CN110156786B - Pyrimido-cyclic compounds, process for their preparation and their use - Google Patents

Pyrimido-cyclic compounds, process for their preparation and their use Download PDF

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CN110156786B
CN110156786B CN201810144135.3A CN201810144135A CN110156786B CN 110156786 B CN110156786 B CN 110156786B CN 201810144135 A CN201810144135 A CN 201810144135A CN 110156786 B CN110156786 B CN 110156786B
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azaspiro
compound
tert
decan
pyrimidin
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CN110156786A (en
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邹斌
张睿
付贤磊
马世超
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Shanghai Blueray Biopharma Co ltd
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Qingyu Pharmaceutical R & D Shanghai Co ltd
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Priority to CN202210427468.3A priority Critical patent/CN115448923B/en
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Priority to CN201810144135.3A priority patent/CN110156786B/en
Priority to MA051845A priority patent/MA51845A/en
Priority to SG11202007740TA priority patent/SG11202007740TA/en
Priority to JP2020543947A priority patent/JP7335882B2/en
Priority to US16/969,392 priority patent/US11498930B2/en
Priority to AU2019222026A priority patent/AU2019222026B2/en
Priority to KR1020207026395A priority patent/KR102614939B1/en
Priority to EP19754599.9A priority patent/EP3753941A4/en
Priority to PCT/CN2019/074685 priority patent/WO2019158019A1/en
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Abstract

Pyrimido compounds, pharmaceutically acceptable salts thereof, and solvates thereof are disclosed. The invention also provides a preparation method of the compounds, a composition containing the compounds and application of the compounds in preparing medicaments for treating diseases or symptoms related to abnormal activity of SHP 2.

Description

Pyrimido-cyclic compounds, process for their preparation and their use
Technical Field
Pyrimido compounds, pharmaceutically acceptable salts thereof, and solvates thereof are disclosed. The invention also provides a preparation method of the compounds, a composition containing the compounds and application of the compounds in preparing medicaments for treating diseases or symptoms related to abnormal activity of SHP 2.
Background
The tyrosine phosphatase SHP2 consists of two N-terminal Src homology 2 domains (N-SH2 and C-SH2) and a protein tyrosine phosphatase catalytic domain (PTP). In the basal state, N-SH2 can be combined with PTP to form a ring structure, so that the combination of PTP and substrate is blocked, and the enzyme catalytic activity is inhibited; when tyrosine of the upstream receptor protein is phosphorylated, N-SH2 is combined with the tyrosine, the PTP catalytic domain is released, and phosphatase activity is exerted.
At the cellular level, SHP2 is involved in multiple tumor cell signaling pathways, such as RTK/Ras/MAPK, JAK/STAT, and PI3K/Akt, among others, through a functional role downstream of the cytoplasm of many receptor tyrosine kinases. Through the regulation of these kinases and signaling pathways, SHP2 is closely related to many important vital cell activities, such as cell proliferation, migration, differentiation, death, cytokine regulation, tumorigenesis, etc.
At the same time, SHP2 is also involved in apoptosis receptor 1(PD1) mediated immune system suppression. After the PD-1 of the T cell is combined with PD-L1, a large amount of SHP2 can be recruited in the cell. SHP2 is capable of dephosphorylating an antigen receptor pathway protein within T cells, thereby inhibiting activation of T cells. Thus, inhibition of SHP2 activity could reverse immunosuppression in the tumor microenvironment.
SHP2 is an important member of the protein tyrosine phosphatase family and is associated with a variety of diseases in humans, such as Noonan Syndrome (Noonan Syndrome), Leopard Syndrome (Leopard Syndrome), juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large-cell lymphoma, and glioblastoma, among others.
A series of patents published recently, such as WO2018/013597a1, WO2017/210134a1, WO2017/211303a1, WO 2017/216706a1, WO 2016/203406a1, WO 2016/203405a1, WO 2016/203404a1, WO2015/107495a1, WO2015/107494a1, and WO2015/107493a1, etc., indicate that SHP2 is attracting increasing attention as a novel druggable target. Surrounding the development of the SHP2 inhibitor, there are two major strategies, inhibitor development for the PTP catalytic domain of SHP2 and allosteric inhibitor development for the non-catalytic domain; due to the problems of selectivity and poor pharmaceutical properties of PTP catalytic domain inhibitors, more research is currently directed towards the development of allosteric inhibitors. The above patents disclose allosteric inhibition, but most of them have low inhibitory activity against tumor cells, and for example, the compound SHP099(6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazine-2-amine) disclosed in WO2015/107493a1 is to be further developed into an SHP2 inhibitor having a novel structure, good biological activity and high pharmaceutical activity.
Disclosure of Invention
The pyrimido-cyclic compound provided by the invention is a brand-new SHP2 inhibitor, shows good inhibitory activity on tumor cells, has good drug-forming property and has wide drug development prospect. And the preparation method of the compound is simple and is beneficial to industrial production.
In a first aspect, the present invention provides a pyrimido ring compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt.
Figure BDA0001579586110000021
Wherein
Z1、Z2Simultaneously is C or one of them is N;
x is independently S or absent;
y is independently C or N;
n is independently 0, 1 or 2;
R1independently 0 to 4R1aSubstituted phenyl, 0 to 4R1aSubstituted containing 1-4 azaaryl groups, 0 to 4R1aSubstituted naphthyl, 0 to 4R1aSubstituted azanaphthalene aryl containing 1-4, 0 to 4R1aSubstituted or unsubstituted benzoheterocycles, 0 to 4R1aSubstituted or unsubstituted aromatic ring containing 1-4 nitrogen, 0 to 4R1aSubstituted containing 1-4N, NR1bHetero aromatic ring of hetero atom such as O or S (O) m, R1cSubstituted or unsubstituted C1-8Alkyl radical, R1cSubstituted or unsubstituted C1-8A haloalkyl group; wherein m is selected from 0, 1 and 2;
R1aindependently of one another is halogen, R1a1Substituted or unsubstituted C1-4Alkoxy radical, R1a1Substituted or unsubstituted C1-4Alkyl, trifluoromethyl, C (═ O) OR1a2、NR1a2R1a3、NHC(＝O)R1a4、R1a1Substituted or unsubstituted C3-8A cycloalkyl group; r1a1Independently is halogen or C1-4An alkyl group; r1a2、R1a3Independently of one another is hydrogen, C1-4An alkyl group; r1a4Independently is C1-4Alkyl, substituted or unsubstituted alkenyl, amide, C3-12Mono-or poly-heterocyclic;
R1bindependently of each other is hydrogen, R 1a1Substituted or unsubstituted C1-4An alkyl group;
R1cindependently hydrogen, -C (═ O) OR1a2、R1a1Substituted or unsubstituted C1-4An alkyl group;
R2a、R2b、R3aand R3bIndependently of each other is hydrogen, R1a1Substituted or notSubstituted C1-4An alkyl group;
when Y is N, R4Independently of each other is hydrogen, R1a1Substituted or unsubstituted C1-4An alkyl group; r5Is absent;
when Y is ═ C, R4、R5Independently of one another hydrogen, aryl, C1-4Alkyl radical, C1-4Alkoxy, -O-C1-4Alkyl, amino, C1-4Alkyl substituted amino, -O-C1-4Alkyl-substituted amino, or R4And R5Together with Y form 0 to 3R4aA substituted 3-to 7-membered saturated or partially unsaturated spirocyclic ring, which ring may optionally contain 1 to 3 heteroatoms or groups independently selected from N, C (═ O) and/or O;
R4aindependently hydrogen, halogen, R1a1Substituted or unsubstituted C1-4Alkoxy radical, R1a1Substituted or unsubstituted C1-4Alkyl, hydroxy, amino, C1-4An alkylamino group.
In one preferred embodiment, the pyrimido compound of the invention has the structure of formula (II)
Figure BDA0001579586110000031
In another preferred embodiment, R1Selected from the following structures:
Figure BDA0001579586110000041
wherein o is 0, 1, 2, 3 or 4; ring a is a heteroaryl group containing 1 to 4N atoms; ring B is a heteroaryl group containing 1 to 4 heteroatoms such as N, S, O; g is independently a heteroatom or group such as C, C (═ O), N, S, or O; r1aa、R1abIndependently is R 1a；R1acIndependently is R1cSubstituted or unsubstituted C1-8Alkyl, R1cSubstituted or unsubstituted C1-8An alkyl halide;
in another preferred embodiment, R2a、R2b、R3aAnd R3bIndependently hydrogen or methyl;
in another preferred embodiment, when Y ═ N, R4Independently hydrogen, methyl; r5Is absent;
in another preferred embodiment, when Y ═ C, R4、R5Independently hydrogen, methyl, ethyl, phenyl, amino, methylamino or ethylamino;
in another preferred embodiment, when Y ═ C, R4And R5The ring formed with Y is selected from the following structures:
Figure BDA0001579586110000042
wherein p is 0, 1, 2 or 3; r4aAs defined above;
in another preferred embodiment, when Y ═ C, R4And R5The ring formed with Y is selected from the following configurations:
Figure BDA0001579586110000043
wherein, p and R4aAs defined above;
in another preferred embodiment, the compound is selected from any one of the following compounds:
Figure BDA0001579586110000051
Figure BDA0001579586110000061
Figure BDA0001579586110000071
Figure BDA0001579586110000081
Figure BDA0001579586110000091
Figure BDA0001579586110000101
Figure BDA0001579586110000111
Figure BDA0001579586110000121
Figure BDA0001579586110000131
in another aspect, the present invention provides an isotopically labeled compound of a pyrimido ring compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. The atom capable of being isotopically labeled in the compound represented by the formula (I) includes, but is not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine and the like. Each of which can be isotopically substituted2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl and125i, and the like.
In another aspect, the present invention provides a process for preparing pyrimido compounds represented by formula (I) and intermediates thereof, which comprises the following steps:
The invention provides a preparation method of a formula (I), which comprises the following steps:
halogenated intermediate compounds
Figure BDA0001579586110000141
With boric acid, mercaptans or sodium thionates(F) After the coupling reaction, the formula (I) is obtained, and the reaction equation is as follows:
Figure BDA0001579586110000142
wherein, W1Represents halogen, preferably Br, I; z1、Z2、X、Y、n、R1、R2a、R2b、R3a、R3b、R4And R5Is as defined above.
In one preferred embodiment, the preparation method of formula (II) comprises the steps of:
the halogenated intermediate compound A and boric acid, mercaptan or sodium (F) are subjected to coupling reaction to obtain a compound shown in a formula (II), wherein the reaction equation is as follows:
Figure BDA0001579586110000143
wherein, W1Represents halogen, preferably Br, I; x, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5Is as defined above.
The present invention also provides a process for the preparation of compound A,
Figure BDA0001579586110000151
wherein, W1Represents halogen, preferably Br, I; r2a、R2b、R3a、R3b、R4、R5Y, n are as defined above.
The invention also provides a preparation method of the compound A, which comprises the following steps:
the halogenated intermediate E is substituted by the intermediate amine C under the alkaline condition to obtain an intermediate compound A, and the reaction equation is as follows:
Figure BDA0001579586110000152
wherein, W1Represents halogen, preferably Br, I; w2Represents halogen, preferably Cl, Br, I; y, n, R2a、R2b、R3a、R3b、R4And R5Is as defined above.
The present invention also provides a compound of formula C-1,
Figure BDA0001579586110000153
wherein U is independently C or O; q is selected from 0, 1 or 2; pg is selected from protecting groups Boc, Ac, S (═ O) tBu；n、R2a、R2b、R3a、R3bAnd R4aIs as defined above.
The invention also provides a preparation method of the compound C-1, which comprises the following steps:
the spirocyclic ketone compound C-1a is subjected to reductive amination to obtain an intermediate C-1 b; c-1b is selectively deprotected to obtain C-1, the reaction equation is as follows:
Figure BDA0001579586110000154
wherein Pg1 is selected from protecting groups such as Boc, benzoyl and benzyl; pg, U, q, n, R2a、R2b、R3a、R3bAnd R4aIs as defined above.
The present invention also provides a compound of formula C-2,
Figure BDA0001579586110000161
wherein R is6Independently is C1-8An alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkenyl group; u, q, Pg, n, R2a、R2b、R3a、R3bAnd R4aIs as defined inAs described above.
The invention also provides a preparation method of the compound C-2, which comprises the following steps:
spirocyclic ketone compounds C-1a and R6The substituted nucleophilic reagent is added to obtain a hydroxyl compound C-2 a; the compound C-2a is converted into an amino compound C-2b, and then the protecting group Pg1 is selectively removed to obtain C-2, wherein the reaction equation is as follows:
Figure BDA0001579586110000162
wherein R is6、U、q、Pg1、Pg、n、R2a、R2b、R3a、R3bAnd R4aIs as defined above.
The present invention also provides a compound of formula C-3,
Figure BDA0001579586110000163
wherein R is6、Pg、n、R2a、R2b、R3aAnd R3bIs as defined above.
The invention also provides a preparation method of the compound C-3, which comprises the following steps:
ester group ortho-dehydrogenation of Compound C-3a with R6The substituted electrophile is substituted to obtain a compound C-3 b; hydrolyzing the ester group by the compound C-3b to obtain acid C-3C; rearrangement of acid C-3C to obtain amine C-3d, selective removal of protecting group Pg1 to obtain C-3, the reaction equation is as follows:
Figure BDA0001579586110000171
Wherein R is6、Pg1、Pg、n、R2a、R2b、R3aAnd R3bIs as defined above.
The present invention also provides a compound of formula C-4,
Figure BDA0001579586110000172
wherein R is6、Pg、n、R2a、R2b、R3aAnd R3bIs as defined above.
The invention also provides a preparation method of the compound C-4, which comprises the following steps:
reducing cyano compound C-4a and protecting amino to obtain intermediate C-4b, and then selectively removing protecting group Pg1 to obtain C-4, wherein the reaction equation is as follows:
Figure BDA0001579586110000173
wherein Pg1, Pg, R6、n、R2a、R2b、R3aAnd R3bIs as defined above.
The present invention also provides a compound of formula (I),
Figure BDA0001579586110000181
wherein, W1Represents halogen, preferably Br, I; w2Represents halogen, preferably Cl, Br, I;
the invention also provides a preparation method of the compound E, which comprises the following steps:
halogenating the hydroxyl intermediate B-3 to obtain a double-halogen substituted compound E, wherein the reaction equation is as follows:
Figure BDA0001579586110000182
wherein, W1Represents halogen, preferably Br, I; w2Represents halogen, preferably Cl, Br, I;
the invention also provides compounds F-1, F-2,
Figure BDA0001579586110000183
wherein, V is independently C or N; r1aIs as defined above.
The invention also provides a preparation method of the compound F-1, which comprises the following steps:
halogenated compound F-1a and methyl mercaptopropionate are subjected to catalytic coupling to obtain intermediate F-1b, and then corresponding sodium sulfide compound F-1 is obtained under alkaline condition;
the invention also provides a preparation method of the compound F-2, which comprises the following steps:
The halogenated compound F-1a is condensed with mercaptan to obtain an intermediate F-2b, and then the thiophenol compound F-2 is obtained under the acidic condition.
The reaction equations for preparing F-1 and F-2 are as follows:
Figure BDA0001579586110000191
wherein, W3Is halogen, preferably Br, I; v, R1aIs as defined above.
The present invention also provides another process for preparing a pyrimido-cyclic compound represented by formula (I), comprising the steps of:
intermediates
Figure BDA0001579586110000192
Substitution with amine C gives formula (I), the reaction equation is as follows:
Figure BDA0001579586110000193
wherein, W2Represents halogen, preferably Cl, Br, I; z1、Z2、X、Y、n、R1、R2a、R2b、R3a、R3b、R4And R5Is as defined above.
In one preferred embodiment, the preparation method of formula (II) comprises the steps of:
substitution of the halogenated intermediate compound B with an amine C gives the formula (II) as follows:
Figure BDA0001579586110000194
wherein, W2Represents halogen, preferably Cl, Br, I; x, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5Is as defined above.
The present invention also provides a compound B,
Figure BDA0001579586110000201
wherein, W2Represents halogen, preferably Cl, Br, I; r1And X is as defined above;
the invention also provides a preparation method of the compound B, which comprises the following steps:
substituting dichloro pyrimidine compound B-1 with amine to obtain intermediate B-2; the intermediate B-2 is condensed, cyclized and hydrolyzed under the strong acid condition to obtain a halogenated intermediate B-3; halogenated intermediate B-3 is subjected to catalytic coupling to obtain intermediate B-4, and then converted into intermediate B, wherein the reaction equation is as follows:
Figure BDA0001579586110000202
Wherein W1Represents halogen, preferably Br, I; w2Represents halogen, preferably Cl, Br, I; r1And X is as defined above.
In another preferred embodiment, the preparation method of the compound II-A comprises the following steps:
coupling the sodium sulfur intermediate compound D with a halide to obtain a compound of formula (II-A), wherein the reaction equation is as follows:
Figure BDA0001579586110000203
wherein, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5Is as defined above.
The present invention also provides a compound D which is,
Figure BDA0001579586110000211
wherein, Y, n, R2a、R2b、R3a、R3b、R4And R5Is as defined above.
The present invention also provides a process for the preparation of compound D comprising the steps of:
the intermediate compound A and methyl mercaptopropionate obtain an intermediate D-1 under the condition of catalytic coupling, and then obtain a corresponding sodium sulfide compound D under the alkaline condition, wherein the reaction equation is as follows:
Figure BDA0001579586110000212
wherein, W1Represents halogen, preferably Br, I; y, n, R2a、R2b、R3a、R3b、R4And R5Is as defined above.
In another preferred embodiment, the preparation method of the compound II-B comprises the following steps:
removing the amino protecting group of the intermediate II-B1 under acidic or basic conditions to obtain a compound II-B, wherein the reaction equation is as follows:
Figure BDA0001579586110000213
wherein Pg is selected from protecting groups Boc, Ac, S (═ O)tBu；R4Pg、R5PgTogether with the linking carbon, is selected from the following structures：
Figure BDA0001579586110000221
R4、R5Together with the linking carbon, is selected from the following structures:
Figure BDA0001579586110000222
X、n、R1、R2a、R2b、R3a、R3b、R4、R5And R4aAs defined above; p is 0, 1,2 or 3.
In another preferred embodiment, the process for the preparation of compounds II-C comprises the following steps:
aminoacylation of intermediate II-C1 yields compound II-C, the reaction equation is as follows:
Figure BDA0001579586110000223
wherein, X, Y, n, R1、R2a、R2b、R3a、R3b、R4、R5、R1aAnd R1a4Is as defined above.
The solvent involved in the present invention is selected from: dichloromethane, chloroform, 1, 2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF, or a combination thereof.
The base to which the present invention relates includes organic bases and inorganic bases.
The organic base to which the present invention relates is preferably: TEA, DIPEA, or a combination thereof.
The inorganic base according to the present invention is preferably: sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, LiHMDS, LDA, butyllithium or combinations thereof.
Isotopically labeled compounds of pyrimido ring compounds of formula (I) described in this invention can be prepared by analogous synthetic procedures to those for unlabeled compounds, except that the unlabeled starting materials and/or reagents are replaced with isotopically labeled starting materials and/or reagents.
In another aspect, the present invention also provides a pharmaceutical composition comprising a pyrimido-cyclic compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or an isotopically labeled compound of a pyrimido-cyclic compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipients are preferably selected from diluents, absorbents, wetting agents, binders, disintegrants, lubricants.
In another aspect, the invention also provides the use of the pyrimido-cyclic compound shown as the formula (I), the pharmaceutically acceptable salt thereof or the solvate thereof in preparing a medicament for treating diseases or symptoms related to abnormal activity of SHP 2. Preferably, the disease or disorder includes, but is not limited to, noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large-cell lymphoma or glioblastoma.
In another aspect, the present invention provides a pharmaceutical preparation comprising the pyrimido-cyclic compound of formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, which can be administered in a suitable manner, such as in the form of a suspension, syrup, emulsion, solution, etc., in the form of tablets, capsules (e.g., sustained release or timed release capsules), pills, powders, granules (e.g., small particles), elixirs, tinctures, suspensions (e.g., nanosuspensions, microsuspensions) and spray-dried dispersions, and can be administered orally, sublingually, by injection including subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, infusion, etc., nasally (e.g., nasal inhalation), topically (e.g., creams and ointments), rectally (e.g., suppositories), etc. The compounds disclosed herein may be administered alone or in combination with a suitable pharmaceutical carrier.
In another aspect, the invention provides that the pharmaceutical formulation of the previous aspect may be formulated in an appropriate dosage to facilitate and control the dosage of the drug. The dosage regimen of the compounds disclosed herein will vary with such factors as the pharmacodynamics and mode of administration, the subject, sex, age, health, weight, condition, other concurrent conditions, frequency of administration, liver and kidney function, and the effect desired, etc. The compounds disclosed herein may be administered in a single dose per day, or may be administered in a total dose divided into multiple doses (e.g., two to four times per day).
In another aspect, the present invention also provides a pyrimido compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in combination with another drug selected from the group consisting of: anticancer drugs, tumor immunity drugs, antiallergic drugs, antiemetics, analgesics, cytoprotective drugs, etc., which have a better effect when used in combination. It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
The invention has the following advantages:
1. the pyrimido-cyclic compound disclosed by the invention is a novel allosteric inhibitor and can be combined with a non-catalytic region of SHP2 to lock a basic state with weak activity of SHP2, so that the aim of inhibiting the activity of the pyrimido-cyclic compound is fulfilled. The pyrimido-cyclic compound disclosed by the invention overcomes the defects of poor general selectivity and druggability and the like of a PTP catalytic domain inhibitor, shows good biological activity and druggability, and has a good drug development prospect.
2. In the same evaluation system of SHP2 enzyme activity inhibition experiment, phosphorylation protein kinase (p-ERK) cell experiment, MOLM-13 cell proliferation experiment and the like, the invention shows more excellent activity compared with the compound SHP099(6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazine-2-amine) disclosed in WO 2015/107493A 1 and literature (Nature 2016,535, 148-.
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
Radical definitions
Definitions for the terms of the standardization sector can be found in the literature references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols.A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the instructions of the kit from the manufacturer, or according to the methods known in the art or the instructions of the present invention. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds. When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH 2O-is equivalent to OCH2-。
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C1-6Alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.
In addition to the foregoing, the following terms, when used in the specification and claims of this application, have the meanings indicated below, unless otherwise specifically indicated.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
"hydroxy" means an-OH group. Alkoxy "refers to an alkyl group as defined below substituted with a hydroxyl (-OH) group.
"carbonyl" refers to a-C (═ O) -group. "cyano" means-CN.
"amino" refers to-NH 2.
"substituted amino" refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, e.g., monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino.
"carboxyl" means-COOH.
In this application, the term "alkyl" as a group or as part of another group (e.g., as used in halo-substituted alkyl and the like groups) refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and attached to the remainder of the molecule by a single bond, including, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like. For the purposes of the present invention, the term "alkyl" refers to alkyl groups containing from 1 to 6 carbon atoms.
In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "cycloalkyl" as a group or as part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, which may include fused, bridged or spiro ring systems, having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be attached to the rest of the molecule by a single bond via any suitable carbon atom. Unless otherwise specifically indicated in the specification, carbon atoms in the cyclic hydrocarbon group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2, 3-indanyl, 1,2,3, 4-tetrahydro-naphthyl, 5,6,7, 8-tetrahydro-naphthyl, 8, 9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9, 10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo [2.2.1] heptyl, 7 dimethyl-bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, bicyclo [2.2.2] octyl, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, Bicyclo [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene-1H-indenyl, octahydro-2, 5-methylene-pentalenyl and the like.
In this application, the term "heterocyclyl" as a group or part of another group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused ring systems, bridged ring systems or spiro ring systems; wherein the nitrogen, carbon or sulfur atom in the heterocyclic group thereof may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In this application, the term "aryl" as a group or as part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or higher polycyclic ring system and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2, 3-dihydro-1H isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like.
In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
In this application, the term "heteroaryl" as a group or part of another group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5-to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5-to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [1,2,4] triazolo [4,3-b ] pyridazine, [1,2,4] triazolo [4,3-a ] pyrazine, [1,2,4] triazolo [4,3-c ] pyrimidine, [1,2,4] triazolo [4,3-a ] pyridine, imidazo [1,2-b ] pyridazine, imidazo [1,2-a ] pyrazine and the like.
In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted with a heteroaryl group as defined above. In this application, "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
The "optionally" substituents described in the claims and the description section of the present invention are selected from alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl.
The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities that are embedded in or attached to a molecule.
When the compounds of the present invention contain olefinic double bonds, the compounds of the present invention are intended to include both E-and Z-geometric isomers unless otherwise specified.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule.
All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention. The compounds of the present invention or pharmaceutically acceptable salts thereof may contain one or more chiral carbon atoms and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms. Each chiral carbon atom may be defined as (R) -or (S) -, based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms thereof. The compounds of the invention may be prepared by selecting as starting materials or intermediates racemates, diastereomers or enantiomers. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, e.g., crystallization and chiral chromatography.
Substituents of the invention or representing symbols, e.g. Z1、Z2、X、Y、U、V、W1、W2、W3、n、o、p、q、R1、R2a、R2b、R3a、R3b、R4、R5Pg1, Pg, etc., and like reference numerals refer to like definitions in various places unless otherwise specified.
Conventional techniques for the preparation/separation of individual isomers include Chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, Chiral high performance liquid chromatography, as described, for example, in Gerald Gubitz and Martin G.Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; m. Stalcup, Chiral Separations, Annu. Rev. anal. chem.3:341-63, 2010; fumiss et al (eds.), VOGEL' S ENCYCOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. TH ED., Longman Scientific and Technical Ltd., Essex,1991, 809-816; heller, acc, chem, res, 1990,23,128.
In the present application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, 2 dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamate, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
In the present application, "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivering biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to a living body, facilitate absorption of the active ingredient, and exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition. As used herein, "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental agency of authorities for use in humans or livestock.
The "tumor" of the present invention includes, but is not limited to, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, sarcoma, melanoma, articular chondroma, cholangioma, leukemia, gastrointestinal stromal tumor, diffuse large B-cell lymphoma, lymphoid cancer such as follicular lymphoma, histiocytic lymphoma, non-small cell lung cancer, pancreatic cancer, squamous cell lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer, multiple myeloma, mesothelioma, malignant rhabdoid tumor, endometrial cancer, head and neck cancer, thyroid cancer, parathyroid tumor, uterine tumor, and soft tissue sarcoma.
The terms "preventing", "prevention" and "prevention" as used herein include reducing the likelihood that a disease or disorder will occur or worsen in a subject.
As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii) inhibiting the disease or disorder, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., resolving the state of the disease or condition; or
(iv) Alleviating the symptoms caused by the disease or disorder.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant remission effect of the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay. The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Administration techniques useful for The compounds and methods described herein are well known to those skilled in The art, for example, in Goodman and Gilman, The pharmaceutical Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
The terms "drug combination", "administering other treatment", "administering other therapeutic agent" and the like as used herein refer to a drug treatment obtained by mixing or combining more than one active ingredient, including fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one co-agent to a patient in the form of a single entity or a single dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one synergistic formulation are administered to a patient as separate entities either simultaneously, in combination, or sequentially at variable intervals. These also apply to cocktail therapy, for example the administration of three or more active ingredients. It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include-C (O) -R "(where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters. Protecting groups may be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting Groups is described in detail in Greene, T.W. and P.G.M.Wuts, Protective Groups in organic Synthesis, (1999),4th Ed., Wiley. The protecting group may also be a polymeric resin.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
The starting materials used in the following examples are commercially available from chemical vendors such as Aldrich, TCI, Alfa Aesar, Bidey, Annelgie, etc., or can be synthesized by known methods.
In the following examples, the ice bath refers to-5 ℃ to 0 ℃, the room temperature refers to 10 ℃ to 30 ℃, and the reflux temperature refers to the solvent reflux temperature under normal pressure. The reaction overnight means a time of 8-15 hours. In the following examples, the operation temperature is not limited and is at room temperature.
In the following examples, the separation and purification of intermediates and final products are by normal phase or reverse phase chromatographic column separation or other suitable methods. The normal phase flash chromatographic column uses ethyl acetate and n-hexane or methanol and dichloromethane and the like as mobile phases. Reverse phase preparative High Pressure Liquid Chromatography (HPLC) was carried out using a C18 column with UV 214nm and 254nm detection and mobile phases A (water and 0.1% formic acid), B (acetonitrile) or mobile phases A (water and 0.1% ammonium bicarbonate), B (acetonitrile).
In each example: LCMS apparatus: pump Agilent 1260 UV detector: agilent 1260DAD Mass Spectrometer API 3000
A chromatographic column: waters sunfire C18, 4.6X 50mm,5um
Mobile phase: A-H2O (0.1% HCOOH); b-acetonitrile NMR
The instrument comprises the following steps: bruker Ascend 400M (1H NMR:400MHz；13C NMR:100MHz)。
Example 1: preparation of intermediate 5-chloro-8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidine (B1)
The method comprises the following steps: 2-chloro-N- (2, 2-dimethoxyethyl) -5-iodopyrimidin-4-amine
Figure BDA0001579586110000331
To a dry 2L flask were added 2, 4-dichloro-5-iodopyrimidine (110g,400mmol) and 2, 2-dimethoxyethylamine (84g,800mmol) followed by absolute ethanol (1.2L). After triethylamine (109mL,800mmol) was slowly added dropwise thereto under nitrogen at 0 ℃ the mixture was stirred at room temperature for 10 hours. After completion of the reaction, concentration was performed in vacuo, and the resulting concentrate was added with 1L of water and extracted with methylene chloride (3X 300mL), washed with saturated brine and the organic layer was mixed, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting brown black solid was washed with anhydrous ethanol (3X 50mL) to give 2-chloro-N- (2, 2-dimethoxyethyl) -5-iodopyrimidin-4-amine (110g, yield: 78%) as a brown solid.
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),4.58(t,J＝5.4Hz,1H),3.47(t,J＝5.6Hz,2H),3.29(s,6H)ppm；LC-MS:m/z 344.1[M+H]+。
Step two: 8-iodoimidazo [1,2-c ] pyrimidin-5-ol
Figure BDA0001579586110000341
To a dry 2L flask were added 2-chloro-N- (2, 2-dimethoxyethyl) -5-iodopyrimidin-4-amine (110g,317mmol) and 800mL of concentrated sulfuric acid in that order. The mixture was heated to 65 ℃ under nitrogen and the reaction stirred for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the mixture was slowly poured into ice water, and then the pH was adjusted to about 6.0 with a 4M NaOH solution and extracted with ethyl acetate (3 × 300mL), the organic layers were mixed and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 8-iodoimidazo [1,2-c ] pyrimidin-5-ol (70g, yield 84.5%).
1H NMR(400MHz,DMSO-d6)δ11.80(s,1H),7.92(d,J＝1.5Hz,1H),7.60(d,J＝3.9Hz,1H),7.40(d,J＝1.5Hz,1H)；LC-MS:m/z 262.1[M+H]+。
Step three: 8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-ol
Figure BDA0001579586110000342
Sequentially adding 8-iodoimidazo [1,2-c ] into a dry 250mL three-neck flask]Pyrimidin-5-ol (2.61g,10mmol), cuprous iodide (190mg,1mmol), 1, 10-phenanthroline (360mg,2mmol), 2, 3-dichlorothiophenol (2.15g,12mmol), potassium phosphate (4.2g,20mmol), and 50mL of dioxane solvent. The mixture was heated under nitrogen for 3 hours. After the reaction is finished, saturated NH is added4Cl solution (200 mL). It was extracted with ethyl acetate (3 × 200 mL). The combined organic phases are washed with Na2SO4Drying, filtering, concentrating the filtrate under reduced pressure, and purifying the resulting residue by silica gel chromatography (0 to 10% gradient of methanol: ethyl acetate) to give 8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c as a pale yellow solid ]Pyrimidin-5-ol (2.3g, yield: 74%).
LC-MS:m/z 312.1[M+H]+.
Step four: 5-chloro-8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidine (B1)
Figure BDA0001579586110000351
To a dry 100mL single neck flask were added sequentially 8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-ol (2.3g,7.3mmol) and phosphorus oxychloride (30mL), then N, N-diisopropylethylamine (1mL) was added slowly dropwise under nitrogen, after which the mixture was heated to 120 ℃ and stirred for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and then the mixture was concentrated in vacuo and quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3 × 30mL), washed with saturated brine and the organic layer was mixed, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel chromatography (gradient 0 to 10% methanol: ethyl acetate) to give 5-chloro-8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidine B1(660mg, yield: 27.4%) as a white solid.
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝1.4Hz,1H),8.07(s,1H),7.76(d,J＝1.4Hz,1H),7.52(dd,J＝8.0,1.3Hz,1H),7.17(t,J＝8.0Hz,1H),7.00(dd,J＝8.1,1.2Hz,1H)ppm；LC-MS:m/z 330.1[M+H]+.
Example 2: preparation of intermediate 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine (E1)
Figure BDA0001579586110000352
To a dry 250mL single neck flask were added 8-iodoimidazo [1,2-c ] pyrimidin-5-ol (5g,19.1mmol) and phosphorus oxychloride (50mL) in that order, N-diisopropylethylamine (1mL) was added slowly dropwise under a nitrogen blanket, after which the mixture was heated to 120 ℃ and stirred for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated in vacuo, then quenched by addition of saturated sodium bicarbonate solution, extracted with ethyl acetate (3 × 100mL), the organic layers were mixed and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified by silica gel chromatography (0 to 10% gradient of methanol: ethyl acetate) to give 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine E1(1.6g, yield: 29.8%).
1H NMR(400MHz,Methanol-d4)δ8.28(s,1H),8.16(d,J＝1.6Hz,1H),7.81(d,J＝1.6Hz,1H)ppm；LC-MS:m/z 280.1[M+H]+.
Example 3: preparation of intermediate (R) -2-methyl-N- ((R) -8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1A)
The method comprises the following steps: (R) -1- ((R) -1, 1-Dimethylethylsulfonamido) -8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000361
1-carbonyl-8-azaspiro [4.5] was added to a dry 100mL single-neck bottle in sequence]Tert-butyl decane-8-carboxylate (2.53g,10mmol), titanium tetraethoxide (6.84g,30mmol) and 50mL of tetrahydrofuran were stirred under reflux with heating for 4 hours. After cooling to room temperature, methanol (10mL) was added followed by lithium borohydride (0.65g,30 mmol). The resulting mixture was stirred at room temperature for 3 hours. Methanol was added slowly to quench excess borohydride, followed by addition of brine. The resulting mixture was stirred for 15 minutes and then filtered through celite. The aqueous mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with MgSO4Dry, filter, and remove volatiles under reduced pressure. The residue obtained is purified by chromatography on silica gel (gradient 0 to 50% ethyl acetate: petroleum ether) to give (R) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] as a white solid]Tert-butyl decane-8-carboxylate (2.86g, yield: 80%).
LC-MS:m/z 359.1[M+H]+.
Step two: (R) -2-methyl-N- ((R) -8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1A)
Figure BDA0001579586110000362
Reacting (R) -1- ((R) -1, 1-dimethylethylsulfineAmido) -8-azaspiro [4.5]A solution of tert-butyl decane-8-carboxylate (2.86g,8mmol) and concentrated sulfuric acid (2.0mL, 32mmol) in dioxane (50mL) was stirred at room temperature for 2 hours. Adding Na2CO3The aqueous solution was saturated until pH 11 and the aqueous mixture was extracted with DCM (3 × 50 mL). The combined organic phases were washed with brine, washed with Na2SO4Drying, filtering and removing volatiles under reduced pressure to give (R) -2-methyl-N- ((R) -8-azaspiro [4.5] as a white solid]Decan-1-yl) propane-2-sulfinamide C-1A (1.86g, yield: 90%)
1H NMR(400MHz,DMSO-d6)δ4.82(d,J＝7.5Hz,1H),3.04(d,J＝7.6Hz,1H),2.81(ddd,J＝12.1,8.0,4.0Hz,2H),2.60-2.51(m,2H),1.92-1.14(m,10H),1.12(s,9H)ppm；LC-MS:m/z259.1[M+H]+.
Following the synthetic procedure of example 1, using similar starting materials, the following intermediate C-1B, C-1C, C-1D, C-1E, C-1F, C-1G was obtained.
Figure BDA0001579586110000371
Example 4: preparation of intermediate (R) -2-methyl-N- ((S) -2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1H)
The method comprises the following steps: 4- (2- (benzyloxy) -1-hydroxyethyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl-4-methyl ester
Figure BDA0001579586110000381
To a dry 500mL three-necked flask, 1-tert-butyl-4-methylpiperidine-1, 4-dicarboxylate (45g,180mmol) and tetrahydrofuran (400mL) were added successively under nitrogen, and the solution was cooled to-78 deg.C, and LiHMDS (261mL,261mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred at room temperature for 3 hours. It was then cooled again to-78 ℃ and a solution of benzyloxyacetaldehyde (46g,300mmol) in tetrahydrofuran (50mL) was slowly added dropwise. The reaction was slowly warmed to room temperature and stirred for 2.5 hours. After the reaction is finished, adding saturated NH 4The reaction was quenched with Cl solution (200 mL). It was extracted with ethyl acetate (3 × 200 mL). The combined organic phases are treated with Na2SO4Drying, filtration, concentration of the filtrate under reduced pressure and purification of the resulting residue by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) gave 4- (2- (benzyloxy) -1-hydroxyethyl) piperidine-1, 4-dicarboxylic acid 1-tert-butyl-4-methyl ester (52g, yield: 73.3%).
1H NMR(400MHz,CDCl3)δ7.36-7.30(m,5H),4.50(s,2H),3.97(s,2H),3.73-3.65(m,2H),3.62(s,3H),3.59-3.48(m,3H),2.88(d,J＝6.2Hz,1H),2.23(dd,J＝13.7,2.7Hz,1H),2.04-1.88(m,2H),1.74(d,J＝14.7Hz,1H),1.56(d,J＝4.2Hz,1H),1.44(s,9H)ppm；LC-MS:m/z 294.1[M+H]+.
Step two: 4- (2- (benzyloxy) -1-hydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000382
To a dry 500mL three-necked flask was added a solution of 4- (2- (benzyloxy) -1-hydroxyethyl) piperidine-1, 4-dicarboxylic acid-1-tert-butyl-4-methyl ester (51.4g,130mmol) and tetrahydrofuran (500mL) in this order, and then LiBH was added to the solution4(11.44g,520mmol) and stirred at room temperature for 6 hours. After the reaction was complete, saturated NaHCO was used3The reaction was quenched (200 mL). Extract with ethyl acetate (3 × 200 mL). The combined organic phases were washed with Na2S04Drying, filtration, concentration of the filtrate under reduced pressure and purification of the resulting residue by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) gave 4- (2- (benzyloxy) -1-hydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester (27g, yield: 57%).
LC-MS:m/z 266.1[M+H]+.
Step three: 4- (1, 2-dihydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000391
To a dry 500mL one-necked flask were added tert-butyl 4- (2- (benzyloxy) -1-hydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylate (27g,74mmol), methanol (270mL) and Pd/C (20g) in this order, followed by replacement three times with a hydrogen balloon and stirring at room temperature for 12 hours. The reaction mixture was filtered and concentrated to give tert-butyl 4- (1, 2-dihydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylate (18.9g, yield: 93%).
LC-MS:m/z 176.1[M+H]+.
Step four: 4-hydroxy-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000392
To a dry 500mL single-neck flask were added tert-butyl 4- (1, 2-dihydroxyethyl) -4- (hydroxymethyl) piperidine-1-carboxylate (18.9g, 69mmol), triphenylphosphine (25.2g,86.25mmol) and tetrahydrofuran (350mL) in that order, the reaction was cooled to 0 deg.C and DEAD (12.46mL,86mmol) was added, then warmed to room temperature and stirred for 5 hours. After completion of the reaction, the reaction was quenched by addition of saturated water (200 mL). It was extracted with ethyl acetate (3 × 200 mL). The organic phases were combined and washed with Na2SO4Drying, filtering, concentrating the filtrate under reduced pressure and purifying the resulting residue by silica gel chromatography (0 to 2% gradient of methanol/dichloromethane) to give 4-hydroxy-2-oxa-8-azaspiro [4.5]]Tert-butyl decane-8-carboxylate (13.2g, yield: 74%).
1H NMR(400MHz,CDCl3)δ4.04(dd,J＝10.0,4.6Hz,1H),3.98-3.90(m,1H),3.71-3.63(m,2H),3.64-3.49(m,3H),3.20(dt,J＝13.4,6.3Hz,1H),3.07(ddd,J＝13.2,9.2,3.5Hz,1H),1.95(d,J＝5.2Hz,1H),1.74-1.66(m,1H),1.53-1.46(m,1H),1.39(s,9H),1.27-1.11(m,1H)ppm；LC-MS:m/z 202.1[M-56+H]+.
Step five: 4-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000401
To a dry 500mL single neck flask was added 4-hydroxy-2-oxa-8-azaspiro [4.5] in sequence]Tert-butyl decane-8-carboxylate (13.2g,51mmol), dichloromethane (280mL) and Dess-Martin oxidant (32.2g,76.5mmol) were stirred for 5 h in an ice bath. After the reaction is finished, adding NaHCO3：Na2S2O3(1: 1) saturated solution (200mL), the organic phase was separated and the aqueous phase was extracted with DCM (3X 100 mL). The combined organic phases are treated with Na2SO4Drying, and concentrating the filtrate under reduced pressure. The residue obtained is purified by chromatography on silica gel (0 to 40% gradient of ethyl acetate/petroleum ether) to give 4-carbonyl-2-oxa-8-azaspiro [4.5] as a colourless solid]Tert-butyl decane-8-carboxylate (12g, yield: 92.1%).
1H NMR(400MHz,CDCl3)δ4.05(d,J＝13.6Hz,4H),3.87(d,J＝12.9Hz,2H),3.09(ddd,J＝13.5,9.8,3.5Hz,2H),1.73(ddd,J＝13.9,9.8,4.3Hz,2H),1.53(d,J＝15.1Hz,2H),1.46(s,9H)ppm；LC-MS:m/z 200.0[M-56+H]+。
Step six: (S) -4- ((R) -1, 1-Dimethylethylsulfonamido) -2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000402
Using the same synthesis as in the step C-1A of example 3, tert-butyl 4-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylate was reductively aminated to give (S) -4- ((R) -1-methylethylsulfonamido) -2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester as a white solid.
1H NMR(400MHz,CDCl3)δ4.14(dd,J＝9.3,6.2Hz,1H),3.90(d,J＝13.8Hz,2H),3.77(s,2H),3.70(dd,J＝9.2,5.3Hz,1H),3.63(q,J＝6.1Hz,1H),3.27(d,J＝6.4Hz,1H),2.90(t,J＝12.4Hz,2H),1.71(dt,J＝16.6,7.9Hz,2H),1.51(s,2H),1.45(s,9H),1.22(s,9H)ppm；LC-MS:m/z 361.1[M-100]+。
Step seven: (R) -2-methyl-N- ((S) -2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1H)
Figure BDA0001579586110000411
Using the same synthesis as step two of intermediate C-1A of example 3, (S) -4- ((R) -1-methylethylsulfonamido) -2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester was stripped of the Boc protecting group to give (R) -2-methyl-N- ((S) -2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfonamid C-1H as a white solid.
1H NMR(400MHz,DMSO-d6)δ5.30(s,1H),5.23(d,J＝8.9Hz,1H),3.93(dd,J＝8.6,7.2Hz,1H),3.69(d,J＝8.6Hz,1H),3.58(d,J＝8.6Hz,1H),3.46(dd,J＝8.5,7.0Hz,2H),2.89-2.73(m,2H),2.48-2.42(m,1H),1.69-1.50(m,2H),1.39-1.21(m,3H),1.12(s,9H)ppm；LC-MS:m/z261.1[M+H]+.
Example 5: preparation of (R) -2-methyl-N- ((R) -1-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1I)
The method comprises the following steps: 3-methoxyprop-1-yne
Figure BDA0001579586110000412
To a stirred solution of prop-2-yn-1-ol (50g, 892.8mmol) in water (40mL) was added 50% aqueous NaOH solution (98.2g) and the reaction mixture was heated to 70 ℃. Dimethyl sulfate (67.4g, 535.7mmol) was slowly added to the reaction mixture at below 70 ℃. The reaction mixture was stirred at 60 ℃ for 2 h. The product was distilled from the reaction mass at 60 ℃ and collected in a receiver flask cooled at-70 ℃. The distillate was dried with calcium chloride overnight and redistilled to give 3-methoxyprop-1-yne (30g, yield: 48%) as a colorless liquid.
1H NMR(CDCl3,400MHz)δ4.10(d,J＝2.0Hz,2H),3.39(s,3H),2.43(t,J＝2.0Hz,1H)ppm.
Step two: 1-methoxy-1, 2-propadiene
Figure BDA0001579586110000413
A suspension of potassium tert-butoxide (3.9g, 35.7mmol) and 3-methoxyprop-1-yne (50g, 714.2mmol) was stirred at 70 ℃ for 2 h. The product was distilled from the reaction mass at 50 ℃ and collected in a receiver cooled at-70 ℃ to give 1-methoxypropan-1, 2-diene (35g, yield: 70%) as a colorless liquid. The compound was dried with KOH and kept at 0 ℃ for storage.
1H NMR(CDCl3,400MHz)δ6.76(t,J＝8.0Hz,1H),5.48(d,J＝6.0Hz,2H),3.41(s,3H)ppm。
Step three: 4-hydroxy-4- (1-methoxypropan-1, 2-dien-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000421
To a stirred solution of 1-methoxypropan-1, 2-diene (0.527g, 7.5mmol) in THF (10mL) was added n-butyllithium (2.5M in THF) (2.8mL, 7.0mmol) slowly dropwise at-78 deg.C, and the reaction was stirred at this temperature for an additional 30 minutes. A solution of tert-butyl 4-carbonylpiperidine-1-carboxylate (1.0g, 5.0mmol) in THF (5mL) was then added to the reaction mixture and stirring was continued at-78 deg.C for 4 hours. The reaction mixture was saturated with NaHCO3The aqueous solution was quenched and extracted with ethyl acetate (3X 10 mL). The combined organic layers were washed with brine (50mL) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave tert-butyl 4-hydroxy-4- (1-methoxypropan-1, 2-dien-1-yl) piperidine-1-carboxylate (1.0g, yield: 90%) as a brown gum
Step four: 4-methoxy-1-oxa-8-azaspiro [4.5] dec-3-ene-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000422
To a stirred solution of tert-butyl 4-hydroxy-4- (1-methoxyprop-1, 2-dien-1-yl) piperidine-1-carboxylate (6.0g, 22.3mmol) in tert-butanol (60mL) were added potassium tert-butoxide (12.5g, 111.5mmol) and dicyclohexyl-18-crown-6 (0.42g, 1.1 mmol). The reaction mixture was stirred at reflux for 9 hours. The reaction mixture was cooled to 10 ℃, neutralized with 5% HCl (pH 7.0), and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (200mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-methoxy-1-oxa-8-azaspiro [4.5] dec-3-ene-8-carboxylate (4.0g), which was used in the next step without purification.
1H NMR(CDCl3,400MHz)δ4.56(s,2H),3.97(s,1H),3.69(s,3H),3.08(s,1H),1.79-1.74(m,1H),1.52(s,9H),1.45-1.26(m,1H)ppm；LCMS:m/z 214[M-55]+.
Step five: 4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000431
Reacting 4-methoxy-1-oxa-8-azaspiro [4.5]]Tert-butyl dec-3-ene-8-carboxylate (38.0g, 141.3mmol) and p-TSA. H2A mixture of O (29.6g, 155.4mmol) and acetone (400mL) was stirred at room temperature for 1 hour, and the reaction mixture was saturated with NaHCO3The aqueous solution was quenched, extracted with ethyl acetate (3X 500mL), and the combined organic phases were washed with brine (1000mL), dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to give 4-carbonyl-1-oxa-8-azaspiro [4.5] as a brown gum]Tert-butyl decane-8-carboxylate (25g), which was used directly in the next reaction.
LCMS:m/z 278[M+Na]+.
Step six and step seven: synthesis of (R) -2-methyl-N- ((R) -1-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1I)
Figure BDA0001579586110000432
Following the same synthetic procedure as for intermediate C-1A in example 3, the ketone intermediate 4-carbonyl-1-oxa-8-azaspiro [4.5]]Reductive amination of tert-butyl decane-8-carboxylateAnd removing Boc protecting group to obtain (R) -2-methyl-N- ((R) -1-oxa-8-azaspiro [ 4.5)]Synthesis of decan-4-yl) propane-2-sulfinamide (C-1I). LCMS M/z 261[ M + Na ]]+.
Example 6: preparation of (R) -2-methyl-N- ((3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1J)
The method comprises the following steps: (S) -2- ((tert-butyldimethylsilyl) oxy) propionic acid ethyl ester
Figure BDA0001579586110000433
To a solution of ethyl (S) -2-hydroxypropionate (30g, 254mmol) in dichloromethane (300mL) was added imidazole (2.75g, 304.9mmol) and cooled to 0 ℃. To the solution was added tert-butyldimethylsilyl chloride (46.0g, 304.9mmol) in portions, and stirred at room temperature for 16 hours. After completion of the reaction as judged by TLC analysis, the reaction mixture was quenched with water and extracted with dichloromethane (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave ethyl (S) -2- ((tert-butyldimethylsilyl) oxy) propionate (50g, 84% yield) as a colorless liquid.
1H NMR(400MHz,CDCl3)δ4.32-4.27(m,1H),4.21-4.12(m,2H),1.37(d,J＝6.8Hz,3H),1.27(d,J＝7.2Hz,3H),0.90(s,9H),0.08(s,6H)ppm.
Step two: (S) -2- ((tert-butyldimethylsilyl) oxy) propanal
Figure BDA0001579586110000441
To a solution of ethyl (S) -2- ((tert-butyldimethylsilyl) oxy) propionate (25g, 107.6mmol) in diethyl ether (500mL) at-78 deg.C was added diisobutylaluminum hydride (1M in hexane) (129mL, 129.1mmol) slowly dropwise and stirred at-78 deg.C for 1 hour. After completion of the reaction was confirmed by TLC analysis, the reaction mixture was warmed to-40 deg.C and quenched with saturated aqueous Rochelle salt (1L), then diethyl ether (5L) was added 00 mL). The resulting mixture was stirred at room temperature for 2 hours. Then extracted with ether (200 mL). The organic layer was washed with saturated brine (250mL) and Na2SO4Drying, filtration and concentration under reduced pressure gave (S) -2- ((tert-butyldimethylsilyl) oxy) propanal (19g, yield: 94%).
1H NMR(400MHz,CDCl3)δ9.61(s,1H),4.12-4.06(m,1H),1.27(d,J＝6.8Hz,3H),0.91(s,9H),0.10(s,6H)ppm.
Step three: 4- ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) piperidine-1, 4-dicarboxylic acid 1- (tert-butyl)
Figure BDA0001579586110000442
To a stirred solution of 1- (tert-butyl) -4-ethylpiperidine-1, 4-dicarboxylate (30g, 116.6mmol) in THF (250mL) at 0 deg.C was added lithium diisopropylamide (2M in THF) (93.3mL, 186.6mmol) and stirring continued at 0 deg.C for 30 min. Then a solution of (S) -2- ((tert-butyldimethylsilyl) oxy) propanal (22g, 116.6mmol) in THF (50mL) was added. The resulting reaction mixture was stirred at 0 ℃ for 1 hour and then kept at room temperature for 1 hour. After completion of the reaction as judged by TLC analysis, the reaction mixture was taken up with saturated NH4The Cl solution was quenched and extracted with ethyl acetate (2X 250 mL). The combined organic layers were washed with water (150mL), brine (150mL) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 25% ethyl acetate in petroleum ether as eluent to give 1- (tert-butyl) 4- ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) piperidine-1, 4-dicarboxylic acid 1- (tert-butyl) (17g, yield: 32%) as a pale red oil.
1H NMR(400MHz,CDCl3)δ4.29-4.09(m,2H),3.96-3.94(m,2H),3.86-3.80(m,1H),3.56-3.54(m,1H),2.86-2.76(m,2H),2.46(d,J＝5.2Hz,1H),2.16-2.13(m,1H),2.13-2.04(m,1H),1.77-1.60(m,2H),1.46(s,9H),1.29-1.24(m,3H),1.12(d,J＝4Hz,3H),0.89(s,9H),0.05(s,6H)ppm；LCMS:m/z 346[M-100]+.
Step four: ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000451
To the stirred solution was added a solution of 4- ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) piperidine-1, 4-dicarboxylic acid 1- (tert-butyl) (5g, 11.21mmol) in THF (50mL) and LiBH was added portionwise4(0.73g, 33.65mmol) and stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO at 0 deg.C3The solution was quenched and stirred at room temperature for 15 minutes. The precipitated solid was filtered off and the aqueous phase was extracted with ethyl acetate (2X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by column chromatography on silica gel (100-200 mesh) using a gradient mixture of 25% ethyl acetate in petroleum ether as an eluent to give tert-butyl ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylate (3g, yield: 66%).
1H NMR(400MHz,CDCl3)δ4.55(t,J＝4.8Hz,1H),4.43(d,J＝6.4Hz,1H),3.52-3.47(m,5H),3.31-3.28(m,1H),3.05-3.01(m,2H),1.58-1.49(m,2H),1.42-1.38(m,11H),1.11(d,J＝6.4Hz,3H),0.85(m,9H),0.04(s,6H)ppm；LC-MS:m/z 404.3[M+H]+。
Step five: 4- ((2S) -1, 2-dihydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000452
To a solution of tert-butyl ((2S) -2- ((tert-butyldimethylsilyl) oxy) -1-hydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylate (25g, 61.93mmol) in THF (500mL) was added tetrabutylammonium fluoride (1M in THF) (93mL, 92.89mmol) and the resulting reaction mixture was stirred at room temperature for 2 hours. By passing After completion of the reaction as judged by TLC analysis, the reaction mixture was quenched with saturated NaHCO3The solution was quenched and extracted with ethyl acetate (2X 500 mL). The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained was filtered and concentrated under reduced pressure and purified by column chromatography on silica gel (60-120 mesh) using a solvent gradient mixture of 70-90% ethyl acetate in petroleum ether as an eluent to give tert-butyl 4- ((2S) -1, 2-dihydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylate (12g, yield: 67%) as a colorless liquid.
1H NMR(400MHz,DMSO-d6)δ4.72(t,J＝4.8Hz,1H),4.61(d,J＝5.2Hz,1H),4.50(d,J＝7.2Hz,1H),3.72-3.68(m,1H),3.53-3.44(m,4H),3.11-2.98(m,3H),1.68-1.53(m,2H),1.42-1.35(m,11H),1.10(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 290.1[M+H]+。
Step six: (3S) -4-hydroxy-3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000461
To a stirred suspension of NaH (60% in mineral oil) (1.45g, 60.5mmol) in THF (30mL) at 0 deg.C was added a solution of tert-butyl 4- ((2S) -1, 2-dihydroxypropyl) -4- (hydroxymethyl) piperidine-1-carboxylate (5g,17.3mmol) and p-toluenesulfonyl chloride (3.29g, 17.3mmol) in THF (20mL), and the resulting reaction mixture was reacted at 0 deg.C for 3 hours. After the reaction was complete, the reaction mixture was saturated with NH at-20 deg.C4The Cl solution (250mL) was quenched and extracted with ethyl acetate (2X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by column chromatography on silica gel (100-200 mesh) using a solvent gradient mixture of 40% ethyl acetate in petroleum ether as eluent to give (3S) -4-hydroxy-3-methyl-2-oxa-8-azaspiro [ 4.5% ]Tert-butyl decane-8-carboxylate (2.1g, yield: 44%).
1H NMR(400MHz,CDCl3)δ3.83-3.62(m,5H),3.43(d,J＝6.0,1H),3.07-2.97(m,2H),1.72-1.55(m,3H),1.51-1.42(m,11H),1.33(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 172.2[M-100]+。
Step seven: (S) -tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid ester
Figure BDA0001579586110000471
Tert-butyl (3S) -4-hydroxy-3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylate (2.1g, 7.74mmol) was added to a solution of tetrahydrofuran (50mL) and stirring was maintained for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure. The resulting residual product was purified by column chromatography on silica gel (100-200 mesh) using a solvent gradient mixture of 30% ethyl acetate in petroleum ether as an eluent, followed by flash chromatography using 0.1% formic acid and acetonitrile as eluents to give (S) -tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid ester (1.2g, yield: 57%).
1H NMR(400MHz,CDCl3)δ4.20(d,J＝9.5Hz,1H),3.94-3.90(m,4H),3.16-3.10(m,1H),3.03-2.97(m,1H),1.81-1.75(m,1H),1.67-1.62(m,1H),1.61-1.57(m,1H),1.42-1.45(m,10H),1.32(d,J＝6.0Hz,3H)ppm；LC-MS:m/z 214.1[M-55]+。
Step eight: (3S,4S) -4- ((R) -tert-butylsulfinyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000472
(S) -tert-butyl-3-methyl-4-carbonyl-2-oxa-8-azaspiro [4.5]A stirred solution of decane-8-carboxylic acid ester (1.2g, 4.46mmol) in THF (15mL) was charged with (R) -2-methylpropane-2-sulfinamide (1.07g, 8.91mmol) and tetraethyltitanate (4.07g, 17.84mmol), respectively. The resulting reaction mixture was stirred at 90 ℃ for 20 hours. The reaction mixture was cooled to-4 ℃ and MeOH (2mL) was added followed by the addition of LiBH in portions 4(282mg, 12.99mmol) and stirring was maintained at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was dissolved with saturated brine at 0 ℃The solution was quenched and stirred at room temperature for 15 minutes. Filtration and the solution extracted with ethyl acetate (2X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained is filtered and concentrated under reduced pressure and purified by GRACE flash chromatography using 0.1% formic acid and acetonitrile as eluent to yield (3S,4S) -4- ((R) -tert-butylsulfinyl) amino) -3-methyl-2-oxa-8-azaspiro [ 4.5%]Tert-butyl decane-8-carboxylate (1.2g, yield: 72%).
1H NMR(400MHz,CDCl3)δ4.20-4.15(m,1H),3.90-3.84(m,2H),3.63-3.59(m,1H),3.49-3.43(m,1H),3.31-3.29(m,1H),2.95-2.81(m,2H),1.90-1.71(m,2H),1.49-1.40(m,11H),1.25(s,9H),1.19(d,J＝6.5Hz,3H)ppm；LC-MS:m/z 375.2[M+H]+。
Step nine: (R) -2-methyl-N- ((3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide (C-1J)
Figure BDA0001579586110000481
To a solution of tert-butyl (3S,4S) -4- ((R) -tert-butylsulfinyl) amino) -3-methyl-2-oxa-8-azaspiro [4.5] decane-8-carboxylate (1.1g, 2.936mmol) in dichloromethane (10mL) was added trifluoroacetic acid (1.12mL, 14.68mmol) dropwise and stirred at room temperature for 6 hours. After completion of the reaction, the crude product obtained by concentrating the reaction mixture under reduced pressure was purified by chromatography using 0.1% formic acid and acetonitrile to give (R) -2-methyl-N- ((3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-yl) propane-2-sulfinamide C-1J (850mg, yield: 72%).
1H NMR(400MHz,DMSO-d6)δ8.40(brs,D2O Exchangeable,1H),8.30(brs,D2OExchangeable,1H),5.28(d,J＝12.0Hz,1H),4.13-4.09(m,1H),3.77(d,J＝9.0Hz,1H),3.50-3.45(m,2H),3.29-3.26(m,1H),3.19-3.15(m,1H),2.94-2.85(m,2H),1.87-1.80(m,2H),1.69-1.59(m,2H),1.17(s,9H),1.08(d,J＝6.0Hz,3H)ppm；LC-MS:m/z 275.2[M+H]+。
Example 7: preparation of intermediate (R) -2-methyl-N- ((1R) -2-methyl-8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1K)
The method comprises the following steps: 2-methyl-1-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000482
1-carbonyl-8-azaspiro [4.5] is added into a 100mL dry single-neck flask in sequence under the protection of nitrogen at 0 DEG C]Tert-butyl decane-8-carboxylate (1g,3.95mmol) and dried tetrahydrofuran (15mL), then LiHMDS (3.95mL,3.95mmol) was slowly added dropwise, and after stirring at that temperature for 1 hour, iodomethane (0.25mL,3.95mmol) was added thereto and stirring was continued for 2 hours. After completion of the reaction, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3X 20mL), and the combined organic phases were Na2SO4Drying, concentrating the filtrate under reduced pressure and purifying by column silica gel chromatography (0 to 20% gradient of ethyl acetate/petroleum ether) to give 2-methyl-1-carbonyl-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester. LCMS M/z 368.0[ M + H ]]+.
Step two and step three: (R) -2-methyl-N- ((1R) -2-methyl-8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1K)
Figure BDA0001579586110000491
Following the same synthetic procedure as intermediate C-1A in example 3, tert-butyl ester of the ketone intermediate 2-methyl-1-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid was reductively aminated and the Boc-protecting group was removed to give (R) -2-methyl-N- ((1R) -2-methyl-8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide C-1K.
1H NMR(400MHz,CDCl3)δ5.07-4.97(m,1H),3.32-3.20(m,1H),3.01-2.84(m,2H),2.81-2.61(m,2H),2.20-2.11(m,1H),2.02-1.34(m,8H),1.25-1.20(m,9H),1.06-0.99(m,3H)ppm；LCMS:m/z 273.0[M+H]+.
Example 8: preparation of (R) -N- ((R) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide (C-1L)
The method comprises the following steps: 3, 3-dimethyl-4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000492
4-carbonyl-1-oxa-8-azaspiro [4.5] n at-78 ℃ under the protection of nitrogen]To a solution of tert-butyl decane-8-carboxylate (5g, 19.6mmol) in THF (50mL) was added LiHMDS (1M in THF; 19.6mL, 19.6mmol) slowly dropwise and stirred at-78 deg.C for 2 h. Then, after the reaction mixture was warmed to room temperature, methyl iodide (1.22mL, 19.6mmol) was added thereto in portions. The resulting reaction mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was diluted with ethyl acetate (150mL) and saturated NaHCO3The solution was quenched (150mL) and then extracted with ethyl acetate (2X 300 mL). The combined organic phases were dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel (0 to 15% gradient of ethyl acetate/petroleum ether) to give 3, 3-dimethyl-4-carbonyl-1-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (1g, yield: 18%) and 3-methyl-4-carbonyl-1-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (0.7g, yield: 14%)
3, 3-dimethyl-4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester:
1HNMR(400MHz,CDCl3)δ3.94(brs,2H),3.89(s,2H),3.16-3.10(m,2H),1.70-1.61(m,4H),1.48(s,9H),1.14(s,6H)ppm；LCMS:m/z 306[M+Na]+.
3-methyl-4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester:
1H-NMR(400MHz,CDCl3)δ4.38(t,J＝8.8Hz,1H),3.96(brs,2H),3.67(t,J＝9.6Hz,1H),3.14-3.09(m,2H),2.65-2.58(m,1H),1.75-1.46(m,13H),1.15(d,J＝7.2Hz,3H)ppm；LCMS:m/z 292[M+Na]+.
step two: (S) -4- ((tert-butylsulfinyl) imino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000501
To a stirred solution of tert-butyl 3, 3-dimethyl-4-carbonyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylate (2.0g, 7.1mmol) in THF (5.0mL) was added (R) -2-methylpropane-2-sulfinamide (2.56g, 21.2mmol) and tetraethyltitanate (8.05g, 35.3 mmol). The resulting reaction mixture was stirred at 90 ℃ for 48 hours. The reaction mixture was quenched with methanol (10mL) and diluted with ethyl acetate (50mL), then filtered over celite, and the crude product obtained by concentration was separated by reverse phase flash chromatography using 0.1% formic acid and acetonitrile as eluent to give tert-butyl (S) -4- ((tert-butylsulfinyl) imino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylate (1.5g, yield: 55%).
1HNMR(400MHz,CDCl3)δ4.10-3.88(brs,2H),3.80-3.72(m,2H),3.04(brs,2H),1.70-1.59(m,5H),1.46-1.41(m,14H),1.24-1.14(m,9H)ppm；LCMS:m/z 331[M-55]+.
Step three: (R) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester and (S) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester)
Figure BDA0001579586110000511
To (S) -4- ((tert-butylsulfinyl) imino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5]]Decane-8-carboxylic acid tert-butyl ester (1.5g, 3.88mmol) to a mixed solvent of MeOH: THF (3: 1; 30mL) was added NaBH4(886mg, 23.3mmol) and then stirred under reflux for 16 hours. After cooling to room temperature, part of the solvent was concentrated to 10mL under reduced pressure, and the mixture was poured into ice-water (100mL) and stirred for 10 minutes. The resulting solid precipitate was removed by filtration, extracted with ethyl acetate (3X 50mL), and the combined organic phases were concentrated by drying. The obtained crude product is purified and separated to obtain (R) -4- (((R) -tert-butylsulfinyl) Amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5]Decane-8-carboxylic acid tert-butyl ester (350mg, yield: 23%) and (S) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [ 4.5%]Tert-butyl decane-8-carboxylate (350mg, yield: 23%) and a mixture of the two (400mg, yield: 28%).
(S) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [ 4.5%]Decane-8-carboxylic acid tert-butyl ester:1HNMR(400MHz,CDCl3)δ3.94(brs,2H),3.61(d,J＝9.2Hz,1H),3.54(d,J＝9.2Hz,1H),3.22(d,J＝10Hz,1H),3.07-3.00(m,3H),1.54-1.49(m,4H),1.45(s,9H),1.24(s,9H),1.21(s,3H),1.03(s,3H)ppm；LCMS:m/z 411[M+Na]+；[α]25 D＝+19.62(c 0.25,MeOH)；retention time:1.835min
(R) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [ 4.5%]Decane-8-carboxylic acid tert-butyl ester:1HNMR(400MHz,CDCl3)δ4.03-3.93(m,2H),3.62-3.58(m,1H),3.50-3.47(m,1H),3.30(brs,1H),3.11-2.96(m,3H),1.91-1.76(m,2H),1.54-1.56(m,merged in DMSO,2H)1.43(s,9H),1.25(s,9H),1.03(s,3H),0.99(s,3H)ppm；LCMS:m/z 411[M+Na]+；[α]25 D＝-43.56(c 0.25,MeOH)；retention time:2.009min.
step four: (R) -N- ((R) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide (C-1L)
Figure BDA0001579586110000521
Using the same synthesis as in step nine, intermediate C-1J, of Synthesis example 6, (R) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester was freed from the Boc-protecting group to give (R) -N- ((R) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide C-1L.
1H-NMR(400MHz,DMSO-d6)δ4.92(d,D2O Exchangeable,J＝11.5Hz,1H),3.50(d,J＝9.0Hz,1H),3.43(d,J＝9.0Hz,1H),3.20-3.14(m,2H),3.09(d,J＝12.0,1H),3.00-2.89(m,2H),1.92-1.86(m,1H),1.82-1.80(m,2H),1.73-1.70(m,1H),1.19(s,9H),0.97(s,3H),0.94(s,3H)ppm；LCMS:m/z 289[M+H]+。
Example 9: preparation of (R) -N- ((S) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide (C-1M)
Figure BDA0001579586110000522
Using the same synthesis as in step nine, intermediate C-1J, of Synthesis example 6, (S) -4- (((R) -tert-butylsulfinyl) amino) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester was freed from the Boc-protecting group to give (R) -N- ((S) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide C-1M.
1HNMR(400MHz,DMSO-d6)δ8.40(brs,D2O Exchangeable,1H),8.40(brs,D2O Exchangeable,1H),5.27(d,J＝11.0Hz,1H),4.12-4.10(m,1H),3.77(d,J＝8.5Hz,1H),3.47-3.44(m,2H),3.28-3.24(m,1H),3.17-3.15(m,1H),2.95-2.87(m,2H),1.86-1.82(m,2H),1.69-1.59(m,2H),1.17(s,9H),1.08(d,J＝6.0Hz,3H)ppm；LCMS:m/z 289[M+H]+.
Example 10: preparation of intermediate (R) -2-methyl-N- ((1R) -3-methyl-8-aza-spiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1N)
The method comprises the following steps: 4-allyl-4-formylpiperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000531
To a dry 1L flask was added tert-butyl 4-formylpiperidine-1-carboxylate (35.0g,164mmol), lithium tert-butoxide (15.77g,197mmol) and allyl bromide (11.54mL,189mmol) in that order and the mixture was stirred at 0 ℃ for 1 h. After the reaction is completed, the mixture is poured into a reactor containing saturated NH 4Aqueous Cl solution H2O (1:1,500mL) in a separatory funnel,using Et2O (5X 50 mL). The combined organic phases were washed with MgSO4Drying, filtering, and concentrating the filtrate under reduced pressure. The resulting residue was purified by silica gel chromatography (0 to 25% gradient of ethyl acetate/petroleum ether) to give tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (24g, yield: 48%) as a colorless oil.
1H NMR(400MHz,CDCl3)δ9.52(s,1H),5.53-5.76(m,1H),4.96-5.19(m,2H),3.80(br.s.,2H),2.97(t,J＝11.49Hz,2H),2.26(d,J＝7.33Hz,2H),1.95(dt,J＝13.71,3.13Hz,2H),1.38-1.58(m,11H)ppm.
Step two: 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylic acid tert-butyl ester (C-1N-C)
Figure BDA0001579586110000532
To a dry 1L three-necked flask was added 4-allyl-4-formylpiperidine-1-carboxylic acid tert-butyl ester (24g,95mmol) and THF (300mL) in that order, the solution was cooled to-78 deg.C and vinyl magnesium bromide (1M in THF, 118mL,118mmol) was slowly added dropwise under nitrogen. The resulting solution was allowed to warm slowly to room temperature over 1 hour. After the reaction is completed, the mixture is poured into a reactor containing saturated NH4Aqueous Cl (250mL) was separated onto a separatory funnel and extracted with EtOAc (4 × 50 mL). The combined organic phases were washed with MgSO4Drying, filtration and concentration of the filtrate under reduced pressure gave tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (26.7g), which was used in the next step without further purification.
1H NMR(400MHz,CDCl3)δ6.05-5.83(m,2H),5.32-5.21(m,2H),5.12(s,1H),5.08(d,J＝3.5Hz,1H),4.05-3.97(m,1H),3.71(s,2H),3.12(ddd,J＝13.8,10.4,3.6Hz,2H),2.33(dd,J＝14.3,7.8Hz,1H),2.20(dd,J＝14.3,7.2Hz,1H),1.60(q,J＝4.3Hz,2H),1.57-1.50(m,2H),1.45(s,9H)ppm.
Step three: 4-Enopropionyl-4-allylpiperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000541
To a dry 1L three-necked flask were added tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (26.7g,95mmol), Dess-Martin oxidant (44.3g,105mmol) and anhydrous dichloromethane (380mL) in that order, and the mixture was stirred at room temperature for 1 hour. After the reaction is finished, the mixture is poured into a reactor containing NaHCO3:Na2SO3Saturated aqueous (1:1,300mL) in a separatory funnel and then extracted with DCM (4X 50 mL). The combined organic phases were washed with MgSO4Drying, filtering, and concentrating the filtrate under reduced pressure to obtain white solid. The white solid was suspended in petroleum ether (250mL) and sonicated for 20 min. The white suspension was filtered through a celite pad and removed under reduced pressure, and the filtrate was concentrated under reduced pressure to give 4-levulinyl-4-allylpiperidine-1-carboxylic acid tert-butyl ester as yellow oil (25g, two-step yield: 94%).
1H NMR(400MHz,CDCl3)δ6.80(dd,J＝16.8,10.3Hz,1H),6.39(dd,J＝16.8,1.9Hz,1H),5.70(dd,J＝10.3,1.9Hz,1H),5.55(ddt,J＝17.5,10.2,7.4Hz,1H),5.09-4.98(m,2H),3.77(s,2H),2.94(s,2H),2.31(d,J＝7.4Hz,2H),2.08(d,J＝13.8Hz,2H),1.47-1.41(m,11H)ppm。
Step four: 1-carbonyl-8-azaspiro [4.5] decan-2-ene-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000542
To a dry 1L three-necked flask was added sequentially tert-butyl 4-levulinyl-4-allylpiperidine-1-carboxylate (25g,89.6mmol), toluene (degassed, 850mL), and a solution of Grubbs' second generation catalyst (2.02g,2.38mmol) in toluene (degassed, 100 mL). The resulting mixture was stirred at 85 ℃ under nitrogen for 45 minutes. After the reaction was complete, the solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give tert-butyl 1-carbonyl-8-azaspiro [4.5] dec-2-ene-8-carboxylate (19g,83mmol) as a brown solid. A solution of this compound and DDQ (565mg,2.49mmol) in toluene (540mL) was stirred at room temperature for 15 minutes. The resulting bright red solution was filtered through a pad of celite. Charcoal (100g) was added and the resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered through a celite pad, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give tert-butyl 1-carbonyl-8-azaspiro [4.5] dec-2-ene-8-carboxylate (12g, yield: 53.3%) as a white solid.
Step five: 3-methyl-1-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000551
CuI (3.8g,20mmol) and anhydrous tetrahydrofuran (100mL) were added sequentially to a nitrogen blanketed 250mL dry three-necked flask, the solution was cooled to-20 ℃ and MeLi (1.6M in THF, 25mL,40mmol) was slowly added dropwise to the solution, after which the reaction was allowed to react at-20 ℃ until the solution was clear. Then slowly dropwise adding 1-carbonyl-8-azaspiro [4.5] at the temperature]A solution of tert-butyl decan-2-ene-8-carboxylate (2.51g,10mmol) in tetrahydrofuran (20 mL). After the reaction is finished, the mixture is poured into a reactor containing saturated NH4Aqueous Cl was extracted with ethyl acetate (3 × 15mL) in a separatory funnel. The combined organic phases were washed with MgSO4Drying, filtering and concentrating the filtrate under reduced pressure and purification by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give 3-methyl-1-carbonyl-8-azaspiro [4.5]]Tert-butyl dec-2-ene-8-carboxylate (1.6g, yield: 60%).
1H NMR(400MHz,CDCl3)δ3.92(s,1H),3.81(s,1H),3.55(d,J＝5.0Hz,1H),3.13-3.04(m,1H),2.96(t,J＝10.9Hz,1H),2.56-2.46(m,1H),2.31-2.21(m,2H),1.94-1.75(m,2H),1.62-1.49(m,1H),1.45(s,9H),1.41-1.35(m,2H),1.15(d,J＝6.0Hz,3H),0.90(t,J＝6.9Hz,3H)ppm.
Step six and step seven: (R) -2-methyl-N- ((1R) -3-methyl-8-aza-spiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1N)
Figure BDA0001579586110000552
Using the same synthetic procedure as for the synthesis of intermediate C-1J Steps eight and nine, the ketone intermediate, tert-butyl 3-methyl-1-carbonyl-8-azaspiro [4.5] decan-2-ene-8-carboxylate, was reductively aminated and the Boc protecting group removed to give (R) -2-methyl-N- ((1R) -3-methyl-8-aza-spiro [4.5] decan-1-yl) propane-2-sulfinamide C-1N.
1H NMR(400MHz,CDCl3)δ1H NMR(400MHz,DMSO-d6)δ3.04-2.95(m,1H),2.75(s,2H),2.62-2.53(m,2H),1.93-1.57(m,5H),1.52-1.27(m,13H),0.96(d,J＝6.5Hz,3H)ppm；LCMS:m/z 273[M+H]+.
Example 11: preparation of intermediate (R) -2-methyl-N- ((1R,3R) -3-methyl-8-azaspiro [4.5] decan-1-yl) propane-2-sulfinamide (C-1O)
The method comprises the following steps: (R) -3- ((tert-butyldimethylsilyl) oxy) -1-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000561
To a dry 100mL three-necked flask, CuCl (19mg,0.19mmol),(s) -TolBlNAP (129mg,0.19mmol), sodium tert-butoxide (18mg,0.19mmol) and THF (9mL) were added in this order, and the mixture was stirred at room temperature for 30 minutes. Adding B2Pin2(1.78g,7.01mmol) in THF (2.5mL) and the resulting mixture was stirred at room temperature for 10 min. Then adding 1-carbonyl-8-azaspiro [4.5]]A solution of tert-butyl decan-2-ene-8-carboxylate (1.60g,6.37mmol) in THF (9mL) was followed by MeOH (0.53mL, 12.74 mmol). The resulting mixture was stirred at room temperature for 16 hours. After the reaction is finished, H is added2O (20mL), followed by sodium perborate (4.84g,32mmol) and the resulting mixture stirred vigorously at room temperature for l hours. The resulting green suspension was filtered through a pad of celite and poured into a container containing NaHCO3Saturated aqueous solution: na (Na)2SO3The separatory funnel was saturated with aqueous solution (40mL) and extracted with EtOAc (4 × 40 mL). The combined organic phases were washed with MgSO 4Drying, filtering and concentrating the filtrate under reduced pressure to obtain crude product of (R) -3-hydroxy-1-carbonyl-8-azaspiro [4.5]Decane-8-carboxylic acid tert-butyl ester.
Crude (R) -3-hydroxy-1-carbonyl-8-azaspiro [4.5] product was added to a 100mL single-neck flask in sequence]Tert-butyl decane-8-carboxylate (theoretical amount, 6.37mmol), imidazole (650mg, 9.56mmol), TBSCl (1.20g, 7.96mmol) and DMF (16mL), and the mixture was stirred at room temperature for 16 hours. After the reaction is complete, the reaction mixture is poured into a container containing saturated NH4Aqueous Cl (30mL) was separated from the funnel and extracted with ethyl acetate (5 × 50 mL). The combined organic phases were washed with MgSO4The residue obtained is dried, filtered and concentrated under reduced pressure to give (R) -3- ((tert-butyldimethylsilyl) oxy) -1-carbonyl-8-azaspiro [4.5] by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether)]Tert-butyl decane-8-carboxylate (1.26g, yield: 51.6%) as a colorless oil.
LCMS:m/z 328[M-56+H]+.
Step two (1R,3R) -3- ((tert-butyldimethylsilyl) oxy) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000571
Using the same synthetic procedure as for step eight of the synthesis of intermediate C-1J, the reductive amination of the ketone intermediate, tert-butyl (R) -3- ((tert-butyldimethylsilyl) oxy) -1-carbonyl-8-azaspiro [4.5] decane-8-carboxylate, gave (tert-butyl (1R,3R) -3- ((tert-butyldimethylsilyl) oxy) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decane-8-carboxylate as a white solid (1.24g, yield: 77%).
1H NMR(400MHz,CDCl3)δ4.23(s,1H),3.84(d,J＝13.6Hz,2H),3.24(s,1H),2.77(td,J＝12.7,12.0,3.0Hz,2H),2.27(d,J＝8.8Hz,1H),1.72-1.54(m,5H),1.38(s,9H),1.19(d,J＝2.5Hz,3H),1.14(s,9H),0.80(s,9H),-0.03(s,6H)ppm；LCMS:m/z 488.9[M+H]+.
Step three: (R) -N- ((1R,3R) -3-hydroxy-8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide (C-1O)
Figure BDA0001579586110000572
(1R) -3- ((tert-butyldimethylsilyl) oxy) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] was placed in an ice bath]To a solution of tert-butyl decane-8-carboxylate (49mg, 0.1mmol) in 1, 4-dioxane (1mL) was added concentrated sulfuric acid (0.023mL, 0.4 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was adjusted to PH 12 with sodium hydroxide solution and extracted with DCM (4 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and the volatiles were removed under reduced pressure to give (R) -N- ((1R,3R) -3-hydroxy-8-azaspiro [ 4.5)]Decan-1-yl) -2-methylpropane-2-sulfinamide C-1O (20mg, yield: 70%). LC-MS M/z 275[ M + H ]]+。
Example 12: preparation of intermediate (R) -tert-butyl 1- ((tert-butoxycarbonyl) amino) -3, 3-difluoro-8-azaspiro [4.5] decane-8-carboxylate (C-1P)
The method comprises the following steps: (1R,3R) -1-amino) -3-hydroxy-8-azaspiro [4.5] decane
Figure BDA0001579586110000581
To a solution of tert-butyl (1R,3R) -3- ((tert-butyldimethylsilyl) oxy) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decane-8-carboxylate (100mg,0.2mmol) in methanol (5mL) at room temperature was slowly added a solution of 1, 4-dioxane hydrochloride (4M,2mmol,0.5mL) and the reaction was heated at 40 ℃ for 1 hour. Concentrating under reduced pressure to obtain (1R,3R) -1-amino) -3-hydroxy-8-azaspiro [4.5] decane which is directly used for the next reaction.
LC-MS:m/z 171.0
Step two: (1R,3R) -1- ((tert-butoxycarbonyl) amino) -3-hydroxy-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (C-1P-b)
Figure BDA0001579586110000582
Mixing the above (1R,3R) -1-amino) -3-hydroxy-8-azaspiro [4.5]Decane (0.2mmol) was dissolved in tetrahydrofuran solution (10mL), followed by addition of (Boc)2O (109mg,0.5mmol), DIPEA (516mg,4.0mmol) was then added, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride and then extracted with diethyl ether (5 × 50mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give (1R,3R) -1- ((tert-butoxycarbonyl) amino) -3-hydroxy-8-azaspiro [ 4.5%]Decane-8-carboxylic acid tert-butyl ester C-1P-b (60mg, two-step yield: 80%).
1H NMR(400MHz,CDCl3)δ5.11(s,1H),4.36(s,1H),3.86-3.62(m,3H),2.94(t,J＝11.7Hz,2H),2.20-2.08(m,1H),1.81(d,J＝8.5Hz,1H),1.64-1.55(m,3H),1.49-1.42(m,3H),1.37(d,J＝4.9Hz,18H)ppm；LC-MS:m/z 393.2[M+H]+.
Step three: (R) -1- ((tert-butoxycarbonyl) amino) -3-carbonyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000583
Tert-butyl (1R,3R) -1- ((tert-butoxycarbonyl) amino) -3-hydroxy-8-azaspiro [4.5] decane-8-carboxylate (60mg,0.16mmol) was dissolved in dichloromethane (5mL) at 0 ℃ and Dess-Martin (76mg,0.18mmol) was added slowly at 0 ℃ and the reaction was left at 0 ℃ for further reaction for 2 hours. After the reaction was complete, quenched by addition of water (4mL) followed by extraction with dichloromethane (5X50mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (0 to 80% gradient of ethyl acetate/petroleum ether) to give tert-butyl (R) -1- ((tert-butoxycarbonyl) amino) -3-carbonyl-8-azaspiro [4.5] decane-8-carboxylate (30mg, yield: 50%).
1H NMR(400MHz,CDCl3)δ4.46(d,J＝9.4Hz,1H),4.07(d,J＝7.0Hz,1H),3.92(s,2H),2.73(t,J＝12.7Hz,2H),2.63(dd,J＝19.0,8.1Hz,1H),2.41(d,J＝18.3Hz,1H),2.14-2.01(m,2H),1.68(td,J＝12.9,4.6Hz,1H),1.59(d,J＝4.8Hz,1H),1.39(d,J＝2.5Hz,18H),1.26(d,J＝2.9Hz,1H)ppm；LC-MS:m/z 369.1[M+H]+.
Step four: (R) -tert-butyl 1- ((tert-butoxycarbonyl) amino) -3, 3-difluoro-8-azaspiro [4.5] decane-8-carboxylate
Figure BDA0001579586110000591
Tert-butyl (R) -1- ((tert-butoxycarbonyl) amino) -3-carbonyl 8-azaspiro [4.5] decane-8-carboxylate (80mg, 0.22mmol) was dissolved in dichloromethane (10mL), followed by addition of DeoxoFluor (162. mu.L, 0.88mmol), and the reaction solution was further heated and stirred at 50 ℃ for 48 hours. After completion of the reaction, the reaction solution was quenched with a saturated sodium bicarbonate solution at 0 ℃ and extracted with ethyl acetate (3X 20mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (R) -1- ((tert-butoxycarbonyl) amino) -3, 3-difluoro-8-azaspiro [4.5] decane-8-carboxylate (46mg, yield: 54%)
1H NMR(400MHz,CDCl3)δ4.49(d,J＝9.9Hz,1H),3.92(dd,J＝24.5,15.9Hz,3H),2.87-2.68(m,2H),2.58-2.42(m,1H),2.21(td,J＝17.7,16.8,9.6Hz,1H),2.06-1.86(m,2H),1.60(t,J＝6.6Hz,1H),1.38(d,J＝4.0Hz,21H)ppm；LC-MS:m/z 391.1[M+H]+
Step five: (R) -1-amino) -3, 3-difluoro-8-azaspiro [4.5] decane (C-1P)
Figure BDA0001579586110000592
To (R) -1- ((tert-butoxycarbonyl) amino) -3, 3-difluoro-8-azaspiro [4.5] at room temperature]To a solution of tert-butyl decane-8-carboxylate (46mg,0.12mmol) in methanol (5mL) was slowly added a solution of 1, 4-dioxane hydrochloride (4M,1.2mmol,0.3mL), and the reaction mixture was reacted at room temperature for 1 hour. Concentrating under reduced pressure to obtain (R) -1-amino) -3, 3-difluoro-8-azaSpiro [4.5]]Decane (C-1P). LC-MS M/z 191.1[ M + H ]]+.
Example 13: preparation of intermediate 1-methyl-8-azaspiro [4.5] decan-1-amine (C-2A)
The method comprises the following steps: 1-hydroxy-1-methyl-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester
Figure BDA0001579586110000601
A solution of methyl magnesium bromide in tetrahydrofuran (1M,2.2mmol, 2.2mL) was slowly added dropwise to a solution of tert-butyl 1-carbonyl-8-azaspiro [4.5] decane-8-carboxylate (500mg, 2.0mmol) in toluene (20mL) at 0 deg.C, and the reaction mixture was stirred at 0 deg.C for an additional 1 hour. After the reaction was complete, saturated aqueous ammonium chloride was added and quenched, then extracted with ethyl acetate (3 × 20mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give tert-butyl 1-hydroxy-1-methyl-8-azaspiro [4.5] decane-8-carboxylate (410mg, yield: 77%).
1H NMR(400MHz,CDCl3)δ4.16-4.04(m,2H),3.12-2.56(m,2H),1.98-1.49(m,8H),1.49(s,9H),1.42-1.29(m,2H),1.16(s,3H)ppm；LC-MS:m/z 270.2[M+H]+.
Step two: n- (1-methyl-8-azaspiro [4.5] decan-1-yl) acetamide
Figure BDA0001579586110000602
Tert-butyl 1-hydroxy-1-methyl-8-azaspiro [4.5] decane-8-carboxylate (410mg, 1.52mmol) was dissolved in acetonitrile (1.82mL), concentrated sulfuric acid (1.56mL) was added at 0 ℃, and the reaction solution was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was poured into ice water, followed by basification with aqueous NaOH (50%) solution to pH 12, followed by extraction with ethyl acetate (3 × 20mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product of N- (1-methyl-8-azaspiro [4.5] decan-1-yl) acetamide (260mg, yield: 81%) which was used directly in the next reaction.
LC-MS:m/z 211.0[M+H]+.
Step three: 1-methyl-8-azaspiro [4.5] decan-1-amine (C-2A)
Figure BDA0001579586110000611
The crude N- (1-methyl-8-azaspiro [4.5] decan-1-yl) acetamide (260mg,1.23mmol) was dissolved in 6M hydrochloric acid solution (5mL) at room temperature, and the reaction mixture was reacted at 120 ℃ for 4 hours under microwave heating. After completion, the reaction solution was concentrated under reduced pressure and then lyophilized to give a crude product, 1-methyl-8-azaspiro [4.5] decan-1-amine C-2A (200mg, yield: 97%), which was used in the next reaction without purification.
LC-MS:m/z 169.1[M+H]+.
Example 14: preparation of intermediate tert-butyl (4-ethylpiperidin-4-yl) carbamate (C-3A)
The method comprises the following steps: 1-benzyl-4-ethylpiperidine-4-carboxylic acid methyl ester
Figure BDA0001579586110000612
To a solution of methyl 1-benzylpiperidine-4-carboxylate (1g, 4.3mmol) in tetrahydrofuran (10mL) was slowly added dropwise LDA solution in tetrahydrofuran (1M,5.1mmol,5.1mL) under nitrogen at-78 deg.C, the reaction mixture was stirred at-78 deg.C for 1 hour, iodoethane (795mg, 5.1mmol) in tetrahydrofuran (1mL) was then added slowly, and the reaction mixture was allowed to react at-78 deg.C for 4 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added to quench, followed by extraction with ethyl acetate (3 × 30mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/petroleum ether) to give methyl 1-benzyl-4-ethylpiperidine-4-carboxylate (800mg, yield: 71%).
LC-MS:m/z 262.2[M+H]+.
Step two: 1-benzyl-4-ethylpiperidine-4-carboxylic acid
Figure BDA0001579586110000613
Methyl 1-benzyl-4-ethylpiperidine-4-carboxylate (800mg, 3.23mmol) was dissolved in an aqueous ethanol solution (ethanol: water ═ 4: 1,20mL), NaOH (517mg,12.9mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, then acidified with 1N hydrochloric acid to pH 3, then extracted with ethyl acetate (3 × 30mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1-benzyl-4-ethylpiperidine-4-carboxylic acid (720mg, yield: 90%) which was used directly in the next reaction.
LC-MS:m/z 248.2[M+H]+.
Step three: 1-methyl-8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000621
1-benzyl-4-ethylpiperidine-4-carboxylic acid (250mg,1.0mmol) was dissolved in tert-butanol (5mL) at room temperature, and then triethylamine (306mg, 3.0mmol) and diphenylphosphoryl azide (330mg, 2.0mmol) were added, followed by heating and refluxing of the reaction solution for 8 hours. After the reaction was complete, water was added to quench the reaction, which was then extracted with ethyl acetate (3X30mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography (0 to 70% gradient ethyl acetate/petroleum ether) to give 1-methyl-8-azaspiro [4.5] decan-1-amine (160mg, yield: 50%).
LC-MS:m/z 319.2[M+H]+.
Step four: (4-ethylpiperidin-4-yl) carbamic acid tert-butyl ester
Figure BDA0001579586110000622
1-methyl-8-azaspiro [4.5] decan-1-amine (160mg, 0.5mmol) was dissolved in 10mL of methanol at room temperature, and then Pd/C (16mg, 10%) was added to react the reaction mixture under a hydrogen atmosphere for 16 hours. Celite was filtered, then washed with ethyl acetate, and concentrated under reduced pressure to give tert-butyl (4-ethylpiperidin-4-yl) carbamate (110mg, yield: 95%). The product can be used directly in the next reaction.
LC-MS:m/z 229.2[M+H]+.
Step five: (4-ethylpiperidin-4-yl) carbamic acid tert-butyl ester (C-3A)
Figure BDA0001579586110000623
Tert-butyl (4-ethylpiperidin-4-yl) carbamate (110mg, 0.5mmol) was dissolved in methanol (3mL) at room temperature, and then 1, 4-dioxane solution (4N,5mmol, 1.1Ml) hydrochloride was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to give tert-butyl (4-ethylpiperidin-4-yl) carbamate (C-3A) (50mg, yield: 95%) as a product, which was used directly in the next reaction.
LC-MS:m/z 128.2[M+H]+.
Example 15: preparation of intermediate tert-butyl ((4-methylpiperidin-4-yl) methyl) carbamate (C-4A)
The method comprises the following steps: 1-benzoyl-4-methylpiperidine-4-carbonitrile
Figure BDA0001579586110000631
To a 100mL dry single-neck flask, under nitrogen, was added 4-methylpiperidine-4-carbonitrile (496mg,4mmol), DCM (10mL) and triethylamine (611mg,6mmol) in that order, followed by slow dropwise addition of benzoyl chloride (670mg,4.8mmol) at room temperature. The mixture was stirred at room temperature for a further 1 hour and the reaction was monitored by TLC until the starting material was reacted. After quenching the reaction with 1N HCl solution, dichloromethane (3X 20mL) was extracted and the combined organic phases were Na 2SO4Drying, concentrating the filtrate under reduced pressure and purifying by column silica gel chromatography (gradient of 0 to 40% of ethyl acetate)Ethyl acetate/petroleum ether) to give 1-benzoyl-4-methylpiperidine-4-carbonitrile (650mg, yield: 70.72%).
LC-MS:m/z 229[M+H]+.
Step two: 1-benzoyl- ((4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester
Figure BDA0001579586110000632
To a 100mL dry flask, 1-benzoyl-4-methylpiperidine-4-carbonitrile (650mg,2.85mmol), nickel chloride hexahydrate (135mg,0.67mmol), di-tert-butyl dicarbonate (1.86g,8.54mmol) and methanol (12mL) were added sequentially under nitrogen at 0 deg.C, and sodium borohydride (754mg,20mmol) was added. The reaction was then stirred at room temperature for 12 hours and monitored by TLC until the starting material was reacted. After completion of the reaction, the reaction was concentrated and extracted with dichloromethane (3X 20mL), and the combined organic phases were extracted with Na2SO4Drying, concentration of the filtrate under reduced pressure and purification by column silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) gave tert-butyl 1-benzoyl- ((4-methylpiperidin-4-yl) methyl) carbamate (620mg, yield: 65.50%)
LC-MS:m/z 333[M+H]+.
Step three: ((4-methylpiperidin-4-yl) methyl) carbamic acid tert-butyl ester (C-4A)
Figure BDA0001579586110000641
To a 100mL single-neck flask were added tert-butyl ((1-benzoyl-4-methylpiperidin-4-yl) methyl) carbamate (620mg,1.87mmol), ethanol (8mL) and 7N NaOH (2mL) in this order, the mixture was heated to 90 ℃ under nitrogen and stirred for 8 hours, after the mixture was cooled to room temperature, the mixture was filtered, diluted with water and extracted with ethyl acetate (3X 20mL), and the combined organic phases were extracted with Na 2SO4Drying, concentrating the filtrate under reduced pressure and purifying by column silica gel chromatography (0 to 80% gradient of ethyl acetate/petroleum ether) to give ((4-methyl ether)Piperidin-4-yl) methyl) carbamic acid tert-butyl ester C-4A (300mg, yield: 70.5%).
1H NMR(400MHz,DMSO-d6)δ3.97(q,J＝7.0Hz,2H),2.80(d,J＝6.4Hz,2H),2.65(d,J＝30.3Hz,2H),1.38(s,9H),1.27(dd,J＝16.2,7.0Hz,2H),1.10(d,J＝12.8Hz,2H),0.81(s,3H)ppm；LC-MS:m/z 229[M+H]+.
EXAMPLE 16 preparation of intermediate tert-butyl ((4-phenylpiperidin-4-yl) methyl) carbamate (C-4B)
The method comprises the following steps: 4-cyano-4-phenylpiperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000642
To a solution of tert-butyl (2-chloroethyl) carbamate (2g,8.26mmol) and 2-phenylacetonitrile (968mg,8.26mmol) in anhydrous DMF (20mL) at 0 deg.C was added NaH (60% dispersed in mineral oil, 1.6g,41.3mmol) in portions. The reaction mixture was heated at 60 ℃ for 16 hours. After completion of the reaction, the reaction mixture was quenched with ice water (30mL) and then extracted with 3X 50 mL). The combined organic layers were washed with saturated brine (2 × 50mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to give tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (500mg, yield: 21%).
LCMS:m/z 187.2[M-100]+.
Step two: 4- (aminomethyl) -4-phenylpiperidine-1-carboxylic acid tert-butyl ester
Figure BDA0001579586110000651
Tert-butyl 4-cyano-4-phenylpiperidine-1-carboxylate (0.5g,1.75mmol) was dissolved in 20mL of methanol, palladium on carbon (50mg) was added thereto, and the reaction mixture was reacted under hydrogen for 16 hours. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4- (aminomethyl) -4-phenylpiperidine-1-carboxylate (0.4g, yield: 80%).
1H NMR(400MHz,CDCl3)δ7.38(t,J＝7.6Hz,2H),7.30(d,J＝7.5Hz,2H),7.24(d,J＝7.2Hz,1H),3.75(d,J＝7.8Hz,2H),3.04(t,J＝11.2Hz,2H),2.58(brs,2H),2.21(d,J＝13.9Hz,2H),1.76-1.61(m,2H),1.44(s,9H)ppm；LC-MS:m/z 191.0[M-100]+.
Step two: (4-Phenylpiperidin-4-yl) methanamine (C-4B)
Figure BDA0001579586110000652
Tert-butyl 4- (aminomethyl) -4-phenylpiperidine-1-carboxylate (0.4g,1.37mmol) was dissolved in 10mL of methanol, and 1, 4-dioxane hydrochloride (4M,13.7mmol) was added thereto at room temperature, and the reaction mixture was allowed to react at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give (4-phenylpiperidin-4-yl) methylamine C-4B (0.25g, yield: 95%) and the crude product was used directly in the next reaction.
LC-MS:m/z 191.2[M+H]+.
EXAMPLE 17 preparation of intermediate sodium 6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-thiolate (F-1A)
The method comprises the following steps: (6-Chloropyridin-2-yl) carbamic acid tert-butyl ester
Figure BDA0001579586110000653
6-chloropyridin-2-amine (8g,62.2mmol) and THF (80mL) were added under nitrogen to a dry 250mL three-necked flask, the mixture stirred at 0 ℃ for 10 minutes, then NaHDMS (124.4mL,1.0M in THF) was added, then a solution of di-tert-butyl dicarbonate (16.3g,74.7mmol) in tetrahydrofuran (50mL) was slowly added maintaining the system at 0 ℃ and the reaction continued at 0 ℃ for 4 hours. After the reaction is finished, H is added2O (40mL) and then extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with MgSO4The residue obtained by drying, filtration and concentration under reduced pressure was purified by silica gel chromatography (0 to 10% gradient of ethyl acetate/petroleum ether) to give tert-butyl (6-chloropyridin-2-yl) carbamate (7g, yield: 49%).
1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),7.79-7.58(m,2H),7.02(dd,J＝5.5,2.9Hz,1H),1.38(s,9H)ppm；LCMS:m/z 288.1[M+H]+.
Step two: (5, 6-dichloropyridin-2-yl) carbamic acid tert-butyl ester
Figure BDA0001579586110000661
To a dry 100mL round bottom flask was added tert-butyl (6-chloropyridin-2-yl) carbamate (7g,30.6mmol) and N, N-dimethylformamide (50mL), the mixture was stirred at room temperature for 10 minutes, then N-chlorosuccinimide (4.50g,33.67mmol) was added and the mixture was reacted at 100 ℃ for 4 hours. After the reaction is finished, the temperature of the reaction solution is reduced to room temperature, and H is added2O (50mL) was then extracted with ethyl acetate (3x80mL) and washed with saturated aqueous lithium chloride (2x40 mL). The organic phase was washed with MgSO4Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel chromatography (0 to 5% gradient of ethyl acetate/petroleum ether) to give tert-butyl (5, 6-dichloropyridin-2-yl) carbamate (5.3g, yield: 65.8%).
1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.7Hz,1H),7.69(d,J＝8.7Hz,1H),7.24(s,1H),1.51(s,9H)；LCMS:m/z 207.1[M-55]+.
Step three: (5, 6-dichloro-4-iodopyridin-2-yl) carbamic acid tert-butyl ester
Figure BDA0001579586110000662
To a dry 100mL round bottom flask was added under nitrogen (5, 6-dichloropyridin-2-yl) carbamic acid tert-butyl ester (5.3g,20.14mmol) and tetrahydrofuran (50mL), n-butyllithium (44.3mmol,2.5M in THF) was slowly added dropwise at-78 deg.C and the reaction stirred at this temperature for 1 h. A solution of iodine (3.07g,24.17mmol) in tetrahydrofuran (20mL) was then added dropwise slowly and the reaction was continued at-78 deg.C for 3 hours. After the reaction is finished, H is added 2O (50mL), followed by EtOAc (3X 80mL) extraction. The combined organic phases were washed with MgSO4Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel chromatography (0 to 5% gradient of ethyl acetate/petroleum ether) to give tert-butyl (5, 6-dichloro-4-iodopyridin-2-yl) carbamate (4.3g, yield: 55%).
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.36(s,1H),1.46(s,9H)ppm；LCMS:m/z334.1[M-55]+.
Step four: 3- ((6- ((tert-Butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propionic acid methyl ester
Figure BDA0001579586110000671
To a dry 100mL round bottom flask was added tert-butyl (5, 6-dichloro-4-iodopyridin-2-yl) carbamate (3.2g,8.22mmol), palladium acetate (92mg, 0.41mmol), Xantphos (285mg,0.49mmol), DIPEA (2.12g,16.46mmol) and 1, 4-dioxane (30mL) in that order under nitrogen. The reaction mixture was heated and stirred at 100 ℃ for 2 hours. Filtration and concentration under reduced pressure gave a residue which was purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/petroleum ether) to give methyl 3- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propanoate (3g, yield: 96%).
1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.73(s,1H),3.64(s,3H),3.26(t,J＝6.9Hz,2H),2.82(t,J＝6.9Hz,2H),1.46(s,9H)ppm；LCMS:m/z 326.3[M-55]+.
Step five: sodium 6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-thiolate (F-1A)
Figure BDA0001579586110000672
To a dry 100mL round bottom flask were added methyl 3- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propionate and tetrahydrofuran (30mL) in that order, and then a solution of sodium ethoxide in ethanol (21%, 6mL) was added slowly dropwise at room temperature, and the reaction was stirred at room temperature for 1 hour. After concentration under reduced pressure, methylene chloride (10mL) was added to precipitate a large amount of a brown solid, which was filtered, washed with methylene chloride, and dried to obtain sodium 6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-thiolate F-1A (2.1g, yield: 84%).
1H NMR(400MHz,DMSO-d6)δ9.05(s,1H),7.61(s,1H),1.41(s,9H)ppm；LCMS:m/z262.2[M-55]+.
Following the synthetic procedure of example 17, the following intermediate F-1B, F-1C, F-1D, F-1E, F-1F, F-1G, F-1H, F-1I, F-1J, F-1K, F-1L, F-1M, F-1N, F-1O, F-1P was obtained by reaction with similar starting intermediates.
Figure BDA0001579586110000681
Figure BDA0001579586110000691
EXAMPLE 18 preparation of intermediate sodium 3-chloro-2-methylpyridin-4-thiolate (F-1Q)
The method comprises the following steps: 3- ((3-chloro-2-methylpyridin-4-yl) thio) propanoic acid methyl ester
The intermediate methyl 3- ((2, 3-dichloropyridin-4-yl) thio) propanoate obtained during the synthesis of intermediate F-1G was used in the following reaction.
Figure BDA0001579586110000692
To a dry 100mL round bottom flask under nitrogen was added methyl 3- ((2, 3-dichloropyridin-4-yl) thio) propionate (500mg,1.88mmol), Pd (PPh) in that order3)4(217mg,0.188mmol), trimethylcyclotriboroxane (354mg,2.82mmol), potassium carbonate (389mg,2.82mmol) and 1, 4-dioxane (10 mL). The reaction mixture was heated and stirred at 100 ℃ for 6 hours under nitrogen. The residue obtained is filtered and concentrated under reduced pressure and purified by chromatography on silica gel (0 to 40% gradient of ethyl acetate/petroleum ether) to give 3- ((3-chloro-2-methyl ether)Pyridin-4-yl) thio) propionic acid methyl ester (320mg, yield: 69%).
Step two: 3-chloro-2-methylpyridine-4-thiol sodium (F-1Q)
Figure BDA0001579586110000701
To a dry 100mL round bottom flask were added methyl 3- ((3-chloro-2-methylpyridin-4-yl) thio) propionate (320mg,1.30mmol) and tetrahydrofuran (10mL) in that order, and then a solution of sodium ethoxide in ethanol (21%, 2mL) was slowly added dropwise at room temperature, and the reaction was stirred at room temperature for 1 hour. After concentration under reduced pressure, methylene chloride (10mL) was added to precipitate a large amount of brown solid, which was filtered, washed with methylene chloride, and dried to obtain sodium 3-chloro-2-methylpyridin-4-thiolate F-1Q (200mg, yield: 85%).
1H NMR(400MHz,DMSO-d6)δ7.37(d,J＝4.8Hz,1H),6.97(d,J＝4.8Hz,1H),2.31(s,3H)ppm；LCMS:m/z 160.0[M+H]+.
Following the synthetic procedure of example 18, using similar intermediate starting materials, the reaction gave the following intermediate F-1R.
Figure BDA0001579586110000702
Example 19: preparation of intermediate sodium 6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridin-4-thiolate (F-1S)
The method comprises the following steps: 3- ((6- ((tert-Butoxycarbonyl) amino) -3-chloro-2-methylpyridin-4-yl) thio) propionic acid methyl ester
The intermediate methyl 3- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propanoate obtained during the synthesis of intermediate F-1A was used in the following reaction.
Figure BDA0001579586110000703
To a dry 100mL round bottom flask was added methyl 3- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) propanoate (600mg,1.57mmol), [1,1' -bis (tert-butylphosphino) ferrocene dichloropalladium (103mg, 0.157mmol), trimethylcyclotriboroxane (301mg,2.4mmol), potassium carbonate (331mg,2.4mmol), 1, 4-dioxane (10mL) and water (1mL) in that order under nitrogen. The reaction mixture was heated and stirred at 100 ℃ for 6 hours under nitrogen. The resulting residue was filtered and concentrated under reduced pressure to purify by silica gel chromatography (0 to 40% gradient of ethyl acetate/petroleum ether) to obtain methyl 3- ((6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridin-4-yl) thio) propionate (420mg, yield: 74%).
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.64(s,1H),3.64(s,3H),3.21(t,J＝6.9Hz,2H),2.80(t,J＝6.9Hz,2H),1.46(s,9H)ppm；LCMS:m/z 361.1[M+H]+.
Step two: sodium 6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridine-4-thiol (F-1S)
Figure BDA0001579586110000711
To a dry 100mL round bottom flask were added methyl 3- ((6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridin-4-yl) thio) propanoate (420mg,1.17mmol) and tetrahydrofuran (10mL) in that order, followed by slow dropwise addition of a solution of sodium ethoxide in ethanol (21%, 2mL) at room temperature, and the reaction was stirred at room temperature for 1 hour. After concentration under reduced pressure, methylene chloride (10mL) was added to precipitate a large amount of a brown solid, which was filtered, washed with methylene chloride, and dried to give sodium 6- ((tert-butoxycarbonyl) amino) -3-chloro-2-methylpyridin-4-thiolate F-1S (320mg, yield: 92%).
1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),7.63(s,1H),3.64(s,3H),1.46(s,9H)ppm；LCMS:m/z 275.0[M+H]+.
EXAMPLE 20 preparation of intermediate 3-amino-2-chlorobenzenethiol hydrochloride (F-2A)
The method comprises the following steps: 2-chloro-3-aminothiophenol tert-butyl ester
Figure BDA0001579586110000712
To a dry 100mL round bottom flask was added 2-chloro-3-fluoroaniline (5g,34.3mmol) followed by N-methylpyrrolidinone (50mL) under nitrogen, then 2-methylpropane-2-thiol (8.66g, 96.04mmol) and cesium carbonate (22.36g,68.6mmol) and the reaction mixture was stirred at 120 ℃ for 16 h. After cooling to room temperature, the reaction solution was diluted with 60mL of ethyl acetate, washed with a saturated aqueous lithium chloride solution (30mL), water (30mL) and a saturated aqueous sodium chloride solution (30mL) in this order, then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 2-chloro-3-aminophenethiolate (6.04g, yield: 82%).
LCMS:m/z 216.1[M+H]+.
Step two: 3-amino-2-chlorobenzenethiol hydrochloride (F-2A)
Figure BDA0001579586110000721
To a dry 100mL round bottom flask was added tert-butyl 2-chloro-3-aminothiophenol (6.04g,28mmol) and concentrated hydrochloric acid (50mL) and the reaction mixture was heated with stirring at 45 ℃ for 8 hours. After naturally cooled to room temperature, the reaction solution was further cooled to 0 ℃ to precipitate a large amount of white solid, which was then filtered and washed with concentrated hydrochloric acid and petroleum ether in this order to give 3-amino-2-chlorobenzenethiol hydrochloride F-2A (4.9g, yield: 90%).
LCMS:m/z 160.0[M+H]+.
EXAMPLE 21 preparation of the compound 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-amine
The method comprises the following steps: (1- (8-Iodoimidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester
Figure BDA0001579586110000722
Under the protection of nitrogen, 5-chloro-8-iodoimidazo [1,2-c ] is added into a dry 50mL single-neck flask in sequence]Pyrimidine E1(50mg, 0.1)8mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (77mg,0.36mmol), DIEA (46mg,0.36mmol) and NMP (5mL), and the reaction was stirred at 90 ℃ for 2 hours. After completion of the reaction, the obtained residue was poured into water (10mL), and stirred at room temperature for 5 minutes. Then extracted with ethyl acetate (3 × 50mL) and the combined organic phases were extracted with MgSO4The residue obtained is dried, filtered and concentrated under reduced pressure, purified by chromatography on silica gel (0 to 80% gradient of ethyl acetate/petroleum ether) to give a pale yellow solid (1- (8-iodoimidazo [1,2-c ]) ]Pyrimidin-5-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (70mg, yield: 43%)
1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.89(d,J＝1.5Hz,1H),7.62(d,J＝1.4Hz,1H),3.49(d,J＝13.4Hz,2H),3.21(ddd,J＝13.3,10.8,2.6Hz,2H),2.18(d,J＝13.9Hz,2H),1.65(ddd,J＝14.1,10.7,3.8Hz,2H),1.40(s,9H),1.28(s,3H)ppm；LCMS:m/z 458.1[M+H]+.
Step two: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester
Figure BDA0001579586110000731
To a dry 50mL three-necked flask, 1- (8-iodoimidazo [1,2-c ] was added in order]Pyrimidin-5-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (70mg,0.15mmol), cuprous iodide (3mg,0.015mmol), 1, 10-phenanthroline (6mg,0.030mmol), 2, 3-dichlorothiophenol (32mg,0.18mmol), potassium phosphate (66mg,0.30mmol), and 5mL of dioxane. The mixture was heated under nitrogen for 3 hours. After the reaction is finished, saturated NH is added4Cl solution (10 mL). Then extracted with ethyl acetate (3 × 50 mL). The combined organic phases are washed with Na2SO4Drying, filtering, concentrating the filtrate under reduced pressure, and purifying the resulting residue by silica gel chromatography (0 to 60% gradient of ethyl acetate/petroleum ether) to give (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1, 2-c) as a pale yellow solid]Pyrimidin-5-) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (30mg, yield: 39%).
LC-MS:m/z 508.1[M+H]+.
Step three: 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-amine
Figure BDA0001579586110000732
To a dry 50mL round bottom flask were added tert-butyl (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-) -4-methylpiperidin-4-yl) carbamate (30mg,0.059mmol) and 1, 4-dioxane solution of hydrochloric acid (7M,5mL) in this order, and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by high performance liquid chromatography to give the product 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidine-4-amine (15mg, yield: 62%).
1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.84(d,J＝1.3Hz,1H),7.55(d,J＝1.2Hz,1H),7.41(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(dd,J＝8.1,1.2Hz,1H),3.60(t,J＝4.2Hz,4H),1.73-1.60(m,4H),1.19(s,3H)ppm；LC-MS:m/z 408.1[M+H]+.
Using the synthesis method of example 21, the following compounds can be synthesized:
example 22- ((2, 3-dichlorophenyl) thio) -5- (1, 8-diazaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidine
Figure BDA0001579586110000741
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.89(s,1H),7.57(s,1H),7.41(d,J＝8.1Hz,1H),7.12(t,J＝8.0Hz,1H),6.72(d,J＝8.1Hz,1H),3.79(ddd,J＝13.9,7.1,3.7Hz,2H),3.49(ddd,J＝12.8,8.0,3.4Hz,2H),3.19(t,J＝6.9Hz,2H),2.04(ddd,J＝12.3,8.1,3.5Hz,2H),1.93(dt,J＝20.5,6.5Hz,6H)ppm；LC-MS:m/z 434.1[M+H]+.
EXAMPLE 23 preparation of the Compound 8- ((2, 3-dichlorophenyl) thio) -5- (piperidin-1-yl) imidazo [1,2-c ] pyrimidine
Figure BDA0001579586110000742
To a dry 50mL single neck flask was added 5-chloro-8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c]Pyrimidine B1(50mg,0.15mmol), piperidine (20mg,0.23mmol), DIEA (39mg,0.3mmol) and NMP (5mL), and the reaction was stirred at 90 ℃ for 2 hours. After completion of the reaction, the obtained residue was poured into water (100mL), and stirred at room temperature for 5 minutes. Then extracted with ethyl acetate (3X 50mL) and the combined organic phases were MgSO4The residue obtained by drying, filtration and concentration under reduced pressure is purified by chromatography on silica gel (0 to 80% gradient of ethyl acetate/petroleum ether) and by high performance liquid chromatography to give the product ((1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1, 2-c)]Pyrimidin-5-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester (20mg, yield: 35%)
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.83(d,J＝1.4Hz,1H),7.55(d,J＝1.4Hz,1H),7.41(dd,J＝8.0,1.3Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(dd,J＝8.1,1.3Hz,1H),3.50(d,J＝5.6Hz,4H),1.79-1.63(m,6H)ppm；LC-MS:m/z 378.7[M+H]+.
Using the synthesis of example 23, the following compounds can be synthesized:
example 24: 8- ((2, 3-dichlorophenyl) thio) -5- (3, 5-dimethylpiperazin-1-yl) imidazo [1,2-c ] pyrimidine
Figure BDA0001579586110000751
1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.03(s,1H),7.92(d,J＝1.2Hz,1H),7.55(d,J＝1.2Hz,1H),7.44-7.37(m,1H),7.12(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.1Hz,1H),3.89(d,J＝12.0Hz,2H),3.02(d,J＝6.6Hz,2H),2.72-2.59(m,2H),1.05(t,J＝6.0Hz,7H)ppm；LC-MS:m/z 407.7[M+H]+.
Example 25: 8- ((2, 3-dichlorophenyl) thio) -5- (4-methylpiperazin-1-yl) imidazo [1,2-c ] pyrimidine
Figure BDA0001579586110000752
1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.04(s,1H),7.91(d,J＝1.4Hz,1H),7.57(d,J＝1.4Hz,1H),7.41(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.0Hz,1H),6.70(dd,J＝8.1,1.2Hz,1H),3.59-3.50(m,4H),2.59-2.53(m,4H),2.27(s,3H)ppm；LC-MS:m/z 393.8[M+H]+.
Example 26: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-phenylpiperidin-4-yl) methylamine
Figure BDA0001579586110000753
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.88(s,1H),7.54(s,1H),7.50-7.33(m,5H),7.28(t,J＝6.8Hz,1H),7.10(t,J＝8.0Hz,1H),6.67(d,J＝8.1Hz,1H),3.77(d,J＝12.5Hz,2H),3.31-3.22(m,2H),3.09(s,1H),2.82(s,1H),2.32(s,2H),2.06(t,J＝10.3Hz,2H)；LC-MS:m/z484.7[M+H]+.
Example 27: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000761
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.81(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),7.42(dd,J＝8.0,1.3Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.4Hz,1H),3.93(t,J＝14.9Hz,2H),3.31(d,J＝19.3Hz,2H),3.28-3.16(m,3H),2.252.06(m,2H),1.90(dd,J＝32.1,11.8Hz,2H),1.61-1.45(m,2H)ppm；LC-MS:m/z 484.1[M+H]+.
Example 28: (R) -3- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-azaspiro [5.5] undecan-7-amine
Figure BDA0001579586110000762
1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.82(d,J＝1.2Hz,1H),7.56(d,J＝1.2Hz,1H),7.41(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.1Hz,1H),6.68(dd,J＝8.1,1.2Hz,1H),3.80(d,J＝4.8Hz,2H),3.33(dd,J＝29.0,11.6Hz,2H),2.77(d,J＝5.2Hz,1H),2.04(dd,J＝30.0,14.7Hz,2H),1.85-1.12(m,10H)ppm；LC-MS:m/z 461.7[M+H]+.
Example 29: 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-ethylpiperidin-4-amine
Figure BDA0001579586110000763
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.88(d,J＝1.5Hz,1H),7.58(d,J＝1.4Hz,1H),7.42(dd,J＝8.0,1.3Hz,1H),7.12(t,J＝8.1Hz,1H),6.70(dd,J＝8.1,1.4Hz,1H),3.71-3.64(m,4H),1.90-1.73(m,4H),1.69(q,J＝7.3Hz,2H),0.93(t,J＝7.5Hz,3H)ppm；LC-MS:m/z 422.1[M+H]+.
Example 30: 8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -1-methyl-8-aza-spiro [4.5] decan-1-amine
Figure BDA0001579586110000771
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.83(s,1H),7.56(s,1H),7.41(d,J＝8.1Hz,1H),7.17-7.08(m,1H),6.69(d,J＝8.2Hz,1H),4.08-3.93(m,2H),3.18-3.04(m,2H),3.04-2.94(m,1H),2.45(s,1H),1.90-1.29(m,8H),0.95(t,J＝6.3Hz,3H)ppm；LC-MS:m/z 462.1[M+H]+.
Example 31: preparation of the compound 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-amine
The method comprises the following steps: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-yl) carbamic acid tert-butyl ester
Figure BDA0001579586110000772
Using the same procedure as in example 23, B1 was substituted with the corresponding amine to give tert-butyl (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-yl) carbamate.
LC-MS:m/z 424.1[M+H]+.
Step two: the compound 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-amine
Figure BDA0001579586110000773
Following removal of the Boc protecting group from tert-butyl (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-yl) carbamate using the same procedure as step three of example 21, the compound 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-amine was obtained.
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.93(d,J＝1.1Hz,1H),7.46(s,1H),7.40(d,J＝8.0Hz,1H),7.13(t,J＝8.0Hz,1H),6.63(d,J＝8.1Hz,1H),4.14(d,J＝9.3Hz,1H),4.05(d,J＝5.9Hz,1H),3.82(d,J＝11.2Hz,3H),2.24(d,J＝7.3Hz,1H),2.02(s,1H)ppm；LC-MS:m/z379.9[M+H]+.
Using the synthesis of example 31, the following compounds can be synthesized:
example 32: 1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) piperidin-4-amine
Figure BDA0001579586110000781
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.03(s,1H),7.86(s,1H),7.57(s,1H),7.42(d,J＝7.6Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.1Hz,1H),4.00(d,J＝13.0Hz,2H),3.13(d,J＝11.5Hz,2H),2.02-1.86(m,3H),1.62(dd,J＝21.0,9.8Hz,2H),1.23(s,1H)；LC-MS:m/z394.7[M+H]+.
Example 33: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) pyrrolidin-3-yl) methylamine
Figure BDA0001579586110000782
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝1.6Hz,1H),7.91(s,1H),7.45(d,J＝1.5Hz,1H),7.39(d,J＝7.7Hz,1H),7.12(t,J＝8.0Hz,1H),6.63(d,J＝8.1Hz,1H),4.04(ddd,J＝11.5,8.9,5.5Hz,2H),3.94-3.86(m,1H),3.72(dd,J＝10.8,7.6Hz,2H),2.93(d,J＝7.2Hz,2H),2.16(dq,J＝11.9,6.2Hz,1H),1.79(dq,J＝12.3,8.3Hz,1H)ppm；LC-MS:m/z 394.1[M+H]+.
Example 34: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -4-methylpiperidin-4-yl) methylamine
Figure BDA0001579586110000791
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.83(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),7.42(dd,J＝8.0,1.3Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.3Hz,1H),3.68(dt,J＝13.7,4.6Hz,2H),3.44(td,J＝9.6,4.8Hz,2H),2.76(s,2H),1.70(ddd,J＝13.3,9.2,3.7Hz,2H),1.62-1.49(m,2H),1.08(s,3H)ppm；LC-MS:m/z 422.1[M+H]+.
Example 35: (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) piperidin-4-yl) methylamine
Figure BDA0001579586110000792
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.03(s,1H),7.83(s,1H),7.57(s,1H),7.42(d,J＝7.7Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),4.05(d,J＝13.2Hz,2H),3.07(t,J＝12.3Hz,2H),2.75(d,J＝5.9Hz,2H),1.88(d,J＝11.8Hz,3H),1.53-1.35(m,2H)ppm；LC-MS:m/z 409.8[M+H]+.
Example 36: 2- (1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) piperidin-4-yl) ethan-1-amine
Figure BDA0001579586110000793
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.85(d,J＝1.2Hz,1H),7.56(d,J＝1.2Hz,1H),7.41(dd,J＝8.0,1.2Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(dd,J＝8.1,1.2Hz,1H),4.02(d,J＝12.9Hz,2H),3.03(t,J＝12.0Hz,2H),2.87-2.78(m,2H),1.82(d,J＝12.5Hz,2H),1.70(s,1H),1.55(dd,J＝14.7,6.9Hz,2H),1.40(dd,J＝21.6,11.5Hz,2H)ppm；LC-MS:m/z 422.7[M+H]+.
Example 37: synthesis of compound (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine
The method comprises the following steps: (R) -N- ((S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide
Figure BDA0001579586110000801
Using the same procedure as in example 23, B1 was substituted with the corresponding amine to give (R) -N- ((S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide.
LC-MS:m/z 554.1[M+H]+.
Step two: (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110000802
To a 50mL one-neck flask were added (R) -N- ((S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-yl) -2-methylpropane-2-sulfinamide (70mg,0.13mmol) and methanol (0.5mL) in this order under nitrogen, a 1, 4-dioxane solution (0.05mL,4M) of hydrochloric acid was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was cooled to room temperature, filtered and concentrated under reduced pressure to give a residue which was purified by high performance liquid preparative chromatography to give (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine (10mg, yield: 17%).
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.83(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),7.42(dd,J＝8.0,1.4Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(dd,J＝8.1,1.4Hz,1H),4.00(dd,J＝8.8,6.4Hz,1H),3.87-3.71(m,2H),3.66(d,J＝8.5Hz,1H),3.29-3.27(m,1H),3.17(t,J＝5.8Hz,2H),1.92-1.76(m,2H),1.57(dd,J＝12.5,5.8Hz,2H),1.24(d,J＝3.2Hz,1H)ppm；LC-MS:m/z 450.1[M+H]+.
According to the synthesis method of example 37, the following compounds can be synthesized:
example 38: (R) -1- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) azepan-4-amine
Figure BDA0001579586110000811
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.95(s,2H),7.48(s,1H),7.40(d,J＝7.9Hz,1H),7.12(t,J＝8.0Hz,1H),6.66(d,J＝8.0Hz,1H),4.03-3.89(m,2H),3.81-3.61(m,2H),3.20(s,1H),2.15(s,1H),1.95(d,J＝14.1Hz,4H),1.56(d,J＝10.7Hz,1H)ppm；LC-MS:m/z 409.8[M+H]+.
Example 39: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110000812
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.03(s,1H),7.84(s,1H),7.56(s,1H),7.41(d,J＝7.9Hz,1H),7.12(t,J＝8.1Hz,1H),6.70(d,J＝8.1Hz,1H),3.94(t,J＝13.7Hz,2H),3.54(d,J＝8.7Hz,1H),3.45(d,J＝8.7Hz,1H),3.32(d,J＝12.2Hz,2H),2.68(s,1H),1.98-1.88(m,2H),1.65(s,2H),1.02(s,3H),0.95(s,3H)；LC-MS:m/z 479.7[M+H]+.
Example 40: (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110000813
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.84(s,1H),7.56(s,1H),7.41(d,J＝7.9Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.1Hz,1H),3.94(t,J＝14.1Hz,2H),3.54(d,J＝8.7Hz,1H),3.45(d,J＝8.7Hz,1H),3.35-3.25(m,2H),2.69(s,1H),1.98-1.85(m,2H),1.71-1.59(m,2H),1.03(s,3H),0.95(s,3H)；LC-MS:m/z 479.7[M+H]+.
Example 41: (1R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-methyl-8-aza-spiro [4.5] decan-1-amine
Figure BDA0001579586110000821
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.81(dd,J＝7.4,1.6Hz,1H),7.56(d,J＝1.6Hz,1H),7.41(dd,J＝8.0,1.4Hz,1H),7.12(t,J＝8.0Hz,1H),6.68(dd,J＝8.1,1.4Hz,1H),3.95(d,J＝11.9Hz,2H),3.12(t,J＝12.0Hz,2H),2.89(d,J＝5.8Hz,1H),2.08-1.44(m,9H),1.00(dd,J＝31.0,6.6Hz,3H)ppm；LC-MS:m/z 462.1[M+H]+.
Example 42: (1R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-8-aza-spiro [4.5] decan-1-amine
Figure BDA0001579586110000822
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.80(s,1H),7.56(s,1H),7.41(d,J＝8.0Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(d,J＝8.1Hz,1H),3.99-3.80(m,2H),3.24-2.98(m,3H),2.27-1.14(m,9H),1.04-0.95(m,3H)ppm；LC-MS:m/z 462.1[M+H]+.
Example 43: (4R) -4-amino-8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-2-ol
Figure BDA0001579586110000823
1H NMR(400MHz,DMSO-d6)δ8.37(s,1H),8.04(s,1H),7.81(s,1H),7.57(s,1H),7.42(d,J＝7.9Hz,1H),7.12(t,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),4.15(d,J＝6.5Hz,1H),3.91(d,J＝14.3Hz,2H),3.22(s,2H),2.93(t,J＝7.3Hz,1H),2.27-2.20(m,1H),1.89-1.66(m,5H),1.54(dt,J＝13.4,6.7Hz,1H),1.35(d,J＝12.9Hz,1H)ppm；LC-MS:m/z 465.7[M+H]+.
Example 44: (3S,4S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110000831
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.84(s,1H),7.56(s,1H),7.41(d,J＝7.9Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),4.15-4.06(m,1H),3.73(s,2H),3.56(d,J＝8.5Hz,1H),3.42-3.27(m,3H),3.05(d,J＝4.8Hz,1H),1.91(dt,J＝39.6,9.8Hz,2H),1.67(dd,J＝25.7,13.7Hz,2H),1.12(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 463.7[M+H]+.
Example 45: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -1-oxa-8-aza-spiro [4.5] decan-4-amine
Figure BDA0001579586110000832
1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.60(s,1H),7.48(s,1H),7.20(d,J＝6.4Hz,1H),6.95(t,J＝6.4Hz,1H),6.70(d,J＝6.4Hz,1H),4.00-3.85(m,4H),3.46(t,J＝8.8Hz,2H),3.20(t,J＝5.2Hz,1H),2.39-2.35(m,1H),1.94-1.89(m,2H),1.80-1.74(m,2H),1.68-1.65(m,1H)ppm；LCMS:m/z 450.1[M+H]+.
Example 46: synthesis of compound (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -N-methyl-8-aza-spiro [4.5] decan-1-amine
The method comprises the following steps: (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide
Figure BDA0001579586110000841
Using the same procedure as in example 23, B1 was substituted with an amine to give (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide (70mg, yield: 80%)
LC-MS:m/z 552.1[M+H]+.
Step two: (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -N, 2-dimethylpropane-2-sulfinamide
Figure BDA0001579586110000842
To a dry 50mL round bottom flask was added (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] in sequence]Pyrimidin-5-yl) -8-azaspiro [4.5]Decan-1-yl) -2-methylpropane-2-sulfinamide (70mg,0.13mmol) and DMF (5 mL). NaH (10.4mg,0.26mmol) was then slowly added at 0 deg.C, the mixture was stirred at this temperature for 10 minutes, and CH was then slowly added while maintaining 0 deg.C3I(28mg,0.20mmol) and then stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by addition of water (10mL) and then extracted with ethyl acetate (3X 10mL) and the combined organic phases were MgSO4The residue obtained is dried, filtered and concentrated under reduced pressure to give a light yellow solid (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1, 2-c) by chromatography on silica gel (0 to 80% gradient of ethyl acetate/petroleum ether) ]Pyrimidin-5-yl) -8-azaspiro [4.5]Decane-1-
Yl) -N, 2-dimethylpropane-2-sulfinamide (50mg, yield: 49%)
LC-MS:m/z 566.1[M+H]+.
Step three: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -N-methyl-8-aza-spiro [4.5] decan-1-amine
Figure BDA0001579586110000851
Sulfinyl was removed from (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -N, 2-dimethylpropane-2-sulfinamide using the same procedure as step two of example 37 to give (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -N-methyl-8-aza-spiro [4.5] decan-1-amine.
1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.03(s,1H),7.82(s,1H),7.55(s,1H),7.41(d,J＝8.0Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(d,J＝8.1Hz,1H),3.87(d,J＝13.2Hz,2H),3.22(dd,J＝22.1,10.8Hz,2H),2.56(t,J＝7.3Hz,1H),2.35(s,3H),1.89(ddd,J＝33.1,16.7,7.8Hz,4H),1.72-1.33(m,6H)ppm；LC-MS:m/z 461.7[M+H]+.
Example 47: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
The method comprises the following steps: (R) -N- ((R) -8- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfonamide
Figure BDA0001579586110000852
To a dry 50mL single neck flask was added 5-chloro-8-iodoimidazo [1,2-c ] in sequence]Pyrimidine E1(50mg,0.18mmol), (R) -2-methyl-N- ((R) -8-azaspiro [4.5]]Decan-1-yl) propane-2-sulfinamide (C-1A) (93mg,0.36mmol), DIEA (46mg,0.36mmol) and NMP (5mL), and the reaction was stirred at 90 ℃ for 2 hours. After completion of the reaction, the obtained residue was poured into water (10mL), and stirred at room temperature for 5 minutes. Then extracted with ethyl acetate (3X 20mL) and the combined organic phases were MgSO 4The residue obtained is dried, filtered and concentrated under reduced pressure to give a light yellow solid (R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) by chromatography on silica gel (0 to 80% gradient of ethyl acetate/petroleum ether)]Pyrimidin-5-yl) -8-azaspiro [4.5]Decan-1-yl) -2-methylpropane-2-sulfonamide (80mg, yield: 88%)
1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.79(d,J＝1.4Hz,1H),7.64(d,J＝1.4Hz,1H),4.97(d,J＝8.0Hz,1H),3.77-3.65(m,2H),3.23-3.13(m,1H),3.04(dd,J＝30.0,11.5Hz,2H),2.03-1.78(m,4H),1.67-1.31(m,6H),1.13(s,9H)ppm；LC-MS:m/z 502.1[M+H]+.
Step two: (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide
Figure BDA0001579586110000861
A dry 50mL three-necked flask was charged with (R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) in sequence]Pyrimidin-5-yl) -8-azaspiro [4.5]Decan-1-yl) -2-methylpropane-2-sulfonamide (80mg,0.16mmol), cuprous iodide (3mg,0.016mmol), 1, 10-phenanthroline (6mg,0.032mmol), 2, 3-dichlorothiophenol (34mg,0.192mmol), potassium phosphate (68mg,0.32mmol), and 10mL of dioxane solution. The mixture was heated under nitrogen for 3 hours. After the reaction is finished, saturated NH is added4Cl solution (50 mL). It was extracted with ethyl acetate (3 × 20 mL). The combined organic phases are washed with Na2SO4Drying, filtering, and concentrating the filtrate under reduced pressureThe resulting residue was purified by silica gel chromatography (0 to 10% gradient of methanol/ethyl acetate) to give (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1, 2-c) as a pale yellow solid ]Pyrimidin-5-yl) -8-azaspiro [4.5]Decan-1-yl) -2-methylpropane-2-sulfinamide (60mg, yield: 68%).
1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.76(d,J＝1.4Hz,1H),7.56(d,J＝1.4Hz,1H),7.40(dd,J＝8.0,1.3Hz,1H),7.11(t,J＝8.0Hz,1H),6.68(dd,J＝8.1,1.3Hz,1H),5.00(d,J＝8.1Hz,1H),3.94(dd,J＝12.8,3.4Hz,2H),3.26-3.14(m,3H),2.08-1.84(m,4H),1.69-1.36(m,6H),1.14-1.11(m,9H)ppm；LC-MS:m/z 552.1[M+H]+.
Step three: (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000862
To a dry 50mL round bottom flask were added (R) -N- ((R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide (example 17-2) (60mg,0.11mmol) and a solution of 1, 4-dioxane hydrochloric acid (7M,5mL) in this order and reacted at room temperature for 1 hour. The reaction solution was distilled under reduced pressure, and the obtained crude product was purified by reverse-phase high performance liquid chromatography to give the product (R) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine (25mg, yield: 51%).
1H NMR(400MHz,CD3OD-d4)δ8.54(s,2H),8.04(s,1H),7.81(s,1H),7.58(s,1H),7.33(dd,J＝8.0,1.3Hz,1H),7.05(t,J＝8.0Hz,1H),6.68(dd,J＝8.1,1.3Hz,1H),4.03(t,J＝14.7Hz,2H),3.38(s,2H),2.27(d,J＝5.4Hz,1H),1.97-1.63(m,9H)ppm；LC-MS:m/z 448.1[M+H]+.
Following the synthesis of example 47, the following compounds may be synthesized:
example 48: (R) -7- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -7-aza-spiro [3.5] nonan-1-amine
Figure BDA0001579586110000871
1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.02(s,1H),7.82(d,J＝1.6Hz,1H),7.55(s,1H),7.41(d,J＝7.8Hz,1H),7.12(t,J＝8.1Hz,1H),6.69(d,J＝7.9Hz,1H),3.91(d,J＝13.2Hz,1H),3.84-3.73(m,1H),3.18-3.08(m,3H),2.13(q,J＝8.0Hz,1H),1.83(td,J＝10.7,8.5,4.2Hz,2H),1.80-1.69(m,3H)ppm；LC-MS:m/z 434.1[M+H]+.
Example 49: 7- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -7-aza-spiro [3.5] nonan-2-amine
Figure BDA0001579586110000872
1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.83(d,J＝1.6Hz,1H),7.56(d,J＝1.5Hz,1H),7.41(dd,J＝8.0,1.4Hz,1H),7.12(t,J＝8.0Hz,1H),6.69(dd,J＝8.1,1.4Hz,1H),3.50(d,J＝10.2Hz,2H),3.41(s,2H),2.71-2.64(m,1H),2.36-2.30(m,1H),2.21(s,2H),1.81(d,J＝26.6Hz,5H)ppm；LC-MS:m/z 434.1[M+H]+.
Example 50: (7R) -2- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-aza-spiro [4.4] nonan-7-ylamine
Figure BDA0001579586110000881
1H NMR(400MHz,DMSO-d6)δ8.36(brs,1H),8.18(s,1H),7.89(d,J＝2.4Hz,1H),7.43(s,1H),7.38(d,J＝6.0Hz,1H),7.11(t,J＝6.4Hz,1H),6.64(d,J＝6.0Hz,1H),3.96-3.74(m,4H),3.53-3.51(m,1H),2.00-1.60(m,8H)ppm；LCMS:m/z 434.2[M+H]+.
Example 51: (R) -8- (8- ((6-amino-3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl 1-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110000882
1H NMR(400MHz,DMSO-d6)δ8.17(s,2H),8.08(s,1H),7.90(s,1H),7.65(s,1H),5.67(s,1H),4.09-3.93(m,2H),3.61(dd,J＝14.2,9.1Hz,4H),3.10(d,J＝5.4Hz,1H),2.35(d,J＝15.8Hz,3H),2.03-1.71(m,4H),1.16(s,3H),1.07(s,3H)ppm；LCMS:m/z 474.1[M+H]+.
Example 52: (S) -8- (8- ((2, 3-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000883
1H NMR(DMSO-d6)δ8.43(s,1H),8.02(s,1H),7.79-7.80(d,1H),7.56-7.57(d,1H),7.40-7.42(d,1H),7.11-7.15(t,1H),6.68-6.71(d,1H),3.88(t,2H),3.24(t,2H),3.01(t,1H),1.60-1.90(m,5H),1.30-1.59(m,5H)ppm；LC-MS:m/z 448.1[M+H]+.
Example 53: (R) -8- (8- ((2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000891
1H NMR(400MHz,DMSO-d6)δ7.97(s,1H),7.80(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),7.49(dd,J＝7.7,1.6Hz,1H),7.15(dtd,J＝19.6,7.4,1.6Hz,2H),6.76(dd,J＝7.7,1.7Hz,1H),3.93-3.80(m,2H),3.21(td,J＝11.2,2.7Hz,2H),3.00(s,1H),2.05-1.75(m,4H),1.75-1.35(m,6H)ppm；LCMS:m/z 414.1[M+H]+.
Example 54: (R) -8- (8- ((3-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000892
1H NMR(CD3OD-d4)δ7.96(s,1H),7.78(s,1H),7.58(s,1H),7.23-7.27(m,3H),7.14-7.16(m,1H),3.83(m,2H),3.24(m,2H),2.89(m,1H),1.77-1.83(m,4H),1.51-1.62(m,2H),1.354-1.46(m,4H)ppm；LCMS:m/z 414.1[M+H]+.
Example 55: (R) -8- (8- ((4-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000893
1H NMR(400MHz,DMSO-d6)δ7.91(s,1H),7.79-7.75(m,1H),7.58(d,J＝1.2Hz,1H),7.33(d,J＝8.5Hz,2H),7.23(d,J＝8.5Hz,2H),3.91-3.71(m,2H),3.18(t,J＝12.3Hz,2H),3.00(s,1H),2.05-1.66(m,5H),1.64-1.34(m,5H)ppm；LCMS:m/z 414.1[M+H]+.
Example 56: (R) -8- (8- ((2, 6-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000901
1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.66(s,1H),7.64(s,1H),7.60(s,1H),7.51(t,J＝8.1Hz,1H),7.09(s,1H),3.64(s,2H),3.04(q,J＝12.4Hz,2H),2.74(t,J＝7.2Hz,1H),1.89-1.74(m,4H),1.52(s,2H),1.42-1.24(m,4H)ppm；LCMS:m/z 450.0[M+H]+.
Example 57: (R) -8- (8- ((2, 4-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000902
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.81(d,J＝1.6Hz,1H),7.69(d,J＝2.3Hz,1H),7.56(d,J＝1.4Hz,1H),7.20(dd,J＝8.6,2.3Hz,1H),6.75(d,J＝8.6Hz,1H),3.94-3.79(m,2H),3.20(q,J＝11.9Hz,2H),2.77(t,J＝7.3Hz,1H),1.90-1.77(m,4H),1.67-1.52(m,2H),1.37(td,J＝27.0,26.1,12.9Hz,4H)ppm；LCMS:m/z 450.0[M+H]+.
Example 58: (R) -8- (8- ((2, 5-dichlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000903
1H NMR(CD3OD-d4)δ8.02(s,1H),7.82(s,1H),7.52-7.58(m,2H),7.22-7.25(m,1H),6.71(s,1H),3.88-3.89(m,2H),3.22-3.24(m,2H),2.81-2.83(m,1H),1.77-1.83(m,4H),1.51-1.62(m,2H),1.354-1.46(m,4H)ppm；LCMS:m/z 450.0[M+H]+.
Example 59: (R) -8- (8- ((2-isopropylphenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000911
1H NMR(400MHz,DMSO-d6)δ7.76(s,1H),7.58(s,2H),7.37(d,J＝7.7Hz,1H),7.24(s,1H),7.06(d,J＝6.1Hz,2H),3.73(s,2H),3.52(s,1H),3.11(d,J＝12.8Hz,2H),2.76(s,1H),1.83(d,J＝31.7Hz,4H),1.58(d,J＝42.0Hz,2H),1.36(s,4H),1.24(d,J＝7.0Hz,6H)ppm；LCMS:m/z 423.2[M+H]+.
Example 60: (R) -8- (8- ((2-methoxyphenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000912
1H NMR(400MHz,DMSO-d6)δ7.77(s,1H),7.73(s,1H),7.58(s,1H),7.19(t,J＝7.9Hz,1H),7.05(d,J＝8.2Hz,1H),6.82-6.69(m,2H),3.87(s,3H),3.77(d,J＝12.4Hz,2H),3.17(s,2H),2.97(s,2H),1.97(s,1H),1.77-1.30(m,9H)ppm；LCMS:m/z 410.1[M+H]+.
Example 61: (R) -methyl 2- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) benzoate
Figure BDA0001579586110000913
1H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.95(dd,J＝7.8,1.6Hz,1H),7.78(d,J＝1.5Hz,1H),7.53(d,J＝1.4Hz,1H),7.30(td,J＝7.7,1.6Hz,1H),7.21(t,J＝7.5Hz,1H),6.77(d,J＝8.1Hz,1H),3.91(s,3H),3.85(d,J＝13.4Hz,2H),3.23(d,J＝12.8Hz,2H),2.97(t,J＝7.0Hz,1H),1.97(d,J＝7.0Hz,2H),1.82-1.40(m,8H)ppm；LC-MS:m/z 438.1[M+H]+.
Example 62: (R) -8- (8- ((4-aminophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000921
1H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.61(s,1H),7.24(d,J＝7.5Hz,2H),7.13(s,1H),6.58(d,J＝7.5Hz,2H),5.48(s,2H),3.60(s,2H),3.17(s,2H),3.04-3.01(m,1H),1.40(s,10H)ppm；LC-MS:m/z 396.2[M+H]+.
Example 63: (R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000922
1H NMR(400MHz,DMSO-d6)δ8.31(s,2H),7.85(s,1H),7.78(s,1H),7.58(s,1H),6.80(t,J＝7.9Hz,1H),6.59(d,J＝8.0Hz,1H),5.94(d,J＝7.8Hz,1H),5.50(s,2H),3.84(t,J＝13.1Hz,2H),3.17(s,2H),3.04(s,1H),2.00(q,J＝7.2Hz,2H),1.83-1.37(m,10H)ppm；LC-MS:m/z429.1[M+H]+.
Example 64: (R) -8- (8- ((3- (trifluoromethyl) phenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000923
1H NMR(400MHz,DMSO-d6)δ8.31(s,2H),8.00(s,1H),7.79(d,J＝1.6Hz,1H),7.59-7.52(m,1H),7.47(dd,J＝16.9,9.2Hz,5H),3.84(t,J＝13.0Hz,2H),3.22(d,J＝13.1Hz,2H),2.98(s,1H),1.79(d,J＝13.8Hz,5H),1.60-1.36(m,5H)ppm；LC-MS:m/z 448.1[M+H]+.
Example 65: (R) -N- (4- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) phenyl) acetamide
Figure BDA0001579586110000931
1H NMR(400MHz,DMSO-d6)δ10.04(d,J＝5.3Hz,1H),8.35(s,1H),7.74(s,1H),7.61(d,J＝13.9Hz,2H),7.54(d,J＝8.5Hz,2H),7.31(d,J＝8.4Hz,2H),3.73(t,J＝12.0Hz,2H),3.12(s,2H),2.97(s,1H),2.02(s,3H),1.96(s,1H),1.74(dt,J＝53.1,26.6Hz,5H),1.50(d,J＝35.3Hz,4H)ppm；LC-MS:m/z 396.2[M+H]+.
Example 66: (R) -5- ((5- (1-amino-8-aza-spiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -1,3, 4-thiadiazol-2-amine
Figure BDA0001579586110000932
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.96(s,1H),7.81(d,J＝1.5Hz,1H),7.66(d,J＝1.4Hz,1H),7.33(s,2H),3.83(td,J＝11.2,9.7,4.9Hz,2H),3.20(s,2H),3.05(d,J＝6.9Hz,1H),1.99(t,J＝6.5Hz,1H),1.86-1.69(m,4H),1.62-1.38(m,5H)ppm；LC-MS:m/z 403.1[M+H]+.
Example 67: (R) -8- (8- ((1-methyl-1H-imidazol-2-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000933
1H NMR(400MHz,DMSO-d6)δ7.76(d,J＝1.5Hz,1H),7.60(dd,J＝6.8,1.4Hz,1H),7.39(d,J＝1.1Hz,1H),7.35(d,J＝7.0Hz,1H),7.00(d,J＝1.1Hz,1H),3.80(d,J＝2.6Hz,3H),3.63(d,J＝10.4Hz,2H),3.08(t,J＝12.2Hz,2H),2.73(t,J＝7.3Hz,1H),1.90-1.67(m,4H),1.65-1.51(m,2H),1.50-1.29(m,4H)ppm；LC-MS:m/z 384.1[M+H]+.
Example 68: (R) -8- (8- (naphthalen-1-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000941
1H NMR(CD3OD-d4)δ8.35-8.40(m,2H),7.99-8.02(m,1H),7.89-7.91(m,1H),7.76(m,1H),7.57-7.64(m,4H),7.43-7.47(m,2H),3.73(m,2H),3.11(m,2H),2.95(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LC-MS:m/z 430.2[M+H]+.
Example 69: (R) -8- (8- (thiazol-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000942
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),8.11(s,1H),7.82(s,1H),7.69(d,J＝3.3Hz,1H),7.62(s,1H),7.58(d,J＝3.3Hz,1H),3.89(d,J＝4.1Hz,2H),3.25(t,J＝12.2Hz,2H),3.07(s,1H),2.32-2.25(m,2H),2.06-1.69(m,5H),1.65-1.40(m,5H)ppm；LC-MS:m/z 387.1[M+H]+.
Example 70: (R) -8- (8- (oxazol-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000943
1H NMR(CD3OD-d4)δ8.12(s,1H),8.04(s,1H),7.80(s,1H),7.60(s,1H),7.22(s,1H),3.86(m,2H),3.22(m,2H),2.98(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LC-MS:m/z 371.1[M+H]+.
Example 71: synthesis of compound (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) acrylamide
The method comprises the following steps: n- (2-chloro-3- ((5- ((R) -1- ((R) -1, 1-dimethylethylidene) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2d ] pyrimidin-8-yl) thio) phenyl) acrylamide
Figure BDA0001579586110000951
In the procedure of synthetic example 63, the obtained intermediate (R) -N- ((R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-cyclobutane-1-yl) -2-methylpropane-2-sulfinamide was used in the following reaction.
To a 100mL round bottom flask was added (R) -N- ((R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-cyclobutane-1-yl) -2-methylpropane-2-sulfinamide (60mg,0.11mmol), triethylamine (22mg,0.22mmol), and dichloromethane (5mL) in that order at 0 deg.C, then acryloyl chloride (23mg,0.22mmol) was slowly added dropwise to the reaction solution at 0 deg.C, and after completion of the addition, the reaction solution was reacted at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with 10mL of water, extracted with ethyl acetate (3X 20mL), and the organic phase was washed with water (20mL X1) and saturated brine (20mL X1) in succession. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude product, N- (2-chloro-3- ((5- ((R) -1, 1-dimethylethyleneimino) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2d ] pyrimidin-8-yl) thio) phenyl) acrylamide, was obtained by column chromatography (petroleum ether: ethyl acetate ═ 1: 1) (30mg, yield: 46%).
LC-MS:m/z 587.2[M+H]+.
Step two: (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) acrylamide
Figure BDA0001579586110000952
In the same manner as in the second step of example 37, sulfinyl group was removed to give (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) acrylamide.
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.99(s,1H),7.80(s,1H),7.57(s,1H),7.49(s,1H),7.10(t,J＝8.0Hz,1H),6.72-6.51(m,2H),6.29(d,J＝16.9Hz,1H),5.81(d,J＝10.3Hz,1H),3.87(dd,J＝14.9,10.9Hz,2H),3.20(s,2H),3.01(t,J＝6.8Hz,1H),2.05-1.34(m,10H)ppm；LC-MS:m/z 482.8[M+H]+.
Following the synthesis of example 71, the following compounds can be synthesized:
example 72: (R) -N1- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -N2, N2-dimethyloxyalkanamide
Figure BDA0001579586110000961
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.80(s,1H),7.57(s,1H),7.41(d,J＝8.0Hz,1H),7.13(t,J＝8.0Hz,1H),6.62(d,J＝8.2Hz,1H),5.49(s,1H),3.86(d,J＝12.7Hz,2H),3.81(s,3H),3.23(t,J＝12.7Hz,2H),3.11(s,3H),3.02(d,J＝6.8Hz,1H),2.05-1.75(m,5H),1.54(dd,J＝41.2,13.2Hz,5H)ppm；LC-MS:m/z 528.2[M+H]+.
Example 73: synthesis of compound (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide
The method comprises the following steps: 2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxylic acid ethyl ester
Figure BDA0001579586110000962
Triethyl methanetricarboxylate (4.64g,20mmol) was added to a solution of pyridin-2-amine (940mg,10mmol) in xylene (10mL) under nitrogen. The mixture was further stirred at 140 ℃ for 4 hours, TLC monitored the reaction until the reaction of the starting materials was completed, and the reaction mixture was filtered and washed with ethyl acetate to give ethyl 2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (1.95g, yield: 83%)
1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),8.93(dd,J＝7.4,1.5Hz,1H),8.19(ddd,J＝8.6,7.1,1.6Hz,1H),7.43-7.34(m,2H),4.15(q,J＝7.1Hz,2H),1.23(t,J＝7.1Hz,3H)ppm；LCMS:m/z 235[M+H]+.
Step two: n- (2-chloro-3- ((5- ((R) -1- ((R) -1, 1-dimethylethylidene) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2d ] pyrimidin-8-yl) thio) phenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide
In the procedure of synthetic example 63, the obtained intermediate (R) -N- ((R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decanocyclobutan-1-yl) -2-methylpropane-2-sulfinamide was used in the following reaction.
Figure BDA0001579586110000971
To a solution of ethyl 2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (40mg, 0.169mmol) in DMF (2mL) under nitrogen was added (R) -N- ((R) -8- (8- ((3-amino-2-chlorophenyl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-cyclobutan-1-yl) -2-methylpropane-2-sulfinamide (60mg, 0.113 mmol). The mixture was reacted at 160 ℃ for 1 hour by microwave. After the mixture was cooled to room temperature, the mixture was filtered, diluted with water and extracted with ethyl acetate (20mL × 3), washed with saturated brine and the organic layer was mixed, dried over anhydrous sodium sulfate, filtered and concentrated to give N- (2-chloro-3- ((5- ((R) -1, 1-dimethylethyleneimino) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2d ] pyrimidin-8-yl) thio) phenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide (20mg, yield 21.7%).
LCMS:m/z 721[M+H]+.
Step three: (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide
Figure BDA0001579586110000972
According to the same manner as in the second step of example 37, sulfinyl group was removed to give (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide.
1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.43(s,1H),7.94(s,1H),7.79(s,1H),7.63(d,J＝34.6Hz,2H),7.03(d,J＝8.2Hz,1H),6.61-6.51(m,1H),6.40(d,J＝8.2Hz,1H),6.00(d,J＝6.9Hz,1H),5.45(s,1H),3.94-3.80(m,2H),3.23(s,2H),3.05(s,1H),2.09-1.34(m,10H)ppm；LC-MS:m/z 617.1[M+H]+.
Example 74: synthesis of compound (R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide
The method comprises the following steps: 2-hydroxy-4-carbonyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxylic acid ethyl ester
Figure BDA0001579586110000981
To a 100mL round bottom flask were added ethyl 2-hydroxy-4-carbonyl-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (from step one, example 69) (1g,4.12mmol), methanol (25mL) and 10% Pd/C (862mg) in that order. The mixture was further stirred under hydrogen (hydrogen balloon) at room temperature for 2.5 hours, TLC monitored until the reaction of the starting materials was completed, and the reaction mixture was filtered through celite and concentrated in vacuo to give ethyl 2-hydroxy-4-carbonyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (700mg, yield: 69.4%).
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),4.09(q,J＝7.1Hz,2H),3.66(t,J＝6.0Hz,2H),2.77(t,J＝6.4Hz,2H),1.88-1.80(m,2H),1.78-1.71(m,2H),1.19(t,J＝7.1Hz,3H)ppm；LCMS:m/z[M+H]+.
(R) -N- (3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -2-chlorophenyl) -2-hydroxy-4-carbonyl-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxamide was obtained in the same manner as in step two and step three of example 73.
Figure BDA0001579586110000982
1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.24(s,1H),7.96(s,1H),7.85(s,1H),7.81-7.72(m,2H),7.58(s,1H),3.86(dd,J＝30.5,16.1Hz,4H),3.29-3.15(m,4H),2.85-2.78(m,1H),2.11-1.61(m,14H)；LC-MS:m/z 621.1[M+H]+.
Example 75: synthesis of (R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
The method comprises the following steps: (R) -N- ((R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide
Figure BDA0001579586110000991
(R) -N- ((R) -8- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfonamide (60mg,0.12mmol), 1, 4-dioxane (2mL), purified water (0.5mL), (2, 3-dichlorophenyl) boronic acid (50mg, 0.24mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (9mg, 0.012mmol) and potassium carbonate (50mg, 0.36mmol) were added sequentially at room temperature in a 20mL stoppered tube. Nitrogen was bubbled for one minute, the tube was sealed and heated to 80 ℃ and the reaction was allowed to proceed for 6 hours. After completion of the reaction, 20mL of water was added to the reaction solution and extracted with ethyl acetate (50 mL. times.3). The organic phase was washed successively with water (20 mL. times.1), and saturated brine (20 mL. times.1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude product (R) -N- ((R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide was obtained by column chromatography (petroleum ether: ethyl acetate ═ 1: 1). (30mg, yield: 48%) as a pale yellow solid.
LC-MS:m/z 520.1[M+H]+.
Step two: (R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110000992
Following the same procedure as in step two of example 37, (R) -N- ((R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinylamide-sulfinyl group was removed to give (R) -8- (8- (2, 3-dichlorophenyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine.
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.75(s,3H),7.60(s,1H),7.49(s,1H),3.79(s,2H),3.21-3.12(m,2H),2.93(s,1H),1.82(s,5H),1.46(s,7H)ppm；LCMS:m/z 416.1[M+H]+.
Example 76: synthesis of compound (R) -8(8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
The method comprises the following steps: (R) -N- ((R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide
Figure BDA0001579586110001001
Crude (R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) was added to a 100mL single-neck flask in sequence under nitrogen]Pyrimidin-5-yl) -8-azaspiro [4.5]Decan-1-yl) -2-methylpropane-2-sulfonamide (100mg, 0.20mmol), sodium 2-amino-3-chloropyridine-4-mercaptide (43mg,0.26mmol), Pd2(dba)3(20mg,0.02mmol), Xantphos (23mg,0.040mmol), DIPEA (52mg,0.40mmol) and 1, 4-dioxane solution (10mL) and the mixture was heated to 100 ℃ under nitrogen and stirred for 6 h. After completion of the reaction, it was cooled to room temperature, filtered and the residue obtained was concentrated under reduced pressure and purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/methanol) to give (R) -N- ((R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1, 2-c) ]Pyrimidin-5-yl) -8-azaspiro [4.5]Decan-1-yl) -2-methylpropane-2-sulfinamide (40mg, yield: 37%).
LC-MS:m/z 534.2[M+H]+.
Step two: (R) -8(8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001002
Following the same procedure as in step two of example 37, (R) -N- ((R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide is desulphenylated to give (R) -8(8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine.
1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝6.9Hz,1H),8.02(s,1H),7.81(s,1H),7.58(d,J＝1.4Hz,1H),7.54(d,J＝5.4Hz,1H),6.35(s,1H),5.78(d,J＝5.4Hz,1H),3.89(t,J＝12.5Hz,2H),3.29-3.17(m,3H),3.00(s,1H),1.97(s,1H),1.89-1.33(m,6H)ppm；LCMS:m/z 430.1[M+H]+.
Following the synthetic procedure of example 76, the following compounds can be synthesized:
example 77: (R) -8- (8- ((3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001011
1H NMR(CD3OD-d4)δ8.54(s,1H),8.35(s,1H),8.15-8.16(m,1H),8.09(s,1H),7.83-7.84(m,1H),7.57-7.58(m,1H),6.67-6.68(m,1H),3.92(m,2H),3.26(m,2H),3.00(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LCMS:m/z 415.1[M+H]+.
Example 78: (R) -8- (8- ((3- (trifluoromethyl) pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001012
1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.41(d,J＝5.5Hz,1H),8.31(s,1H),8.10(s,1H),7.84(s,1H),7.57(s,1H),6.90(d,J＝5.4Hz,1H),3.93(s,2H),3.28-3.20(m,2H),2.94(s,1H),1.90-1.32(m,10H)；LCMS:m/z 449.1[M+H]+.
Example 79: (3S,4S) -8- (8- ((2-amino-5-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001021
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.87(s,1H),7.83(s,1H),7.62(d,J＝1.3Hz,1H),5.91(s,2H),5.65(s,1H),4.13(d,J＝5.2Hz,1H),3.77(d,J＝8.5Hz,3H),3.60(d,J＝8.6Hz,1H),3.40(s,1H),3.14(s,1H),1.81(dd,J＝82.1,33.6Hz,5H),1.14(d,J＝6.3Hz,3H)ppm；LC-MS:m/z 462.1[M+H]+.
Example 80 (3S,4S) -8- (8- ((6-amino-3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001022
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.04(s,1H),7.85(s,1H),7.63(s,1H),5.82(s,2H),5.51(s,1H),4.26-4.18(m,1H),3.88(t,J＝13.0Hz,3H),3.70(d,J＝8.9Hz,1H),3.42(d,J＝4.3Hz,1H),3.27(s,2H),2.31(s,3H),1.99(d,J＝10.0Hz,2H),1.80(d,J＝13.5Hz,1H),1.69(d,J＝12.8Hz,1H),1.23(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 459.8[M+H]+.
Example 81: (R) -8- (8- ((3-chloro-2-cyclopropylpyrimidin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001023
1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.97(d,J＝5.3Hz,1H),7.82(d,J＝1.5Hz,1H),7.57(d,J＝1.4Hz,1H),6.40(d,J＝5.3Hz,1H),3.91(t,J＝13.1Hz,2H),3.25(t,J＝11.7Hz,2H),3.02(t,J＝6.6Hz,1H),2.03-1.65(m,5H),1.67-1.37(m,5H),1.04(ddt,J＝8.0,5.6,2.4Hz,2H),0.97(dq,J＝6.9,4.2,3.4Hz,2H)ppm；LCMS:m/z 455.1[M+H]+.
Example 82: (R) -8- (8- ((3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001031
1H NMR(400MHz,DMSO-d6)δ8.35-8.29(m,1H),8.07(s,1H),8.02(d,J＝5.4Hz,1H),7.83(s,1H),7.57(d,J＝1.4Hz,1H),6.50(d,J＝5.3Hz,1H),3.91(t,J＝12.9Hz,2H),3.26(t,J＝12.3Hz,2H),3.01(s,1H),2.55(s,3H),2.02-1.77(m,4H),1.75-1.38(m,6H)ppm；LCMS:m/z429.1[M+H]+.
Example 83: (R) -8- (8- ((2-amino-5-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001032
1H NMR(CD3OD-d4)δ8.38(s,1H),8.04(s,1H),7.82-7.84(m,2H),7.61(m,1H),5.93(s,2H),5.66(m,1H),3.87-3.93(m,2H),3.21-3.28(m,2H),2.98(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LCMS:m/z 430.1[M+H]+.
Example 84: (R) -8- (8- ((2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001033
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.00(d,J＝5.3Hz,1H),7.83(d,J＝1.5Hz,1H),7.59(d,J＝1.4Hz,1H),6.72(d,J＝5.3Hz,1H),4.03-3.87(m,2H),3.27(d,J＝13.6Hz,2H),3.14(t,J＝6.3Hz,1H),2.05(q,J＝6.4Hz,1H),1.87-1.42(m,9H)ppm；LCMS:m/z 449.1[M+H]+.
Example 85: (R) -8- (8- ((2-methylpyridin-3-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001041
1H NMR(400MHz,DMSO-d6)δ8.25(dd,J＝4.7,1.5Hz,1H),7.89(s,1H),7.79(d,J＝1.4Hz,1H),7.56(d,J＝1.4Hz,1H),7.23(dd,J＝7.9,1.5Hz,1H),7.06(dd,J＝7.9,4.7Hz,1H),3.89-3.70(m,2H),3.17(dd,J＝22.2,10.5Hz,2H),2.80(t,J＝7.2Hz,1H),2.60(s,3H),1.88-1.20(m,10H)ppm；LCMS:m/z 395.2[M+H]+.
Example 86: (R) -8- (8- ((2- (trifluoromethyl) pyridin-3-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001042
1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.35(s,1H),7.75(s,1H),7.21(d,J＝8.2Hz,2H),6.52(d,J＝8.4Hz,2H),5.39(s,2H),4.69(s,2H),2.87(s,1H),1.93-1.30(m,10H)ppm；LCMS:m/z 449.1[M+H]+.
Example 87: (R) -8- (8- ((2-chloropyridin-3-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001043
1H NMR(CD3OD-d4)δ8.38(s,1H),8.16-8.18(m,1H),8.06(s,1H),7.81(m,2H),7.23(m,1H),7.14-7.22(m,2H),3.88(m,2H),3.23(m,2H),2.97(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LCMS:m/z 415.1[M+H]+.
Example 88: (R) -8- (8- ((6-amino-2-chloropyridin-3-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001051
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.74(d,J＝1.4Hz,1H),7.61(d,J＝1.4Hz,1H),7.51(d,J＝8.5Hz,1H),7.40(s,1H),6.73(s,2H),6.38(d,J＝8.4Hz,1H),3.68(d,J＝12.5Hz,3H),3.10(s,2H),2.97(t,J＝6.8Hz,1H),2.01-1.31(m,10H)ppm.LC-MS:m/z 431.1[M+H]+.
Example 89: (R) -8- (8- (benzo [ d ] thiazol-7-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001052
1HNMR(CD3OD-d4)δ9.43(m,1H),8.35(s,3H),8.00-8.02(m,1H),7.88(s,1H),7.76(m,1H),7.56-7.58(m,1H),7.47-7.51(m,1H),7.38-7.40(m,1H),3.80(m,2H),3.17(m,2H),2.98(m,1H),1.71-2.05(m,4H),1.35-1.68(m,6H)ppm；LC-MS:m/z 437.1[M+H]+.
Example 90: (R) -8- (8- (phenylsulfanyl) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001053
1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.83(s,1H),7.76(s,1H),7.59(s,1H),7.25(tq,J＝14.0,7.4Hz,5H),3.84-3.70(m,2H),3.16(d,J＝12.4Hz,2H),3.01(t,J＝6.8Hz,1H),1.97(dd,J＝13.2,7.2Hz,1H),1.86-1.26(m,9H)ppm；LCMS:m/z 380.1[M+H]+.
Example 91: (R) -8- (8- ((1-methyl-1H-pyrrolo [2,3-b ] pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001061
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.97(d,J＝5.1Hz,1H),7.80(s,1H),7.61-7.49(m,2H),6.56-6.39(m,2H),3.84(d,J＝22.6Hz,5H),3.22(t,J＝12.5Hz,2H),2.98(t,J＝6.9Hz,1H),2.03-1.33(m,10H)ppm；LC-MS:m/z 433.9[M+H]+.
Example 92: (R) -8- (8- ((2, 3-dihydrobenzofuran-5-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001062
1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.62(s,1H),7.46(s,1H),7.39(s,1H),7.27(d,J＝8.2Hz,1H),6.77(d,J＝8.3Hz,1H),4.54(t,J＝8.7Hz,2H),3.69(t,J＝11.9Hz,2H),3.11(dt,J＝29.5,12.5Hz,6H),1.99(s,1H),1.87-1.36(m,9H)ppm；LC-MS:m/z 422.1[M+H]+.
Example 93: (R) -8- (8- (quinolin-4-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001063
1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝4.8Hz,1H),8.26(dd,J＝8.4,1.3Hz,1H),8.12(s,1H),8.04(dd,J＝8.5,1.2Hz,1H),7.89-7.79(m,2H),7.73(ddd,J＝8.2,6.8,1.3Hz,1H),7.56(d,J＝1.4Hz,1H),6.82(d,J＝4.8Hz,1H),3.91(dd,J＝15.3,11.3Hz,2H),3.37-3.16(m,2H),3.05(t,J＝6.5Hz,1H),2.10-1.65(m,5H),1.67-1.38(m,5H)ppm；LC-MS:m/z 431.2[M+H]+.
Example 94: (1R) -8- (8- ((2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001071
1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.09(d,J＝6.5Hz,1H),8.00(d,J＝5.3Hz,1H),7.84(s,1H),7.57(s,1H),6.71(d,J＝5.3Hz,1H),4.03-3.85(m,2H),3.26-3.15(m,2H),2.98(d,J＝21.9Hz,1H),2.14(dd,J＝25.3,11.9Hz,2H),1.87(dd,J＝41.5,14.7Hz,3H),1.43(dd,J＝32.2,18.7Hz,2H),1.28(dd,J＝18.2,8.7Hz,1H),1.12(d,J＝12.5Hz,1H),1.05-0.93(m,3H)ppm；LC-MS:m/z 462.8[M+H]+.
Example 95: (1R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001072
1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.02(s,1H),7.80(s,1H),7.63-7.49(m,2H),6.34(s,2H),5.78(d,J＝5.4Hz,1H),3.98-3.83(m,2H),3.18(dd,J＝27.6,14.3Hz,2H),3.06-2.94(m,1H),2.23-2.07(m,2H),1.96-1.89(m,1H),1.86-1.67(m,2H),1.51-1.33(m,2H),1.33-1.20(m,1H),1.21-1.09(m,1H),1.08-0.94(m,3H)ppm；LC-MS:m/z 443.8[M+H]+.
Example 96: (1R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-8-aza-spiro [4.5] decan-1-amine
Figure BDA0001579586110001073
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.06(s,1H),7.84(s,1H),7.61(s,1H),6.33(s,2H),5.62(s,1H),4.00-3.86(m,2H),3.17(d,J＝13.0Hz,1H),3.07-2.95(m,1H),2.25-2.07(m,2H),1.94(dd,J＝12.0,8.2Hz,2H),1.79(dd,J＝28.2,13.0Hz,2H),1.45(dd,J＝33.4,19.7Hz,2H),1.34-1.11(m,2H),1.01(dd,J＝18.3,10.3Hz,3H)；LCMS:m/z 447.8[M+H]+.
Example 97: (S) -8- (8- ((2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001081
1H NMR(400MHz,DMSO-d6)δ8.19(s,1H),8.10(s,1H),8.00(d,J＝5.3Hz,1H),7.86(s,1H),7.58(s,1H),6.72(d,J＝5.3Hz,1H),4.02(dd,J＝8.8,6.4Hz,1H),3.85(dd,J＝17.4,13.7Hz,2H),3.72(dd,J＝21.2,8.6Hz,2H),3.43(dd,J＝9.0,4.8Hz,2H),3.25(dd,J＝15.2,9.6Hz,2H),1.98-1.86(m,1H),1.85-1.73(m,1H),1.61(s,2H)；LC-MS:m/z 451.7[M+H]+.
Example 98: (S) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001082
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.04(s,1H),7.83(s,1H),7.60(s,1H),7.55(d,J＝5.4Hz,1H),6.35(s,2H),5.78(d,J＝5.4Hz,1H),4.10(dd,J＝9.9,6.0Hz,1H),3.92-3.76(m,4H),3.69(dd,J＝10.1,3.1Hz,1H),3.53(s,1H),3.24(d,J＝10.8Hz,1H),1.99-1.83(m,2H),1.73(d,J＝12.0Hz,2H),1.24(d,J＝6.4Hz,1H)ppm；LC-MS:m/z 431.8[M+H]+.
Example 99: (3S,4S) -8- (8- ((2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001091
1H NMR(400MHz,DMSO-d6)δ8.17(s,1H),8.10(s,1H),8.00(d,J＝5.3Hz,1H),7.87(s,1H),7.57(d,J＝1.0Hz,1H),6.72(d,J＝5.3Hz,1H),4.12(dt,J＝12.1,6.1Hz,1H),3.85-3.67(m,3H),3.57(d,J＝8.5Hz,1H),3.41(dd,J＝26.4,9.0Hz,2H),3.06(d,J＝4.9Hz,1H),1.99-1.81(m,2H),1.68(dd,J＝27.9,14.6Hz,2H),1.13(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 464.8[M+H]+.
Example 100: (3S,4S) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001092
1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.02(s,1H),7.84(s,1H),7.61-7.50(m,2H),6.34(s,2H),5.79(d,J＝5.4Hz,1H),4.11(dt,J＝12.3,6.3Hz,1H),3.73(d,J＝8.5Hz,3H),3.56(d,J＝8.5Hz,1H),3.38-3.26(m,2H),3.05(d,J＝4.9Hz,1H),1.99-1.81(m,2H),1.67(dd,J＝26.4,15.3Hz,2H),1.18-1.02(m,3H)ppm；LC-MS:m/z 445.8[M+H]+.
Example 101: 4- ((5- (4-amino-4-methylpiperidin-1-yl) imidazo [1,2-c ] pyrimidin-8-yl) sulfanyl) -3-chloropyridin-2-amine
Figure BDA0001579586110001093
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.83(s,1H),7.54(d,J＝5.8Hz,2H),6.29(s,2H),5.79(d,J＝5.4Hz,1H),3.60(d,J＝4.3Hz,4H),1.77-1.53(m,4H),1.19(s,3H)ppm；LC-MS:m/z 390.1[M+H]+.
Example 102: (R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001101
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.85(d,J＝1.5Hz,1H),7.60(d,J＝1.4Hz,1H),6.32(s,2H),5.62(s,1H),3.90(dd,J＝13.2,8.5Hz,2H),3.23(q,J＝11.9,11.0Hz,2H),2.77(t,J＝7.3Hz,1H),1.90-1.77(m,4H),1.67-1.53(m,2H),1.45-1.28(m,4H)ppm；LCMS:m/z466.1[M+H]+.
Example 103: (R) -8- (8- ((6-amino-3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001102
1H NMR(400MHz,DMSO-d6)δ7.88(s,4H),7.66(d,J＝11.1Hz,1H),5.81(s,1H),3.96(t,J＝13.9Hz,2H),3.37-3.23(m,3H),2.42(s,3H),2.14-2.05(m,1H),1.88-1.46(m,9H)；LC-MS:m/z 443.8[M+H]+.
Example 104: (S) -8- (8- ((6-amino-3-chloro-2-methylpyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001103
1H NMR(400MHz,DMSO-d6)δ8.17(d,J＝4.9Hz,3H),7.91(s,1H),7.68(s,1H),5.81(s,1H),4.13(dd,J＝10.4,5.8Hz,1H),3.90(d,J＝9.0Hz,3H),3.80(d,J＝9.0Hz,1H),3.74(dd,J＝10.3,2.6Hz,1H),3.63(s,1H),3.40(dd,J＝12.6,8.6Hz,1H),3.30(dd,J＝12.6,9.4Hz,1H),2.42(s,3H),1.95-1.81(m,2H),1.75(d,J＝10.3Hz,2H)；LC-MS:m/z 445.8[M+H]+.
Example 105: (S) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001111
1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.07(s,1H),7.87(s,1H),7.63(s,1H),6.33(s,2H),5.62(s,1H),4.06(dd,J＝9.6,6.2Hz,1H),3.93-3.74(m,4H),3.56(dd,J＝9.5,4.0Hz,1H),3.26(s,3H),1.98-1.80(m,2H),1.67(s,2H)ppm；LC-MS:m/z 466.6[M+H]+.
Example 106: (3S,4S) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001112
1H NMR(400MHz,DMSO-d6)δ8.18(s,3H),8.08(s,1H),7.87(s,1H),7.65(s,1H),6.35(s,2H),5.64(s,1H),4.31-4.16(m,1H),4.03-3.83(m,3H),3.71(d,J＝9.0Hz,1H),3.46(s,1H),3.24(d,J＝11.2Hz,2H),2.03(t,J＝12.3Hz,2H),1.75(dd,J＝41.2,13.7Hz,2H),1.24(d,J＝6.5Hz,3H)；LCMS:m/z 479.7[M+H]+.
Example 107: (3S,4S) -8- (8- ((3-chloro-2-methylpyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001121
1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),8.01(d,J＝5.3Hz,1H),7.85(d,J＝1.5Hz,1H),7.56(d,J＝1.4Hz,1H),6.50(d,J＝5.3Hz,1H),4.15-4.05(m,1H),3.74-3.66(m,5H),3.45-3.42(m,1H),3.03(d,J＝4.9Hz,1H),2.55(s,3H),2.00-1.60(m,4H),1.12(d,J＝6.4Hz,3H)ppm；LC-MS:m/z 445.2[M+H]+.
Example 108: (S) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001122
1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.06(s,1H),7.88(s,1H),7.61(s,1H),6.34(s,2H),5.64(s,1H),3.95(d,J＝14.3Hz,2H),3.55(s,1H),3.44(s,1H),3.31(d,J＝11.5Hz,2H),2.69(s,1H),1.94(d,J＝12.4Hz,2H),1.66(t,J＝11.9Hz,2H),1.06-0.99(m,3H),0.94(d,J＝14.9Hz,3H)；LC-MS:m/z 493.7[M+H]+.
Example 109: (S) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001123
1H NMR(400MHz,DMSO-d6)δ8.15(s,2H),7.89(s,1H),7.64(s,1H),6.33(s,1H),5.63(s,1H),4.03(s,2H),3.59(d,J＝14.4Hz,2H),3.38(s,2H),3.09(s,1H),1.83(s,4H),1.16(s,3H),1.07(s,3H)；LC-MS:m/z 493.7[M+H]+.
Example 110: (S) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001131
1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.02(s,1H),7.84(s,1H),7.61-7.51(m,2H),6.33(s,2H),5.80(d,J＝5.4Hz,1H),4.00-3.88(m,2H),3.55(d,J＝8.7Hz,1H),3.46(d,J＝8.8Hz,1H),3.32-3.27(m,2H),2.73(s,1H),1.98-1.86(m,2H),1.68(s,2H),1.00(d,J＝29.6Hz,6H)；LC-MS:m/z 459.8[M+H]+.
Example 111: (R) -8- (8- ((2-amino-3-chloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-dimethyl-1-oxa-8-azaspiro [4.5] decan-4-amine
Figure BDA0001579586110001132
1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.84(s,1H),7.57(s,1H),7.55(d,J＝5.4Hz,1H),6.33(s,2H),5.80(d,J＝5.3Hz,1H),4.01-3.91(m,2H),3.56(d,J＝8.8Hz,1H),3.48(d,J＝8.9Hz,1H),3.32-3.26(m,2H),2.80(s,1H),1.97-1.88(m,2H),1.70(d,J＝12.3Hz,2H),1.06(s,3H),0.99(s,3H)；LC-MS:m/z 459.8[M+H]+.
EXAMPLE 112 Synthesis of (R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Step one methyl ((R) -1- ((R) -tert-butylsulfinyl) amino) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) propionate
Figure BDA0001579586110001141
To a 100mL single-neck flask, under nitrogen, was added (R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) in sequence ]Pyrimidin-5-yl) -8-azaspiro [4.5]Decan-1-yl) -2-methylpropane-2-sulfonamide (500mg, 1.0mmol), methyl mercaptopropionate (132mg,1.1mmol), Pd2(dba)3(46mg,0.05mmol), Xantphos (58mg,0.10mmol), DIPEA (258mg,2.0mmol) and 1, 4-dioxane solution (30mL) and the mixture was heated to 100 ℃ under nitrogen and stirred for 4 h. After completion of the reaction, it is cooled to room temperature, filtered and the residue obtained is concentrated under reduced pressure and purified by chromatography on silica gel (0 to 30% gradient of acetic acid)Ethyl ester/petroleum ether) to give ((R) -1- ((R) -tert-butylsulfinyl) amino) -8-azaspiro [4.5]Decan-8-yl) imidazo [1,2-c]Pyrimidin-8 yl) thio) propionic acid methyl ester (380mg, yield: 77%).
LCMS:m/z 494.2[M+H]+.
Step two ((R) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidine-8-thiolate
Figure BDA0001579586110001142
To a dry 100mL round bottom flask were added methyl ((R) -1- ((R) -tert-butylsulfinyl) amino) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8 yl) thio) propanoate (380mg,0.77mmol) and tetrahydrofuran (20mL) in that order, and then a solution of sodium ethoxide in ethanol (21%, 3mL) was slowly added dropwise at room temperature, and the reaction was stirred at room temperature for 1 hour. Concentration under reduced pressure gave crude ((R) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidine-8-thiolate (400mg) without purification.
LC-MS:m/z 408.2[M+H]+.
Step three (R) -N- ((R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide)
Figure BDA0001579586110001151
To a 100mL one-neck flask, under nitrogen, was added the crude ((R) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] in sequence]Decan-8-yl) imidazo [1,2-c]Pyrimidine-8-thiolate (100mg, 0.23mmol), 3-chloro-4-iodo-2-methoxypyridine (71mg,0.26mmol), Pd2(dba)3(22mg,0.024mmol), Xantphos (28mg,0.048mmol), DIPEA (62mg,0.48mmol) and 1, 4-dioxane solution (10mL) and the mixture was heated to 100 ℃ under nitrogen and stirred for 4 h. After the reaction is finished, cooling to room temperature and reactingThe residue obtained is filtered and concentrated under reduced pressure to give (R) -N- ((R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1, 2-c) by chromatography on silica gel (0 to 30% gradient of ethyl acetate/methanol)]Pyrimidin-5-yl) -8-azaspiro [4.5]Decan-1-yl) -2-methylpropane-2-sulfinamide (51mg, yield: 40%).
LCMS:m/z 549.2[M+H]+.
Step four (R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001152
To a 100mL one-neck flask were added (R) -N- ((R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-yl) -2-methylpropane-2-sulfinamide (40mg, 0.09mmol) and methanol (2.3mL) in this order under nitrogen, a solution of 1, 4-dioxane hydrochloride (0.23mL,4M) was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was cooled to room temperature, filtered and the resulting residue was concentrated under reduced pressure to give (R) -8- (8- ((3-chloro-2-methoxypyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine (15mg, yield: 37%) by high performance liquid preparative chromatography.
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.83(d,J＝1.6Hz,1H),7.77(d,J＝5.5Hz,1H),7.56(d,J＝1.5Hz,1H),6.28(d,J＝5.5Hz,1H),3.93(s,3H),3.88(d,J＝9.4Hz,2H),3.23(d,J＝11.6Hz,2H),2.76(t,J＝7.2Hz,1H),1.80(d,J＝11.4Hz,4H),1.66-1.52(m,2H),1.44-1.29(m,4H).LCMS:m/z 445.1[M+H]+.
Following the synthetic procedure of example 112, the following compounds can be synthesized:
example 113 methyl (R) -3- ((5- (1-amino-8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) propionate
Figure BDA0001579586110001161
1H NMR(400MHz,DMSO-d6)δ7.73(d,J＝2.7Hz,2H),7.64(d,J＝1.3Hz,1H),3.70(d,J＝4.0Hz,2H),3.56(s,3H),3.26(t,J＝7.0Hz,2H),3.15-3.04(m,3H),2.61(t,J＝7.0Hz,2H),2.05-1.68(m,5H),1.66-1.37(m,5H)ppm；LC-MS:m/z 390.1[M+H]+.
Example 114: (R) -8- (8- ((3-chloro-2-fluoropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001162
1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.86-7.80(m,2H),7.58(d,J＝1.4Hz,1H),6.66(d,J＝5.4Hz,1H),3.95(d,J＝12.7Hz,2H),3.28(s,2H),2.95(s,1H),1.97-1.80(m,4H),1.66(d,J＝32.2Hz,2H),1.56-1.41(m,4H)ppm；LCMS:m/z 434.1[M+H]+.
Example 115: (R) -8- (8- ((3-chloro-2- (dimethylamino) pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001163
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.83(d,J＝1.6Hz,1H),7.79(d,J＝5.3Hz,1H),7.56(d,J＝1.4Hz,1H),6.15(d,J＝5.3Hz,1H),3.98-3.79(m,2H),3.23(d,J＝11.6Hz,3H),2.90(s,6H),2.77(t,J＝7.3Hz,1H),1.83-1.74(m,7H),1.69-1.51(m,3H),1.49-1.27(m,5H)ppm；LCMS:m/z 458.2[M+H]+.
Example 116: (R) -4- ((5- (1-amino-8-aza-spiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) indoline-2, 3-dione
Figure BDA0001579586110001171
1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),8.02(s,1H),7.81(s,1H),7.58(s,1H),7.24(t,J＝8.0Hz,1H),6.58(d,J＝7.7Hz,2H),6.21(d,J＝8.3Hz,1H),3.90(s,3H),3.24(s,3H),2.97(s,1H),1.69(d,J＝93.3Hz,9H)ppm；LC-MS:m/z 449.1[M+H]+.
EXAMPLE 117 Synthesis of the Compound (R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Step one (R) -N- ((R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decancyclobutane-1-yl) -2-methylpropane-2-sulfinamide
Figure BDA0001579586110001172
To a 100mL one-neck flask, crude ((R) -1- ((R) -1, 1-dimethylethylsulfonamido) -8-azaspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidine-8-thiolate (50mg, 0.12mmol), 3, 4-dichloropyridazine (19mg,0.13mmol) and acetonitrile (3mL) were added in this order under nitrogen, followed by DIPEA (31mg,0.24mmol), and the reaction was heated at 80 ℃ and stirred for 16 hours. After the reaction liquid was cooled, the obtained residue was condensed under reduced pressure to obtain (R) -N- ((R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-cyclobutan-1-yl) -2-methylpropane-2-sulfinamide (10mg, yield: 16%) by silica gel chromatography (gradient of ethyl acetate/methanol from 0 to 30%).
LCMS:m/z 520.2[M+H]+.
Step two (R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidine-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001181
To a 50mL one-neck flask were added (R) -N- ((R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decylen-N-1-yl) -2-methylpropane-2-sulfinamide (10mg,0.02mmol) and methanol (0.5mL) in that order under nitrogen, a 1, 4-dioxane solution of hydrochloric acid (0.05mL,4M) was added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was cooled to room temperature, filtered, and the resulting residue was concentrated under reduced pressure to give (R) -8- (8- ((3-chloropyridazin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine (2mg, yield: 24%) by high performance liquid preparative chromatography.
1H NMR(400MHz,DMSO-d6)δ8.79(d,J＝5.4Hz,1H),8.36(s,2H),8.12(s,1H),7.84(s,1H),7.58(s,1H),7.01(d,J＝5.4Hz,1H),3.88(d,J＝9.4Hz,2H),3.23(d,J＝11.6Hz,2H),2.76(t,J＝7.2Hz,1H),1.70-1.32(m,9H)；LCMS:m/z 416.1[M+H]+.
According to the synthesis method of example 117, the following compounds can be synthesized:
example 118 (R) -8- (8- ((2-Chloropyrimidin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001182
1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝5.5Hz,1H),8.29(s,1H),8.09(s,1H),7.84(s,1H),7.61(d,J＝1.2Hz,1H),7.06(d,J＝5.5Hz,1H),3.93(t,J＝12.9Hz,2H),3.25(s,2H),3.09(s,1H),2.03(s,1H),1.81(dd,J＝19.3,13.3Hz,4H),1.65-1.46(m,5H)ppm；LCMS:m/z 416.1[M+H]+.
EXAMPLE 119 preparation of the Compound (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
The method comprises the following steps: (R) -2-methyl-N- (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-piperazin-1-yl) propane-2-sulfinamide
Figure BDA0001579586110001191
To a 100mL single-neck flask, under nitrogen atmosphere, (R) -N- ((R) -8- (8-iodoimidazo [1, 2-c) was added in sequence]Pyrimidine-5-yl) -8-azaspiro [ 2 ]4.5]Decan-1-yl) -2-methylpropane-2-sulfonamide (50mg, 0.10mmol), pyridine-2-thiol (13mg,0.12mmol), Cu (OTf)2(4mg,0.01mmol), BINAM (3mg,0.01mmol) and 1, 4-dioxane (3mL), followed by cesium carbonate (65mg,0.2mmol), the reaction was heated at 100 ℃ and stirred for 16 h. After cooling the reaction solution, the residue obtained by decompression was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate/methanol) to give (R) -2-methyl-N- (R) -8- (8- (pyridin-2-ylthio) imidazo [1, 2-c)]Pyrimidin-5-yl) -8-azaspiro [4.5]Decapiperazin-1-yl) propane-2-sulfinamide (20mg, yield: 41%).
LCMS:m/z 485.2[M+H]+.
Step two: (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001192
Using the same procedure as in step two of example 37, (R) -2-methyl-N- (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decanepiperazin-1-yl) propane-2-sulfinylamide the sulfinyl group was removed to give (R) -8- (8- (pyridin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine. .
1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝3.1Hz,2H),8.02(s,1H),7.78(s,1H),7.63-7.48(m,2H),7.11(dd,J＝7.3,4.9Hz,1H),6.93(d,J＝8.1Hz,1H),3.86(t,J＝13.0Hz,2H),3.22(t,J＝12.4Hz,2H),3.03(t,J＝6.5Hz,1H),2.04-1.35(m,10H)ppm；LCMS:m/z 381.2[M+H]+.
Following the synthesis of example 119, the following compounds can be synthesized:
example 120 (R) -8- (8- (pyridazin-3-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001201
1H NMR(400MHz,DMSO-d6)δ8.97(d,J＝4.8Hz,1H),8.09(s,1H),7.80(s,1H),7.58(s,1H),7.48(dd,J＝8.9,4.9Hz,1H),7.33(d,J＝8.8Hz,1H),3.90(s,2H),3.25(d,J＝12.2Hz,3H),3.18(s,1H),1.86-1.46(m,9H)；LCMS:m/z 382.1[M+H]+.
Example 121 (R) -8- (8- (pyrazin-2-ylthio) imidazo [1,2-c ] pyrimidin-5-yl) -8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001202
1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.36(s,1H),8.31(s,1H),8.07(s,1H),7.79(s,1H),7.58(s,1H),3.89(t,J＝12.8Hz,2H),3.24(d,J＝12.2Hz,2H),2.06-1.46(m,9H)；LCMS:m/z 382.1[M+H]+.
Example 122: preparation of the compound 8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -1-methyl-8-azaspiro [4.5] decan-1-amine
The method comprises the following steps: 8- (8-iodoimidazo [1,2-c ] pyrimidin-5-yl) -1-methylspiro [4.5] decan-1-amine
Figure BDA0001579586110001203
To a solution of 5-chloro-8-iodoimidazo [1,2-c ] pyrimidine (56mg, 0.2mmol) in anhydrous DMF (10mL) at 0 deg.C was added 1-methyl-8-azaspiro [4.5] decan-1-amine (40mg, 0.24mmol) followed by diisopropylethylamine (51.6mg, 0.4mmol) and the reaction was stirred at 0 deg.C for 1 h. After the reaction is finished, the reaction solution is directly used for the next reaction.
LCMS:m/z 412.0[M+H]+.
Step two: (8- (8-Iodoimidazo [1,2-c ] pyrimidin-5-yl) -1-methylspiro [4.5] decan-1-yl) carbamic acid tert-butyl ester
Figure BDA0001579586110001211
Will be in the previous stepTo the solution was added (Boc)2O (87mg, 0.4mmol) was then added diisopropylethylamine (51.6mg, 0.4mmol) and the reaction was stirred at room temperature for 4 h. After completion of the reaction, water was added to quench the reaction, followed by extraction with ethyl acetate (3X 10 mL). The combined organic phases were dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography (0 to 30% gradient of ethyl acetate/petroleum ether) to give (8- (8-iodoimidazo [1, 2-c) ]Pyrimidin-5-yl) -1-methylspiro [4.5]Decan-1-yl) carbamic acid tert-butyl ester (15mg, two-step yield above: 7%)
LC-MS:m/z＝512.0[M+H]+.
Step three: tert-butyl (8- (8- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -methylspiro [4.5] decan-1-yl) carbamate.
Figure BDA0001579586110001212
Following the synthesis of step one in example 76, (8- (8-iodoimidazo [1, 2-c)]Pyrimidin-5-yl) -1-methylspiro [4.5]Coupling of tert-butyl decan-1-yl carbamate with sodium 6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-thiolate gave (8- (8- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c]Pyrimidin-5-yl) -methylspiro [4.5]Decan-1-yl) carbamic acid tert-butyl ester (4mg, yield: 15%). LC-MS M/z 678.2[ M + H ]]+.
Step four: 4- ((5- (1-amino-1-methylspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) sulfanyl) -5, 6-dichloropyridin-2-amine.
Figure BDA0001579586110001221
Following the synthesis procedure of example 21, step three, (8- (8- ((6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -methylspiro [4.5] decan-1-yl) carbamic acid tert-butyl ester was de-Boc protected to give 4- ((5- (1-amino-1-methylspiro [4.5] decan-8-yl) imidazo [1,2-c ] pyrimidin-8-yl) thio) -5, 6-dichloropyridin-2-amine (2mg, yield: 60%)
1HNMR(400MHz,DMSO-d6)δ8.10(s,1H),7.87(s,1H),7.64(s,1H),6.42(s,2H),5.63(s,1H),4.06(s,2H),3.18(t,J＝12.4Hz,2H),1.96-1.37(m,9H),1.26(s,3H),0.98-0.84(m,1H)ppm；LC-MS:m/z＝478.2[M+H]+。
Following the synthesis of example 122, the following compounds may be synthesized:
example 123 (R) -8- (8- ((6-amino-3-chloro-2-methyl-pyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001222
1H NMR(400MHz,DMSO-d6)δ8.19(s,2H),8.07(s,1H),7.84(s,1H),7.65(s,1H),5.65(s,1H),3.99(t,J＝15.1Hz,2H),3.62-3.55(m,3H),2.74-2.63(m,2H),2.44-2.33(m,5H),2.01(t,J＝11.8Hz,1H),1.85-1.60(m,3H)ppm；LC-MS:m/z＝480.2[M+H]+.
Example 124: preparation of the compound (R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine
Step one and step two: 5, 6-dichloro-4- ((5-chloroimidazo [1,2-c ] pyrimidin-8-yl) thio) pyridin-2-amine
Figure BDA0001579586110001231
Following the synthesis procedure of steps three and four in example 1, 8-iodoimidazo [1,2-c ] pyrimidin-5-ol was coupled with sodium 6- ((tert-butoxycarbonyl) amino) -2, 3-dichloropyridine-4-thiolate and halogenated to give 5, 6-dichloro-4- ((5-chloroimidazo [1,2-c ] pyrimidin-8-yl) thio) pyridin-2-amine.
LC-MS:m/z 347.9[M+H]+
Step three: (R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine
Figure BDA0001579586110001232
Following the synthesis procedure of example 23, substitution of 5, 6-dichloro-4- ((5-chloroimidazo [1,2-c ] pyrimidin-8-yl) thio) pyridin-2-amine with (R) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine gave (R) -8- (8- ((6-amino-2, 3-dichloropyridin-4-yl) thio) imidazo [1,2-c ] pyrimidin-5-yl) -3, 3-difluoro-8-azaspiro [4.5] decan-1-amine.
1H NMR(400MHz,DMSO-d6)δ8.35(s,2H),8.06(s,1H),7.86(s,1H),7.61(s,1H),6.31(s,2H),5.62(s,1H),3.92(d,J＝14.9Hz,2H),3.21(d,J＝12.8Hz,3H),3.07(t,J＝8.1Hz,2H),2.12-1.98(m,3H),1.91(d,J＝12.4Hz,2H),1.47(t,J＝16.6Hz,3H)ppm；LC-MS:m/z 501.7[M+H]+.
Example 125 Pharmacology related example 127
Example 125: SHP2 enzyme activity inhibition assay
The compound powder was dissolved in DMSO to prepare a mother solution. In the experiments, compound stock solutions were diluted in DMSO in 3-fold gradients, with 10 different test concentrations set for the same compound. mu.L of each concentration point of compound was dispensed into assay plate (Corning, Costar 3915) wells, and 2 replicates were placed at each concentration point. The protein is active protein SHP2 with mutation of amino acid at position 76E76AThe substrate used was DiFMUP (Invitrogen, E12020). SHP2E76AProteins and substrates were diluted to 1.2nM and 20. mu.M with buffer (0.1M NaAc (pH 7.2), 0.02% Tween 20, 0.1% BSA,1mM EDTA,5mM DTT), respectively. To the assay well, 50. mu.L of enzyme solution was added followed by 50. mu.L of substrate. The rate of accumulation of the product was calculated to characterize the enzyme activity by recording (Ex 358nm/Em 455nm) the fluorescence signal every 1 minute on a Spectra max i3(Molecular Devices) instrument. Nonlinear regression analysis was performed using GraphPad Prism 5 and a curve of enzyme activity as a function of compound concentration was fitted by the Y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC50-X) · HillSlope)) equation. Determination of IC of each Compound50The value is obtained.
Results
The following table shows the IC of some of the compounds of the invention 50The value is obtained.
Letter A stands for IC50Less than 100 nM;
letter B stands for IC50100nM to 1000 nM;
Figure BDA0001579586110001241
Figure BDA0001579586110001251
example 126: phosphoprotein kinase (p-ERK) cell assay
The phosphorylation level of a compound inhibiting intracellular protein kinase (ERK) was examined by AlphaLISA method.
The first step is the treatment of the cells with the compound. Firstly, diluting a compound to be detected by 3-fold with 100% DMSO, and setting 9 different concentration gradients in total; then, 30000 cells per hole are inoculated into MOLM13 cells to a 96-hole plate, and each hole volume is 100 mu L; subsequently, 0.5. mu.L of DMSO or different concentrations of test compound were added to each well, each concentration was set at 2 replicates, and the final concentration of DMSO was controlled at 0.5%.
Second step cell lysis. After 2 hours of cell treatment, the medium was removed, the cells were washed 3 times with phosphate buffered saline, 50 μ l of freshly prepared lysis buffer was added to each well, shaken and left at room temperature for 10 minutes.
The third step
Figure BDA0001579586110001262
UltraTMp-ERK 1/2(Thr202/Tyr204) kit (Perkin Elmer, ALSU-PERK-A10K)) detects phosphorylated extracellular signal-regulated kinase (p-ERK). Mu.l of the lysate were transferred to 384 well plates (Perkin Elmer,6005350) and the samples were tested for the level of extracellular signal-regulated kinase phosphorylation according to the product instructions. AlphaScreen detection on Spectra max i3(Molecular Devices) was used The detector reads the signal. The inhibition percentage (%) was calculated by the following formula:
percent (%) inhibition (1-p-ERK signal from compound-treated cells/p-ERK signal from DMSO-treated cells) × 100 results
The following table shows the IC of some of the compounds of the invention50The value is obtained.
Letter A stands for IC50Less than 100 nM;
letter B stands for IC50100nM to 1000 nM;
Figure BDA0001579586110001261
Figure BDA0001579586110001271
Figure BDA0001579586110001281
example 127: MOLM-13 cell proliferation assay
MOLM-13 cells suspended in medium (RPMI-1640, containing 10% FBS and 1% Penicillin-Streptomyces, Gibco) were seeded onto 384-well plates at 800 cells (40. mu.L/well). The cells are immediately treated with the test compound at concentrations of 50, 16.67, 5.56, 1.85, 0.617, 0.206, 0.069, 0.023, 0.0076 μm, respectively. After 3 days, 5. mu.L of CellTiter-Glo reagent (Promega, ZG7572) was added to each well, and the mixture was left for 10 minutes at room temperature in the dark. Fluorescence signals were detected by Spectra max i3(Molecular Devices). The relative growth rate of the treated cells was compared to the DMSO control.
Results
The following table shows the IC of some of the compounds of the invention50The value is obtained.
Letter A stands for IC50Less than 100 nM;
letter B stands for IC50100nM to 1000 nM;
Figure BDA0001579586110001282
Figure BDA0001579586110001291
in accordance with the same test methods as those of the SHP2 enzyme activity inhibition assay described in example 125, the phosphoprotein kinase (p-ERK) cell assay described in example 126 and the MOLM-13 cell proliferation assay described in example 127, the applicant carried out corresponding assays with respect to SHP099(6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine), a compound disclosed in WO 2015/107493A 1 or the publication (Nature 2016,535, 148-152), and the data of the comparative experiments between the compounds obtained in some examples of the present invention and SHP099 are shown in the following table, and it was found that the pyrimido-cyclic compounds of the present invention have superior activity after comparison.
Figure BDA0001579586110001301
Figure BDA0001579586110001311
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (27)

1. A pyrimido-cyclic compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure FDA0003466616770000011
wherein
X is independently S;
y is independently C;
n is independently 0, 1 or 2;
R1is selected from 0 to 4R1aSubstituted phenyl, 0 to 4R1aSubstituted pyridyl, 0 to 4R1aSubstituted naphthyl or 0 to 4R1aA substituted quinolinyl group;
R1aindependently of one another is halogen, R1a1Substituted or unsubstituted C1-4Alkoxy radical, R1a1Substituted or unsubstituted C1-4Alkyl, trifluoromethyl, C (═ O) OR1a2、NR1a2R1a3、NHC(＝O)R1a4、R1a1Substituted or unsubstituted C3-8A cycloalkyl group; r1a1Independently is halogen or C1-4An alkyl group; r1a2、R1a3Independently of one another is hydrogen, C1-4An alkyl group; r1a4Independently is C1-4Alkyl, substituted or unsubstituted alkenyl, amide, C3-12Mono-or poly-heterocyclic;
R2a、R2b、R3aand R3bIndependently of each other is hydrogen, R1a1Substituted or unsubstituted C1-4An alkyl group;
R4and R5Together with Y form 0 to 3R4aA substituted 3-to 7-membered saturated or partially unsaturated spirocyclic ring, which ring may optionally contain 1 to 3 heteroatoms or groups independently selected from N, C (═ O) and/or O;
R4aIndependently of one another hydrogen, halogen, R1a1Substituted or unsubstituted C1-4Alkoxy radical, R1a1Substituted or unsubstituted C1-4Alkyl, hydroxy, amino, C1-4An alkylamino group;
wherein formula (II) is not any of the following compounds:
Figure FDA0003466616770000012
2. pyrimido according to claim 1A cyclic compound or a pharmaceutically acceptable salt thereof, wherein R2a、R2b、R3aAnd R3bIndependently hydrogen or methyl.
3. The pyrimido compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R4And R5The ring formed with Y is selected from the following structures:
Figure FDA0003466616770000021
wherein p is 0 or 1; r4aAs defined in claim 1.
4. The pyrimido compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R4And R5The ring formed with Y is of the following configuration:
Figure FDA0003466616770000022
wherein p is 0 or 1; r4aAs defined in claim 1.
5. The pyrimido compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, R1Is selected from
Figure FDA0003466616770000023
Figure FDA0003466616770000024
Figure FDA0003466616770000031
6. The pyrimido compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4,R1aindependently of one another, halogen, C1-4Alkoxy radical, C1-4Alkyl, trifluoromethyl, C (═ O) OR1a2,NH2,NHC(＝O)R1a4、C3-8A cycloalkyl group.
7. The pyrimido compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, R 1aIndependently F, Cl, isopropyl, trifluoromethyl, NH2Cyclopropyl, methyl.
8. A pyrimido ring compound or a pharmaceutically acceptable salt thereof according to claim 1, selected from any one of the following compounds:
Figure FDA0003466616770000032
Figure FDA0003466616770000041
Figure FDA0003466616770000051
Figure FDA0003466616770000061
9. a method for preparing a pyrimido-cyclic compound represented by formula (II) comprises the following steps:
the halogenated intermediate compound A and boric acid, mercaptan or sodium sulfide are subjected to coupling reaction to obtain a formula (II), and the reaction equation is as follows:
Figure FDA0003466616770000062
wherein, W1Represents halogenA peptide; x, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5As defined in any one of claims 1 to 7.
10. A process for the preparation of intermediate compound a comprising the steps of:
the halogenated intermediate E is substituted by the intermediate amine C under the alkaline condition to obtain a halogenated intermediate compound A, and the reaction equation is as follows:
Figure FDA0003466616770000063
wherein, Y, n, R2a、R2b、R3a、R3b、R4And R5As defined in any one of claims 1 to 4; w1Represents halogen, W2Represents halogen.
11. A method for preparing a pyrimido-cyclic compound represented by formula (II) comprises the following steps:
substitution of the halogenated intermediate compound B with an amine C gives the formula (II) as follows:
Figure FDA0003466616770000064
wherein, W2Represents halogen; x, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5As defined in any one of claims 1 to 7.
12. A process for the preparation of intermediate compound B comprising the steps of:
Substituting dichloropyrimidine compound B-1 by amine to obtain an intermediate B-2; condensing, cyclizing and hydrolyzing the intermediate B-2 under the condition of strong acid to obtain a halogenated intermediate B-3; halogenated intermediate B-3 is subjected to catalytic coupling to obtain intermediate B-4, and then converted into halogenated intermediate B, wherein the reaction equation is as follows:
Figure FDA0003466616770000071
wherein, X, R1As defined in any one of claims 1, 5 to 7; w is a group of1Represents halogen; w2Represents halogen.
13. A process for producing a pyrimido-cyclic compound represented by formula (II-A), comprising the steps of:
coupling the sodium sulfur intermediate compound D with a halide to obtain a compound of formula (II-A), wherein the reaction equation is as follows:
Figure FDA0003466616770000072
wherein, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5As defined in any one of claims 1 to 7.
14. A process for the preparation of intermediate compound D comprising the steps of:
the intermediate compound A and methyl mercaptopropionate obtain an intermediate D-1 under the condition of catalytic coupling, and then obtain a corresponding sodium sulfide compound D under the alkaline condition, wherein the reaction equation is as follows:
Figure FDA0003466616770000081
wherein, Y, n, R2a、R2b、R3a、R3b、R4And R5As defined in any one of claims 1 to 4; w1Represents halogen.
15. A process for producing a pyrimido-cyclic compound represented by formula (II-B), comprising the steps of:
removing the protecting group of the intermediate II-B1 under acidic or basic conditions to obtain a compound II-B, wherein the reaction equation is as follows:
Figure FDA0003466616770000082
Wherein Pg is selected from protecting groups Boc, Ac, S (═ O)tBu；R4Pg、R5PgTogether with the attached carbon, is selected from the following structures:
Figure FDA0003466616770000083
R4、R5together with the attached carbon, is selected from the following structures:
Figure FDA0003466616770000091
X、n、R1、R2a、R2b、R3a、R3b、R4aas defined in any one of claims 1-2, 5-7; p is 0 or 1.
16. A process for producing a pyrimido-cyclic compound represented by formula (II-C), comprising the steps of:
aminoacylation of intermediate II-C1 yields compound II-C, the reaction equation is as follows:
Figure FDA0003466616770000092
wherein, X, Y, n, R2a、R2b、R3a、R3b、R4、R5、R1aAnd R1a4As defined in any one of claims 1 to 4 and 6 to 7.
17. An intermediate for preparing the pyrimido compound of claim 1, said intermediate compound selected from the group consisting of:
Figure FDA0003466616770000093
x, R therein1、Y、n、R2a、R2b、R3a、R3b、R4And R5Is as defined in any one of claims 1 to 7, W1Represents halogen, W2Represents halogen.
18. A method for preparing a pyrimido-cyclic compound shown as a formula (I) comprises the following steps:
halogenated intermediate compounds
Figure FDA0003466616770000094
After the coupling reaction with boric acid, mercaptan or sodium sulfate, the formula (I) is obtained, and the reaction equation is as follows:
Figure FDA0003466616770000101
wherein, W1Represents halogen; x, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5As defined in any one of claims 1 to 7; z1, Z2 are independently C.
19. A method for preparing a pyrimido-cyclic compound shown as a formula (I) comprises the following steps:
Intermediate product
Figure FDA0003466616770000102
Substitution with amine C gives formula (I), the reaction equation is as follows:
Figure FDA0003466616770000103
wherein, W2Represents halogen; x, Y, n, R1、R2a、R2b、R3a、R3b、R4And R5As defined in any one of claims 1 to 7; z1, Z2 are independently C.
20. The method according to any one of claims 9 to 12, 14 and 17 to 19, wherein W is1Selected from Br, I and/or W2Selected from Cl, Br and I.
21. Use of a pyrimido ring compound according to any of claims 1 to 8 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease or condition associated with abnormal SHP2 activity.
22. A use according to claim 21, wherein the disease or disorder associated with aberrant activity of SHP2 is selected from noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, squamous cell carcinoma of the head and neck, gastric cancer, anaplastic large-cell lymphoma or glioblastoma.
23. A pharmaceutical composition comprising a pyrimido-ring compound according to any of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
24. A pharmaceutical formulation comprising the pyrimido ring compound of any of claims 1 to 8 or a pharmaceutically acceptable salt thereof, said pharmaceutical formulation being selected from the group consisting of tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, solutions.
25. A pharmaceutical formulation according to claim 24, which is administered in a manner selected from the group consisting of: oral, sublingual, subcutaneous, intravenous, intramuscular, intrasternal, nasal, topical or rectal administration.
26. A pharmaceutical formulation according to claim 24, which is administered in a single dose or in multiple doses per day.
27. Use of a pyrimido ring compound according to any of claims 1 to 8 or a pharmaceutically acceptable salt thereof in combination with an additional agent selected from the group consisting of: anticancer drugs, tumor immunity drugs, antiallergic drugs, antiemetic drugs, analgesics, cytoprotective drugs.
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