydrazinecarboxylate (5.9g, 34mmol), 2-bromo-1- (5-bromo-1-methyl-1H-pyrazol-4-yl) ethanone (from the previous step, 8.00g, ca. 24mmol) and N, N-diisopropylethylamine (10.9mL, 62.6mmol) were heated to reflux in a mixture of 2-methyltetrahydrofuran (200mL) and 1, 2-dimethoxyethane (50 mL). After 2.5 hours, the reaction was cooled and washed with 50% saturated aqueous sodium chloride (75 mL). The aqueous layer was extracted with 2-methyltetrahydrofuran (50mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (gradient: 0% to 8% methanol in dichloromethane), and the purified material (7.5g) was dissolved in diethyl ether (25mL), treated with hexane (4 drops), and allowed to crystallize. The resulting solid was collected and washed with a small amount of cold diethyl ether to give the product as a very pale pink solid. Yield: 6.49g, 18.2mmol, 59% by 2 steps. LCMS M/z358.4(M + 1).1H NMR(500MHz，CDCl3)δ1.49(br s，9H)，2.16(br s，3H)，3.85(s，3H)，7.17(s，1H)，7.89(s，1H)，8.8-9.3(v br s，1H)。
Step 5.4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -2-methyl-1H-imidazol-1-amine, Synthesis of trifluoroacetate salt
Reacting [4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -2-methyl-1H-imidazol-1-yl]Tert-butyl carbamate (5.00g, 14.0mmol) was dissolved in dichloromethane (120mL), treated with trifluoroacetic acid (20.9mL, 281mmol), and stirred for 2.5 h. After removal of volatiles in vacuo, the oily residue was diluted with ether (100 mL). The resulting suspension was stirred at room temperature for 30 minutes, and then the solid was collected and washed with diethyl ether to give an ashProduct as white solid. Yield: 4.98g, 13.5mmol, 96%. LCMS M/z256.3(M + 1).1H NMR(500MHz，CD3OD)δ2.65(s，3H)，3.95(s，3H)，7.68(s，1H)，7.86(s，1H)。
Step 6 Synthesis of N- [4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -2-methyl-1H-imidazol-1-yl ] iminocarboxamide
4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -2-methyl-1H-imidazol-1-amine, trifluoroacetate (4.90g, 113.2mmol) and formamidine acetate (98%, 4.92g, 46.3mmol) were combined in 2-butanol (40mL), and the reaction mixture was heated at 100 ℃ for 6 hours, then allowed to cool to room temperature and stirred for 18 hours. The off-white solid was collected by filtration and washed with 2-propanol followed by diethyl ether. The solid was then triturated with aqueous ammonium hydroxide (7.5M, 40 mL); filtration gave a white solid which was washed with 2-propanol followed by diethyl ether to give the product. Yield: 2.70g, 9.54mmol, 72%.1H NMR(500MHz，CD3OD), assumed to be a rotamer or a mixture of tautomers: δ 2.26 and 2.31(2s, 3H), 3.89 and 3.89(2s, 3H), 7.26 and 7.40(2s, 1H), 7.41 and 7.96(2br s, 1H), 7.85 and 7.82(2s, 1H).
Step 7.5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one (C3) Synthesis
1,1' -carbonylbis (1H-1,2, 4-triazole) (90%, 2.69g, 14.8mmol) and N- [4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -2-methyl-1H-imidazol-1-yl]Iminoformamide (2.69g, 9.50mmol) was combined in 1, 4-dioxane (63mL) and the mixture was stirred at room temperature for 3.5 hours and then heated to 50 ℃ for 1 hour. Additional 1,1' -carbonylbis (1H-1,2, 4-triazole) (90%, 1.34g, 7.35mmol) was added and heating continued for 30 min. After addition of another 1,1' -carbonylbis (1H-1,2, 4-triazole) (90%, 269mg, 1.48mmol), heating was carried out at 50 ℃ for another 75 minutes. The reaction was allowed to cool to room temperature and then concentrated to half its original volume; the precipitate was collected and washed with ethyl acetate to give a white solid. This was dissolved in methanol (50mL), concentrated to dryness and triturated with water (25 mL). Collecting solidsThereafter, the solid was washed with 2-propanol followed by diethyl ether to give C3 as a white solid. Yield: 1.95g, 6.31mmol, 66%. LCMS M/z309.4(M + 1).1H NMR(500MHz，DMSO-d6)δ2.53(s，3H)，3.87(s，3H)，7.87(s，1H)，8.17(s，1H)，11.69(br s，1H)。
Step 8.5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methyl-4- (1H-1,2, 4-triazol-1-yl) imidazo [5,1-f ] [1,2,4] triazine Synthesis
1H-1,2, 4-triazole (4.49g, 65.0mmol) was mixed with acetonitrile (40mL) and cooled to 0 ℃. Phosphorus oxychloride (1.78mL, 19.4mmol) was added followed by triethylamine (10.9mL, 78.2mmol) added dropwise. After the addition was complete, the temperature was maintained at 15-20 ℃ for 30 minutes. At this time, 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5,1-f ] was added][1,2,4]Triazin-4 (3H) -one (2.0g, 6.5mmol) and the reaction mixture was allowed to warm to room temperature and then to 70 ℃ for 18H. The reaction was cooled and poured into a solution of potassium phosphate (97%, 6.56g, 30.0mmol) in water (30mL) at 10 ℃. After stirring for 5 minutes, the mixture was treated with solid sodium chloride (5g) and stirred for another 5 minutes. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The solvent was removed in vacuo to give the crude product as an orange slurry (2.1 g; in order1HNMR measurements contained some triethylamine) which was used for the next reaction without additional purification.1H NMR(400MHz，CDCl3) And product peak: δ 2.86(s, 3H), 3.89(s, 3H), 7.66(s, 1H), 7.94(s, 1H), 8.36(s, 1H), 8.95(s, 1H).
Step 9.5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine (C4) Synthesis
Methylamine (4.31mL of a 2M solution in tetrahydrofuran, 8.62mmol) was added to cesium carbonate (9.78g, 30.0mmol) and 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methyl-4- (1H-1,2, 4-triazol-1-yl) imidazo [5,1-f [ ]][1,2,4]Triazine (from the previous reaction, 2.1g) in a mixture of N, N-dimethylformamide (12mL) and reaction inStir at room temperature for 1 hour. It was quenched with a 1:1 mixture of water and saturated aqueous sodium chloride solution, then extracted with ethyl acetate (2X 20mL) and with tetrahydrofuran (10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford C4. Yield: 1.65g, 5.12mmol, 78% were subjected to 2 steps. LCMS M/z322.1(M + 1).1H NMR(500MHz，CDCl3)δ2.70(s，3H)，3.10(d，J=4.9Hz，3H)，4.00(s，3H)，5.46-5.52(m，1H)，7.69(s，1H)，7.97(s，1H)。
Step 10 Synthesis of N, 7-dimethyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine
Reacting 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ]][1,2,4]Triazin-4-amine (13.26g, 41.16mmol) and [4- (trifluoromethyl) phenyl]Boric acid (98%, 9.72g, 50.2mmol) was combined in ethanol (126mL) and the resulting slurry was treated with a solution of potassium phosphate (98%, 11.13g, 51.39mmol) in water (42mL) and heated to 70 ℃ for 40 minutes, during which a vigorous nitrogen flow was applied with a bubbler. After addition of tetrakis (triphenylphosphine) palladium (0) (482mg, 0.417mmol), the reaction mixture was heated at reflux for 3.5 hours, then cooled to room temperature and stirred for another 16 hours. The mixture was filtered through a cotton column and the filtrate was concentrated in vacuo and then reconcentrated with 2-methyltetrahydrofuran (2X 200 mL). The residue was reconstituted in 2-methyltetrahydrofuran (150mL) and extracted with aqueous hydrochloric acid (1M, 70mL, stirred for 20 min). The aqueous layer was removed (pH 2-3). This step removes most of the debrominated starting material; importantly, the method comprises the following steps: pH of HCl washing is more than or equal to 2]. The organic layer was extracted twice with 1M aqueous hydrochloric acid: first 100mL (40 min of stirring) and then 75mL (20 min of stirring). The 100mL aqueous layer was back extracted with 2-methyltetrahydrofuran (80mL, stirred for 30 min) to remove some color. The two hydrochloric acid layers were combined and treated with aqueous sodium hydroxide (5M, 35.5mL) to adjust the pH to 6. The resulting mixture was extracted with 2-methyltetrahydrofuran (130 mL); the organic layer was passed through a sodium sulfate column (74g) and concentrated in vacuo to a volume of about 150 mL. Use itG-60 activated carbon (5.03G) was treated and spun on a rotary evaporator in a water bath at 50 ℃ for 1 hour. The warm solution was filtered through a pad of celite, rinsing with 2-methyltetrahydrofuran, and the filtrate was concentrated under reduced pressure. The resulting pale yellow vesicles were treated with t-butyl methyl ether (150mL) and rotated in a water bath at 50 ℃ for 5 minutes, then cooled to room temperature and stirred for 1 hour. The resulting slurry was cooled in an ice bath and held for an additional 30 minutes. The solid was collected by filtration and rinsed with cold tert-butyl methyl ether (cooled with a bath of ice-saturated aqueous sodium chloride solution; 79mL) and then slurried in heptane (150 mL). The mixture was concentrated in vacuo to a small volume and reconcentrated with heptane (2X 150mL) to a final volume of about 50 mL. Filtration afforded the product as a white solid. Yield: 11.91g, 30.75mmol, 75%. LCMS M/z388.2(M + 1).1H NMR(400MHz，CDCl3) δ 2.65(br s,3H), 3.00(d, J =5.0Hz, 3H), 3.95(s, 3H), 5.49-5.57(m, 1H), 7.61(br AB quartet, J)AB=8.2Hz，ΔνAB=41.4Hz，4H)，7.73(s，1H)，7.91(br s，1H)。
Example 4
4- (azetidin-1-yl) -5- [5- (4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine
Step 1.Synthesis of 4-chloro-7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazine
Phosphoryl chloride (16.07g, 104.8mmol) was added to 7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5, 1-f) over 5 minutes][1,2,4]Slurry of triazin-4 (3H) -one (11.98g, 52.03mmol) in toluene (180 mL). N, N-diisopropylethylamine (27.04g, 209.2mmol) was added and the reaction mixture was heated at 100 ℃ for 15 h. The mixture was cooled to room temperature, at which time LCMS analysis indicated incomplete reaction;additional phosphorus oxychloride (3.98g, 26.0mmol) was added and the reaction was heated at 100 ℃ for 22 h. The mixture was cooled to room temperature, diluted with dichloromethane (24mL) and stirred at room temperature for 48 hours. Over 50 minutes, the reaction mixture was added to a mixture of triethylamine (58mL), toluene (60mL) and water (120mL) while maintaining the internal temperature below 34 ℃. Stirring was continued for another 15 minutes. The aqueous layer was extracted once with toluene (120mL), and the combined organic layers were washed with saturated aqueous sodium chloride (200mL) and dried over a sodium sulfate column (71 g). The filtrate was concentrated in vacuo to give the crude product as a dark orange solid (9.77 g); this was treated with tetrahydrofuran (60mL) and heated to reflux for 15 minutes to give a solution. The solution was cooled to room temperature over 30 minutes, granulated for 30 minutes, then cooled in an ice bath and stirred for 30 minutes. The resulting solid and filter cake were collected by filtration and washed with pre-cooled tert-butyl methyl ether (cooled with a bath of ice-saturated aqueous sodium chloride solution; 65 mL). The product was obtained as a bright orange solid. Yield: 7.59g, 30.5mmol, 59%. LCMS M/z249.0(M + 1).1H NMR(400MHz，CDCl3)δ2.75(s，3H)，3.99(s，3H)，7.90(s，1H)，8.00(s，1H)，8.12(s，1H)。
Step 2.4- (azetidin-1-yl) -7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazine Synthesis
A solution of azetidine (9.21g, 161mmol) in dichloromethane (75mL) was added to 4-chloro-7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f][1,2,4]A solution of triazine (38.14g, 153.4mmol) in dichloromethane (310 mL). After stirring for 5 minutes, the reaction was treated with aqueous sodium bicarbonate (0.89M, 260mL, 231mmol) and stirred vigorously for 2 hours. After phase separation, the white solid was collected by filtration and mixed with water and dichloromethane; it did not dissolve completely. Filtration provided a second water/dichloromethane mixture, which was combined with the original filtrate. The layers were separated and the aqueous layer was extracted with dichloromethane (3X 100 mL). The combined organic layers were washed with saturated aqueous sodium chloride (250mL), then dried over sodium sulfate and filtered. The filtrate was concentrated on a rotary evaporator at 45 ℃ until the solid began to form in the flaskAnd (4) obtaining. Tert-butyl methyl ether (400mL) was added and stirred, and the mixture was granulated for 1 hour. Filtration afforded the product as a white solid. Yield: 36.07g, 133.9mmol, 87%.1H NMR(400MHz，CDCl3)δ2.23-2.31(m，2H)，2.65(s，3H)，3.97(s，3H)，3.98-4.08(m，4H)，7.61(s，1H)，7.62(s，1H)，7.85(s，1H)。
Step 3.4- (azetidin-1-yl) -5- [5- (4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine Synthesis
Reacting 4- (azetidin-1-yl) -7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f][1,2,4]Triazine (10.0g, 37.1mmol), 1-bromo-4-chlorobenzene (14.2g, 74.2mmol), freshly ground potassium carbonate (15.4g, 111mmol) and allylpalladium (II) chloride dimer (970mg, 2.60mmol) were combined in a reaction flask; the flask was then evacuated under vacuum and flushed with nitrogen. 1, 4-dioxane (180mL) was added and the reaction was stirred at room temperature. The mixture was degassed under vacuum and nitrogen was bubbled through it over 5 minutes. The evacuation-nitrogen flush step was repeated two additional times. The reaction was heated to 100 ℃ for 72 hours, then cooled to room temperature and quenched with 5.0g of 4- (azetidin-1-yl) -7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f][1,2,4]The same reactions carried out on the triazines were combined. After the combined reaction mixture was concentrated in vacuo and suspended in ethyl acetate, the residue was applied to a pad of celite-covered silica gel. The pad was eluted with ethyl acetate (1.5L) followed by a 9:1 mixture of ethyl acetate/methanol (1L). The combined eluates were concentrated in vacuo to give (25g), which was dissolved in ethyl acetate (500mL) and extracted with aqueous hydrochloric acid (1M, 300 mL). The aqueous layer was basified with 1M aqueous sodium hydroxide solution and extracted with ethyl acetate (2X 250 mL). The two organic layers were combined and washed with aqueous citric acid (1M, 200mL), and the aqueous citric acid layer was extracted with ethyl acetate (8X 100 mL). The combined organic layers were then washed with a 1:1 the mixture was washed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was stirred in a hot mixture of heptane (. about.100 mL) and ethyl acetate (. about.15 mL) and cooled to room temperatureWarm and stir for 16 hours. The solid was isolated by filtration to give a white powder (10.6 g). To remove residual palladium (0.3%, QTI Analytical Services analysis), this material was dissolved in a mixture of ethyl acetate (100mL) and 2-methyltetrahydrofuran (150mL) at room temperature and usedThiol (SiliCycle, 1.35mmol/g, 5g, 6.75mmol activity). The mixture was stirred for 20 hours and then filtered through celite. The filtrate is usedActivated carbon (500mg) and was stirred for 15 min before filtration and concentrated under reduced pressure. The resulting oil was azeotroped with a 1:1 mixture of heptane and ethyl acetate to give a white solid (9.9g), which was triturated with a mixture of heptane (80mL) and ethyl acetate (10mL) under reflux, then cooled to room temperature and stirred for an additional 36 hours. Filtration afforded the product as a white solid. Yield: 9.48g, 25.0mmol, 67%. LCMS M/z380.0(M + 1).1H NMR(500MHz，CDCl3)δ2.21-2.28(m，2H)，2.63(s，3H)，3.4-4.4(v br m，4H)，3.90(s，3H)，7.31-7.36(m，4H)，7.64(s，1H)，7.80(s，1H)。
Example 5
Synthesis of 4- (azetidin-1-yl) -5- [5- (5-chloropyridin-2-yl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine
The title product was obtained according to the procedure used in example 2 for the synthesis of 4- (azetidin-1-yl) -7-methyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-4-yl } imidazo [5,1-f][1,2,4]The triazine step is carried out except that 2-bromo-5-chloropyridine is used instead of 2-bromo-5- (trifluoromethyl) pyridine. In this case, after the citric acid wash, the organic phase is washedThe layers were dried, filtered and concentrated under reduced pressure to give a pale yellow solid, which was then recrystallized from methanol. The solid was dissolved in 2-methyltetrahydrofuran (300mL), treated with silica gel and stirred for 18 hours. AddingActivated carbon (2g) and the mixture was stirred for 30 minutes, at which time it was filtered through a pad of celite and concentrated in vacuo to give the product as a white solid. Yield: 17.6g, 46.2mmol, 52%. LCMS M/z381.0(M + 1).1H NMR(400MHz，CDCl3)δ2.16-2.25(m，2H)，2.69(s，3H)，3.3-3.8(v br m，2H)，3.8-4.3(v br m，2H)，4.12(s，3H)，7.40(dd，J=8.5，0.7Hz，1H)，7.54(dd，J=8.5，2.5Hz，1H)，7.64(s，1H)，7.81(s，1H)，8.65(dd，J=2.5，0.7Hz，1H)。
Example 6
5- {5- [4- (difluoromethyl) phenyl ] -1-methyl-1H-pyrazol-4-yl } -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine
Step 1.2 Synthesis of- [4- (difluoromethyl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (dioxaborolane) (C5).
A.1-bromo-4- (difluoromethyl) benzene synthesis.
(diethylamino) sulfur trifluoride (46g, 0.29mol) was added portionwise over 20 minutes to a solution of 4-bromobenzaldehyde (37.7g, 0.204mmol) in dichloromethane (170mL) and the reaction mixture was heated at reflux for 1 hour. It was then allowed to cool to room temperature, stirred for 18 hours, and slowly added to a stirred solution of saturated aqueous sodium bicarbonate (377mL) over 30 minutes at 0 ℃. The biphasic mixture was allowed to warm to room temperature and stirred for 15 minutes. The aqueous layer was extracted with dichloromethane (2X 80mL) and the combined organic layers were washed with saturated aqueous sodium chloride (80mL)Washed, dried over magnesium sulfate and concentrated in vacuo to give a gold oil. The reaction was repeated another 10 times using 60g batches of 4-bromobenzaldehyde (total starting material: 638g, 3.45mol) and the resulting oils were combined and purified by distillation (b.p.102 ℃ C. at 37mm Hg) to give the product as a colourless oil. Yield: 577.3g, 2.79mol, 81%.1H NMR(400MHz，CDCl3)δ6.62(t，J=56.3Hz，1H)，7.40(br d，J=8.4Hz，2H)，7.61(br d，J=8.6Hz，2H)。
Synthesis of 2- [4- (difluoromethyl) phenyl ] -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
Reacting [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (25.25g, 34.5mmol) was added in whole portions to a degassed mixture of 1-bromo-4- (difluoromethyl) benzene (160g, 0.77mol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bi-1, 3, 2-dioxaborolane (392.5g, 1.55mol) and potassium acetate (303g, 3.09mol) in 1, 4-dioxane (2.42L) and the reaction was heated to 100 ℃ for 18 hours. The mixture was then cooled to room temperature and filtered through celite, washing with ethyl acetate (3L). The filtrate was concentrated in vacuo to give a dark brown oil. The reaction was repeated an additional 3 times using 50g, 160g and 156g batches of 1-bromo-4- (difluoromethyl) benzene (total starting material, 526g, 2.54mol) and the combined crude product was purified twice by chromatography on silica gel (gradient: 0% to 3% ethyl acetate in heptane) to give a yellow-white solid (803 g). This was recrystallized from methanol (1.6L) at-20 ℃ and the filtrate was concentrated to half of its original volume, cooled and the resulting solid collected by filtration. The combined solids (426g) were recrystallized from heptane (500mL) at-20 deg.C, then melted and poured into methanol (200mL) cooled in a methanol-ice bath. The mixture was triturated and filtered to yield C5 as a solid. Yield: 250.7g, 0.987mmol, 39%.1H NMR(400MHz，CDCl3)δ1.37(s，12H)，6.65(t，J=56.4Hz，1H)，7.52(br d，J=8.1Hz，2H)，7.92(br d，J=8.0Hz，2H)。
Step 2.5 Synthesis of- {5- [4- (difluoromethyl) phenyl ] -1-methyl-1H-pyrazol-4-yl } -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine
Mixing [5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -N, 7-dimethyl imidazo [5,1-f ]][1,2,4]Triazin-4-amine (13.01g, 40.38mmol) and 2- [4- (difluoromethyl) phenyl]-4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (12.75g, 50.18mmol) is combined in ethanol (126mL) and the resulting slurry is treated with a solution of potassium phosphate (98%, 11.04g, 50.97mmol) in water (42mL) and heated to 70 ℃ for 30 minutes during which a vigorous nitrogen flow is applied with a bubbler. After addition of tetrakis (triphenylphosphine) palladium (0) (481mg, 0.416mmol), the reaction mixture was heated at reflux for 4 hours, then cooled to room temperature and stirred for another 16 hours. The mixture was filtered through a cotton column and the filtrate was concentrated in vacuo and then reconcentrated with 2-methyltetrahydrofuran (2X 150 mL). The residue was reconstituted in 2-methyltetrahydrofuran (150mL) and extracted with aqueous hydrochloric acid (1M, 70mL, stirred for 20 min). The aqueous layer was removed (pH 2-3). The organic layer was extracted twice with 1M aqueous hydrochloric acid: first 100mL (stirred for 1 hour) and then 75mL (stirred for 20 minutes). The 100mL aqueous layer was back extracted with 2-methyltetrahydrofuran (75mL, stirred for 20 min) to remove the pale yellow color; a solid precipitated from this organic layer, which was collected and washed with tert-butyl methyl ether to give X-ray quality crystals. Single crystal X-ray analysis showed this material to be the monohydrate of the hydrochloride salt of the product. The two hydrochloric acid layers were combined and treated with aqueous sodium hydroxide (5M, 35.5mL) to adjust the pH to 6. The resulting mixture was extracted with 2-methyltetrahydrofuran (150 mL); the organic layer was passed through a sodium sulfate column (58g) and concentrated in vacuo to a volume of about 150 mL. The yellow solution is usedG-60 activated carbon (5.03G) was treated and spun on a rotary evaporator in a water bath at 50 ℃ for 1.5 hours. The warm solution was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The resulting pale yellow solid was treated with t-butyl methyl ether (250mL) and rotated on a rotary evaporator in a water bath at 55 ℃ for 1 hour. Approximately 100mL of solvent was removed using a rotary evaporator and the resulting mixture was cooled to room temperature and stirred for 1 hour. The slurry was then placed in an ice bathCool and stir for an additional 30 minutes. The solid was collected by filtration and washed with cold tert-butyl methyl ether (cooled in a bath of ice-saturated aqueous sodium chloride solution; 50mL) to give the product as a powdery white solid. Yield: 11.27g, 30.51mmol, 76%. LCMS M/z370.2(M + 1).1H NMR(400MHz，CDCl3) δ 2.65(br s,3H), 2.98(d, J =5.1Hz, 3H), 3.94(s, 3H), 5.48-5.55(m, 1H), 6.65(t, J =56.3Hz, 1H), 7.52(br AB quartet, J ″)AB=8.4Hz，ΔνAB=17.9Hz，4H)，7.73(s，1H)，7.90(br s，1H)。
Example 7
N, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl } -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine
Step 1 Synthesis of N- (4-methoxybenzyl) -N, 7-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine (C6)
In analogy to the preparation of 4- (azetidin-1-yl) -7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f in example 2][1,2,4]Triazine the product was synthesized in the manner described, except that 1- (4-methoxyphenyl) -N-methyl methylamine was used instead of azetidine hydrochloride, and the treatment was somewhat modified: after the slurry was extracted with dichloromethane, the combined organic layers were washed with 1N aqueous sodium hydroxide solution, washed with saturated aqueous sodium chloride solution, and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo and passed through a short column of silica gel (eluent: 5% methanol in ethyl acetate). The eluate was concentrated under reduced pressure and the resulting solid was washed with tert-butyl methyl ether followed by diethyl ether to afford C6. Yield: 36.0g, 99.1mmol, 76%. LCMS M/z364.2(M + 1).1H NMR(400MHz，CDCl3)δ2.67(s，3H)，2.84(s，3H)，3.77(s，3H)，3.88(s，3H)，4.66(s，2H)，6.82(br d，J=8.7Hz，2H)，7.07(br d，J=8.6Hz，2H)，7.58(s，1H)，7.62(s，1H)，7.89(s，1H)。
Step 2 Synthesis of N- (4-methoxybenzyl) -N, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine
Mixing N- (4-methoxybenzyl) -N, 7-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f][1,2,4]Triazin-4-amine (10.0g, 27.5mmol), 2-bromo-5- (trifluoromethyl) pyridine (12.4g, 54.9mmol) and powdered potassium carbonate (11.4g, 82.5mmol) were combined in 1, 4-dioxane (90mL) and heated at reflux for 10 min. Allyl Palladium chloride dimer (98%, 514mg, 1.38mmol) was added, and Q-Tube was coveredTMThe reaction was heated at 160 ℃ for 22 hours in a sealed tube (Q Labtech). The reaction was cooled to room temperature and concentrated in vacuo. The residue was suspended in ethyl acetate, filtered through celite and concentrated under reduced pressure. Silica gel chromatography (gradient: 50% to 100% ethyl acetate in heptane) afforded light brown bubbles (7.85g), which were crystallized from heptane (-100 mL) and ethyl acetate (-5 mL) to afford the product as a light brown powder. Yield: 7.00g, 13.8mmol, 50%. LCMS M/z509.1(M + 1).1H NMR(500MHz，CDCl3)δ2.54(s，3H)，2.72(s，3H)，3.75(s，3H)，4.14(s，3H)，4.34(br s，2H)，6.76(br d，J=8.8Hz，2H)，6.94(br d，J=8.5Hz，2H)，7.39(d，J=8.3Hz，1H)，7.72(s，1H)，7.76(dd，J=8.3，2.2Hz，1H)，7.85(s，1H)，8.95-8.96(m，1H)。
Step 3 Synthesis of N, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine
Mixing N- (4-methoxybenzyl) -N, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl]-1H-pyrazol-4-yl } imidazo [5,1-f][1,2,4]Triazin-4-amine (7.00g, 13.8mmol) was dissolved in dichloromethane (46mL) and treated with trifluoroacetic acid (40mL, 520mmol) and methoxybenzene (99.7%, 7.0mL, 64 mmol). The reaction mixture was heated at 40 ℃ for 4 hours and then concentrated in vacuo. 1N aqueous sodium hydroxide solution was added thereto, followed by ethyl acetateThe mixture is extracted. The organic layer was concentrated under reduced pressure to give crude product (12g), which was combined with crude product from two further runs of this reaction (total starting material: 18.09g, 35.57 mmol). The combined materials were dissolved in hot methanol, allowed to cool slightly, and usedActivated carbon (8g) treatment; the mixture was heated at 50 ℃ for 1 hour and filtered through celite. The volume of the filtrate was reduced and the solution was left to crystallize for 18 hours. To be provided with1H NMR measurement of the resulting beige crystals contained residual methoxybenzene. Trituration with ether afforded the product as a white solid. The combined yield was: 8.73g, 22.5mmol, 63%. LCMS M/z389.2(M + 1).1H NMR(400MHz，CD3OD)δ2.58(s，3H)，2.85(s，3H)，4.15(s，3H)，7.38(br d，J=8.3Hz，1H)，7.73(s，1H)，7.85(s，1H)，7.98-8.01(m，1H)，9.02-9.04(m，1H)。
Alternative preparation of N- (4-methoxybenzyl) -N, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine
Step 1.5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -4-chloro-7-methylimidazo [5,1-f ] [1,2,4] triazine Synthesis
Reacting 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5, 1-f)][1,2,4]A mixture of triazin-4 (3H) -one (10.00g, 32.35mmol) in toluene (100mL) was treated with phosphorus oxychloride (9.05mL, 97.1 mmol). After dropwise addition of N, N-diisopropylethylamine (28.2mL, 162mmol), the mixture was heated at 105 ℃ for 24 hours. The reaction was cooled to room temperature and then diluted with dichloromethane (20mL) and added over 10 minutes to a solution consisting of triethylamine (30mL), toluene (50mL) and water (80mL) while maintaining the internal temperature below 36 ℃. After stirring for an additional 20 minutes, the phases were separated and the aqueous layer was extracted with toluene (100mL) (pH 7). The combined organic layers were washed with aqueous citric acid (1M, 150mL) and then with saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to giveA solid product. Yield: 9.80g, 29.9mmol, 92%. LCMS M/z328.9(M + 1).1H NMR(400MHz，CDCl3)δ2.78(s，3H)，3.97(s，3H)，7.75(s，1H)，8.18(s，1H)。
Step 2.5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -N- (4-methoxybenzyl) -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine Synthesis
Treatment of 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -4-chloro-7-methylimidazo [5,1-f ] with 1- (4-methoxyphenyl) -N-methylmethanamine (4.52g, 29.9mmol)][1,2,4]A solution of triazine (9.80g, 29.9mmol) in dichloromethane (100 mL). After stirring at room temperature for 10 minutes, the reaction was diluted with a saturated aqueous sodium bicarbonate solution (100mL) and stirred for another hour. The organic layer was then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the product as a solid. Yield: 12.9g, 29.2mmol, 98%. LCMS M/z443.9(M + 1).1H NMR(400MHz，CDCl3)δ2.71(s，3H)，2.79(s，3H)，3.78(s，3H)，3.89(s，3H)，4.67(br s，2H)，6.82(br d，J=8.7Hz，2H)，7.10(br d，J=8.6Hz，2H)，7.64(s，1H)，7.92(s，1H)。
Step 3 Synthesis of N- (4-methoxybenzyl) -N, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine
Reacting 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -N- (4-methoxybenzyl) -N, 7-dimethylimidazo [5, 1-f)][1,2,4]A solution of triazin-4-amine (3.35g, 7.57mmol) in tetrahydrofuran (75mL) was cooled to-78 deg.C and treated with n-hexyllithium (2.3M solution in hexane, 3.46mL, 7.96mmol) for 5 min. The reaction mixture was stirred for 30 minutes and then treated as a whole with a-78 ℃ solution of zinc chloride (99.5%, 1.30g, 9.49mmol) in tetrahydrofuran (20 mL). After stirring at-78 ℃ for 5 minutes, the reaction was heated to room temperature for 30 minutes. After addition of 2-bromo-5- (trifluoromethyl) pyridine (2.57g, 11.4mmol), the reaction mixture was heated to 50 ℃, treated with tetrakis (triphenylphosphine) palladium (0) (99.9%, 87.9mg, 0.076mmol) and maintained at refluxFor 4 hours. The reaction was cooled and concentrated in vacuo; the residue was dissolved in ethyl acetate and washed with water, saturated aqueous ammonium chloride solution and saturated aqueous sodium bicarbonate solution in this order. After drying over magnesium sulfate, the product solution was filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane) gave a pale yellow oil (2.3g), which was crystallized from heptane to give the product as a white powder. Yield: 1.58g, 3.11mmol, 41%. APCI M/z509.5(M + 1).1H NMR(400MHz，CDCl3)δ2.54(s，3H)，2.72(s，3H)，3.76(s，3H)，4.14(s，3H)，4.34(br s，2H)，6.76(br d，J=8.8Hz，2H)，6.94(br d，J=8.5Hz，2H)，7.39(d，J=8.3Hz，1H)，7.72(s，1H)，7.76(dd，J=8.4，2.2Hz，1H)，7.85(s，1H)，8.94-8.96(m，1H)。
Example 8
4- (azetidin-1-yl) -5- [5- (4-methoxy-2-methylphenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine
Step 1.4- (azetidin-1-yl) -5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5,1-f ] [1,2,4] triazine (C7) Synthesis
Reacting 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5, 1-f)][1,2,4]A mixture of triazin-4 (3H) -one (5.02g, 16.2mmol) and toluene (100mL) was treated with phosphorus oxychloride (7.50mL, 80.5mmol) and heated to 45 ℃. N, N-diisopropylethylamine (17.0mL, 97.6mmol) was added in four equal portions and the exotherm was waited for before adding another portion. The reaction mixture was heated to 95 ℃ for 42 hours, cooled to 35 ℃ and added to an aqueous solution of potassium phosphate (2.5M, 45.0mL), also at 35 ℃, in four portions; during this addition the temperature rose to 63 ℃. The resulting mixture was filtered through celite, then washed with additional toluene. The organic layer of the filtrate was washed with citric acid waterThe solution (0.57M, 30mL) was washed, then washed with saturated aqueous sodium chloride (25mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated in vacuo to a volume of about 100 mL. This was added to a solution of azetidine (2.34g, 41.0mmol) in tetrahydrofuran (20mL) and the reaction mixture was stirred at room temperature for 1 hour, at which time it was poured in four portions into aqueous sodium bicarbonate (0.65M, 125mL) and stirred vigorously. The aqueous layer was extracted with toluene (3 × 50mL) and the combined organic layers were washed with saturated aqueous sodium chloride (25mL), dried over sodium sulfate, filtered and concentrated in vacuo to a volume of about 75 mL. Heptane (100mL) was added and stirred vigorously, and the mixture was granulated at room temperature for 2 hours and then cooled in an ice bath for 15 minutes. The resulting solid was collected by vacuum filtration to give C7. Yield: 4.45g, 12.8mmol, 79%.1H NMR(400MHz，CDCl3)δ2.24-2.33(m，2H)，2.68(s，3H)，3.5-4.5(v br m，4H)，3.96(s，3H)，7.65(s，1H)，7.88(s，1H)。
Step 2.4 Synthesis of 4- (azetidin-1-yl) -5- [5- (4-methoxy-2-methylphenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine
Reacting 4- (azetidin-1-yl) -5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5, 1-f)][1,2,4]Triazine (200mg, 0.574mmol) was combined with (4-methoxy-2-methylphenyl) boronic acid (180mg, 1.08mmol), potassium phosphate dihydrate (98%, 571mg, 2.25mmol), tetrakis (triphenylphosphine) palladium (0) (99.9%, 65.9mg, 0.057mmol), and N, N-dimethylformamide (12mL) and heated in a microwave reactor at 150 ℃ for 60 minutes. This reaction mixture was combined with the crude reaction product from three other identical reactants and poured into water. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with water and then with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic extract was filtered and concentrated in vacuo. Purification by silica gel chromatography (eluent: heptane/ethyl acetate/methanol mixture, 90:15:10 followed by 60:30:10, 45:55:10, 30:70:10 ratio) gave the product as a solid. The combined yield was: 508mg, 1.30mmol, 56%. LCMS M/z390.2 (M)+1)。1H NMR(400MHz，CDCl3)δ2.08(s，3H)，2.26-2.35(m，2H)，2.60(s，3H)，3.69(s，3H)，3.79(s，3H)，3.8-4.2(v brm，4H)，6.72-6.76(m，2H)，7.17-7.24(br m，1H)，7.67(s，1H)，7.78(s，1H)。
Example 9
[4- (methylamino) -5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-7-yl } methanol
Mixing N, 7-dimethyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl]-1H-pyrazol-4-yl } imidazo [5,1-f][1,2,4]Triazine-4-amine was incubated with rat liver microsomes and NADPH (1mM) (21.1mg/mL protein concentration; 25mL culture volume) at a reactant concentration of 50. mu.M for 1 hour. The culture was extracted with 4 volumes of acetonitrile. Followed by centrifugation at 3400rpm and evaporation of the supernatant in Turbovap at 25 ℃. The residue was reconstituted with 5% aqueous acetonitrile and purified by preparative reverse phase HPLC (column: Zorbax Rx-C8[ Agilent ]]250X 9.6mm, 5 μm; mobile phase A: 5mM aqueous ammonium formate, pH 3; mobile phase B: acetonitrile; gradient: 10% to 90% B; UV detection at 254 mm). The fraction containing the M +16 metabolite is dried to give the product as a solid. MS M/z404(M + H).1H NMR(600MHz，DMSO-d6)δ2.71(d，J=4.8Hz，3H)，3.86(s，3H)，4.69(s，2H)，6.68(brq，J=4.7Hz，1H)，7.55(d，J=8.0Hz，2H)，7.70(s，1H)，7.76(d，J=8.0Hz，2H)，7.85(s，1H)。
Example 10
7-methyl-N- (methyl-d)3) -5- { 1-methyl-5- [4- (trifluoromethyl) phenyl]-1H-pyrazol-4-yl]Imidazo [5, 1-f)][1,2,4]Triazine-4-amines
Step 1.7 Synthesis of methyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one
Reacting 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5, 1-f)][1,2,4]Triazin-4 (3H) -one (200mg, 0.647mmol), [4- (trifluoromethyl) phenyl]Boric acid (96%, 128mg, 0.647mmol), tetrakis (triphenylphosphine) palladium (0) (60.1mg, 0.052mmol) and sodium carbonate (206mg, 1.94mmol) were combined in ethanol (4mL) and subjected to microwave irradiation at 130 ℃ for 45 minutes, then heated at 100 ℃ for 18 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were concentrated in vacuo and chromatographed on silica gel (gradient: 50% to 100% [5% methanol/5% triethylamine/90% ethyl acetate in heptane)]) Purification to give the product. Yield: 90mg, 0.24mmol, 37%. LCMS M/z375.4(M + 1).1H NMR(400MHz，CD3OD)δ2.47(s，3H)，3.84(s，3H)，7.56(br d，J=8Hz，2H)，7.63(s，1H)，7.71(br d，J=8Hz，2H)，7.98(s，1H)。
Step 2.7-methyl-N- (methyl-d)3) -5- { 1-methyl-5- [4- (trifluoromethyl) phenyl]-1H-pyrazol-4-yl } imidazo [5,1-f][1,2,4]Synthesis of triazin-4-amines
Synthesis of 4- (azetidin-1-yl) -7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [1,5-f ] according to example 2][1,2,4]General procedure for triazines 7-methyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl]-1H-pyrazol-4-yl } imidazo [5,1-f][1,2,4]Conversion of triazin-4 (3H) -one to product, except using methyl-d3Amines instead of azetidine hydrochloride. In this case, the reaction was worked up by removing the solvent in vacuo, followed by addition of water and extraction with ethyl acetate. The combined organic layers were concentrated under reduced pressure and chromatographed using silica gel (gradient: 0% to 100% [5% methanol/5% triethylamine/90% ethyl acetate in heptane)]) Purification to give the product as a viscous oil. Yield: 20mg, 0.051mmol, 42%. LCMS M/z391.4(M +1)。1H NMR(400MHz，CD3OD)δ2.57(s，3H)，3.94(s，3H)，7.51(br d，J=8.1Hz，2H)，7.70(br d，J=8.2Hz，2H)，7.75(s，1H)，7.79(s，1H)。
Example 11
4- (azetidin-1-yl) -5- [5- (5-chloro-3-fluoropyridin-2-yl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine
Step 1.5 Synthesis of chloro-3-fluoro-2- (trimethylstannyl) pyridine
2, 5-dichloro-3-fluoropyridine (98%, 254mg, 1.50mmol) was dissolved in anhydrous 1, 4-dioxane (10mL) in a sealed tube. Hexamethyldisilazane (99%, 0.346mL, 1.65mmol), dichlorobis (triphenylphosphine) palladium (II) (99%, 138mg, 0.195mmol), and triphenylarsine (97%, 47.4mg, 0.150mmol) were added; the tube was then flushed with nitrogen, sealed and heated at 80 ℃ for 16 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue was chromatographed twice (gradient: 0% to 20% ethyl acetate in heptane) on basic alumina to give the product. Yield: 390mg, 1.32mmol, 88%. LCMS M/z296.0(M + 1).1H NMR(400MHz，CDCl3)δ0.34-0.49(m，9H)，7.29(dd，J=6.5，1.9Hz，1H)，8.59(dd，J=2.0，2.0Hz，1H)。
Step 2.4- (azetidin-1-yl) -5- [5- (5-chloro-3-fluoropyridin-2-yl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine Synthesis
4- (azetidin-1-yl) -5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -7-methylimidazo [5,1-f ] in a sealed tube][1,2,4]Triazine (35mg, 0.10mmol) and 5-chloro-3-fluoro-2- (trimethylstannyl) pyridine (59.5mg, 0.202mmol) were combined in toluene (1mL) and treated with dichlorobis (triphenylphosphine) palladium (II) (99%, 3.50mg, 0.0050 mmol). Sealing the tube and mixing the reactionThe material was heated at 120 ℃ for 24 hours. The reaction was cooled, filtered through celite and the pad was washed with ethyl acetate. After removing the solvent from the filtrate under reduced pressure, the residue was purified by silica gel chromatography (eluent: 1% methanol in ethyl acetate) to give the product as a solid. Yield: 20mg, 0.050mmol, 50%. LCMS M/z399.1(M + 1).1H NMR(400MHz，CDCl3)δ2.21-2.30(m，2H)，2.59(s，3H)，3.86-4.14(br m，4H)，3.98(s，3H)，7.40(dd，J=9.0，2.0Hz，1H)，7.72(s，1H)，7.80(s，1H)，8.51-8.53(m，1H)。
Example 12
4- (azetidin-1-yl) -5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine, trifluoroacetate salt
Step 1.2 Synthesis of methyl- { [ (4-methoxybenzyl) amino ] methylene } hydrazine carboxylate.
Methyl 2- (ethoxymethylene) hydrazinecarboxylate (prepared according to the method of N.Shao et al, tetrahedron Lett.2006, 47, 6743-S6746; 5.00g, 34.2mmol) and 4-methoxybenzylamine (4.44mL, 34.2mmol) were dissolved in ethanol (20mL) and the reaction was heated to 50 ℃ for 2 hours and then allowed to stir at room temperature for 18 hours. Filtration gave the product as a solid. Yield: 4.80g, 20.2mmol, 59%.1H NMR(400MHz，CD3OD) δ 3.69(br s,3H), 3.78(s, 3H), 4.27(br s, 2H), 6.80 and 7.62(2br s, 1H), 6.89(br d, J =8.5Hz, 2H), 7.19-7.28(br m, 2H).
Step 2.2 Synthesis of methyl 2- [2- (5-bromo-1-methyl-1H-pyrazol-4-yl) -2-oxoethyl ] -2-formylhydrazinecarboxylate.
Coupling 2- { [ (4-methoxybenzyl) amino]Methylene } hydrazinecarboxylic acid methyl ester (3.28g, 13.8mmol), 2-bromo-1- (5-bromo-1-methyl-1H-pyrazol-4-yl) ethanone (3.90 g)13.8mmol) and sodium carbonate (1.16g, 13.8mmol) are combined in a mixture of N, N-diisopropylethylamine (99.5%, 2.30mL, 13.8mmol) and acetonitrile (30 mL). The reaction was heated at 80 ℃ for 18 hours, at which time water was added and heating continued for 10 minutes. After removal of the solvent in vacuo, the aqueous residue was partitioned between water and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (4 × 100mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification using silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane) gave the product (1.20g), contaminated with some impurities. This material was taken directly to the following steps. LCMS M/z319.0(M + 1).1H NMR(400MHz，CD3OD) δ, product peak: 3.74(s, 3H), 3.92(s, 3H), 4.82(br s, 2H), 8.14(s, 1H), 8.24(s, 1H).
Step 3 synthesis of methyl [4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl ] carbamate.
Reacting 2- [2- (5-bromo-1-methyl-1H-pyrazol-4-yl) -2-oxoethyl]Methyl-2-formylhydrazinecarboxylate (1.20g, 3.76mmol) was combined with ammonium acetate (1.16g, 15.0mmol), formamide (4mL) and acetonitrile (5 mL). The reaction was heated to 130 ℃ and the acetonitrile was boiled for 10 minutes. Heating was continued for another 4 hours. After addition of water, the crude mixture was extracted eight times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo; chromatography on silica gel (gradient: 0% to 100% in heptane [ 10% methanol in ethyl acetate ]]) Purification of (c) gave the product as a pink solid. Yield: 800mg, 2.67mmol, 19% were subjected to two steps. LCMS M/z299.8(M + 1).1H NMR(400MHz，CD3OD)δ3.80(br s，3H)，3.90(s，3H)，7.52(d，J=1.3Hz，1H)，7.77(d，J=1.3Hz，1H)，7.85(s，1H)。
Step 4.4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-amine synthesis.
Reacting [4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-yl]A mixture of methyl carbamate (400mg, 1.33mmol) and aqueous sodium hydroxide (1M, 1.33mL, 1.33mmol) at 100 deg.CThe mixture was heated for 18 hours. After cooling, the aqueous mixture was extracted five times with 2-butanol, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the product as a beige solid. Yield: 310mg, 1.28mmol, 96%.1H NMR(400MHz，CD3OD)δ3.89(s，3H)，7.46(d，J=1.2Hz，1H)，7.61(d，J=1.3Hz，1H)，7.82(s，1H)。
Step 5.5- (5-bromo-1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one synthesis.
Formamidine acetate (98%, 132mg, 1.24mmol) and 4- (5-bromo-1-methyl-1H-pyrazol-4-yl) -1H-imidazol-1-amine (300mg, 1.24mmol) were combined in 2-butanol (10mL) and heated at 110 ℃ for 3 hours. Additional formamidine acetate (98%, 132mg, 1.24mmol) was added and heating continued for an additional 18 hours. After the reaction was cooled, water and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the intermediate amidine (260mg, 0.966mmol) as a white solid. LCMS M/z269.1(M + 1). This was dissolved in 1, 4-dioxane (4mL) and treated with 1,1' -carbonylbis (1H-1,2, 4-triazole) (212mg, 1.16 mmol); the reaction was heated at 70 ℃ for 18 hours and then concentrated under reduced pressure. After dichloromethane and methanol were added to the residue, the mixture was filtered and the filtrate was applied to a silica gel column and eluted (gradient: 0% to 100% in heptane [ 90: 5:5 ethyl acetate/triethylamine/methanol)]) To obtain the product. Yield: 55mg, 0.19mmol, 19%. LCMS M/z295.0(M + 1).1H NMR(400MHz，CD3OD)δ3.95(s，3H)，7.73(s，1H)，8.10(s，1H)，8.34(s，1H)。
Step 6.4- (azetidin-1-yl) -5- (5-bromo-1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazine (C8) synthesis.
Phosphoryl chloride (0.046mL, 0.503mmol) was added to 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) imidazo [5, 1-f)][1,2,4]A mixture of triazin-4 (3H) -one (50mg, 0.17mmol) in toluene (1 mL). After addition of N, N-diisopropylethylamine (99.5%, 0.149mL, 0.84mmol), the reaction was allowed to stand at room temperatureStirred for 18 hours. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane and treated with azetidine (0.023mL, 0.34 mmol). After 66 hours, the reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography (gradient: 0% to 10% methanol in ethyl acetate) to give C8. Yield: 25mg, 0.075mmol, 44%. LCMS M/z336.1(M + 1).1H NMR(400MHz，CD3OD)δ2.26-2.34(m，2H)，3.5-4.4(v br m，4H)，3.97(s，3H)，7.70(s，1H)，7.84(s，1H)，8.47(s，1H)。
Step 7.4- (azetidin-1-yl) -5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine Synthesis of trifluoroacetate
4- (azetidin-1-yl) -5- (5-bromo-1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazine (15mg, 0.045mmol), [4- (trifluoromethyl) phenyl ] boronic acid (9.50mg, 0.0500mmol), tetrakis (triphenylphosphine) palladium (0) (4.6mg, 0.0040mmol) and sodium carbonate (9.5mg, 0.090mmol) were combined in ethanol (4mL) and the reaction mixture was heated at reflux for 18 hours. After filtration, the filtrate was concentrated in vacuo and purified by reverse phase HPLC (column: Waters Sunfire C18, 19X 100mm, 5 μm; mobile phase A: 0.05% TFA in water (v/v); mobile phase B: 0.05% TFA in acetonitrile (v/v); gradient: 5% to 100% B). Yield: 4.5mg, 0.011mmol, 24%. Retention time: 2.32 min (column: Waters Atlantis dC18, 4.6X 50mm, 5 μm; mobile phase A: 0.05% TFA in water (v/v); mobile phase B: 0.05% TFA in acetonitrile (v/v); gradient: linear, 5% to 95% B over 4.0 min; flow rate: 2 mL/min). LCMS M/z400.2(M + 1).
Method A
Suzuki reaction under microwave conditions: alternative synthesis of N, 7-dimethyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine
Reacting 5- (5-bromo-1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f ]][1,2,4]Triazin-4-amine (500mg, 1.55mmol), [4- (trifluoromethyl) phenyl]Boric acid (590mg, 3.11mmol), sodium carbonate (329mg, 3.10mmol), tetrakis (triphenylphosphine) palladium (0) (179mg, 0.155mmol), and ethanol (10mL) were combined in a microwave vessel. The reaction was subjected to microwave irradiation at 200W for 45 minutes at 130 ℃. The reaction was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography (eluent: 20% tetrahydrofuran in dichloromethane) gave the product as a pale yellow solid. Yield: 423mg, 1.13mmol, 73%. LCMS M/z388.2(M + 1).1H NMR(400MHz，CDCl3) δ 2.62(s, 3H), 2.99(d, J =4.9Hz, 3H), 3.96(s, 3H), 5.46-5.53(m, 1H), 7.60(br AB quartet, J £ t @)AB=8Hz，ΔνAB=48Hz，4H)，7.73(s，1H)，7.90(s，1H)。
Method B
Fluorination of the carbonyl group: alternative synthesis of 5- {5- [4- (difluoromethyl) phenyl ] -1-methyl-1H-pyrazol-4-yl } -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine
Step 1.4 Synthesis of- { 1-methyl-4- [ 7-methyl-4- (methylamino) imidazo [5,1-f ] [1,2,4] triazin-5-yl ] -1H-pyrazol-5-yl } benzaldehyde
5-bromo-1-methyl-1H-pyrazol-4-yl) -N, 7-dimethylimidazo [5,1-f][1,2,4]Triazin-4-amine (1.18g, 3.66mmol), (4-formylphenyl) boronic acid (604mg, 4.03mmol), tetrakis (triphenylphosphine) palladium (0) (423mg, 0.366mmol) and sodium carbonate (776mg, 7.32mmol) were combined in ethanol (20mL) and the reaction mixture was heated at reflux for 18 h. After cooling, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. By chromatography on silica gelMethod (gradient: 0% to 100% in heptane [ 18: 1:1 ethyl acetate/methanol/triethylamine]) Purification of (2) gave the crude product (900mg), which was taken directly to the next step. LCMS M/z348.2(M + 1).1H NMR(400MHz，CD3OD), only product peak: δ 2.57(s, 3H), 2.82(s, 3H), 3.95(s, 3H), 7.51(br d, J =8.2Hz, 2H), 7.75(s, 1H), 7.78(s, 1H), 7.92(br d, J =8.5Hz, 2H), 9.98(s, 1H).
Step 2.5 Synthesis of- {5- [4- (difluoromethyl) phenyl ] -1-methyl-1H-pyrazol-4-yl } -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine
Mixing 4- { 1-methyl-4- [ 7-methyl-4- (methylamino) imidazo [5, 1-f)][1,2,4]Triazin-5-yl]-1H-pyrazol-5-yl } benzaldehyde (900mg from the previous step) was dissolved in dichloromethane (8.6mL) and treated with (diethylamino) sulfur trifluoride (0.34mL, 2.6 mmol). After the reaction had stirred for 18 hours, additional (diethylamino) sulfur trifluoride (0.40mL, 3.0mmol) was added and stirring was continued for 3 hours. (diethylamino) sulfur trifluoride (0.40mL, 3.0mmol) was fed again, followed by stirring for 1 hour. The reaction was then diluted with dichloromethane and aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate (4X 400 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo; purification by silica gel chromatography (gradient: 0% to 100% { 18: 1:1 ethyl acetate/methanol/triethylamine } in heptane) gave the product as a beige foam. Yield: 370mg, 1.00mmol, 27% were subjected to 2 steps. LCMS M/z370.1(M + 1).1H NMR(400MHz，CD3OD) δ 2.57(s, 3H), 2.82(s, 3H), 3.93(s, 3H), 6.76(t, J =56.1Hz, 1H), 7.50(br AB quartet, J £ t @AB=8Hz，ΔνAB=54Hz，4H)，7.74(s，1H)，7.78(s，1H)。
1. Palladium (II) acetate was used instead of allylpalladium (II) chloride dimer.
2. In this case, tris (dibenzylideneacetone) dipalladium (0) and tricyclohexylphosphine were used instead of tetrakis (triphenylphosphine) palladium (0), and the reaction was carried out in 1, 4-dioxane aqueous solution.
3. The intermediate 5- [5- (2-fluoro-4-methoxyphenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazin-4 (3H) -one is converted with phosphoryl chloride to 4-chloro-5- [5- (2-fluoro-4-methoxyphenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine; reaction with azetidine according to the general procedure for preparation of C2 in example 4 provided the product.
C1 was converted to N, 7-dimethyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-amine using the general procedure for preparation of C4 in example 3. Reaction with lithium bis (trimethylsilyl) amide and di-tert-butyl dicarbonate affords tert-butylmethyl [ 7-methyl-5- (1-methyl-1H-pyrazol-4-yl) imidazo [5,1-f ] [1,2,4] triazin-4-yl ] carbamate, which is converted to the product according to the method of example 7.
5. Copper (I) chloride (1 eq) and potassium bromide (1 eq) were added to a Suzuki reaction, which was carried out in 1, 2-dimethoxyethane.
6. In this case, the reaction is carried out with a 4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl derivative instead of boric acid.
7. This preparation used 5-chloro-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile prepared from 2-bromo-5-chlorobenzonitrile using the general method for preparation of C5 in example 6.
8. The desired aryl bromide is prepared from 2-bromo-5-methylbenzoic acid by converting the carboxylic acid to a cyano group.
9. The desired pyridyl bromide is prepared from 6-bromonicotinaldehyde by treatment with (diethylamino) sulfur trifluoride.
10. The synthesis was performed with 2-bromo-5- (2-methyl-1, 3-dioxaborolan-2-yl) pyridine, which can be prepared as described in m.hatanaka et al (bioorg.med.chem.2005, 13, 6763-za 6770).
11. This preparation used 5-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile prepared from 2-bromo-5-methylbenzonitrile using the general method of preparation C5 in example 6.
12. The compound of example 70 was hydrogenated over palladium on carbon and the resulting aniline was subjected to Sandmeyer reaction using tert-butyronitrile and copper (II) bromide.
1- (diphenylmethyl) azetidin-3-amine was reacted with methyl chloroformate followed by hydrogenation over palladium hydroxide to provide the desired amine reagent.
14. The final compound was purified using one of the following methods: a) reversed phase HPLC; column: WatersSunfire C18, 19X 100mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid (v/v) in water; mobile phase B: 0.05% trifluoroacetic acid (v/v) in acetonitrile; gradient: 5% to 100% B; b) reversed phase HPLC; column: waters Xbridge C18, 19X 100mm, 5 μm; mobile phase A: 0.03% ammonium hydroxide in water (v/v); mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); gradient: 15% to 100% B.
HPLC conditions: column: waters Atlantis dC18, 4.6X 50mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid (v/v) in water; mobile phase B: 0.05% trifluoroacetic acid (v/v) in acetonitrile; gradient: linear, 5% to 95% B over 4.0 min; flow rate: 2 mL/min.
TABLE 2
a) Single assay
b) Values representing 6-13 ICs50Geometric mean of determination
Biological analysis and data
The compounds of formula I (and formulae Ia-Ix) are effective in modulating or inhibiting PDE2 activity. Certain compounds of the present invention are selective modulators or inhibitors of PDE2, as compared to other PDE receptor subtypes. Accordingly, these compounds of the present invention are effective in preventing and/or treating diseases or disorders of the central nervous system such as cognitive disorders, schizophrenia and dementia in mammals, preferably humans.
The term "inhibiting PDE 2", as used herein, means significantly reducing PDE2 activity, either prophylactically or therapeutically. One skilled in the art can readily determine whether a compound inhibits PDE2 activity. For example, an assay that can be conveniently used to assess PDE2 inhibition can be found in U.S. patent application publication No. 2006/0154931(USSN11/326,221), published at 13.07/2006, which is incorporated herein by reference in its entirety. Generally, if it has an IC of less than or about 10. mu.M (preferably less than or about 0.1. mu.M)50The substance is considered to selectively inhibit PDE2 activity.
For example, a "selective PDE2 inhibitor" can be determined by comparing the ability of a substance to inhibit the activity of PDE2 with its ability to inhibit PDE enzymes from other PDE families. For example, a substance can be assayed for its ability to inhibit PDE2 activity, as well as PDE1A, PDE1B, PDE1C, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5, PDE6, PDE7, PDE8, PDE9, PDE10, and PDE11 activity. In one embodiment, the selective PDE 2inhibitor is K having the ability to inhibit PDE2iLess than the substance has any other PDE enzyme inhibiting effect or about one tenth of KiThe compound of the present invention. In other words, the compound inhibits PDE2 activity to the same extent at a concentration of about one tenth or less than that required to inhibit any other PDE enzyme.
Measurement of recombinant human PDE2A3 inhibition by SPA technology
In this assay, the activity of the test substance on the human full-length PDE2A3 enzyme was modified using a designation from Amersham TRKQ7100 (GE Healthcare, USA) ([ 2 ])3H]Scintillation junction of cGMPA near detection (SPA) assay. The PDE2A3 protein (anti-FLAG M2, sigmaldrich) was obtained from FLAG purification of sf21 insect cells using standard affinity purification procedures for this tag. Briefly, SPA assays were performed using PDE SPA yttrium silicate beads (Perkin elmer rpnq0024), which preferentially bind to linear nucleotides (GMP) as compared to cyclic nucleotides (cGMP). Detection Using Wallac Microbeta scintillation counter3H-GMP product. The reaction time is chosen relative to the amount of time in which 10-20% of the substrate is hydrolyzed by the enzyme.
Prior to testing representative compounds of the invention, the assay was validated using PDE 2-selective literature compounds, erythro-9- (2-hydroxy-3-nonyl) adenine (EHNA) and BAY60-7550 as controls (Podzuweit et al, Isozyme selective Inhibition of cGMP-stimulated cyclic nucleotide phosphate-9- (2-hydroxy-3-nonyl) adenosine, Cell Signal, 7 (7): 733-8, 1995, Boess et al, Inhibition of phosphor 2-interactive cGMP, synthetic pathology and mechanical compliance, neuropathology, 47 (7): 1081-92, 2004). The obtained IC50Values are within 3X of literature values, EHNA 1.7. mu.M and BAY60-7550 4.66. mu.M. Corresponding IC of Compounds that inhibit PDE Activity50Values were determined from concentration effect curves using non-linear regression.

Claims (22)

1. A compound of formula I
Or a pharmaceutically acceptable salt thereof, wherein:
“-A-R5"is:
R1is hydrogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C15) Cycloalkyl, - (C)1-C6) alkyl-OH, - (C)1-C6) alkyl-CN, -SF5、-CF3、-CHF2or-CH2F；
R2Is- (C)1-C6) alkyl-R9、-NHR3、-N(R3)2、-O-(C1-C6) alkyl-R9、-OR8、(C3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl or (C)1-C14) A heteroaryl group; wherein (C) is3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups; and wherein the- (C)1-C6) alkyl-R9、-NHR3、-N(R3)2、-O-(C1-C6) alkyl-R9、-OR8、(C3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl or (C)1-C14) Heteroaryl moieties may optionally be substituted by 1-3 substituents independently selected from (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halogen and-CF3Substituted with the substituent(s);
each R3Independently selected from: - (C)1-C6) alkyl-R9、-(C2-C6) alkenyl-R9、-(C2-C6) alkynyl-R9And- (C)3-C15) cycloalkyl-R9Or when R is2is-N (R)3)2When two R are present3Can form together with the nitrogen atom to which they are attached an optionally oxo-group (O =) optionally containing 1 or 2 and optionally being independently selected from hydrogen, fluoro, -CN, -CF3、-CHF2、-CH2F、-OH、-O-(C1-C6) Alkyl, NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, - (C = O) -R8、-(C=O)-OR8、-(C=O)-N(R8)2、-O-(C=O)-R8、-OR8、-O-(C=O)-OR8、-SR8、-S(O)R8、-S(O)2R8、-S(O)2N(R8)2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-O-(C=O)-N(R8)2、-NH-(C=O)-N(R8)2、-N[(C1-C6) Alkyl radical](C=O)-R8、-N[(C1-C6) Alkyl radical](C=O)-OR8、-N[(C1-C6) Alkyl radical](C=O)-N(R8)2、(C3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl and (C)1-C14) A 4-6 membered heterocycle substituted with a substituent for heteroaryl; wherein (C) is3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups;
each R4Independently selected from: hydrogen, halogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, -CF3、-CHF2、-CH2F and (C)3-C15) A cycloalkyl group;
R4ais hydrogen, (C)1-C6) Alkyl, (C)3-C4) Alkenyl, (C)3-C4) Alkynyl, -CF3、-CHF2、-CH2F or (C)3-C15) A cycloalkyl group;
R5comprises the following steps:
wherein n is 0, 1,2,3 or 4;
each R6Independently selected from: hydrogen, halogeno, (C)1-C6) Alkyl, -CF3、-CHF2、-CH2F、-CF2-(C1-C6) Alkyl, -SF5、-CN、-(C1-C6) alkyl-CN, -NO2、-(C=O)-R8、-(C=O)-OR8、-OR8、-O-(C=O)-N(R8)2、-SR8、-S(O)R8、-S(O)2R8、NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-N[(C1-C6) Alkyl radical](C=O)-R8、-N[(C1-C6) Alkyl radical](C=O)-OR8、(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C15) Cycloalkyl group, (C)1-C14) Heterocyclic group, (C)6-C10) Aryl and (C)1-C14) A heteroaryl group; wherein (C) is3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups;
each R7Independently selected from: hydrogen, halogen, (C)1-C6) Alkyl, (C)2-C4) Alkenyl, (C)2-C6) Alkynyl, -CN, -CF3、-CHF2、-CH2F、-O-(C1-C6) Alkyl and (C)3-C15) A cycloalkyl group;
each R8Independently selected from wherever it appears: hydrogen, (C)1-C6) Alkyl, (C)3-C15) Cycloalkyl, -CF3and-CHF2(ii) a And is
Each R9Independently selected from: hydrogen, halogen, -CF3、-CHF2、-CH2F、-CF2-(C1-C6) Alkyl, -CN, - (C)1-C6) alkyl-CN, -NO2、-(C=O)-R8、-(C=O)-OR8、-OR8、-O-(C=O)-N(R8)2、-SR8、-S(O)R8、-S(O)2R8、NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-N[(C1-C6) Alkyl radical](C=O)-R8、-N[(C1-C6) Alkyl radical](C=O)-OR8、(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)3-C15) Cycloalkyl group, (C)1-C14) Heterocyclic group, (C)6-C10) Aryl and (C)1-C14) Heteroaryl group of which (C)3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups; and wherein each of (C)3-C15) Cycloalkyl group, (C)1-C14) Heterocyclic group, (C)6-C10) Aryl and (C)1-C14) Heteroaryl moieties may optionally be substituted by 1-3 substituents independently selected from (C)1-C6) Alkyl, (C)1-C6) Alkoxy, halo and-CF3Is substituted with the substituent(s).
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
“-A-R5"is:
R1is- (C)1-C6) An alkyl group;
R2is-NHR3or-N (R)3)2；
Each R3Independently selected from: - (C)1-C6) alkyl-R9、-(C2-C6) alkenyl-R9、-(C2-C6) alkynyl-R9And- (C)3-C15) cycloalkyl-R9(ii) a Or when R is2is-N (R)3)2When two R are present3May form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring optionally containing 1 or 2 oxo groups (O =); and the heterocycle may be optionally substituted with 1-3 substituents independently selected from the group consisting of: hydrogen, fluorine, -CN, -CF3、-CHF2、-CH2F、-OH、-O-(C1-C6) Alkyl, NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, - (C = O) -R8、-(C=O)-OR8、-(C=O)-N(R8)2、-O-(C=O)-R8、-OR8、-O-(C=O)-OR8、-SR8、-S(O)R8、-S(O)2R8、-S(O)2N(R8)2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-O-(C=O)-N(R8)2、-NH-(C=O)-N(R8)2、-N[(C1-C6) Alkyl radical](C=O)-R8、-N[(C1-C6) Alkyl radical](C=O)-OR8、-N[(C1-C6) Alkyl radical](C=O)-N(R8)2、(C3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl and (C)1-C14) A heteroaryl group; wherein (C) is3-C15) Cycloalkyl and (C)1-C14) Heterocyclyl may optionally contain 1 double or triple bond and 1-2 oxo (O =) groups;
R4is hydrogen;
R4ais (C)1-C6) An alkyl group;
R5comprises the following steps:
wherein n is 0, 1,2,3 or 4.
3. The compound of claim 1, wherein formula I is substituted with a group A1R5Together have the formula:
4. the compound of claim 1, wherein formula I is substituted with a group A2R5Together have the formula:
5. the compound of claim 1, wherein formula I is substituted with a group A3R5Together have the formula:
6. a compound according to any one of the preceding claims wherein R is5Comprises the following steps:
7. the compound of claims 1-5, wherein R5Comprises the following steps:
8. the compound of claims 1-5, wherein R5Comprises the following steps:
9. the compound of claims 1-5, wherein R5Comprises the following steps:
10. the compound of claims 1-5, wherein R of formula I5Comprises the following steps:
11. the compound of claims 1-5, wherein R of formula I5Comprises the following steps:
12. the compound of claims 1-5, wherein R of formula I5Comprises the following steps:
13. a compound according to any one of the preceding claims wherein R is2Is- (C)1-C6) alkyl-R9、-NHR3、-N(R3)2、-O-(C1-C6) alkyl-R9OR-OR8。
14. The compound of any one of claims 1-12, wherein R2is-N (R)3)2or-NHR3。
15. The compound of any one of claims 1-12, wherein R2Is (C)3-C15) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C14) Heterocyclyl or (C)1-C14) A heteroaryl group; wherein (C) is3-C15) Cycloalkyl and (C)1-C14) The heterocyclyl group may optionally contain 1 or 2 double or triple bonds and 1-3 oxo (O =) groups.
16. A compound according to any one of the preceding claims wherein R is6Is hydrogen, halo, -CF3、-CHF2or-CH2F。
17. The compound of any one of claims 1-15, wherein R6Is- (C = O) -R8、-(C=O)-OR8、-OR8、-O-(C=O)-N(R8)2、-SR8、-S(O)R8、-S(O)2R8、NH2、-NH-(C1-C6) Alkyl, -N [ (C)1-C6) Alkyl radical]2、-NH-(C=O)-R8、-NH-(C=O)-OR8、-O-(C=O)-N(R8)2、-N((C1-C6) Alkyl) - (C = O) -R8or-N ((C)1-C6) Alkyl) - (C = O) -OR8。
18. The compound of any one of claims 1-15, wherein R6Is (C)1-C6) Alkyl or (C)3-C15) A cycloalkyl group.
19. The compound of any one of claims 1-15, wherein R6Is (C)2-C6) Alkenyl, (C)2-C6) Alkynyl, (C)1-C14) Heterocyclic group, (C)6-C10) Aryl or (C)1-C14) A heteroaryl group.
20. The compound of claim 1, wherein the compound is:
4- (azetidin-1-yl) -7-methyl-5- [ 1-methyl-5- (4-methylphenyl) -1H-pyrazol-4-yl ] imidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -7-methyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -7-methyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- [5- (4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- [5- (5-chloropyridin-2-yl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine;
5- {5- [4- (difluoromethyl) phenyl ] -1-methyl-1H-pyrazol-4-yl } -N, 7-dimethylimidazo [5,1-f ] [1,2,4] triazin-4-amine;
7-methyl-N- (d)3) Methyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl]-1H-pyrazol-4-yl } imidazo [5,1-f][1,2,4]Triazin-4-amines;
n, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyridin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine;
4- (azetidin-1-yl) -5- {5- [ 3-fluoro-5- (trifluoromethyl) pyridin-2-yl ] -1-methyl-1H-pyrazol-4-yl } -7-methylimidazo [5,1-f ] [1,2,4] triazine;
n, 7-dimethyl-5- { 1-methyl-5- [4- (trifluoromethoxy) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine;
4- (azetidin-1-yl) -5- {5- [4- (difluoromethyl) phenyl ] -1-methyl-1H-pyrazol-4-yl } -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (3-fluoroazetidin-1-yl) -7-methyl-5- { 1-methyl-5- [4- (trifluoromethyl) phenyl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- [5- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4- (azetidin-1-yl) -5- {5- [4- (difluoromethoxy) phenyl ] -1-methyl-1H-pyrazol-4-yl } -7-methylimidazo [5,1-f ] [1,2,4] triazine;
4-azetidin-1-yl-7-methyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyrazin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazine;
4-azetidin-1-yl-5- [5- (5-bromopyridin-2-yl) -1-methyl-1H-pyrazol-4-yl ] -7-methylimidazo [5,1-f ] [1,2,4] triazine; or
N, 7-dimethyl-5- { 1-methyl-5- [5- (trifluoromethyl) pyrazin-2-yl ] -1H-pyrazol-4-yl } imidazo [5,1-f ] [1,2,4] triazin-4-amine;
or a pharmaceutically acceptable salt thereof.
21. A method of treating cognitive impairment associated with schizophrenia in a human, said method comprising administering to said human a therapeutically effective amount of a compound of formula I according to claim 1.
22. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.
HK14101979.7A 2011-02-23 2012-02-09 IMIDAZO[5, 1-ƒ][1,2-4]TRIAZINES FOR THE TREATMENT OF NEUROLOGICAL DISORDERS HK1188990A (en)

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