CN113831321B - 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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CN113831321B
CN113831321B CN202111101907.3A CN202111101907A CN113831321B CN 113831321 B CN113831321 B CN 113831321B CN 202111101907 A CN202111101907 A CN 202111101907A CN 113831321 B CN113831321 B CN 113831321B
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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, e.g., levodopa treatment can increase 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 (LRRK 2) gene encodes a gene involved in familial Parkinson's disease (ASN Neuro 1, AN 20090007), (Trends in neurosciens 29, 286-293). Some reports indicate that kinase activity of LRRK2 is associated with PD pathophysiology (BMC Med 10, 20), (Neurology 67, 1786-1791). LRRK2 is widely distributed throughout the body, and elevated concentrations of LRRK2 are observed in brain, kidney and various immune cells (Neuron 44, 595-600). LRRK2 is involved in a number of cellular processes including synaptic morphogenesis, neurite outgrowth and membrane trafficking, autophagy, and protein synthesis (The Lancet 386, 896-912). LRRK2 is a multi-domain serine threonine kinase of 286 kDa. 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, pe2-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).
Few mutations of LRRK2, R1441C, R1441G, R1441H, G2019S, N1437H are well known (ELife 5, e12813). LRRK2R1441G mutations 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 occurs in a highly conserved kinase domain, and it is postulated that the G2019S mutation may 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 inhibit s. 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 nanomolar 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 at nanomolar concentrations (JNeurochem 128, 561-576). 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 (US 20170002000 A1), pyrimidin-2-ylamino-1H-pyrazoles (WO 2017218843), aminopyrimidine derivatives are reported in different papers and patents as LRRK2 inhibitors. LRRK2-in-1 and TAE684 were used as reference compounds to explore the biological functions and mechanisms of LRRK 2. Patents WO2017087905, WO2017156493, WO2018217946 all disclose technical solutions of aminopyrimidine derivatives as inhibitors of LRRK 2. In the prior art, selective inhibitors of LRRK2 have good pharmacokinetic characteristics and the ability to cross the blood brain barrier, and are ideal candidates for developing effective drugs, but currently, the inhibitory effect of LRRK2 inhibitors in the treatment of neurodegenerative diseases such as parkinson's disease, alzheimer's disease and other diseases is still low, and there is still a need to improve the inhibitory effect of LRRK2 inhibitors in the treatment of neurodegenerative diseases such as parkinson's disease, alzheimer's disease and other diseases.
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,
W 1 is C or N satisfying the valence bond theory; the invention refers to satisfying valence bond theory, when W 1 When is C, X is present, when W is 1 When N, X is absent;
W 2 is CH or N;
x and Y are each independently selected from hydrogen, halogen, cyano, C 1 -C 3 Fluoroalkyl of, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkyl radical, C 6 -C 10 Aryl radical, C 2 -C 8 Alkenyl radical, C 2 -C 8 One 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 C 1 -C 6 Alkyl chain or
Figure BDA0003270963300000031
Wherein Z is selected from one of the following groups:
Figure BDA0003270963300000032
R 1 is C 1 -C 2 Deuterated alkyl, C 1 -C 2 Deuterated fluoroalkyl or C 1 -C 2 One of fluoroalkyl groups;
R 2 is hydrogen, C 1 -C 3 Alkyl radical, C 1 -C 3 One of fluoroalkyl, cyano, or halogen;
R 3 is 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, C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkyl radical, C 6 -C 10 Aryl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl or nitro.
Further, W 1 Is C, W 2 Is 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-dioxaanilinyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl or tetrahydrothienyl.
Further, wherein R is 1 Is a CD 3 、CD 2 CD 3 、CF 3 、CHF 2 Or CD 2 One of F;
R 3 is one of the following groups:
Figure BDA0003270963300000045
further, the compounds represented by the formula I are compounds 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, neurodegenerative diseases include 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 herein i Meaning that the moiety has i carbon atoms, e.g. C 10 Alkyl means that the alkyl unit has 10 carbon atoms; the term C as used herein i -C j Meaning that the moiety has i to j carbon atoms, e.g. C 1 -C 10 Alkyl 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 -C 10 Meaning 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" refers to a straight or branched chain alkoxy group having the indicated number of carbon atoms. E.g. C 1-6 Alkoxy 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, -CH 2 CH 2 CH 2 CH 2 -，-CH 2 CH＝CHCH 2 -，-CH 2 CCCH 2 -，-CH 2 CH 2 CH(CH 2 CH 2 CH 3 )CH 2 -. The alkyl (or alkylene) group typically has 1 to 24 carbon atoms,and groups having 10 or less carbon atoms are 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. A "fused analog" of a 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 atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heteroatoms O, N, P, S and Si may be placed anywhere within the heteroalkyl group or at the point where the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to-CH 2 -CH 2 -O-CH 3 、 -CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 2 -、-S(O)-CH 3 、 -CH 2 -CH 2 -S(O) 2 -CH 3 、-CH＝CH-O-CH 3 、-Si(CH 3 ) 3 、-CH 2 -CH＝N-OCH 3 、-CH＝CH-N(CH 3 )-CH 3 、 -O-CH 3 、-O-CH 2 -CH 3 and-CN. Up to two or three heteroatoms may be consecutive. For example, -CH 2 -NH-OCH 3 and-CH 2 -O-Si(CH 3 ) 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, -CH 2 -CH 2 -S-CH 2 -CH 2 -and-CH 2 -S-CH 2 -CH 2 -NH-CH 2 -. 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 formula-C (O) OR ' represents-C (O) OR ' and-R ' OC (O) -. Heteroalkyl groups as used herein include those groups attached to the rest of the molecule through a heteroatom, for example-C (O) R ', -C (O) NR') -NR 'R', -OR ', -SR' and/OR-SO 2 R' 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 -C 4 ) Alkyl means include, but are not limited to, trifluoromethyl, 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, column chromatography was carried out using silica gel (100-200 mesh) and various eluents, unless otherwise specified. 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 examples of the present application, the chinese names corresponding to 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: mole; mL: milliliters of the solution; l: lifting; MHz: megahertz; δ: chemical shift; DMSO-d6: 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 synthesis procedure shown in scheme 1 and prepared following the general procedure. X, A listed in Table 1 correspond to the groups 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 (3 a) can be prepared as follows:
to a suspension of NaH (1.51g, 60%,37.64 mmol) in a DMF/DMSO (50/5 mL) mixture at about 0 ℃ under nitrogen was added dropwise a solution of compound (2 a) (5 g, 25.09mmol) in DMF/DMSO (18 mL/2 mL) and the mixture was stirred at 0 ℃ for 30 minutes. Then slowlyA mixed solution of 2,4, 5-trichloropyrimidine (1 a) (9.20g, 50.18mmol) in DMF/DMSO (18 mL/2 mL) was added 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 (20 ml), and the organic phase was extracted with anhydrous Na 2 SO 4 And (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. The characterization of compound 3a resulted in the following:
1 H 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 yield 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 (680)mg,2.997mmol, 1eq) with compound 2a (478mg, 2.398mmol, 0.8 eq), pd 2 dba 3 A mixture of (549mg, 0.599mmol, 0.2eq), xantphos (347mg, 0.599mmol, 0.2eq), t-BuONa (576mg, 5.994mmol, 2eq) in toluene (20 ml) was stirred at 100 deg.C-120 deg.C 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 (15 mL × 3), washed with water and brine, and the organic layers were combined and washed with anhydrous Na 2 SO 4 Drying, 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:
1 HNMR(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 3 2 Corresponding to W in scheme 4 2 。
TABLE 3 Synthesis and yield of Compounds 7a-b
Figure BDA0003270963300000142
Reaction scheme 4
Compound 7a: the preparation of 4-chloro-N- (2- (isopropylsulfonyl) phenyl) -1,3, 5-triazin-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 (3 ml) was heated to 65 ℃ to 70 ℃ under nitrogen and stirred for 2-3 hours. Complete consumption of compound 2a was monitored by TLC, then the reaction mixture was cooled to room temperature, extracted with ethyl acetate (15 mL × 3), washed with water and brine, the combined organic phases were washed with anhydrous Na 2 SO 4 Drying, and vacuum evaporating to remove solventObtaining 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 results for compound 7a are as follows:
1 H NMR(400MHz,CDCl 3 )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 4 2 、R a 、R 1 Corresponding to R in scheme 5 2 、R a 、R 1 。
TABLE 4 Synthesis and yield of Compounds 9a-i
Figure BDA0003270963300000151
Reaction scheme 5
Compound 9a: 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 (25 mL) under nitrogen protection, and after the resulting mixture was stirred at room temperature for 5 to 10 minutes, deuterated methanol (2 mL) was added dropwise to the above solution, and then the resulting mixture was heated to 50 ℃ until the TLC monitoring reaction was completed. 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 Na 2 SO 4 After 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:
1 H NMR(400MHz,DMSO-d 6 ):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 5 2 、R a Corresponding to R in scheme 6 2 、R a 。
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 6 2 、R 1 Corresponding to R in scheme 7 2 、R 1 。
TABLE 6 Synthesis and yield of Compounds 14a-i
Figure BDA0003270963300000162
Figure BDA0003270963300000171
Reaction scheme 7
Compound 14a:4- (5- (methoxy-d) 3 ) -2-methyl-4-nitrobenzene) -3, 6-dihydropyridine-1- (2H) -carboxylic acid tert-butyl ester is prepared as follows:
under nitrogen protection, compound 9a (Table 3) (2g, 9.775mmol, 1eq) was mixed with compound 13 (3.39g, 10.973mmol, 1.1eq), triphenylphosphine (1.046 g,3.99mmol, 0.4eq), pd (OAc) 2 (263mg，1.17mmol，0.12eq)、K 2 CO 3 (2.68 g, 20mmol, 2.0eq) in a mixture of dioxane/H 2 O (6vThe organic phase was washed with water and brine, the organic layers were combined and dried over anhydrous Na 2 SO 4 Drying, filtering, and removing organic phase under reduced pressure to obtain crude product. The crude product was purified by flash chromatography on silica gel (EA-PE solvent 1.
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 7 2 、R 1 Corresponding to R in scheme 8 2 、R 1 。
TABLE 7 Synthesis and yield of Compounds 15a-e
Figure BDA0003270963300000172
Reaction scheme 8
Compound 15a:4- (5- (methoxy-d) 3 ) -2-methyl-4-nitrobenzene) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester is prepared as follows:
to compound 14a (300mg, 0.96mmol, 1.0eq) and NH 4 Adding reduced iron powder (311mg, 5.568mmol, 5.8eq) in portions to a mixed solution of Cl (297mg, 5.568mmol, 5.8eq) in ethanol (3 mL) and water (1 mL), stirring the mixed solution at 30 ℃ to 40 ℃ for 1 to 2 hours until TLC showed complete consumption of compound 14a, distilling off the solvent under reduced pressure to obtain a residue, adding water (20 mL) to the residue, filtering, extracting the filtrate with ethyl acetate (15 mL. Times.3), washing the organic phase with water and brine, and subjecting the combined organic phase to anhydrous Na 2 SO 4 Drying 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 8 2 、R 1 Corresponding to R in scheme 9 2 、R 1 。
TABLE 8 Synthesis and yield of Compounds 16a-i
Figure BDA0003270963300000181
Reaction scheme 9
Compound 16a: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 (1 g) was dissolved in EtOH (20 ml), treated with Pd/C (0.2 g,20% w/w) and the reaction mixture was vigorously stirred at 50-60 ℃ for 20-24 h under 50psi of hydrogen pressure. The reaction completion 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 NaHCO 3 The aqueous solution was washed twice. Then the organic layer was washed with Na 2 SO 4 Dried 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:
1 H 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 9 2 、R 1 Corresponding to R in scheme 10 2 、R 1 。
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 (1 mmol) or 12 (1 mmol) and compound cyclic amine 17 (1 mmol), tris (dibenzylideneacetone) dipalladium (Pd) 2 dba 3 ) (0.2 mmol), (. + -.) -2,2 '-bis (diphenylphosphino) -1,1' -Binaphthyl (BINAP) (0.4 mmol), t-BuONa (2 mmol) in dry toluene (15 mL) was stirred at 100 deg.C-120 deg.C for 6-8 hours until TLC monitoring reaction was complete, 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 phases were washed with water and brine, the combined organic layers were washed with dry Na 2 SO 4 Drying 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 eluting solvent to give intermediate yield of product 18.
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 10 2 、R 1 Corresponding to R in scheme 11 2 、R 1 。
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 (1 mmol), compound II (1 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylanthracene (Xantphos) (0.04 mmol), palladium acetate (0.02 mmol) and cesium carbonate (5 mmol) were added to anhydrous tetrahydrofuran (15 mL) and the reaction mixture was heated to reflux for 36 hours. 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).
In the following examples, the synthesis results and yields of the objective compounds in examples, which were partially synthesized 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 + Boc removal 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: compound V (100 mg) above was dissolved in methylene chloride (5 mL)Treated with TFA (5 mL), the reaction mixture was stirred at room temperature for 1-2 h, monitored by TLC for completion, the solvent was removed under reduced pressure to give the crude product, which was then purified with saturated Na 2 CO 3 Adjusting 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 Na 2 SO 4 Drying 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 synthesis results and yields of the objective compounds in examples, which were partially synthesized 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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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:
1 H 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＝7.8,5.9 Hz,2H),2.02(s,3H),1.14(d,J＝6.8Hz,6H).MS m/z:531.2(M+H) + 。
example 2
5-fluoro-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (piperidin-4-yl) phenyl) pyrimidine-2, 4-diamine (I-3)
The compounds were prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 16a (table 8) to afford the desired products. The results of the above characterization of the target compounds are as follows:
1 H 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). 13 C 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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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 results of the above characterization of the target compounds are as follows:
MS m/z:517.2(M+H) + 。
example 5
5-chloro-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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:
1 H NMR(400MHz,CDCl 3 )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＝10.3,6.9 Hz,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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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:
1 H NMR(400MHz,CDCl 3 )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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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:
1 HNMR(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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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
N 2 - (4- (3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -5-chloro-N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-10)
The compounds were prepared according to scheme 13 using intermediate 3a (table 1) and intermediate 19b (table 10) to afford the desired products. The results of the above characterization of the target compounds are as follows:
1 H NMR(400MHz,CDCl 3 )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
N 2 - (4- (3, 6-diazabicyclo [ 3.1.1)]Heptane-6-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -5-chloro-N 4 - (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
N 2 - (4- ((1R, 5S) -3, 8-diazabicyclo [ 3.2.1)]Octane-3-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -5-chloro-N 4 - (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-N 2 - (2- (ethoxy-d) 5 ) -5-methyl-4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -N 4 - (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:
1 H NMR(400MHz,CDCl 3 )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-N 2 - (2- (ethoxy-d) 5 ) -5-methyl-4- (piperidin-4-yl) phenyl) -N 4 - (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:
1 H NMR(400MHz,CDCl 3 )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-N 2 - (2- (ethoxy-d) 5 ) -4- (piperidin-4-yl) phenyl) -N 4 - (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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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 results of the above characterization of the target compounds are as follows:
MS m/z:547.2(M+H) + 。
example 18
5-chloro-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (2, 6-diazaspiro [3.3 ]]Hept-2-yl) phenyl) pyrimidine-2, 4-diamine (I-18)
The compounds were prepared according to scheme 13 using intermediate 3a (Table 1) and intermediate 19g (Table 10) to give the desired products. The above target compounds were characterized as follows:
MS m/z:546.2(M+H) + 。
example 19
N 2 -(2-((2λ 8 -ethynyl-d 5 ) Oxy) -5-methyl-4- (2-azaspiro [3.3 ]]Heptane-2-yl) phenyl) -5-chloro-N 4 - (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
N 2 -(2-((2λ 8 -ethynyl-d 5 ) Oxy) -5-methyl-4- (2-oxy-6-azaspiro [3.3]Heptane-6-yl) phenyl) -5-chloro-N 4 - (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 results of the above characterization of the target compounds are as follows:
MS m/z:563.2(M+H) + 。
example 21
N 2 -(2-((2λ 8 -ethynyl-d 5 ) Oxy) -5-methyl-4- (2, 6-diazaspiro [3.3 ]]Heptane-2-yl) phenyl) -5-chloro-N 4 - (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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (piperazin-1-yl) phenyl) -5-methylpyrimidine-2, 4-diamine (I-25)
The compounds were 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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -4- (1, 2,3, 6-tetrahydropyridin-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-N 2 - (5-chloro-2- (methoxy-d) 3 ) -4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -N 4 - (2- (iso)Propylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-29)
The compounds were 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-d 3 ) -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 results of the above characterization of the target compounds are 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 results of the above characterization of the target compounds are 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 compounds are prepared according to scheme 12 using intermediate 3g (Table 1) and intermediate 19a (Table 10) to give the desired products. The above target compounds were characterized as follows:
MS m/z:536.2(M+H) + 。
example 34
5-chloro-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (5-methyl-4- (piperidin-4-yl) -2- (trifluoromethoxy) phenyl) pyrimidine-2, 4-diamine (I-34)
The compounds were 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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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 results of the above characterization of the target compounds are as follows:
MS m/z:585.5(M+H) + 。
example 37
N 2 - (2- (isopropylsulfonyl) phenyl) -N 4 - (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
N 2 - (2- (isopropylsulfonyl) phenyl) -N 4 - (2- (methoxy-d) 3 ) -4- (piperidin-4-yl) phenyl) -1,3, 5-triazine-2, 4-diamine (I-38)
The compounds were prepared according to scheme 13 using intermediate 7a (table 3) and intermediate 16b (table 8) to afford the desired products. The results of the above characterization of the target compounds are as follows:
MS m/z:486.5(M+H) + 。
example 39
N 2 - (2- (isopropylsulfonyl) phenyl) -N 4 - (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
N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -N 4 -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
N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (piperidin-4-yl) phenyl) -N 4 -methyl-5- (trifluoromethyl) pyrimidine-2, 4-diamine (I-41)
The compounds were 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:
1 H-NMR(400MHz,CD 3 COD)δ8.12(s,1H),7.96(s,1H),6.69(s,1H),4.14(d,2H,J＝13.1 Hz),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
N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (piperazin-1-yl) phenyl) -N 4 -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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) pyridine-2, 4-diamine (I-43)
The 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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (piperidin-4-yl) phenyl) pyridine-2, 4-diamine (I-44)
The 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:
1 H 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-N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (piperazin-1-yl) phenyl) pyridine-2, 4-diamine (I-45)
The compounds are prepared according to scheme 13 using intermediate 5 (scheme 3) and intermediate 19k (table 10) to afford the desired products. The results of the above characterization of the target compounds are as follows:
MS m/z:533.5(M+H) + 。
example 46
N 2 - (4- ((1S, 4S) 2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -5-fluoro-N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-46)
The compounds were 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
N 2 - (4- (3, 6-diazabicyclo [ 3.1.1)]Heptane-3-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -N 4 - (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
N 2 - (4- ((1S, 4S) -2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -N 4 - (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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 6 - (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-N 2 - (4- ((3aR, 6 aS) -hexahydropyrrole [3,4-c]Pyrrol-2 (1H) -yl) -2- (methoxy-d 3 ) -5-methylphenyl) -N 4 - (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:
1 H NMR(400MHz,CDCl 3 )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
N 2 - (4- ((1S, 4S) -2, 5-diazabicyclo [ 2.2.1)]Hept-2-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -5-chloro-N 4 - (2- (isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine (I-51)
The compounds were 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:
1 H NMR(400MHz,CDCl 3 )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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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
N 2 - (4- ((1S, 4S) -2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -N 4 - (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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (1, 2,3, 6-tetrahydropyridin-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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl group-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
N 2 - (4- ((1S, 4S) -2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -N 4 - (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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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 results of the above characterization of the target compounds are as follows:
MS m/z:536.2(M+H) + 。
example 59
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (2- (methoxy-d) 3 ) -5-methyl-4- (piperidin-4-yl) phenyl) -7H-pyrrolo [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
N 2 - (4- ((1S, 4S) -2, 5-diazacyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -N 4 - (2- (isopropylsulfonyl) phenyl) -7H-pyrrole [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
N 4 - (2- (isopropylsulfonyl) phenyl-) -N 2 - (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
N 4 - (2- (isopropylsulfonyl) phenyl) -N 2 - (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
N 2 - (4- ((1S, 4S) -2, 5-diazabicyclo [ 2.2.1)]Heptane-2-yl) -2- (methoxy-d 3 ) -5-methylphenyl) -N 4 - (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, and for IN vitro inhibition of LRRK2 kinase activity, according to the following steps:
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 using a 1-fold concentration of kinase reaction buffer. To each well of the reaction plate 2. Mu.L of LRRK2 kinase was added. 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 in a 1-fold concentration, and 1. Mu.L of the mixture of ATP and substrate at a concentration 4 times that of the kinase reaction buffer 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 40min. Transfer 8. Mu.L of detection solution to 384 reaction plates, centrifuge at 1000rpm/min for 1min, incubate at 25 ℃ for 40min. 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) =100% - (compound-positive control)/(negative control-positive control) × 100%; computing IC 50 And the inhibition curves of the compounds were plotted: IC of the compound was obtained using the following non-linear fit equation 50 (median inhibitory concentration) and data analysis was performed using Graphpad 7.0 software.
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -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 partial Compounds in vitro inhibition assay for kinase LRRK2 IC 50 Test results
Figure BDA0003270963300000361
Some of the target compounds synthesized in examples 1-63 were tested for their in vitro inhibition of LRRK 2G 2019S kinase activity according to the methods described above.
TABLE 14 in vitro inhibition assay IC for part of the Compounds on kinase LRRK 2G 2019S 50 Test results
Figure BDA0003270963300000362
According to the embodiment and the test results, the novel compound provided by the embodiment of the invention has a strong inhibition effect on both kinases LRRK2 and LRRK 2G 2019S, and has a very high application value in preparation of medicines for preventing and/or treating diseases related to the increase of the activity of the 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 (3)

1. Use of a compound of formula i or isotopic forms, stereoisomers, tautomers, pharmaceutically acceptable salts, and polymorphs thereof for the manufacture of a medicament for the inhibition of the activity of leu-rich repeat kinase 2 for the prevention and/or treatment of a disease; the compound shown in the formula I is one of the compounds shown in the following structures:
Figure DEST_PATH_IMAGE002
Figure DEST_PATH_IMAGE003
Figure DEST_PATH_IMAGE005
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE010
。
2. the use according to claim 1, 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.
3. The use according to claim 2, wherein the neurodegenerative disease comprises one or more of parkinson's disease, alzheimer's disease, huntington's disease, amyotrophic lateral sclerosis and motor neuron disease.
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