CN113831321A - Small molecule inhibitor of leucine-rich repeat kinase 2 and application thereof - Google Patents

Small molecule inhibitor of leucine-rich repeat kinase 2 and application thereof Download PDF

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CN113831321A
CN113831321A CN202111101907.3A CN202111101907A CN113831321A CN 113831321 A CN113831321 A CN 113831321A CN 202111101907 A CN202111101907 A CN 202111101907A CN 113831321 A CN113831321 A CN 113831321A
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CN113831321B (en
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洪健
D.达斯
王景炳
谢玲芝
乔丹丹
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Anrun Pharmaceutical Technology Suzhou Co ltd
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Abstract

The invention provides a leucine-rich repeat kinase 2 small molecule inhibitor and application thereof; the compound as the small molecule inhibitor is shown as a compound shown in a formula I or an isotopic form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a hydrate, a prodrug and a polymorphic substance of the compound. The compound has higher LRRK2 inhibitory activity, and has extremely high application value in preparing medicines for treating neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and other diseases.

Description

Small molecule inhibitor of leucine-rich repeat kinase 2 and application thereof
Technical Field
The invention relates to novel compounds, in particular to small molecule inhibitors of leucine-rich repeat kinase 2 and uses thereof.
Background
Neurodegenerative Diseases (NDs) are a heterogeneous group of diseases of the central or peripheral nervous system that lead to dyscommunication between brain cells. These diseases affect one's movement, language, memory and intelligence. Most neuropathies are complex, with the etiology of many of them unclear. Neuropathy occurs when neurons (nerve cells) in the brain and spinal cord begin to degenerate. Parkinson's Disease (PD), Alzheimer's Disease (AD), huntington's disease, Amyotrophic Lateral Sclerosis (ALS) motor neuron disease affect millions of people each year.
Parkinson's Disease (PD) affects 5% of The population over The age of 80 and 12% of The population over The age of 60 (The Lancet 373, 2055-2066). Symptoms include impaired motor function, tremors, stiffness, balance, and speech impairment. Current treatments are limited to treating symptoms associated with reduced dopamine signaling, such as levodopa treatment that increases striatal dopamine levels (JAMA 311,1670). These treatments have side effects and therefore, the development of new treatments remains an important medical need for parkinson's disease.
The leucine-rich repeat kinase 2(LRRK2) gene codes for genes involved in familial Parkinson's disease (ASN Neuro 1, AN20090007), (Trends in neurosciens 29, 286-. Some reports indicate that the kinase activity of LRRK2 is involved in PD pathophysiology (BMC Med 10,20), (Neurology 67, 1786-. LRRK2 was widely distributed throughout the body, and elevated concentrations of LRRK2 were observed in brain, kidney and various immune cells (Neuron 44, 595-600). LRRK2 is involved in many cellular processes including synaptic morphogenesis, neurite outgrowth and membrane trafficking, autophagy, and protein synthesis (The Lancet 386, 896-912). LRRK2 is a 286kDa multi-domain serine threonine kinase. LRRK2 is a member of the ROCO protein family, all of which have five conserved domains.
It has a C-terminal ROC (COR), an N-terminal leucine repeat (LRR), ras (Roc) of the complex GTPase domain, a kinase domain, and a protein-protein interaction domain. (Future medical Chemistry 4, 1701-1713). Because LRRK2 has a complex multi-domain structure, LRRK2 is able to play complex roles in multiple cellular processes, including protein-protein interactions, guanosine triphosphatase (GTPase) activity, and kinase activity. LRRK2 is associated with the mammalian target of rapamycin (mTOR) Signaling pathway through MET kinase, mitogen-activated protein kinase (MAPAK) pathway, Wnt pathway and autophagy (Science Signaling 5, pe 2-pe 2) in papillary renal and thyroid cancers. Over-activation of LRRK2 kinase has also been reported in idiopathic parkinson's disease patients (sci. trans. med.10, ear 5429). The G2019S kinase domain mutation is associated with familial and idiopathic parkinson's disease (Nat Rev Neurol 16, 97-107), (Arch Neurol 67).
A few mutations of LRRK2, R1441C, R1441G, R1441H, G2019S, N1437H are well known (ELife 5, e 12813). Mutations in LRRK2R1441G have been shown to increase the release of pro-inflammatory cytokines in microglia and may lead to direct neuronal toxicity (Neuroscience 208, 41-48). The LRRK2R1628P mutant (COR domain) is associated with Alzheimer's Disease (AD) and may lead to increased apoptosis and cell death (Neurobiology of Aging 32, 1990-1993). The G2019S mutation occurred in a highly conserved kinase domain, and it was postulated that the G2019S mutation might play a role in its activity (Neurology 67, 1786-1791). The G2019S mutation occurs in a highly conserved kinase domain, and is primarily associated with parkinson's disease.
It is speculated that an increase in kinase activity may be associated with neurodegeneration, so inhibition of LRRK2 activity may slow disease progression. The small molecule LRRK2 inhibitor has potential application value in the treatment of Parkinson's disease. In recent years, some LRRK2 inhibitors have been demonstrated. Among them, Gne7915(ACS Med. chem. Lett.4, 85-90), Gne-0877 and Gne-9605(Small Molecule inhibitors. J. Med. chem.57, 921-936), JH-II-127(ACS Med. chem. Lett.6, 584-589), PF-06447475(J. Med. chem.58, 419-432), CZC-25146 were shown to prevent injury to cultured rodents and human neurons of moderate molar potency induced by mutant LRRK2 (ACS chem. biol.6, 1021-1028). LRRK2-In-1 is a potent inhibitor of LRRK2, inhibiting both wild-type and G2019S mutant LRRK2(JNeurochem 128, 561-576) at nanomolar concentrations. Many compounds with different scaffolds have LRRK2 inhibitory activity (Expert Opinion on Therapeutic Patents 30, 275-286). As is well known, 3, 4-disubstituted-1H-pyrrolo [2,3-b ] -pyridines, 4, 5-disubstituted-7H-pyrrolo [2,3-c ] pyridazines (US20170002000a1), pyrimidin-2-ylamino-1H-pyrazoles (WO2017218843), aminopyrimidine derivatives are reported in different papers and patents as LRRK2 inhibitors. The biological functions and mechanisms of LRRK2 are explored by taking LRRK2-in-1 and TAE684 as reference compounds. Patents WO2017087905, WO2017156493, WO2018217946 all disclose technical solutions of aminopyrimidine derivatives as inhibitors of LRRK 2. In the prior art, a selective inhibitor of LRRK2 has good pharmacokinetic characteristics and the capability of crossing blood brain barrier, and is an ideal choice for developing effective drugs, but the inhibition effect of the LRRK2 inhibitor in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other diseases is still low at present, and the improvement of the inhibition effect of the LRRK2 inhibitor in the treatment of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other diseases is still needed.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a leucine-rich repeat kinase 2 small-molecule inhibitor and application thereof, and solves the problem that the prior LRRK2 inhibitor has low inhibition effect in treating neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and other diseases.
The purpose of the invention is realized by the following technical scheme:
in a first aspect, the present invention provides a compound of formula i or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof;
Figure BDA0003270963300000021
wherein the content of the first and second substances,
W1is C or N satisfying the valence bond theory; the invention refers to satisfying valence bond theory, when W1When is C, X is present, when W is1When N, X is absent;
W2is CH or N;
x and Y are each independently selected from hydrogen, halogen, cyano, C1-C3Fluoroalkyl of, C1-C6Alkoxy radical, C1-C6Alkyl radical, C6-C10Aryl radical, C2-C8Alkenyl radical, C2-C8One of alkynyl or nitro; or X, Y and the atoms to which they are attached together form a heteroaromatic ring containing one or more heteroatoms including at least one of a sulfur atom, a nitrogen atom, and an oxygen atom;
a is C1-C6Alkyl chain or
Figure BDA0003270963300000031
Wherein Z is selected from one of the following groups:
Figure BDA0003270963300000032
R1is C1-C2Deuterated alkyl, C1-C2Deuterated fluoroalkyl or C1-C2One of fluoroalkyl groups;
R2is hydrogen, C1-C3Alkyl radical, C1-C3One of fluoroalkyl, cyano or halogenSeed growing;
R3is substituted or unsubstituted 4-8 membered single heterocyclic alkyl, heterocyclic ring containing 4-12 carbon atoms or heterocyclic ring containing 4-12 carbon atoms, wherein the hetero atom in the heterocyclic alkyl, the heterocyclic ring or the heterocyclic ring is selected from one or more of oxygen atom, nitrogen atom and sulfur atom.
In the present invention, "substituted or unsubstituted 4-to 12-membered monocyclic heterocycloalkyl" includes saturated or unsaturated monocyclic heterocycloalkyl.
In the present invention, a hetero ring means that two mono-heterocyclic rings are fused together or one mono-heterocyclic ring and one cycloalkyl ring are fused together, and two rings in the hetero ring share two atoms.
In some embodiments, the compounds of formula I are of formulae Ia-d:
Figure BDA0003270963300000041
further, X and Y are each independently selected from hydrogen, halogen, cyano, trifluoromethyl, C1-C3Alkoxy radical, C1-C3Alkyl radical, C6-C10Aryl radical, C2-C4Alkenyl radical, C2-C4Alkynyl or nitro.
Further, W1Is C, W2Is N, Y is hydrogen, A is methyl or
Figure BDA0003270963300000042
Wherein Z is
Figure BDA0003270963300000043
Figure BDA0003270963300000044
Further, when X, Y and the atoms to which they are attached together form a heteroaromatic ring, the heteroaromatic ring is one of oxazolinyl, oxocycloalkyl, pyranyl, tetrahydropyranyl, azetidinyl, 1, 4-dioxanilino, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolinyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, or tetrahydrothienyl.
Further, wherein R is1Is a CD3、CD2CD3、CF3、CHF2Or CD2One of F;
R3is one of the following groups:
Figure BDA0003270963300000045
further, the compounds represented by the formula I are those represented by the following structural formulae I-1 to I-63:
Figure BDA0003270963300000051
Figure BDA0003270963300000061
Figure BDA0003270963300000071
Figure BDA0003270963300000081
in a second aspect, the present invention also provides a pharmaceutical composition comprising any one of the above compounds or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof.
Further, in the pharmaceutical composition, any of the above compounds or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof are used in combination with other drugs.
In a third aspect, the present invention also provides a use of any one of the above compounds or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof for the manufacture of a medicament for the prevention and/or treatment of a disease by the activity of leucine-rich repeat kinase 2.
Further, the disease includes one or more of neurodegenerative diseases, immune diseases or inflammation, infection, organ transplantation, cardiovascular diseases and metabolic diseases.
Further, the neurodegenerative disease includes one or more of parkinson's disease, alzheimer's disease, huntington's disease, amyotrophic lateral sclerosis, and motor neuron disease.
Further, in the above drugs, any one of the above compounds or its isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs are used in combination with other drugs.
Further, the above drugs are administered orally, by injection, pulmonary or transdermally.
The compounds of the present invention are described by the general structural formula i, and examples are disclosed herein by formula ia, formula ib, formula ic, formula id. The abbreviations used herein have conventional meaning in the chemical and biological arts.
As used herein, the following definitions and terms shall apply unless otherwise indicated.
"R" and "S" describing isomers are descriptors for the stereochemical configuration of an asymmetrically substituted carbon atom. The designation of an asymmetrically substituted carbon atom as "R" or "S" is accomplished by applying CahnIngold Prelog priority rules, well known to those skilled in the art, and is described in International Union of pure and applied chemistry (lUPAC) organic chemistry nomenclature, section E, stereochemistry.
The term C as used hereiniMeaning that the moiety has i carbon atoms, e.g. C10Alkyl means that the alkyl unit has 10 carbon atoms; the term C as used hereini-CjMeaning that the moiety has i-j carbon atoms, e.g. C1-C10Alkyl means that the alkyl unit has any number of carbon atoms between 1 and 10, including 1 and 10.
As used herein, "alkyl" or "alkyl group" refers to a fully saturated straight, branched, or cyclic hydrocarbon chain, or a combination thereof. The alkyl group can be saturated, monounsaturated, or polyunsaturated, and can include divalent or polyvalent groups, having the indicated number of carbon atoms (i.e., C)1-C10Meaning one to ten carbon atoms). In certain embodiments, the alkyl group contains 1-6 carbon atoms. In certain embodiments, the alkyl group contains 1-4 carbon atoms. In certain embodiments, the alkyl group contains 1-3 carbon atoms. In other embodiments, the alkyl group contains 2 to 3 carbon atoms, and in other embodiments, the alkyl group contains 1 to 2 carbon atoms. In certain embodiments, the term "alkyl" or "alkyl group" refers to a cycloalkyl group, also referred to as a carbocycle. Examples of saturated hydrocarbon groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-heptyl, n-octyl, cyclohexyl, cyclohexylmethyl, and the like. Unsaturated alkyl is alkyl having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butenyl, and higher homologs and isomers. Alkyl groups are optionally substituted with one or more halogen atoms. For example, the term "fluoroalkyl" refers to an alkyl group as defined above, wherein one or more hydrogen atoms are replaced by fluorine atoms.
The term "alkoxy" means having the indicated numberA straight chain or branched alkoxy group of a carbon atom of (1). E.g. C1-6Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and the like.
The term "alkylene" by itself or as part of another substituent refers to a divalent group derived from alkyl, such as, but not limited to, -CH2CH2CH2CH2-，-CH2CH＝CHCH2-，-CH2CCCH2-，-CH2CH2CH(CH2CH2CH3)CH2-. The alkyl (or alkylene) group usually has 1 to 24 carbon atoms, and a group having 10 or less carbon atoms is preferred in the present invention.
The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be straight or branched, or a combination thereof. Examples of alkynyl groups include alkynyl, propargyl, 3-methyl-1-pentynyl, 2-heptyl, and the like. Alkynyl groups are optionally substituted with one or more halogen atoms.
The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocycle, each ring having from 3 to 10 carbon atoms. "fused analog" of cycloalkyl refers to a single ring fused to an aryl or heteroaryl group, wherein the point of attachment is on a non-aryl moiety. Examples are cycloalkyl and fused analogues such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, indenyl and the like. The cycloalkyl group is optionally substituted with one or more halogen atoms.
The term "heteroalkyl," by itself or in combination with another term, refers to a stable straight or branched chain consisting of at least one carbon atom and at least one heteroatom or cyclic hydrocarbon group selected from O, N, P, Si and S, or combinations thereof, wherein the nitrogen, phosphorus, or sulfur atom may optionally be oxidized and the nitrogen atom may optionally be quaternized. The heteroatom O, N, P, S and Si can be placed anywhere within the heteroalkyl group or where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2-、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-Si(CH3)3、-CH2-CH＝N-OCH3、-CH＝CH-N(CH3)-CH3、-O-CH3、-O-CH2-CH3and-CN. Up to two or three heteroatoms may be consecutive. For example, -CH2-NH-OCH3and-CH2-O-Si(CH3)3。
The term "cycloalkoxy" refers to a cycloalkyl group as defined above in combination with an oxygen atom, e.g., cyclopropoxy.
Similarly, the term "heteroalkylene" by itself or in combination with other terms refers to a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2-and-CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can be located at either or both ends of the chain, e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Furthermore, for alkylene and heteroalkylene linking groups, the written direction of the linking group formula does not indicate orientation of the linking group. For example, the formulae-C (O) OR ' means-C (O) OR ' and-R ' OC (O) -. As used herein, heteroalkyl groups include those groups attached to the remainder of the molecule through a heteroatom, such as-C (O) R ', -C (O) NR', -NR 'R', -OR ', -SR', and/OR-SO2R' is provided. Where "heteroalkyl" is mentioned and a particular heteroalkyl group, such as-NR 'R ", is mentioned later, it is understood that the terms heteroalkyl and-NR' R" are not repeated and are not mutually exclusive. Rather, for clarity, these specific heteroalkyl groups are referenced.
The term "substituted heterocycle" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclyl substituent substituted with 1 to 5 (e.g., 1 to 3).
"aryl" refers to an aromatic carbocyclic moiety having one or more closed rings. Examples include, but are not limited to, phenyl, naphthyl, anthracyl, benzanthryl, biphenyl, and pyrenyl.
"heteroaryl" refers to a monocyclic or bicyclic moiety containing at least one heteroatom selected from oxygen, nitrogen or sulfur, at least one ring of said rings, wherein at least one of said rings is aromatic, and wherein said one or more rings may independently be fused and/or bridged. Examples include, but are not limited to, pyridyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, furyl, thienyl, quinoxalinyl, indolyloxyl, thieno [2,3-c ] pyrazolyl, benzofuranyl, thiophenylpyrazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazole, furyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, furan (2,3-b) pyridyl, quinolinyl, indolyl, isoquinolinyl, and the like.
Unless otherwise indicated, the term "halogen" or "halogen element" by itself or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is meant to include monohaloalkyl and polyhaloalkyl. For example "halo (C)1-C4) Alkyl means include, but are not limited to, trifluoromethyl, 2,2, 2-trifluoromethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
Optical isomers, diastereomers, geometric isomers, and tautomers: some of the compounds of formula I may contain one or more ring systems and may therefore exist as cis and trans isomers. The present invention is intended to encompass all such cis and trans isomers. The inclusion of olefinic double bonds, unless otherwise specified, is meant to include both E and Z geometric isomers.
Any enantiomer of a compound of formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
In addition, the compounds of formula I may also include a series of stable isotopically labeled analogs. For example, one or more protons in the compound of formula i may be substituted with deuterium atoms, thereby providing deuterated analogs with improved pharmacological activity.
Pharmaceutically acceptable salts "refer to acid or base salts of the compounds of the present invention which salts possess the desired pharmacological activity and are neither biologically nor otherwise desirable. The salts may be formed from salts including, but not limited to, acetate, adipate, benzoate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromic acid hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, oxalate. It is to be understood that the above-described features of the invention and those specifically described below (e.g., the examples) may be combined with each other to form new or preferred embodiments within the scope of the invention.
By means of the technical scheme, the invention at least has the following advantages:
the invention provides a compound shown as a formula I: the compound has high LRRK2 inhibitory activity, and the small molecule inhibitor is combined with LRRK2 kinase to influence the biological function of protein, so that the compound has high application value in preparing medicines for treating neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and other diseases.
The foregoing is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clear and clear, and to implement the technical solutions according to the content of the description, the following is a description of preferred embodiments of the present invention.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
In order to facilitate the technical solution of the present invention to be fully understood by those skilled in the art, the separation and purification methods and the test methods, english abbreviations, the synthesis methods of raw materials or intermediates, and the synthesis methods of target compounds, which are based on the examples of the present application, are described as follows:
1. in the following examples of the present application, the separation and purification methods and the test methods were as follows:
in the following examples of the present invention, unless otherwise specified, column chromatography was carried out using silica gel (100-200 mesh) and various eluents. Solvent removal was performed using a Buchii rotary evaporator or a Genevac centrifugal evaporator. LC/MS was performed under acidic mobile phase conditions using a Waters autosurifier and a 19X 100mm XTerra 5 micron MSCI8 column. Nuclear magnetic resonance spectra were recorded using a warian 400MHz spectrometer. When the term "inert" is used to describe a reactor (e.g., reaction vessel, flask, glass reactor, etc.), it means that the air in the reactor has been replaced with an inert gas that is substantially free of water or dry (e.g., nitrogen, argon, etc.).
2. In the following embodiments of the present application, the chinese names corresponding to the english abbreviations are as follows:
HATU: 2- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluracil hexafluorophosphate; DPCI: n, N' -diisopropylcarbodiimide; DIEA: n, N-diisopropylethylamine; TEA: triethylamine; DMAP: 4-dimethylaminopyridine; DMF: n, N-dimethylformamide; NMP: n-methylpyrrolidine; THF: tetrahydrofuran; DCM: dichloromethane; TFA: trifluoroacetic acid; DMA: n, N-dimethylacetamide; TLC: thin layer chromatography; TMOF: trimethyl orthoformate; PTSA: p-toluenesulfonic acid; NIS: n-iodosuccinimide; eq: equivalents thereof; mmol: haomole; mole: molar ratio; mL: ml; l: lifting; MHz: megahertz; δ: chemical shift; DMSO-d 6: deuterated dimethyl sulfoxide; hrs, hr, h, hours: hours; ms: mass spectrometry; m/z: mass to charge ratio.
3. In the following examples of the present application, the synthesis methods of the reaction raw materials or reaction intermediates used are as follows:
synthesis of Compounds 3 a-g:
compounds 3a-g (as shown in Table 1) were synthesized according to the synthetic procedure shown in scheme 1 and prepared following the general procedure. X, A listed in Table 1 correspond to group X, A in scheme 1.
TABLE 1 Synthesis and yield of Compounds 3a-g
Figure BDA0003270963300000121
Reaction scheme 1
For example, 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine (3a) can be prepared as follows:
to a suspension of NaH (1.51g, 60%, 37.64mmol) in a DMF/DMSO (50/5mL) mixture at about 0 deg.C under nitrogen was added dropwise a solution of compound (2a) (5g, 25.09mmol) in DMF/DMSO (18mL/2mL) and the mixture was stirred at 0 deg.C for 30 min. A mixed solution of 2,4, 5-trichloropyrimidine (1a) (9.20g, 50.18mmol) in DMF/DMSO (18mL/2mL) was then added slowly dropwise. The reaction mixture solution was allowed to spontaneously warm to room temperature and stirred for 2 to 3 hours. The completion of the reaction was monitored by thin layer chromatography, the reaction solution was poured into ice water, extracted twice with ethyl acetate (20ml), and the organic phase was extracted with anhydrous Na2SO4And (5) drying. The organic solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (EA-PE solvent ═ 1:2) to give compound 3a (7.9g, 90.6%) as light cream-colored crystals. The characterization of compound 3a resulted in the following:
1H NMR(400MHz,MeOD)δ8.57(dd,J＝8.4,0.8Hz,1H),8.42(s,1H),7.96(dd,J＝8.0,1.5Hz,1H),7.85–7.76(m,1H),7.48–7.39(m,1H),3.38(dt,J＝13.8,6.9Hz,1H),1.28(d,J＝6.8Hz,6H).MSm/z:346.1(M+H)+
synthesis of Compound 3 h-k:
compounds 3h-k (as shown in Table 2) were prepared according to the synthetic procedure shown in scheme 2, following the general procedure. The Q ring, A listed in Table 2 corresponds to the groups Q ring, A in scheme 2.
TABLE 2 Synthesis and yield of Compound 3h-k
Figure BDA0003270963300000131
Reaction scheme 2
Preparation of compound 3h-k following reaction scheme 2, compound 3h-k was obtained in moderate to good yields using compound 1f-i and compound 2a under the action of sodium hydrogen.
Synthesis of Compound 5:
the preparation of 2, 5-dichloro-N- (2- (isopropylsulfonyl) phenyl) pyridin-4-amine (compound 5) is shown in scheme 3:
Figure BDA0003270963300000141
reaction scheme 3
Under the protection of nitrogen, compound 4(680mg, 2.997mmol, 1eq) was mixed with compound 2a (478mg, 2.398mmol, 0.8eq), Pd2dba3A mixture of (549mg, 0.599mmol, 0.2eq), Xantphos (347mg, 0.599mmol, 0.2eq), t-BuONa (576mg, 5.994mmol, 2eq) in toluene (20ml) was stirred at 100 ℃ to 120 ℃ for 3-4 hours. The complete consumption of compound 2a was monitored by TLC. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (15mL × 3), washed with water and brine, and the organic layers were combined and washed with anhydrous Na2SO4Drying, and vacuum evaporating to remove solvent to obtain crude product. The crude product was purified by flash chromatography on silica gel using a mixture of PE and EA as the eluting solvent to give Compound 5(560mg, 50%). The characterization of compound 5 is as follows:
1HNMR(400MHz,CDCl3)δ8.65(s,1H),8.19(s,1H),7.90(dd,J＝8.0,1.5Hz,1H),7.65–7.56(m,1H),7.53(d,J＝7.8Hz,1H),7.28–7.22(m,1H),7.14(s,1H),3.16–3.01(m,1H),1.22(d,J＝6.9Hz,6H).MS m/z:345.0(M+H)+
synthesis of Compounds 7 a-b:
compounds 7a-b (as shown in Table 3) are prepared according to scheme 4, and following the general procedure for the preparation of compound 7 a. W in Table 32Corresponding to W in scheme 42。
TABLE 3 Synthesis and yield of Compounds 7a-b
Figure BDA0003270963300000142
Reaction scheme 4
Compound 7 a: the preparation method of 4-chloro-N- (2- (isopropylsulfonyl) phenyl) -1,3, 5-triazine-2-amine is as follows:
a mixed solution of compound 6a (208mg, 1.4mmol, 1.1eq), compound 2a (263mg, 1.32mmol, 1eq), DIPEA (171mg, 1eq) in PhMe (3ml) was heated to 65 deg.C-70 deg.C and stirred for 2-3 hours under nitrogen. Complete consumption of compound 2a was monitored by TLC, then the reaction mixture was cooled to room temperature, extracted with ethyl acetate (15mL × 3), washed with water and brine, the combined organic phases were washed with anhydrous Na2SO4Drying, and removing the solvent by evaporation under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography using a mixture of PE and EA as an eluting solvent to give compound 7a (310mg, 75.1%). The characterization of compound 7a resulted in the following:
1H NMR(400MHz,CDCl3)δ9.88(bs,1H),8.61(s,1H),8.50(d,J＝8.3,1H),7.93(dd,J＝8.3,2.1Hz,1H),7.74-7.69(m,1H),7.36-7.31(m,1H),3.27-3.18(m,1H),1.32(d,J＝6.9,6H).MS m/z:313.0(M+H)+
synthesis of Compounds 9 a-i:
compounds 9a-i (as shown in Table 4) were synthesized according to the synthetic procedure shown in scheme 5 and prepared following the general procedure. R in Table 42、Ra、R1Corresponding to R in scheme 52、Ra、R1。
TABLE 4 Synthesis and yield of Compounds 9a-i
Figure BDA0003270963300000151
Reaction scheme 5
Compound 9 a: 1-chloro-5- (methoxy-d)3) The preparation method of the (E) -2-methyl-4-nitrobenzene is as follows:
cesium carbonate (20.8g, 65.9mmol) was added to a solution of compound 8a (2.5g, 13.1mmol) in dimethyl sulfoxide (25mL) under nitrogen protection, the resulting mixture was stirred at room temperature for 5 to 10 minutes, deuterated methanol (2mL) was added dropwise to the above solution, and the resulting mixture was then added dropwiseHeat to 50 ℃ until TLC monitored the reaction was complete. The reaction solution was poured into ice water, extracted twice with ethyl acetate (15 mL. times.3), and the organic phase was extracted with anhydrous Na2SO4After drying, filtration and evaporation of the organic solvent under reduced pressure gave a solid which was recrystallized from methyl tert-butyl ether to give compound 9a (2.2g, 76.9%). The characterization of compound 9a resulted in the following:
1H NMR(400MHz,DMSO-d6):δ＝7.90(s,1H),7.52(s,1H),2.30(s,3H)；LC-MS:m/z＝205.0(M+1)+。
synthesis of Compounds 12 a-c:
compounds 12a-c (shown in Table 5) were synthesized according to the synthetic procedure shown in scheme 6 and prepared following the procedure described in the Chinese patent application publication No. CN 108383849. R in Table 52、RaCorresponding to R in scheme 62、Ra。
TABLE 5 Synthesis and yield of Compounds 12a-c
Figure BDA0003270963300000161
Reaction scheme 6
Synthesis of Compounds 14 a-i:
compounds 14a-i (shown in Table 6) were synthesized according to the synthetic procedure outlined in scheme 7. R in Table 62、R1Corresponding to R in scheme 72、R1。
TABLE 6 Synthesis and yield of Compounds 14a-i
Figure BDA0003270963300000162
Figure BDA0003270963300000171
Reaction scheme 7
Compound 14 a: 4- (5- (methoxy-d)3) -2-methyl-4-nitrobenzene) -3, 6-dihydropyridine-1- (2H) -carboxylic acid tert-butyl ester is prepared as follows:
compound 9a (Table 3) (2g, 9.775mmol, 1eq) and compound 13(3.39g, 10.973mmol, 1.1eq), triphenylphosphine (1.046g, 3.99mmol, 0.4eq), Pd (OAc) under nitrogen protection2(263mg，1.17mmol，0.12eq)、K2CO3(2.68g, 20mmol, 2.0 eq.) of a mixture of dioxane/H2O (6V:4V) was heated to 100 deg.C-110 deg.C and stirred for 2-4 hours until TLC showed complete consumption of Compound 8, then the reaction mixture was cooled to room temperature, extracted with ethyl acetate (20 mL. times.3), the organic phases were washed with water and brine, the organic layers were combined, and anhydrous Na was used2SO4Drying, filtering, and removing organic phase under reduced pressure to obtain crude product. The crude product was purified by silica gel flash chromatography (EA-PE solvent 1:5) to give compound 14a (1.89g, 62.2%).
Synthesis of Compounds 15 a-e:
compounds 15a-e (shown in Table 7) were synthesized according to the synthetic procedure outlined in scheme 8. R in Table 72、R1Corresponding to R in scheme 82、R1。
TABLE 7 Synthesis and yield of Compounds 15a-e
Figure BDA0003270963300000172
Reaction scheme 8
Compound 15 a: 4- (5- (methoxy-d)3) The preparation method of (E) -2-methyl-4-nitrobenzene) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester is as follows:
to compound 14a (300mg, 0.96mmol, 1.0eq) and NH4Adding reduced iron powder (311mg, 5.568mmol, 5.8eq) in portions to a mixed solution of Cl (297mg, 5.568mmol, 5.8eq) in ethanol (3mL) and water (1mL), stirring the mixed solution at 30 ℃ -40 ℃ for 1-2 hours until TLC shows complete consumption of compound 14a, removing the solvent under reduced pressure to obtain a residue, adding water (20mL) to the residue, filtering, extracting the filtrate with ethyl acetate (15 mL. times.3), washing the organic phase with water and brine, and combining the organic phases with anhydrous Na2SO4Drying and filtering, and evaporating the solution under reduced pressure to obtain a crude product. The crude product was purified by silica gel flash chromatography (EA-PE solvent 2:1) to give compound 15a (220mg, 82.1%).
Synthesis of Compounds 16 a-f:
compounds 16a-f (shown in Table 8) were synthesized according to the synthetic procedure outlined in scheme 9. R in Table 82、R1Corresponding to R in scheme 92、R1。
TABLE 8 Synthesis and yield of Compounds 16a-i
Figure BDA0003270963300000181
Reaction scheme 9
Compound 16 a: 4- (5- (methoxy-d)3) The preparation method of (E) -2-methyl-4-nitrobenzene) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester is shown as follows:
compound 14a (1g) was dissolved in EtOH (20ml), treated with Pd/C (0.2g, 20% w/w) and the reaction mixture was stirred vigorously under 50psi of hydrogen at 50-60 ℃ for 20-24 h. The completion of the reaction was monitored by TLC, the reaction mixture was filtered and the filtrate was concentrated in vacuo, the resulting residue was diluted with ethyl acetate and 1N NaHCO3The aqueous solution was washed twice. Then the organic layer was washed with Na2SO4Dried and filtered. The filtrate was concentrated under reduced pressure to give compound 16a (82.5%) which was used in the next step without purification. The characterization of compound 16a is as follows:
1H NMR(400MHz,DMSO)δ9.84(s,2H),9.14(d,J＝9.7Hz,1H),9.03(d,J＝10.9Hz,1H),7.18(s,1H),6.92(s,1H),3.33(s,2H),3.12–2.90(m,3H),2.26(s,3H),1.97(qd,J＝13.3,3.7Hz,2H),1.81(d,J＝13.2Hz,2H).MS m/z:223.2(M+H)+。
synthesis of Compounds 18 a-r:
compounds 18a-r (shown in Table 9) were synthesized according to the synthetic procedure outlined in scheme 10. R in Table 92、R1Corresponding to R in scheme 102、R1。
TABLE 9 Synthesis and yields of Compounds 18a-r
Figure BDA0003270963300000191
Figure BDA0003270963300000201
Reaction scheme 10
The preparation of compound 18 is shown below:
under the protection of nitrogen, compound 9(1mmol) or 12(1mmol) and compound cyclic amine 17(1mmol), tris (dibenzylideneacetone) dipalladium (Pd)2dba3) (0.2mmol), (+ -) -2,2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP) (0.4mmol), t-BuONa (2mmol) in dry toluene (15mL) was stirred at 100 deg.C-120 deg.C for 6-8 hours until TLC monitoring reaction was completed, then the reaction mixture was cooled to room temperature, filtered, the filtrate was concentrated under vacuum, extracted with ethyl acetate (15 mL. times.3), the organic phase was washed with water and brine, the combined organic layers were washed with dry Na2SO4Drying and filtering, and removing the solvent under reduced pressure to obtain a crude product. The crude product was purified by silica gel flash chromatography using PE and EA mixture as the eluting solvent to give product 18 in moderate yield.
Synthesis of Compounds 19 a-r:
compounds 19a-r (shown in Table 10) were synthesized according to the synthetic procedure outlined in scheme 11 and prepared following the general procedure. R in Table 102、R1Corresponding to R in scheme 112、R1。
TABLE 10 Synthesis and yields of Compounds 19a-r
Figure BDA0003270963300000202
Figure BDA0003270963300000211
Reaction scheme 11
Compounds are prepared analogously to scheme 9 using intermediates 18a-r and Pd/C catalyst to obtain compounds 19a-r in moderate to good yields.
4. In the present application, the synthesis method of the target compound is as follows:
the Buchwald reaction process is shown in scheme 12:
Figure BDA0003270963300000212
reaction scheme 12
The reaction route comprises the following steps: under nitrogen protection, compound III (1mmol), compound II (1mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylanthracene (Xantphos) (0.04mmol), palladium acetate (0.02mmol) and cesium carbonate (5mmol) were added to anhydrous tetrahydrofuran (15mL) and the reaction mixture was heated to reflux for 36 h. The reaction completion was monitored by TLC, the mixture was filtered and the filtrate was concentrated in vacuo and the concentrated residue was purified by silica gel column chromatography (EA-PE solvent 1:3) to give the final product I in moderate to good yield.
In the following examples, the results of the synthesis and yields of the objective compounds in some of the examples using scheme 12 are shown in table 11 below:
TABLE 11 Synthesis and yields of part of Compound I
Figure BDA0003270963300000213
Figure BDA0003270963300000221
The Buchwald reaction + removal of Boc reaction procedure is shown in scheme 13:
Figure BDA0003270963300000222
reaction scheme 13
For example, scheme 13 includes the following steps:
the Buchwald reaction was first carried out:
step 1: the compound is prepared according to formula 12 using intermediate II and intermediate IV to give compound V in moderate to good yield.
Then, Boc removal reaction is carried out:
step 2: dissolve compound V (100mg) in dichloromethane (5mL), treat with TFA (5mL), stir the reaction mixture at room temperature for 1-2 hours, monitor by TLC for completion, remove the solvent under reduced pressure to give the crude product, saturate Na2CO3Adjusting pH to 8-9, extracting with ethyl acetate (15 mL. times.3), washing the organic phase with water and brine, and combining the organic phases with anhydrous Na2SO4Drying and evaporation of the solvent under reduced pressure gave the crude product which was purified by flash chromatography on silica gel using a mixture of DCM and MeOH as eluting solvent to give the final product I as an off-white solid in moderate to good yield.
In the following examples, the results of the synthesis and yields of the objective compounds in some of the examples using scheme 13 are shown in table 12 below:
TABLE 12 Synthesis and yields of part of Compound I
Figure BDA0003270963300000223
Figure BDA0003270963300000231
Figure BDA0003270963300000241
A detailed description of some of the target compounds synthesized by the above reaction schemes and the methods of testing, separation and purification is given below in conjunction with examples 1-63:
example 1
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) pyrimidine-2, 4-diamine (I-1)
Compounds were prepared according to scheme 13 using intermediate 3a (Table 1) and intermediate 15a (Table 7) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,MeOD)δ8.36(d,J＝8.3Hz,1H),8.02(s,1H),7.80(dd,J＝8.0,1.5Hz,1H),7.75(s,1H),7.65–7.53(m,1H),7.30–7.18(m,1H),6.62(s,1H),5.60–5.46(m,1H),3.73(dd,J＝5.1,2.2Hz,2H),3.36(t,J＝6.1Hz,2H),3.20(d,J＝1.7Hz,1H),2.51(dd,J＝7.8,5.9Hz,2H),2.02(s,3H),1.14(d,J＝6.8Hz,6H).MS m/z:531.2(M+H)+。
example 2
5-fluoro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (I-2)
The compounds are prepared according to scheme 13 using intermediate 3b (table 1) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:517.2(M+H)+。
example 3
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (I-3)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,DMSO-d6)δ8.51(d,J＝7.6Hz,1H),8.24(d,J＝15.1Hz,2H),7.82(dd,J＝7.9,1.2Hz,1H),7.59(t,J＝7.5Hz,1H),7.42(s,1H),7.32(t,J＝7.5Hz,1H),6.84(s,1H),3.05(d,J＝12.0Hz,2H),2.81–2.69(m,1H),2.62(td,J＝11.7,2.9Hz,2H),2.16(s,3H),1.67–1.49(m,4H),1.24(s,1H),1.16(d,J＝6.8Hz,6H).13C NMR(100MHz,)δ158.74,155.71,155.24,149.76,141.10,138.88,135.24,131.32,126.33,125.67,125.21,124.46,123.64,109.01,104.79,55.24,47.26,33.79,18.76,15.31.MS m/z:533.2(M+H)+。
example 4
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) pyrimidine-2, 4-diamine (I-4)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 15b (table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:517.2(M+H)+。
example 5
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (I-5)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 16b (table 8) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,CDCl3)δ9.48(s,1H),8.48(d,J＝8.4Hz,1H),8.18–8.10(m,1H),8.09(s,1H),7.85(dd,J＝8.0,1.5Hz,1H),7.64–7.53(m,1H),7.47(s,1H),7.23(dd,J＝11.2,4.0Hz,1H),6.69(dd,J＝4.3,2.5Hz,2H),4.30(s,1H),3.62–3.50(m,2H),3.17(dt,J＝10.3,6.9Hz,1H),2.95(td,J＝12.4,2.2Hz,2H),2.69(ddd,J＝12.1,8.1,5.0Hz,1H),2.23–2.05(m,2H),2.05–1.96(m,2H),1.25(d,J＝6.9Hz,6H).MS m/z:519.2(M+H)+。
example 6
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-6)
The compounds are prepared according to scheme 13 using intermediate 3c (table 1) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,CDCl3)δ9.50(s,1H),8.57(d,J＝8.1Hz,1H),8.14(s,1H),8.00(s,1H),7.92(dd,J＝8.0,1.5Hz,1H),7.67–7.55(m,1H),7.40(s,1H),7.26–7.21(m,1H),6.63(s,1H),3.91–3.77(m,4H),3.25(hept,J＝6.8Hz,1H),2.95–2.79(m,4H),2.17(s,3H),1.31(d,J＝6.9Hz,6H).MS m/z:567.2(M+H)+。
example 7
4- ((2- (isopropylsulfonyl) phenyl) amino) -2- ((2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidine-5-carbonitrile (I-7)
The compounds are prepared according to scheme 13 using intermediate 3d (table 1) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:524.2(M+H)+。
example 8
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4-morpholinophenyl) pyrimidine-2, 4-diamine (I-8)
The compounds are prepared according to scheme 12 using intermediate 3a (Table 1) and intermediate 19a (Table 10) to afford the desired products. The above target compounds were characterized as follows:
1HNMR(400MHz,MeOD)δ9.50(s),8.57(d,J＝8.1Hz),8.14(s),8.00(s),7.92(dd,J＝8.0,1.5Hz),7.68–7.56(m),7.40(s),7.26–7.21(m),6.63(s),3.95–3.71(m),3.35–3.19(m),2.96–2.77(m),2.17(s),1.31(d,J＝6.9Hz).MS m/z:535.2(M+H)+。
example 9
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-9)
The compounds are prepared according to scheme 13 using intermediate 3c (table 1) and intermediate 15a (table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:565.2(M+H)+。
example 10
N2- (4- (3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) -2- (methoxy-d3) -5-methylphenyl) -5-chloro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-10)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19b (table 10) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,CDCl3)δ9.45(s,1H),8.50(d,J＝8.0Hz,1H),8.09(s,1H),7.99(s,1H),7.85(d,J＝7.7Hz,1H),7.57(t,J＝7.5Hz,1H),7.44(s,1H),7.27(s,1H),7.17(s,1H),4.29(d,J＝4.0Hz,2H),3.86(d,J＝12.0Hz,2H),3.34(d,J＝11.6Hz,2H),3.23–3.13(m,1H),3.01–2.88(m,1H),2.41(d,J＝9.2Hz,1H),2.11(s,3H),1.24(d,J＝6.7Hz,6H).MS m/z:546.2(M+H)+。
example 11
N2- (4- (3, 6-diazabicyclo [ 3.1.1)]Heptane-6-yl) -2- (methoxy-d3) -5-methylphenyl) -5-chloro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-11)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19c (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:546.2(M+H)+。
example 12
N2- (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (methoxy-d3) -5-methylphenyl) -5-chloro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-12)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19d (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:560.2(M+H)+。
example 13
5-chloro-N2- (2- (ethoxy-d)5) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-13)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 15c (table 7) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,CDCl3)δ9.44(s,1H),8.47(d,J＝8.1Hz,1H),8.10(d,J＝2.7Hz,1H),8.00(s,1H),7.86(dd,J＝8.0,1.5Hz,1H),7.59–7.54(m,1H),7.54(d,J＝3.3Hz,1H),7.21–7.18(d,J＝1.0Hz,1H),6.54(s,1H),5.52(s,1H),3.78(d,J＝2.3Hz,2H),3.37(t,J＝5.8Hz,2H),3.18(dt,J＝13.7,6.9Hz,1H),2.61(d,J＝1.0Hz,2H),2.06(s,3H),1.25(d,J＝6.9Hz,6H).MS m/z:547.2(M+H)+。
example 14
5-chloro-N2- (2- (ethoxy-d)5) -5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-14)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 16c (table 8) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,CDCl3)δ9.44(s,1H),8.49(d,J＝8.5Hz,1H),8.09(d,J＝3.2Hz,1H),7.96(s,1H),7.86(d,J＝7.9Hz,1H),7.71(d,J＝8.1Hz,1H),7.60–7.50(m,1H),7.47(s,1H),7.24–7.10(m,3H),6.69(s,1H),3.60(d,J＝12.5Hz,2H),3.19(dt,J＝13.7,6.9Hz,1H),2.97(t,J＝12.1Hz,1H),2.85(t,J＝11.8Hz,1H),2.22–2.10(m,1H),2.09(s,3H),2.04(s,1H),1.86(d,J＝13.9Hz,2H),1.25(d,J＝6.8Hz,6H).MS m/z:549.2(M+H)+。
example 15
5-chloro-N2- (2- (ethoxy-d)5) -4- (piperidin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-15)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 16d (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:535.2(M+H)+。
example 16
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2-(2-(methoxy-d)3) -5-methyl-4- (2-azaspiro [ 3.3)]Heptane-2-yl) phenyl) pyrimidine-2, 4-diamine (I-16)
The compounds are prepared according to scheme 12 using intermediate 3a (table 1) and intermediate 19e (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:545.2(M+H)+。
example 17
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (2-oxo-6-azaspiro [ 3.3)]Heptane-6-yl) phenyl) pyrimidine-2, 4-diamine (I-17)
The compounds are prepared according to scheme 12 using intermediate 3a (table 1) and intermediate 19f (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:547.2(M+H)+。
example 18
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (2, 6-diazaspiro [3.3 ]]Hept-2-yl) phenyl) pyrimidine-2, 4-diamine (I-18)
The compound is prepared according to scheme 13 using intermediate 3a (Table 1) and intermediate 19g (Table 10) to give the desired product. The above target compounds were characterized as follows:
MS m/z:546.2(M+H)+。
example 19
N2-(2-((2λ8-ethynyl-d5) Oxy) -5-methyl-4- (2-azaspiro [3.3 ]]Heptane-2-yl) phenyl) -5-chloro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-19)
The compounds are prepared according to scheme 12 using intermediate 3a (table 1) and intermediate 19p (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:561.5(M+H)+。
example 20
N2-(2-((2λ8-ethynyl-d5) Oxy) -5-methyl4- (2-oxy-6-azaspiro [ 3.3) yl]Heptane-6-yl) phenyl) -5-chloro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-20)
The compounds are prepared according to scheme 12 using intermediate 3a (table 1) and intermediate 19q (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:563.2(M+H)+。
example 21
N2-(2-((2λ8-ethynyl-d5) Oxy) -5-methyl-4- (2, 6-diazaspiro [3.3 ]]Heptane-2-yl) phenyl) -5-chloro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-21)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19r (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:562.5(M+H)+。
example 22
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (2, 7-diazaspiro [3.5 ]]Non-2-yl) phenyl) pyrimidine-2, 4-diamine (I-22)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19h (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:574.3(M+H)+。
example 23
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (2, 7-diazaspiro [3.5 ]]Non-7-yl) phenyl) pyrimidine-2, 4-diamine (I-23)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19i (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:574.3(M+H)+。
example 24
5-chloro-N4- (2- (isopropylsulfonyl) phenyl)-N2- (2- (methoxy-d)3) -5-methyl-4- (3, 9-diazaspiro [5.5 ]]Undecane-3-yl) phenyl) pyrimidine-2, 4-diamine (I-24)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19j (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:602.3(M+H)+。
example 25
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperazin-1-yl) phenyl) -5-methylpyrimidine-2, 4-diamine (I-25)
The compounds are prepared according to scheme 13 using intermediate 3e (table 1) and intermediate 19k (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:514.3(M+H)+。
example 26
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperazin-1-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-26)
The compounds are prepared according to scheme 13 using intermediate 3c (table 1) and intermediate 19k (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:568.3(M+H)+。
example 27
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-27)
The compounds are prepared according to scheme 13 using intermediate 3c (table 1) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:567.3(M+H)+。
example 28
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -4- (1,2,3, 6-tetrahydro-l)Pyridin-4-yl) -5- (trifluoromethyl) phenyl) pyrimidine-2, 4-diamine (I-28)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 15d (table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:585.2(M+H)+。
example 29
5-chloro-N2- (5-chloro-2- (methoxy-d)3) -4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-29)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 15e (table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:551.2(M+H)+。
example 30
5- ((5-chloro-4- ((2- (isopropylsulfonyl) phenyl) amino) pyrimidin-2-yl) amino) -4- (methoxy-d3) -2- (piperazin-1-yl) benzonitrile (I-30)
The compound was prepared according to scheme 13 using intermediate 3a (Table 1) and intermediate 19l (Table 10) to afford the desired product. The above target compounds were characterized as follows:
MS m/z:545.2(M+H)+。
example 31
2- ((5-chloro-2- ((2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (I-31)
The compound is prepared according to scheme 13 using intermediate 3g (Table 1) and intermediate 16a (Table 8) to give the desired product. The above target compounds were characterized as follows:
MS m/z:534.2(M+H)+。
example 32
2- ((5-chloro-2- ((2- (methoxy-d)3) -5-methyl-4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (I-32)
The compound is prepared according to scheme 13 using intermediate 3g (Table 1) and intermediate 19k (Table 10) to give the desired product. The above target compounds were characterized as follows:
MS m/z:535.2(M+H)+。
example 33
2- ((5-chloro-2- ((2- (methoxy-d)3) -5-methyl-4-morpholinophenyl) amino) pyrimidin-4-yl) amino) -N, N-dimethylbenzenesulfonamide (I-33)
The compound is prepared according to scheme 12 using intermediate 3g (Table 1) and intermediate 19a (Table 10) to afford the desired product. The above target compounds were characterized as follows:
MS m/z:536.2(M+H)+。
example 34
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (5-methyl-4- (piperidin-4-yl) -2- (trifluoromethoxy) phenyl) pyrimidine-2, 4-diamine (I-34)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 16e (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:584.5(M+H)+。
example 35
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (4- (piperidin-4-yl) -2- (trifluoromethoxy) phenyl) pyrimidine-2, 4-diamine (I-35)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 16f (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:570.5(M+H)+。
example 36
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (5-methyl-4- (piperazin-1-yl) -2- (trifluoromethoxy) phenyl) pyrimidine-2, 4-diamine (I-36)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19m (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:585.5(M+H)+。
example 37
N2- (2- (isopropylsulfonyl) phenyl) -N4- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -1,3, 5-triazine-2, 4-diamine (I-37)
The compounds are prepared according to scheme 13 using intermediate 7a (table 3) and intermediate 15a (table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:498.2(M+H)+。
example 38
N2- (2- (isopropylsulfonyl) phenyl) -N4- (2- (methoxy-d)3) -4- (piperidin-4-yl) phenyl) -1,3, 5-triazine-2, 4-diamine (I-38)
The compounds are prepared according to scheme 13 using intermediate 7a (table 3) and intermediate 16b (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:486.5(M+H)+。
example 39
N2- (2- (isopropylsulfonyl) phenyl) -N4- (5-methyl-4- (piperazin-1-yl) -2- (trifluoromethoxy) phenyl) -1,3, 5-triazine-2, 4-diamine (I-39)
The compounds are prepared according to scheme 13 using intermediate 7a (table 3) and intermediate 19m (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:552.2(M+H)+。
example 40
N2- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-40)
The compounds are prepared according to scheme 13 using intermediate 3f (Table 1) and intermediate 15a (Table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:397.2(M+H)+。
EXAMPLE 41
N2- (2- (methoxy-)d3) -5-methyl-4- (piperidin-4-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-41)
The compounds are prepared according to scheme 13 using intermediate 3f (Table 1) and intermediate 16a (Table 8) to afford the desired products. The above target compounds were characterized as follows:
1H-NMR(400MHz,CD3COD)δ8.12(s,1H),7.96(s,1H),6.69(s,1H),4.14(d,2H,J＝13.1Hz),2.96(s,3H),2.89–2.69(m,4H),2.21(s,3H),1.66(m,2H),1.59–1.44(m,2H).MS m/z:399.2(M+H)+。
example 42
N2- (2- (methoxy-d)3) -5-methyl-4- (piperazin-1-yl) phenyl) -N4-methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-42)
The compounds are prepared according to scheme 13 using intermediate 3f (Table 1) and intermediate 19k (Table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:400.2(M+H)+。
example 43
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) pyridine-2, 4-diamine (I-43)
Compounds are prepared according to scheme 13 using intermediate 5 (scheme 3) and intermediate 15a (Table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:530.5(M+H)+。
example 44
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) pyridine-2, 4-diamine (I-44)
Compounds are prepared according to scheme 13 using intermediate 5 (scheme 3) and intermediate 16a (Table 8) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,MeOD)δ7.88(s,1H),7.81(d,J＝7.9Hz,1H),7.61(d,J＝3.7Hz,2H),7.44(s,1H),7.27–7.15(m,1H),6.68(d,J＝2.9Hz,2H),3.40(d,J＝12.7Hz,2H),3.16(dd,J＝13.7,6.8Hz,1H),3.11–2.93(m,3H),2.20(s,3H),1.94–1.71(m,4H),1.13(d,J＝6.8Hz,6H).MS m/z:532.5(M+H)+。
example 45
5-chloro-N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperazin-1-yl) phenyl) pyridine-2, 4-diamine (I-45)
Compounds were prepared according to scheme 13 using intermediate 5 (scheme 3) and intermediate 19k (Table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:533.5(M+H)+。
example 46
N2- (4- ((1S,4S)2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d3) -5-methylphenyl) -5-fluoro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-46)
The compounds are prepared according to scheme 13 using intermediate 3b (table 1) and intermediate 19o (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:530.3(M+H)+。
example 47
N2- (4- (3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) -2- (methoxy-d3) -5-methylphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-47)
The compounds are prepared according to scheme 13 using intermediate 3c (table 1) and intermediate 19b (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:580.3(M+H)+。
example 48
N2- (4- ((1S,4S) -2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d3) -5-methylphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-48)
The compounds are prepared according to scheme 13 using intermediate 3c (table 1) and intermediate 19o (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:580.3(M+H)+。
example 49
N4- (2- (isopropylsulfonyl) phenyl) -N6- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-4, 6-diamine (I-49)
The compounds are prepared according to scheme 13 using intermediate 7b (table 3) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:499.3(M+H)+。
example 50
5-chloro-N2- (4- ((3aR, 6aS) -hexahydropyrrole [3,4-c]Pyrrol-2 (1H) -yl) -2- (methoxy-d3) -5-methylphenyl) -N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-50)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19n (table 10) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,CDCl3)δ9.44(s,1H),8.48(d,J＝8.3Hz,1H),8.07(s,1H),7.90(s,1H),7.85(d,J＝7.8Hz,1H),7.61(d,J＝7.9Hz,1H),7.54(t,J＝7.4Hz,1H),7.32(s,1H),7.07(d,J＝7.8Hz,1H),6.53(s,1H),3.64(dd,J＝5.9,3.4Hz,2H),3.25–3.14(m,1H),3.00(ddd,J＝48.0,12.0,4.2Hz,8H),2.07(s,3H),1.24(d,J＝6.7Hz,6H).MS m/z:560.2(M+H)+。
example 51
N2- (4- ((1S,4S) -2, 5-diazabicyclo [ 2.2.1)]Hept-2-yl) -2- (methoxy-d3) -5-methylphenyl) -5-chloro-N4- (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-51)
The compounds are prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19o (table 10) to afford the desired products. The above target compounds were characterized as follows:
1H NMR(400MHz,CDCl3)δ9.44(s,1H),8.51(d,J＝8.4Hz,1H),8.08(s,1H),7.94(s,1H),7.85(d,J＝7.9Hz,1H),7.56(t,J＝7.8Hz,1H),7.36(s,1H),7.18–7.12(m,1H),6.75(s,1H),3.67(d,J＝5.4Hz,2H),3.27(q,J＝11.0Hz,4H),3.19(dt,J＝13.7,6.7Hz,1H),2.67–2.52(m,1H),2.12(s,3H),2.01(d,J＝8.1Hz,1H),1.25(d,J＝6.8Hz,6H).MS m/z:546.2(M+H)+。
example 52
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) thieno [2,3-d]Pyrimidine-2, 4-diamine (I-52)
The compound is prepared according to scheme 13 using intermediate 3h (table 2) and intermediate 15a (table 7) to afford the desired product. The above target compounds were characterized as follows:
MS m/z:553.2(M+H)+。
example 53
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) thieno [2,3-d]Pyrimidine-2, 4-diamine (I-53)
The compound is prepared according to scheme 13 using intermediate 3h (table 2) and intermediate 16a (table 8) to give the desired product. The above target compounds were characterized as follows:
MS m/z:554.2(M+H)+。
example 54
N2- (4- ((1S,4S) -2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d3) -5-methylphenyl) -N4- (2- (isopropylsulfonyl) phenyl) thieno [2,3-d]Pyrimidine-2, 4-diamine (I-54)
The compound was prepared according to scheme 13 using intermediate 3h (table 2) and intermediate 19o (table 10) to afford the desired product. The above target compounds were characterized as follows:
MS m/z:568.2(M+H)+。
example 55
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydro-l)Pyridin-4-yl) phenyl) thieno [3,2-d]Pyrimidine-2, 4-diamine (I-55)
The compounds are prepared according to scheme 13 using intermediate 3i (table 2) and intermediate 15a (table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:553.2(M+H)+。
example 56
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) thieno [3,2-d]Pyrimidine-2, 4-diamine (I-56)
The compounds are prepared according to scheme 13 using intermediate 3i (table 2) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:554.2(M+H)+。
example 57
N2- (4- ((1S,4S) -2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d3) -5-methylphenyl) -N4- (2- (isopropylsulfonyl) phenyl) thieno [3,2-d]Pyrimidine-2, 4-diamine (I-57)
The compounds are prepared according to scheme 13 using intermediate 3i (table 2) and intermediate 19o (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:568.2(M+H)+。
example 58
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -7H-pyrrolo [2,3-d]Pyrimidine-2, 4-diamine (I-58)
The compounds are prepared according to scheme 13 using intermediate 3j (table 2) and intermediate 15a (table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:536.2(M+H)+。
example 59
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) -7H-pyrrole [2,3-d ]]Pyrimidine-2, 4-diamine (I-59)
The compounds are prepared according to scheme 13 using intermediate 3j (table 2) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:538.2(M+H)+。
example 60
N2- (4- ((1S,4S) -2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d3) -5-methylphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2,3-d]Pyrimidine-2, 4-diamine (I-60)
The compounds are prepared according to scheme 13 using intermediate 3j (table 2) and intermediate 19o (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:551.2(M+H)+。
example 61
N4- (2- (isopropylsulfonyl) phenyl-) -N2- (2- (methoxy-d)3) -5-methyl-4- (1,2,3, 6-tetrahydropyridin-4-yl) phenyl) -5H-pyrrolo [3,2-d]Pyrimidine-2, 4-diamine (I-61)
The compounds are prepared according to scheme 13 using intermediate 3k (table 2) and intermediate 15a (table 7) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:536.2(M+H)+
example 62
N4- (2- (isopropylsulfonyl) phenyl) -N2- (2- (methoxy-d)3) -5-methyl-4- (piperidin-4-yl) phenyl) -5H-pyrrolo [3,2-d]Pyrimidine-2, 4-diamine (I-62)
The compounds are prepared according to scheme 13 using intermediate 3k (table 2) and intermediate 16a (table 8) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:538.2(M+H)+。
example 63
N2- (4- ((1S,4S) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d3) -5-methylphenyl) -N4- (2- (isopropylsulfonyl)Phenyl) -5H-pyrrole [3,2-d]Pyrimidine-2, 4-diamine (I-63)
The compounds are prepared according to scheme 13 using intermediate 3k (table 2) and intermediate 19o (table 10) to afford the desired products. The above target compounds were characterized as follows:
MS m/z:551.2(M+H)+。
a part of the target compounds synthesized IN examples 1 to 63 above was tested for biological activity, using Ceritinib and LRRK2-IN-1 as controls, for IN vitro inhibition of LRRK2 kinase activity, as follows:
compounds to be tested were diluted in DMSO in a 3-fold gradient in dilution plates at an initial concentration of 1 μ M. The test compound was diluted 50-fold into 1-fold concentration of kinase reaction buffer and shaken on a shaker for 20 minutes. A2-fold concentration of LRRK2 kinase was prepared in a 1-fold concentration of kinase reaction buffer. To each well of the reaction plate was added 2. mu.L of LRRK2 kinase. mu.L of the test compound diluted in kinase buffer was added to each well, and the plate was centrifuged at 1000g for 30 seconds with a sealing plate and left at room temperature for 60 minutes. A mixture of ATP and substrate at a concentration 4 times that of the kinase reaction buffer was prepared, and 1. mu.L of a mixture of ATP and substrate at a concentration 4 times was added to the reaction plate. Plates were then centrifuged at 1000g for 30 seconds with a sealing plate membrane and allowed to react at room temperature for 60 minutes. Transfer 4. mu.LADP-Glo to 384 reaction plates, centrifuge at 1000rpm/min for 1min, incubate at 25 ℃ for 40 min. Transfer 8. mu.L of detection solution to 384 reaction plates, centrifuge at 1000rpm/min for 1min, incubate at 25 ℃ for 40 min. RLU signals were read using a Biotek multifunctional plate reader. The signal intensity is used to characterize the degree of activity of the kinase.
And (3) data analysis:
inhibition rate calculation formula: compound inhibition (% inh) is 100% - (compound-positive control)/(negative control-positive control) × 100%; computing IC50And the inhibition curves of the compounds were plotted: IC of the compound was obtained using the following non-linear fit equation50(median inhibitory concentration) and data analysis was performed using Graphpad 7.0 software.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))
Wherein, X is the log value of the concentration of the compound; inhibition (% inhibition); top and Bottom are the minimum and maximum values observed on the curve, respectively, and Hill Slope refers to the absolute value of the maximum Slope of the curve (i.e., the midpoint of the curve).
TABLE 13 in vitro inhibition assay IC for part of the Compounds on the kinase LRRK250Test results
Figure BDA0003270963300000361
Some of the target compounds synthesized in examples 1-63 were tested for their in vitro inhibition of the activity of LRRK 2G 2019S kinase according to the methods described above.
TABLE 14 in vitro inhibition assay IC for part of the Compounds on kinase LRRK 2G 2019S50Test results
Figure BDA0003270963300000362
According to the above embodiments and test results, it is clear that the novel compound provided by the embodiment of the present invention has a strong inhibitory effect on both kinases LRRK2 and LRRK 2G 2019S, and has a very high application value in preparation of a drug for preventing and/or treating a disease associated with an increase in activity of in vivo gene LRRK 2. Especially, the compounds I-1 and I-3 provided in examples 1 and 3 of the application show higher inhibition effect on the kinases LRRK2 and LRRK 2G 2019S.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.

Claims (10)

1. A compound of formula i or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof;
Figure FDA0003270963290000011
wherein the content of the first and second substances,
W1is C or N satisfying the valence bond theory;
W2is CH or N;
x and Y are each independently selected from hydrogen, halogen, cyano, C1-C3Fluoroalkyl of, C1-C6Alkoxy radical, C1-C6Alkyl radical, C6-C10Aryl radical, C2-C8Alkenyl radical, C2-C8One of alkynyl or nitro; or X, Y and the atoms to which they are attached together form a heteroaromatic ring containing one or more heteroatoms including at least one of a sulfur atom, a nitrogen atom, and an oxygen atom;
a is C1-C6Alkyl chain or
Figure FDA0003270963290000012
Wherein Z is selected from one of the following groups:
Figure FDA0003270963290000013
R1is C1-C2Deuterated alkyl, C1-C2Deuterated fluoroalkyl or C1-C2A fluoroalkyl group;
R2is hydrogen, C1-C3Alkyl radical, C1-C3Fluoroalkyl, cyano, or halogen;
R3is a substituted or unsubstituted 4-to 8-membered monoheterocycloalkyl, a bridged heteroring having 4 to 12 carbon atoms, a heterospirocycle having 4 to 12 carbon atoms or a heterocycle having 4 to 12 carbon atoms, said heterocycloalkyl, bridged heterocycle, heterospirocycleThe hetero atom in the ring or the hetero ring is selected from one or more of oxygen atom, nitrogen atom and sulfur atom.
2. The compound according to claim 1, or isotopically-formed, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof, wherein X and Y are each independently selected from the group consisting of hydrogen, halogen, cyano, trifluoromethyl, C1-C3Alkoxy radical, C1-C3Alkyl radical, C6-C10Aryl radical, C2-C4Alkenyl radical, C2-C4Alkynyl or nitro.
3. The compound of claim 2, or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof, wherein W is1Is C, said W2Is N, Y is hydrogen, A is methyl or
Figure FDA0003270963290000021
Wherein Z is
Figure FDA0003270963290000022
4. A compound according to claim 1, or isotopically-formed, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof, wherein when X, Y and the atoms to which they are attached form a heteroaromatic ring, said heteroaromatic ring is oxazolinyl, oxocycloalkyl, pyranyl, tetrahydropyranyl, azetidinyl, 1, 4-dioxaanilinyl, hexahydroazepinylbutyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, indolinyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, or the like, One of dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl or tetrahydrothienyl.
5. The compound of claim 1, or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof, wherein R is wherein1Is a CD3、CD2CD3、CF3、CHF2Or CD2One of F;
the R is3Is one of the following groups:
Figure FDA0003270963290000023
6. the compound of claim 1, or isotopically-forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof, wherein the compound of formula I is a compound represented by the following structural formulae I-1 to I-63:
Figure FDA0003270963290000031
Figure FDA0003270963290000041
Figure FDA0003270963290000051
Figure FDA0003270963290000061
7. a pharmaceutical composition comprising a compound of any one of claims 1-6 or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, hydrates, prodrugs and polymorphs thereof.
8. Use of a compound of any one of the formulae i as defined in any one of claims 1 to 6, or an isotopic form, stereoisomer, tautomer, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, hydrate, prodrug and polymorph thereof, for the manufacture of a medicament for the prevention and/or treatment of a disease wherein the activity of leucine-rich repeat kinase 2 is inhibited.
9. The use of claim 8, wherein the disease comprises one or more of a neurodegenerative disease, an immune disease or inflammation, an infection, an organ transplant, a cardiovascular disease and a metabolic disease.
10. The use of claim 9, wherein the neurodegenerative disease includes one or more of parkinson's disease, alzheimer's disease, huntington's disease, amyotrophic lateral sclerosis, and motor neuron disease.
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