CN117751127A - Five-membered nitrogen-containing heterocyclic heteroaryl derivative and application thereof - Google Patents
Five-membered nitrogen-containing heterocyclic heteroaryl derivative and application thereof Download PDFInfo
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- CN117751127A CN117751127A CN202280052947.XA CN202280052947A CN117751127A CN 117751127 A CN117751127 A CN 117751127A CN 202280052947 A CN202280052947 A CN 202280052947A CN 117751127 A CN117751127 A CN 117751127A
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- compound
- ethyl acetate
- alkyl
- cycloalkyl
- added
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 58
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a five-membered nitrogen-containing heterocyclic heteroaryl derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof as a therapeutic agent, in particular to application as an ATR kinase inhibitor and application in preparing medicines for preventing ATR kinase-mediated diseases.
Description
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a five-membered nitrogen-containing heterocyclic heteroaryl derivative and application thereof.
ATR (telangiectasia ataxia mutation and RAD-3 related protein kinase) belongs to PIKKs (phosphatidylinositol-3-kinase-related kinase) family, and is involved in damage repair of DNA to maintain gene stability. ATR kinase works with ATM ("ataxic telangiectasia mutated") kinase and many other proteins to regulate cellular responses to DNA damage, commonly referred to as DNA damage response ("DDR"). DDR stimulates DNA repair, promotes survival, and quiesces cell cycle progression by activating cell cycle checkpoints that provide repair time. Without DDR, cells are more susceptible to DNA damage and are prone to death from endogenous cellular processes (e.g., DNA repair) or DNA damage induced by exogenous DNA damaging agents commonly used in cancer therapies.
Healthy cells may depend on the host for repair of DNA of different proteins, including DDR kinase ATR. In some cases, these proteins may compensate for each other by functionally activating redundant DNA repair processes. In contrast, many cancer cells harbor defects in some of their DNA repair processes, such as ATM signaling, and thus exhibit greater dependence on their remaining intact DNA repair proteins, including ATR. In addition, many cancer cells express activated oncogenes or lack critical tumor suppressor genes, and this situation can predispose these cancer cells to a deregulation of DNA replication, thereby causing DNA damage.
ATR is activated by DNA single strand structure when DNA double strand breaks undergo excision or replication fork arrest. The DNA polymerase remains in the process of DNA replication, and the replication helicase continues to unwind at the front of the DNA replication fork, resulting in the production of long single stranded DNA (ssDNA) which is then bound by the single stranded DNA and RPA (replication protein a). Replication stress or DNA damage by RPA recruited ATR/ATR action protein complexes to the injury site, RPA-single stranded DNA complexes activated RAD17/rfc2-5 complexes binding to the injury site, DNA-ssDNA junctions activated Rad9-HUS1-RAD1 (9-1-1) heterotrimers, 9-1-1 in turn recruited TopBP1 to activate ATR. Once ATR is activated, ATR promotes DNA repair, stabilizes and restarts the arrested replication fork and transient cell cycle arrest by downstream targets. These functions are achieved by mediating the downstream target Chk1 by ATR. ATR acts as a DNA-damaging cell cycle checkpoint in S phase. It can mediate the degradation of CDC25A through Chk1, thus delay the replication process of DNA, offer time for repairing replication fork. ATR is also the primary regulator of the G2/M cell cycle checkpoint, preventing cells from prematurely entering mitosis before DNA replication is complete or DNA damage. This ATR-dependent G2/M cell cycle arrest is mediated primarily by two mechanisms: degradation of cdc25 a. 2. Cdc25C was phosphorylated by Chk1 to bind 14-3-protein. Binding of Cdc25C to the 14-3-3 protein promotes its export from the nucleus and cytoplasmic isolation, thereby inhibiting its ability to dephosphorylate and activate nuclear Cdc2, which in turn prevents entry into mitosis.
Since ATR is essential for self-replication of cells, and is activated during S phase to regulate the origin of replication and repair damaged replication crosses. Replication fork damage can increase the sensitivity of cancer cells to platinum and hydroxyurea anticancer drugs, and reduce the drug resistance of cancer cells. Thus, inhibition of ATR may be an effective approach in future cancer treatments.
Among the ATR inhibitor compounds which have been disclosed so far are M6620, AZD-6738, etc. Month 4 of 2021, merck (Merck KGaA) announced a key clinical progression of berzoservib (M6620). Berzoservib is a potent, selective ataxia telangiectasia and Rad3 associated protein (ATR) inhibitor under investigation.
Disclosure of Invention
The compound of the present invention has a parent nucleus structure different from the above structure, and the obtained compound can exert a good inhibitory effect on ATR. The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful in the treatment of a variety of cancers.
Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or configurational) forms of the structures; for example, R and S configuration, Z and E double bond isomers, and Z and E configuration isomers of each asymmetric center. Thus, single stereochemical isomers, as well as mixtures of enantiomers, diastereomers and geometric (or configurational) isomers of the compounds of the invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise indicated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having a composition comprising deuterium or tritium substituted for hydrogen or with 13 C or 14 Compounds of the structure of the invention in which C-enriched carbon replaces carbon are within the scope of the invention. The compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents of the invention.
Pharmaceutically acceptable excipient or vehicle refers to a non-toxic carrier, excipient or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, excipients, or vehicles that can be used in the compositions of the invention include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances, such as phosphates; glycine; sorbic acid; potassium sorbate; a partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate (protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; a cellulose-based material; polyethylene glycol; sodium carboxymethyl cellulose; a polyacrylate; a wax; polyethylene-polyoxypropylene-block polymers; polyethylene glycol and lanolin.
In particular embodiments, a combination of two or more therapeutic agents may be administered with a compound of the invention. In particular embodiments, a combination of three or more therapeutic agents may be administered with a compound of the invention.
In particular embodiments, the compounds of the invention, or a pharmaceutically acceptable composition thereof, are administered in combination with an antisense agent, monoclonal or polyclonal antibody, or siRNA therapeutic agent.
Those additional agents may be administered separately from the compounds or compositions of the present invention as part of a multiple-administration regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially or at intervals of time (typically within 5 hours of each other).
The terms "combination," "conjugate," and related terms as used herein refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, the compounds of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, excipient, or vehicle.
The amount of both the compound of the invention and the other therapeutic agent (in those compositions comprising the other therapeutic agent as described above) that can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. Preferably, the composition of the invention should be formulated so that a dose of between 0.01mg and 100mg per kg body weight per day can be administered.
In those compositions comprising other therapeutic agents, the other therapeutic agents and the compounds of the present invention may act synergistically. Thus, the amount of other therapeutic agents in these compositions will be less than would be required in monotherapy using the therapeutic agents alone. In these compositions, other therapeutic agents may be administered in a dosage of between 0.01 μg and 100 μg per kilogram body weight per day.
The amount of the other therapeutic agent present in the compositions of the present invention will not be greater than the amount typically administered in compositions comprising the therapeutic agent as the sole active agent. Preferably, the amount of the other therapeutic agent in the disclosed compositions will be in the range of about 50% to 100% of the amount typically present in compositions comprising the agent as the sole therapeutically active agent.
In order to realize the invention, the following technical scheme is adopted.
A compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein:
X 1 is NR (NR) 5 O or CR 6 Wherein R is 5 And R is 6 Independently is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, halogen or hydroxy, wherein the alkyl, cycloalkyl, alkoxy and hydroxyalkyl are each independently selected from halogen, hydroxy, carboxyl, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl One or more substituents in the group;
X 2 is C or N;
X 3 CH or N;
X 4 CH or N;
X 5 CH or N;
R 1 is thatR 7 Each independently is hydrogen, alkyl, cycloalkyl, alkoxy, cyano, or halogen; wherein the alkyl, cycloalkyl and alkoxy groups are each independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;
R 2 selected from:
R 8 、R 9 and R is 10 Independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano, halogen or NR 11 R 12 Wherein R is 11 And R is 12 Independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano or halogen; wherein the alkyl, cycloalkyl and alkoxy groups are each independently selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl Substituted with one or more substituents selected from the group consisting of C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;
R 3 is alkyl, aryl, heterocyclyl, cycloalkyl, heteroaryl, carbonyl, -S (=o) R 13 -alkyl-S (=o) R 13 -cycloalkyl-S (=o) R 13 、-S(=O) 2 R 13 -alkyl-S (=o) 2 R 13 -cycloalkyl-S (=o) 2 R 13 、-S(=O)(=NH)R 13 -alkyl-S (=o) (=nh) R 13 or-cycloalkyl-S (=o) (=nh) R 13 Wherein the alkyl, aryl, heterocyclyl, cycloalkyl and heteroaryl are each independently substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;
R 13 is alkyl, cycloalkyl, heteroaryl, aryl or heterocyclyl;
R 4 hydrogen, alkyl, cycloalkyl, alkoxy, cyano or halogen; wherein the alkyl, cycloalkyl and alkoxy groups are each independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;
Alternatively, R 4 And X is 2 Together form a carbonyl group, or R 4 And R is 3 Together with the groups to which they are attached form a 5-7 membered ring;
n, m, p represent 0, 1, 2 or 3;
in certain embodiments, the R 1 Is thatIn certain embodiments, R 7 Is methyl or ethyl. In certain embodiments, p is 0 or 1.
In certain embodiments, the R 1 Selected from the following groups:
in certain embodiments, the R 2 Selected from the following groups:
in certain embodiments, the R 3 Is alkyl or cycloalkyl. In certain embodiments, the alkyl and cycloalkyl groups are optionally substituted with 1-3 substituents selected from cycloalkyl, halogen, cyano, or pyridyl.
In certain embodiments, the R 3 Is methyl, cyclopropyl, cyclopentyl, isopropyl, cyclopropylmethylene and the like.
In certain embodiments, the R 3 Is a six-membered or five-membered unsaturated heterocycle containing N. In certain embodiments, the unsaturated heterocycle is optionally substituted with an alkyl group.
In certain embodiments, the R 3 Selected from:
in certain embodiments, the R 3 Is benzene ring. In certain embodiments, the ortho, meta, or para position of the benzene ring is optionally independently substituted with one or more substituents selected from halogen, hydroxy, carboxy, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, isopropylcyano, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl, and alkylsulfinyl.
In certain embodiments, the R 3 is-S (=O) R 13 、-S(=O) 2 R 13 Or S (=o) (=nh) R 13 . In certain embodiments, the R 13 Is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkylalkyl, an optionally substituted benzene ring, an optionally substituted N-containing six-membered saturated heterocyclic ring, or an optionally substituted N-containing six-membered unsaturated heterocyclic ring, which may be substituted with alkyl, halogen, alkoxy.
In certain embodiments, the R 3 is-alkyl-S (=O) R 13 -cycloalkyl-S (=o) R 13 -alkyl-S (=o) 2 R 13 -cycloalkyl-S (=o) 2 R 13 -alkyl-S (=o) (=nh) R 13 or-cycloalkyl-S (=o) (=nh) R 13 . In certain embodiments, the alkyl is methylene, ethylene, propylene, butylene, or-CH (CH) 3 ) -. In certain embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodimentsIn the scheme, the R 13 Is an optionally substituted alkyl group (e.g., methyl, ethyl or propyl).
In certain embodiments, the X 1 Is C, X 2 Is C, X 3 Is N.
In certain embodiments, the X 1 Is N, X 2 Is C, X 3 Is N.
In certain embodiments, the R 4 And R is R 3 Together form a six membered N, O containing heterocycle.
In certain embodiments, each of m and n is independently 0.
In certain embodiments, the R 4 And X is 2 Together forming a carbonyl group.
In certain embodiments, the R 5 H.
In certain embodiments, the R 6 H, C of a shape of H, C 1-6 Alkyl, alkoxy or halogen.
In certain embodiments, the R 8 Is H or halogen.
In certain embodiments, the halogen is a chlorine atom.
In certain embodiments, the R 9 Is H or halogen.
In certain embodiments, the halogen is a chlorine atom.
In certain embodiments, the R 10 H.
In certain embodiments, the R 11 And R is 12 H, C of a shape of H, C 1-6 Alkyl, halogen or alkyl substituted with 1 to 3 halogen atoms.
In certain embodiments, the R 13 Is cyclopropyl, isopropyl, methyl, ethyl or cyclopropylmethylene.
In certain embodiments, the R 13 Selected from the following groups:
in certain embodiments, the structure of the compounds of formula (I) is as follows:
in certain embodiments, the compound is selected from the group consisting of:
in certain embodiments, the pharmaceutical composition contains a therapeutically effective amount of the above compound and at least one pharmaceutically acceptable excipient.
In certain embodiments, the use of the compound in the manufacture of a medicament for the treatment or prevention of ATR kinase mediated diseases; preferably, the disease is cancer.
In certain embodiments, wherein the cancer is liver cancer, melanoma, hodgkin's disease, non-hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, wilms 'tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myelogenous leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, stomach cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myelogenous leukemia, hairy cell leukemia, rhabdomyosarcoma, kaposi's sarcoma, genitourinary system neoplastic disease, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenal cortex cancer, skin cancer, and prostate cancer.
Detailed terminology
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently optionally with one or more substituents selected from the group consisting of H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 2 residues derived from the same carbon atom or two different carbon atoms of the parent alkane, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkylene group containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably containing from 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) 2 (-), 1-ethylene (-CH (CH) 3 ) (-), 1, 2-ethylene (-CH) 2 CH 2 ) -, 1-propylene (-CH (CH) 2 CH 3 ) (-), 1, 2-propylene (-CH) 2 CH(CH 3 ) (-), 1, 3-subunitPropyl (-CH) 2 CH 2 CH 2 (-), 1, 4-butylene (-CH) 2 CH 2 CH 2 CH 2 (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently optionally with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of hydrogen atom, alkyl group, alkoxy group, halogen, haloalkyl group, hydroxyl group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group.
The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from one or more of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, phenyldicyclopentyl, benzocycloheptyl, and the like; preferred are phenyl-cyclopentyl and tetrahydronaphthyl.
Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably independently optionally with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituents independently selected from one or more of H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl. The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, S, S (O) and S (O) 2 Is selected from the group consisting of a heteroatom, but does not include-O-; a ring moiety of O-S-or-S-S-, the remaining ring atoms are carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, or 8) ring atoms, wherein 1-3 (e.g., 1,2, or 3) are heteroatoms; more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groupsIllustrative examples include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
Heterocyclyl rings include those described above (including monocyclic, spiro, fused and bridged) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (fused polycyclic being a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, wherein the ring attached to the parent structure is an aryl ring.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably independently optionally with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, and 10), more preferably 5 or 6 membered, e.g., furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring.
Heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably independently optionally with one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
The cycloalkyl, heterocyclyl, aryl and heteroaryl groups described above have 1 residue derived from the removal of one hydrogen atom from the parent ring atom, or 2 residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".
The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably a tetrahydropyranyl group.
The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "hydroxy" refers to an-OH group.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2 。
The term "cyano" refers to-CN.
Terminology"nitro" means-NO 2 。
The term "carbonyl" refers to c=o.
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" refers to-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
The compounds of the present disclosure may exist as tautomers. For the purposes of the present disclosure, reference to a compound of formula (I) refers to reference to the compound itself, or to any one of its tautomers itself, or to a mixture of two or more tautomers. For example, reference to pyrazolyl is to be understood to include mixtures of either or both tautomers of either structure,
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present disclosure which are safe and effective when used in a mammal, and which possess the desired biological activity.
EXAMPLE 1 Synthesis of Compound R1
(1) Step 1:
to a 25mL single vial was added (R) -4- (2-chloro-9 h-purin-6-yl) -3-methylmorpholine (200 mg), bromoisopropyl alcohol (161 mg) and potassium carbonate (120 mg) at room temperature, followed by DMF (8 mL) and then heated to 80℃with stirring at reflux overnight. TLC monitored the completion of the reaction, and the reaction was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give an off-white solid (145 mg, 62%). LC-MS [ M+H ] ] + =296.20。
(2) Step 2:
a50 mL single-necked flask was charged with Compound R1-1 (230 mg), borate (227 mg), pd (PPh) 3 ) 4 (90 mg) and KOAc (165 mg), then DMSO (20 mL) was added, nitrogen was purged 3 times, heated to 120℃for 8h, TLC was monitored for completion of the reaction, the reaction solution was cooled to room temperature, 60mL of water was poured into the reaction solution, extracted with ethyl acetate, dried by spinning after organic phase drying filtration, and purified by column chromatography (petroleum ether: ethyl acetate=5:1-1:1) to give a pale yellow solid (130 mg, 44%). 1 H NMR(400MHz,MeOD)δ8.30(d,1H),8.20(s,1H),8.14(d,1H),7.50(dd,2H),5.57(s,1H),5.20(s,1H),5.04(dt,1H),4.09(dd,1H),3.89(s,2H),3.80–3.70(m,1H),3.66–3.57(m,1H),1.73(d,6H),1.49(d,3H)。LC-MS[M+H] + =378.30。
EXAMPLE 2 Synthesis of Compound R2
(1) Step 1:
the compound W-1 is 2, 4-dichloro-7-deazapurine, purchased from Leyan reagent, and has a purity of 99.37% or more, as in the following examples.
2, 4-dichloro-7-deazapurine (2.0 g) was taken at room temperature in a 50mL round bottom flask and THF (16 mL) was added. Cooling to 0-5deg.C, and stirring for 5min. 60% sodium hydride (0.51 g) was added thereto, and the reaction was stirred for 15 minutes. Methyl iodide (17.0 g) was added thereto, the temperature was raised to room temperature, and the reaction was stirred overnight. TLC (petroleum ether: ethyl acetate=4:1) monitored the reaction for completion. The reaction mixture was quenched with water, and the resulting mixture was extracted with ethyl acetate (3 times). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give Compound R2-1 (1.76 g, 81.9%) as a white powder. LC-MS [ M+H ] ] + =203。
(2) Step 2:
compound R2-1 (1.0 g), (R) -3-methylmorpholine (600 mg), anhydrous potassium carbonate (2.05 g) was taken at room temperature and placed in a 50mL round bottom flask. DMF (10 mL) was added, heated to 90-100deg.C, and the reaction stirred for 5-6h. TLC monitored until the reaction was complete. Cooled to room temperature, ice water was added/extracted twice with ethyl acetate, the ethyl acetate phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=4:1) to give compound R2-2 (0.99 g, 75%) as an orange oil. LC-MS [ M+H ]] + =267。
(3) Step 3:
compound R2-2 (500 mg), 7-azaindole boronic acid pinacol ester (502 mg), anhydrous potassium carbonate (775 mg), tetraphenylpalladium phosphate (216 mg), 1, 4-dioxane (10 mL) and water (2 mL) were weighed. The nitrogen was replaced 3 times, heated to 90-100℃and stirred overnight. Cooled to room temperature, ice water was added, extracted twice with ethyl acetate, the ethyl acetate phases were combined, washed with water, brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound R2 (45 mg, 70%) as a solid powder. 1 H NMR(400MHz,CD 3 CN)δ9.81(s,1H),8.37(d,1H),8.17(d,1H),7.61(d,1H),7.52(d,1H),7.19(s,1H),6.64(s,1H),4.93(d,1H),4.61(d,1H),4.06(d,1H),3.89(d,3H),3.82(d,2H),3.70–3.67(m,1H),3.59–3.53(m,1H),1.42–1.36(m,3H)。LC-MS[M+H] + =349。
EXAMPLE 3 Synthesis of Compound R3
(1) Step 1:
to a 250mL reaction flask were added dichloromethane (100 mL), 2.4-dichloro-pyrrolopyrimidine (2 g), diisopropylethylamine (5 mL), and the reaction mixture was stirred at room temperature for 10min to give a white cloudy solution. Methanesulfonyl chloride (3 g) was then added, the mixture gradually dissolved, and the mixture was reacted at room temperature for 2h, TLC (Petroleum ether: ethyl acetate=4:1, one drop of toluene was added Alcohol) was monitored until the reaction was complete. The reaction solution was added to water (500 mL), stirred for 30min, triethylamine (10 mL) was added during stirring, and the mixture was allowed to stand, the organic phase was separated, dried over anhydrous sodium sulfate, and filtered, and the filtrate was used directly in the next step. LC-MS [ M+H ]] + =267。
(2) Step 2:
diisopropylethylamine (5 mL) and morpholine (2.5 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 4-5h to give a bright yellow clear solution, which was monitored by TLC (petroleum ether: ethyl acetate=4:1) until the reaction was complete. The reaction solution was washed twice with water (100 ml x 2), dried over anhydrous sodium sulfate, filtered, concentrated, slurried with n-hexane, filtered, and dried to give compound R3-2 (1.8 g, 53%) as an off-white solid. LC-MS [ M+H ]] + =317。
(3) Step 3:
to a 50mL reaction flask, DMSO (20 mL), compound R3-2 (1.4 g), 7-azaindole pinacol borate (1.16 g), sodium fluoride (2.1 g) and tetrakis (triphenylphosphine) palladium (0.29 g) were added under nitrogen, then the reaction mixture was warmed to 120℃and incubated for 4-5h, and TLC (Petroleum ether: ethyl acetate=1:1) monitored until the starting material was complete. The reaction solution was added to a mixture of water (50 mL) and ethyl acetate (50 mL), the layers were stirred, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried, concentrated, and the residue was purified by silica gel column chromatography to give compound R3 (0.1 g, 5%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.36(t,1H),8.06(d,1H),7.65–7.55(m,1H),7.50(dt,1H),7.31(dd,1H),7.05(dd,1H),4.02(t,2H),3.88(t,1H),3.85–3.77(m,4H),2.84(s,3H),1.35(s,3H)。LC-MS[M+H] + =399。
EXAMPLE 4 Synthesis of Compound R5
(1) Step 1:
at room temperature, 4, 6-dichloro-1H pyrazolo [3.4-d ] is added]Pyrimidine (1 g), (R) -3-methylmorpholine (0.6 g), dichloromethane (30 mL) and potassium carbonate (1.5 g) were reacted at 35℃for 12h, washed with water, the organic phase was concentrated and the crude product was used directly in the next step. LC-MS [ M+H ]] + =254。
(2) Step 2:
compound R5-1 (300 mg), isopropyl iodide (1 g), potassium carbonate (320 mg) and DMF (10 mL) were added at room temperature, reacted at 80℃for 5 hours, extracted with water/ethyl acetate, the organic phase concentrated, purified by column chromatography (petroleum ether: ethyl acetate=5:1), and then used in the next step. LC-MS [ M+H ]] + =296。
(3) Step 3:
under nitrogen protection, the compound R5-2 (240 mg), 7-azaindole boronic acid pinacol ester (238 mg), potassium carbonate (281 mg), tetraphenylphosphine palladium (140 mg) and dimethyl sulfoxide (10 mL) were added, and reacted under nitrogen protection at 120℃for 5 hours, with water/acetic acidEthyl ester extraction, concentration of the organic phase and purification by column chromatography (petroleum ether: ethyl acetate=3:1) gave the desired product (90 mg). 1 H NMR(400MHz,CDCl 3 -d)δ9.56(s,1H),8.47(d,1H),8.17(d,1H),7.99(s,1H),7.72(s,1H),7.67(d,1H),7.57–7.54(m,1H),5.39(p,1H),4.87(s,1H),4.22–4.12(m,1H),3.99–3.84(m,2H),3.74(td,1H),3.65(s,1H),1.66(dd,6H),1.54(d,3H)。LC-MS[M+H] + =378。
EXAMPLE 6 Synthesis of Compound R7
(1) Step 1:
4, 6-dichloro-1H pyrazolo [3.4-d ] pyrimidine (1 g), (R) -3-methylmorpholine (0.6 g), dichloromethane (30 mL) and potassium carbonate (1.5 g) were added at room temperature, reacted for 12H at 35℃and washed with water, the organic phase concentrated and the crude product was used directly in the next step.
(2) Step 2:
compound R7-1 (1.09 g), 1-trifluoro-2-iodoethane (1.804 g), cesium carbonate (7.02 g) and DMF (20 mL) were added at room temperature, reacted for 12h at 70 ℃, tlc (petroleum ether: ethyl acetate=2:1), extracted with water/ethyl acetate, the organic phase concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=10:1) and then used for the next step. LC-MS [ M+H ]] + =336。
(3) Step 3:
at room temperature, the compound R7-2 (0.2 g), 7-azaindole boric acid, was addedPinacol ester (0.145 g), cesium carbonate (0.582 g), palladium tetraphenyl phosphine (0.069 g) and water/1, 4-dioxane (V: v=1:10), nitrogen protection at 95 ℃ for 12h, tlc (petroleum ether: ethyl acetate=1:1), extraction with water/ethyl acetate, concentration of the organic phase, purification by column chromatography (petroleum ether: ethyl acetate=3:1) afforded compound R7 (15 mg) as a yellow solid. 1 H NMR(400MHz,CH 3 OH-d 4 )δ8.33(d,1H),8.16(d,1H),7.65(d,1H),7.55(d,1H),7.45(d,1H),5.26(q,2H),4.15(d,1H),3.96–3.88(m,2H),3.75(t,2H),1.52(d,2H),1.33–1.29(m,3H)。LC-MS[M+H] + =418.25。
EXAMPLE 7 Synthesis of Compound R8
(1) Step 1:
2- (1-hydroxyethyl) pyridine (200 mg) was dissolved in DCM (20 mL), 2 drops of DMF were added dropwise, thionyl chloride (227 mg) was added in ice bath, stirred for 30min, and NaHCO was added slowly 3 Adjusting pH to neutral, adding water, extracting with ethyl acetate, TLC monitoring reaction, concentrating under reduced pressure to remove excessive SOCl 2 Adding NaHCO 3 The pH was adjusted to neutral, water was added, extraction was performed with ethyl acetate, and the organic phase was concentrated to give the product as a pale yellow oil (213 mg). LC-MS [ M+H ] ] + =142。
(2) Step 2:
the synthesis of the compound R8-1 is as described for the previous compound R5-1.
(3) Step 3:
a solution of compound R8-1 (200 mg), naH (47 mg), 2- (1-chloroethyl) pyridine (137 mg) and DMF (20 ml) was added under ice-bath, and the mixture was refluxed for 4 hours at 50 ℃. TLC monitored completion of the reaction, extraction with water and ethyl acetate, concentration of the organic phase and purification by column chromatography (petroleum ether: ethyl acetate=4:1) afforded the product as an oily pale yellow product (182 mg). LC-MS [ M+H ]] + =358。
(4) Step 4:
the compound R8-2 (120 mg), 7-azaindole-4-boronic acid ester (97 mg), pd (PPh) 3 ) 4 (36 mg) and potassium carbonate (363 mg) were reacted in DMF (20 mL) at 125℃with stirring for 24h. TLC monitored reaction was complete. The reaction solution was added to water, extracted twice with ethyl acetate, and the organic phases were combined, washed with water, dried and filtered. Concentrated under reduced pressure, purified by column chromatography (petroleum ether: ethyl acetate=1:1), and concentrated under reduced pressure to give pale yellow compound R8 (28 mg). 1 H NMR(500MHz,DMSO-d)δ8.56–8.50(m,2H),7.72(d,1H),7.68(td,1H),7.57(m,1H),7.44(d,1H),7.29(dd,1H),7.21(d,1H),7.16(d,1H),6.80(d,1H),5.47–5.40(m,1H),4.19–4.09(m,1H),3.91–3.83(m,2H),3.83–3.79(m,2H),3.77–3.67(m,2H),1.78(s,3H),1.27(d,3H)。LC-MS[M+H] + =440。
EXAMPLE 5 Synthesis of Compound R10
(1) Step 1:
at room temperature, 4.6-dichloro-1H pyrazolo [3.4-d ] is added]Pyrimidine (1 g), (R) -3-methylmorpholine (0.6 g), dichloromethane (30 mL) and potassium carbonate (1.5 g) were reacted at 35℃for 12h, washed with water, the organic phase was concentrated and the crude product was used directly in the next step. LC-MS [ M+H ]] + =254。
(2) Step 2:
Compound R10-1 (300 mg), methyl iodide (1 g), potassium carbonate (320 mg) and DMF (10 mL) were added at room temperature, reacted at 80℃for 5 hours, extracted with water/ethyl acetate, the organic phase concentrated, purified by column chromatography (petroleum ether: ethyl acetate=5:1), and then used in the next step. LC-MS [ M+H ]] + =268。
(3) Step 3:
compound R10-2 (240 mg), 7-azaindole boronic acid pinacol ester (238 mg), potassium carbonate (281 mg), tetraphenylphosphine palladium (140 mg) and dimethyl sulfoxide (10 mL) were added under nitrogen protection, reacted at 120℃for 5 hours under nitrogen protection, extracted with water/ethyl acetate, the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound R10 (90 mg). 1 H NMR(400MHz,CDCl 3 -d)δ9.56(s,1H),8.47(d,1H),8.17(d,1H),7.99(s,1H),7.72(s,1H),7.67(d,1H),5.39(p,1H),4.87(s,1H),4.22–4.12(m,1H),3.99–3.84(m,3H),3.74(td,1H),3.65(s,3H),1.54(d,3H)。LC-MS[M+H] + =350。
EXAMPLE 6 Synthesis of Compound R11
(1) Step 1:
compound W-4 (1.00 g) and pinacol diboronate (1.25 g) and Pd (dppf) Cl 2 (0.323 g) and potassium acetate (0.867 g) were added to 10mL of the 1, 4-dioxane solution, and the mixture was reacted at 100℃under nitrogen atmosphere for 2 hours. TLC monitored completion of reaction and the reaction was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give compound W-5 (1.01 g, 83.5%) as a white solid.
(2) Step 2:
the synthesis of the compound R11-1 is as described for the compound R8-1.
(3) Step 3:
compound W-5 (0.500 g) and compound R11-1 (0.591 g) and copper acetate (0.435 g) and triethylamine (0.803 g) were added to DCM (50 mL) and the reaction stirred with an oxygen balloon at room temperature for 48h. TLC monitored reaction 30-40%. The reaction was added to water (20 mL), filtered with stirring, the filter cake was washed with 20mL of DCM, the organic phase was dried and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give compound R11-2 (0.136 g, 17.4%) as a pale oil.
(4) Step 4:
compound R11-2 (0.100 g), compound W-6 (0.068 g), tetraphenylpalladium phosphate (0.029 g), potassium carbonate (0.699 g) and DMF (5 mL) were reacted at 110-120℃under stirring for 12h. TLC monitored reaction was complete. The reaction solution was added to water (30 mL), extracted with ethyl acetate (30 ml×3), and the organic phases were combined, washed with saturated sodium chloride solution (20 ml×3), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=5:1-2:1) to give pale yellow compound r11#0.068g,56.7%)。 1 H NMR(400Mz,DMSO)δ11.70(s,1H),8.37(d,1H),8.03(m,3H),7.80(m,3H),7.54(d,1H),7.32(d,1H),7.00(d,1H),4.94(m,1H),4.61(m,1H),4.06(m,1H),3.83(m,2H),3.64(m,2H),1.79(s,6H),1.40(m,3H)。LC-MS[M+H] + =478。
EXAMPLE 7 Synthesis of Compound R13
(1) Step 1:
4-bromo-7-azaindole (0.5 g), m-chloroperoxybenzoic acid (0.85 g) and methyl tert-butyl ether (40 mL) were added at room temperature and reacted for 12h, the reaction solution was filtered, and the filter cake was rinsed with methyl tert-butyl ether to give a white solid which was directly used in the next step. LC-MS [ M+H ]] + =214。
(2) Step 2:
the reaction flask was charged with compound R13-1 (0.5 g) and DMF (10 mL) under nitrogen and then heated to 50deg.C. Methanesulfonyl chloride (0.64 g) was added thereto, and the temperature was raised to 75℃to effect a reaction for 1 hour. Cooling to room temperature after the reaction is finished, adding the reaction solution into ice water, cooling to 0 ℃, adjusting the pH to 7 by using 6N sodium hydroxide solution, stirring for 3 hours at room temperature, carrying out suction filtration, washing a filter cake by using water, and drying to obtain a white solid. Directly used in the next step. LC-MS [ M+H ] ] + =232。
(3) Step 3:
into a reaction flask, under nitrogen, was charged compound R13-2 (226 mg), potassium acetate (287 mg), pinacol biborate (274 mg), pd (pddf) Cl 2 (138 mg) and 1, 4-dioxane (10 mL), then warmed to 90 ℃, reacted for 16h, quenched with water and ethyl acetate after the reaction, dried, concentrated, purified by column chromatography (petroleum ether: ethyl acetate=5:1), and then used in the next step. LC-MS [ M+H ]] + =279。
(4) Step 4:
2, 4-dichloro-pyrrolopyrimidine (1 g), 95% ethanol (20 mL) and (R) -3-methylmorpholine (0.6 g) were added to the reaction flask at room temperature, then warmed to 70℃and reacted for 3 hours, and the reaction solution was concentrated to dryness and then used for the next step. LC-MS [ M+H ]] + =253。
(5) Step 5:
to the reaction flask was added compound R13-4 (200 mg), potassium carbonate (220 mg), methyl iodide (600 mg) and DMF (10 mL) at room temperature, followed by heating to 80 ℃, reacting for 8h, extracting with water/ethyl acetate, concentrating the organic phase, purifying by column chromatography (petroleum ether: ethyl acetate=5:1), and then used in the next step. LC-MS [ M+H ]] + =267。
(6) Step 6:
adding the compound R13-5 (2) under the protection of nitrogen40 mg), compound R13-3 (238 mg), potassium carbonate (281 mg), pd (pddf) Cl 2 (140 mg), DME (8 mL) and H 2 O (2 mL) was reacted at 90℃for 16h under nitrogen protection, extracted with water/ethyl acetate, the organic phase concentrated and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give the desired product (20 mg). 1 H NMR (400 MHz, acetonitrile-d) 3 )δ9.82(s,1H),8.17(s,1H),7.57(dd,1H),7.48(t,1H),7.22(d,1H),6.66(d,1H),4.91(d,1H),4.59(d,1H),4.07(dd,1H),3.88–3.79(m,2H),3.72–3.63(m,1H),3.56(td,1H),1.42(d,3H),1.39–1.31(m,3H)。LC-MS[M+H] + =383。
EXAMPLE 8 Synthesis of Compound R14
(1) Step 1:
2, 6-dichloro-7-deaminated purine (0.5 g), (R) -3-methylmorpholine (0.448 g), dichloromethane (20 mL) and potassium carbonate (1.103 g) were added at room temperature, reacted at 40℃for 12h, washed with water, the organic phase concentrated and dried, and the crude product was used directly in the next step. LC-MS [ M+H ]] + =439。
(2) Step 2:
compound R8-1 (0.3 g), cyclopropylsulfonyl chloride (0.2 g), cesium carbonate (1.16 g) and DMF (10 mL) were added at room temperature, reacted at 60℃for 12 hours, extracted with water/ethyl acetate, the organic phase concentrated, purified by column chromatography (petroleum ether: ethyl acetate=10:1), and then used in the next step. LC-MS [ M+H ]] + =357。
(3) Step 3:
compound R14-1 (0.15 g), 7-azaindole pinacol borate (0.103 g), cesium carbonate (0.41 g), palladium tetraphenylphosphine (0.1 g), water (0.5 mL) and 1, 4-dioxane (5 mL) were added at room temperature, reacted at 95℃for 12 hours under nitrogen protection, extracted with water/ethyl acetate, concentrated in an organic phase, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound R14 (0.04 g). 1 H NMR (400 MHz, methanol-d) 4 )δ8.30(d,1H),8.17(d,1H),7.75(d,1H),7.66–7.63(m,1H),7.60(d,1H),7.53(d,1H),6.92(d,1H),4.66(d,1H),4.16–4.08(m,2H),3.93–3.86(m,2H),3.72(d,1H),3.65(d,1H),3.41–3.36(m,1H),1.50(d,4H),1.35–1.22(m,3H)。LC-MS[M+H] + =439。
EXAMPLE 9 Synthesis of Compound R16
(1) Step 1:
2, 6-dichloropurine (1 g), methyl iodide (432 mg), potassium carbonate (1.345 g) and DMF (30 mL) were reacted at 50-60℃with stirring for 2h. TLC monitored reaction was complete. The reaction solution was added to water, extracted twice with ethyl acetate, and the organic phases were combined, washed with water, dried and filtered. After concentration under reduced pressure, a white powder was precipitated, purified by column chromatography (petroleum ether: ethyl acetate=5:1), filtered and dried to give compound R16-1 (1.05 g). LC-MS [ M+H ] ] + =230。
(2) Step 2:
compound R16-1 (300 mg) and R- (3) -methylmorpholine (176 mg) in ethanol (20 mL) were stirred at reflux overnight. TLC monitoring the completion of the reaction, the reaction solution was concentrated under reduced pressure, and white powder was precipitated and filtered, followed by rinsing with ice-ethanol to give Compound R16-2 (278 mg). LC-MS [ M+H ]] + =295。
(3) Step 3:
the compound R16-2 (100 mg), 7-azaindole-4-boronic acid ester (136 mg), pd [ dppf]Cl 2 (37 mg), potassium carbonate (106 mg), 1, 4-dioxane: h 2 O (10 mL:2 mL) was reacted at 110-120℃with stirring overnight. TLC monitored reaction was complete. The reaction solution was added to water, extracted twice with ethyl acetate, and the organic phases were combined, washed with water, dried and filtered. Concentrated under reduced pressure, and purified by column chromatography to give pale yellow compound R16 (37 mg). 1 H NMR (500 MHz, chloroform-d) delta 8.54 (d, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.22-7.14 (m, 2H), 6.75 (d, 1H), 4.76 (pd, 1H), 4.19-4.09 (m, 1H), 3.92-3.79 (m, 4H), 3.77-3.67 (m, 2H), 1.54 (s, 3H), 1.50 (d, 3H), 1.27 (d, 3H). LC-MS [ M+H ]] + =377。
EXAMPLE 10 Synthesis of Compound R17
(1) Step 1:
2, 4-dichloro-7H-pyrrolopyrimidine (1.0 g), (R) -3-methylmorpholine (0.538 g), potassium carbonate (2.21 g) and DMF were reacted at 60-70℃overnight with stirring, TLC detection of completion of the reaction, addition of water with stirring to dissolve insoluble matter, extraction twice with ethyl acetate, separation of the liquid, washing the ethyl acetate phase once with water, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, purification by column chromatography (petroleum ether: ethyl acetate=10:1) to give compound R17-1 (1.21 g) as an off-white solid.
(2) Step 2:
compounds R17-1 (0.5 g), cesium carbonate (1.93 g) and DMF (20 mL) were stirred at room temperature for 15-30min, 0.365g of bromocyclopropane and 0.1g of cuprous iodide were added and the reaction was stirred under nitrogen at 90-100deg.C overnight. Water and ethyl acetate were added and stirred well, insoluble matter was filtered off, the aqueous phase was extracted once with ethyl acetate, the ethyl acetate phases were combined, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound R17-2 (0.11 g) as a pale yellow oil. LC-MS [ M+H ]] + =293.2。
(3) Step 3:
compounds R17-2 (100 mg), 7-azaindole boronic acid pinacol ester (83.4 mg), potassium carbonate (120 mg), 1, 4-dioxane (10 mL) and H were reacted at room temperature 2 O (2 mL) was stirred for 10min and Pd (dppf) Cl was added 2 (14 mg) was reacted overnight at 90-100℃under nitrogen, and the reaction was detected by TLC, concentrated under reduced pressure, water was added, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the column layer was concentratedPurification by chromatography (petroleum ether: ethyl acetate=1:1) afforded compound R17 (100 mg) as a pale yellow solid. 1 H NMR(400MHz,MeOD)δ11.7(s,1H),8.2(d,1H),8.1(d,1H),7.4(s,2H),7.2(d,1H),6.7(d,1H),4.6(t,1H),4.1(m,1H),3.9(t,2H),3.7(m,2H),3.6(m,2H),1.5(d,3H),1.1(d,4H)。LC-MS[M+H] + =375.3。
EXAMPLE 11 Synthesis of Compound R18
(1) Step 1:
2, 4-dichloro-7H-pyrrolopyrimidine (1.0 g), (R) -3-methylmorpholine (0.538 g), potassium carbonate (2.21 g) and DMF were reacted at 60-70℃overnight with stirring, TLC detection of completion of the reaction, addition of water with stirring to dissolve insoluble matter, extraction twice with ethyl acetate, separation of the liquid, washing the ethyl acetate phase once with water, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, purification by column chromatography (petroleum ether: ethyl acetate=10:1) to give compound R18-1 (1.21 g) as an off-white solid. LC-MS [ M+H ] ] + =253.3。
(2) Step 2:
compound R18-1 (500 mg) and cesium carbonate (1.93 g) were stirred in DMF for 15-30min at room temperature, 0.4g bromomethylcyclopropane was added and the reaction was stirred at 90-100deg.C overnight. Adding water and ethyl acetate, stirring and extracting for 2 times, mixing ethyl acetate phases, washing with water, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (petroleum ether: ethyl acetate=2:1) to obtainCompound R18-2 (0.55 g) was obtained as a pale blue oil. LC-MS [ M+H ]] + =307.3。
Step 3:
compounds R18-2 (100 mg), 7-azaindole boronic acid pinacol ester (80 mg) and potassium carbonate (112.6 mg), 1, 4-dioxane (10 mL) and H were reacted at room temperature 2 O (2 mL) was stirred for 10min and 13.3mg Pd (dppf) Cl was added 2 The reaction was carried out overnight at 90-100℃under nitrogen atmosphere, the solvent was concentrated under reduced pressure, water was added to the residue, extraction was carried out twice with ethyl acetate, drying over anhydrous sodium sulfate, concentration and purification by column chromatography (petroleum ether: ethyl acetate=1:1) gave compound R18 (100 mg). 1 H NMR(400MHz,DMSO)δ11.7(s,1H),8.6(d,1H),8.0(d,1H),7.9(d,2H),7.3(d,2H),4.0(d,2H),3.9(d,1H),3.5~3.7(m,4H),3.2(t,2H),1.5(d,3H),1.1(m,5H)。LC-MS[M+H] + =389.3。LC-MS[M+Na]=411.3。
EXAMPLE 12 Synthesis of Compound R19
(1) Step 1:
stirring 2, 4-dichloro-7H-pyrrolopyrimidine (1.0 g), (R) -3-methylmorpholine (0.538 g) and potassium carbonate (2.21 g) in DMF at 60-70deg.C overnight to detect complete reaction by TLC, adding water, stirring to dissolve insoluble substances, extracting with ethyl acetate twice, separating, washing ethyl acetate phase with water once, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and performing column chromatography (petroleum ether: ethyl acetate= 10:1) to give the compound R19-1 (1.21 g) as an off-white solid. LC-MS [ M+H ]] + =253。
(2) Step 2:
compound R19-1 and cesium carbonate (0.3 g) were stirred in 15mL of DMF at room temperature for 15-30min, cyclopentane bromide (0.265 g) and cuprous iodide (0.0226 g) were added, and the mixture was stirred under nitrogen at 90-100deg.C overnight. The TLC detection reaction system showed that the product of small polarity was formed, water and ethyl acetate were added and stirred uniformly, insoluble matter was filtered, the liquid was separated, the aqueous phase was extracted once again with ethyl acetate, the ethyl acetate phases were combined two times, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound R19-2 (0.2 g) as a pale yellow oil. LC-MS [ M+H ]] + =321.3。
(3) Step 3:
compounds R19-2 (180 mg), 7-azaindole boronic acid pinacol ester (140 mg), potassium carbonate (194 mg), 1, 4-dioxane (10 mL) and H were reacted at room temperature 2 O (2 mL) was stirred for 20min and Pd (dppf) Cl was added 2 (23 mg) was reacted overnight at 90-100℃under nitrogen, the solvent was concentrated under reduced pressure, the residue was added with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:2) to give compound R19 (130 mg) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ11.7(s,1H),8.3(d,1H),8.0(d,1H),7.57(t,1H),7.48(d,1H),7.37(t,1H),6.7(d,1H),5.2(t,1H),4.8(d,1H),4.5(d,1H),4.0(q,1H),3.9(s,1H),3.8(d,2H),3.7(q,1H),1.9(m,8H),1.3(d,3H)。LC-MS[M+H] + =403.3。
EXAMPLE 13 Synthesis of Compound R20
(1) Step 1:
DMSO (400 mL) and H were added to 1000mL single port bottles at room temperature 2 O (50 mL) followed by the sequential addition of 2, 4-dichloro-7H-pyrrole [2,3-D ]]Pyrimidine (20.0 g), (R) -3-methylmorpholine (11.8 g) and DIPEA (20.6 g) were then heated to 55℃and stirred at reflux for 20h. TLC monitored the completion of the reaction, the reaction was poured into 1.2L of water, stirred thoroughly, filtered with suction, the solid was dried in air, slurried with petroleum ether: ethyl acetate=10:1 (300 mL), and then the solid was filtered with suction and dried in air to give an off-white solid (19.8 g, 74%). LC-MS [ M+H ]] + =253.13。
(2) Step 2:
to a 50mL single vial at room temperature was added compound R20-1 (300 mg), pyrimidine-3-boronic acid (250 mg), copper acetate (300 mg), TEA (300 mg), then DCM (20 mL), open reaction 48h, tlc monitored incomplete reaction but significant polarity increase product formation, followed by suction filtration over celite, spin-drying of the filtrate, column chromatography (petroleum ether: ethyl acetate=5:1-3:1) purification to give a pale yellow solid (70 mg, 17%). LC-MS [ M+H ]] + =331.20。
(3) Step 3:
to a 50mL single-necked flask, compound R20-2 (70 mg), a boric acid ester (62 mg), pd (PPh) were added at room temperature 3 ) 4 (24 mg), KOAc (41 mg), then DMSO (20 mL) was added, nitrogen was purged 3 times, heated to 120℃for 8h, TLC monitoring reaction was incomplete with a significant increase in product formation, then after the reaction was allowed to cool to room temperature, the reaction was poured into water (60 mL), extracted with ethyl acetate (20 mL. Times.2), the organic phase was dried after drying filtration, and purified by column chromatography (petroleum ether: ethyl acetate=5:1-1:1) to give a pale yellow solid (13 mg, 15%). 1 H NMR(400MHz,DMSO)δ11.75(s,1H),9.49(s,2H),9.25(s,1H),8.33(d,1H),8.02(d,1H),7.97(d,1H),7.57(t,1H),7.19(s,1H),7.11(d,1H),4.94(s,1H),4.60(d,1H),4.07(d,1H),3.95–3.73(m,2H),3.59(dt,2H),1.40(d,3H)。LC-MS[M+H] + =413.29。
EXAMPLE 14 Synthesis of Compound R21
(1) Step 1:
2, 4-dichloro-7H-pyrrolopyrimidine (1.0 g), (R) -3-methylmorpholine (0.538 g) and potassium carbonate (2.21 g) were added at room temperature and reacted in DMF under stirring at 60-70℃overnight, TLC was checked for completion of the reaction, water was added to stir the dissolved insoluble matter, extraction with ethyl acetate was carried out twice, the liquid was separated, the ethyl acetate phase was washed once with water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and column chromatography (petroleum ether: ethyl acetate=10:1) was purified to give compound R21-1 (1.21 g) as an off-white solid. LC-MS [ M+H ]] + =253.3。
(2) Step 2:
the compound R21-1 (1.0 g), pyridine-3-boronic acid (0.584 g) and copper acetate (0.79 g) were stirred in DCM at room temperature for 15-30min, triethylamine (0.8 g) was added thereto, and the reaction was stirred at room temperature for 48h or more. Dichloromethane was concentrated, water and ethyl acetate were added and stirred well, insoluble matter was filtered off, the liquid was separated, the aqueous phase was extracted once more with ethyl acetate, the ethyl acetate phases were combined twice, washed with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound R21-2 (300 mg) as a pale yellow oil. LC-MS [ m+na ] =330.2.
(3) Step 3:
compounds R21-2 (100 mg), 7-azaindole boronic acid pinacol ester (80 mg), potassium carbonate (112.6 mg), 1, 4-dioxane (10 mL) and H were reacted at room temperature 2 O (2 mL) was stirred for 10min and Pd (dppf) Cl was added 2 (13.3 mg) was reacted overnight at 100-110℃under nitrogen protection, the solvent was concentrated under reduced pressure, the residue was added with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R21 (10 mg) as a brown solid. 1 H NMR(400MHz,DMSO)δ11.7(s,1H),8.7(s,1H),8.6(d,1H),8.46(d,1H),7.9(m,3H),7.5(t,3H),7.2(d,1H),3.5~3.7(m,4H),3.2(t,2H),3.3(m,1H),1.1(d,3H)。LC-MS[M+H] + =389.3,LC-MS[M+Na]=412.3。
EXAMPLE 15 Synthesis of Compound R22
(1) Step 1:
2, 6-dichloro-7-deaminase (1.88 g), (R) -3-methylmorpholine (1.214 g), methylene chloride (20 mL) and potassium carbonate (4.146 g) were added at room temperature, reacted at 40℃for 12h, TLC (Petroleum ether: ethyl acetate=2:1) detected that the reaction was complete, worked up, washed with water, and the organic phase was concentrated and then used for the next step. LC-MS [ M+H ]] + =253。
(2) Step 2:
at room temperature, compound R22-1 (0.15 g), 7-azaindole pinacol borate (0.15 g), cesium carbonate (0.609 g), palladium tetraphenylphosphine (0.1 g), water (1 mL) and DMF (10 mL) were added, reacted at 120 ℃ under nitrogen for 12h, tlc (petroleum ether: ethyl acetate=1:1) was used to detect completion of the reaction, extracted with water/ethyl acetate, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate=3:1) was purified to obtain the objective product. LC-MS [ M+H ]] + =335。
(3) Step 3:
the compound R22-2 (0.1 g), cyclopropylcarbonyl chloride (0.02 g), N-diisopropylethylamine (0.116 g) and DCM (20 mL) were added at room temperature and reacted for 6h at room temperature, tlc (petroleum ether: ethyl acetate=1:1) to detect completion of the reaction, extraction with water/ethyl acetate, concentration of the organic phase and purification by column chromatography (petroleum ether: ethyl acetate=3:1) to give the target product. 1 H NMR (400 MHz, methanol-d 4) delta 8.30 (d, 1H), 8.05 (d, 1H), 7.84 (d, 1H), 7.51 (d, 1H), 7.35 (d, 1H), 6.92 (d, 1H)),4.67–4.58(m,2H),4.41–4.37(m,1H),4.13(d,1H),3.90(d,1H),3.70(d,2H),1.51(m,1H),1.38–1.35(m,4H),1.32(d,3H)。LC-MS[M+H] + =403.2。
EXAMPLE 16 Synthesis of Compound R23
(1) Step 1:
2, 4-dichloro-7H-pyrrolopyrimidine (1.0 g), (R) -3-methylmorpholine (0.538 g) and potassium carbonate (2.21 g) were added at room temperature and reacted in DMF under stirring at 60-70℃overnight, TLC was checked for completion of the reaction, water was added to stir the dissolved insoluble matter, extraction with ethyl acetate was carried out twice, the liquid was separated, the ethyl acetate phase was washed with water once, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and column chromatography (petroleum ether: ethyl acetate=10:1) was purified to give compound R23-1 (1.21 g) as an off-white solid. LC-MS [ M+H ]] + =253.3。
(2) Step 2:
compound R23-1 (1.0 g), methyl pyrazole boronic acid pinacol ester (1.24 g) and copper acetate (0.72 g) were stirred in DCM at room temperature for 15-30min, triethylamine (0.8 g) was added thereto, and the reaction was stirred at room temperature for 48h or more. Concentrating to obtain dichloromethane, adding water and ethyl acetate, stirring, filtering to obtain insoluble substances, separating, extracting the water phase with ethyl acetate once, mixing the two ethyl acetate phases, washing with water, drying with anhydrous sodium sulfate, concentrating, and purifying by column chromatography (petroleum ether: ethyl acetate=2:1) to obtain pale yellow oily compound R23-2(300mg)。LC-MS[M+H] + =333.2。
(3) Step 3:
compounds R23-2 (250 mg), 7-azaindole boronic acid pinacol ester (184 mg), potassium carbonate (260 mg) were added to 1, 4-dioxane (15 mL) and H at room temperature 2 O (3 mL) was stirred for 10min and Pd (dppf) Cl was added 2 (31 mg) was reacted overnight at 100-110℃under nitrogen, the solvent was concentrated under reduced pressure, the residue was added with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:2) to give compound R23 (150 mg) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ11.7(s,1H),8.3(d,1H),7.98(d,1H),7.67(d,1H),7.55(d,1H),7.51(t,1H),7.0(m,2H),6.5(d,1H),1.9(s,1H),4.0(m,4H),3.85(d,2H),3.7(s,3H),3.62(d,1H),3.6(s,1H),1.4(d,3H),1.1(t,1H)。LC-MS[M+H] + =415.3。
EXAMPLE 17 Synthesis of Compound R26
(1) Step 1:
2, 6-dichloropurine (300 mg), R- (3) -methylmorpholine (180 mg) and TEA (480 mg) were placed in a solution of ethanol (5 mL) at room temperature and refluxed with stirring for 6h. TLC monitoring the completion of the reaction, the reaction solution was concentrated under reduced pressure to precipitate a white powder, which was filtered and rinsed with ice-ethanol to give compound R26-1 (300 mg, 74.8%). LC-MS [ M+H ]] + =254。
(2) Step 2:
compound R26-1 (300 mg), methyl iodide (250 mg) and anhydrous potassium carbonate (490 mg) were placed in a solution of DMF (5 mL) at room temperature, and the reaction was stirred at 50-60℃for 2h. TLC monitored the completion of the reaction, the reaction mixture was added to water, extracted twice with ethyl acetate, the organic phases combined, washed with water, dried and filtered. After concentration under reduced pressure, a white powder was precipitated, filtered and dried to give compound R26-2 (300 mg, 94.9%). LC-MS [ M+H ] ] + =268。
(3) Step 3:
the compound R26-2 (100 mg), 7-azaindole-4-boronic acid ester (100 mg), tetraphenylpalladium phosphate (30 mg), potassium carbonate (150 mg) and DMSO (5 mL) were reacted at 110-120℃under stirring at room temperature for 5h. TLC monitored reaction was complete. The reaction solution was added to water, extracted twice with ethyl acetate, and the organic phases were combined, washed with water, dried and filtered. Concentrating under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain pale yellow compound R26. 1 H NMR(400MHz,C 2 H 3 N-d 3 )δ9.76(s,1H),8.36(d,1H),8.13(d,Hz,1H),7.93(s,1H),7.53–7.47(m,2H),5.58(s,1H),5.23(s,1H),4.08–4.02(m,1H),3.88(s,3H),3.82(d,2H),3.71–3.51(m,2H),1.43(d,3H)。LC-MS[M+H] + =350。
EXAMPLE 18 Synthesis of Compound R38
(1) Step 1:
compound W-8 (400 mg), carbon tetrabromide (1600 mg), triphenylphosphine (550 mg) and toluene (10 mL) were added at room temperature. The reaction was stirred at room temperature for 4h. Washing with water, drying the organic phase, concentrating to dryness to obtain the compound W-9, which is directly used in the next step.
(2) Step 2:
at room temperature, 4, 6-dichloro-1H-pyrazolo [3,4-D ] is added]Pyrimidine (300 mg), R- (3) -methylmorpholine (180 mg), TEA (480 mg) and ethanol (5 mL). The reaction was stirred at 80℃for 6h. The reaction solution was concentrated under reduced pressure to precipitate a white powder, which was filtered, rinsed and dried to give compound R38-1, which was used directly in the next step. LC-MS [ M+H ]] + =254。
(3) Step 3:
compound R38-1 (300 mg), compound W-9 (250 mg), anhydrous potassium carbonate (490 mg) and DMF (5 mL) were added at room temperature. The reaction was stirred at 120℃for 6h. The organic phase was extracted with water/ethyl acetate, washed with water, dried, filtered, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound R38-2, which was used directly in the next step. LC-MS [ M+H ] ] + =350。
(4) Step 4:
at room temperature, the compound R38-2 (100 mg), 7-azaindole-4-boronic acid ester (100 mg), (Dppf) -PdCl were added 2 (30 mg), potassium carbonate (150 mg) and DMSO (5 mL). The mixture is stirred and reacted for 5 hours at the temperature of 110 to 120 ℃. Extraction with water/ethyl acetate and purification of the organic phase by water, drying, filtration, concentration and column chromatography (petroleum ether: ethyl acetate=1:1) afforded compound R38 (50 mg). 1 H NMR (500 MHz, chloroform-d) δ8.54 (d, 1H), 8.05 (s, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 7.16 (d, 1H), 5.02 (dd, 1H), 4.19-4.10 (m, 1H), 3.91-3.77 (m, 4H), 3.76-3.67 (m, 2H), 1.47 (s, 3H), 1.27 (d, 3H). LC-MS [ M+H ]] + =432。
EXAMPLE 19 Synthesis of Compound R39
(1) Step 1:
4, 6-dichloro-1H-pyrazolo [3,4-D]Pyrimidine (2 g), (R) -3-methylmorpholine (1.3 g) and potassium carbonate (4.4 g) are stirred in 1, 4-dioxane at 60-70 ℃ for 7-8h, TLC detects that the reaction raw materials are complete, a product with polarity greater than that of the raw materials is generated, yellow solid is precipitated, water is added, stirring is carried out at room temperature for 1h, filtering is carried out, filter cake is washed by water, normal hexane is pulped, filtering is carried out, and drying is carried out, thus obtaining a compound R39-1 (2.5 g) in a yellow-like solid state. LC-MS [ M+H ]] + =254.2。
(2) Step 2:
stirring compound R39-1 (400 mg), cesium carbonate (1.54 g) and DMF (15 mL) for 15min, adding bromopentane (0.35 g) and potassium iodide (0.1 g), stirring at 90-100deg.C for overnight, adding water and ethyl acetate, stirring and extracting twice, mixing the ethyl acetate phases, washing with water, and anhydrous sulfuric acid Sodium was dried, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound R39-2 (300 mg) as a nearly colorless oil. LC-MS [ M+H ]] + =322.2。
(3) Step 3:
compound 39-2 (300 mg), 7-azaindole boronic acid pinacol ester (227.5 mg), potassium carbonate (322 mg) in 1, 4-dioxane (15 mL) and H 2 O (3 mL) was stirred for 10min and Pd (dppf) Cl was added 2 (34.1 mg) was reacted overnight at 90-100℃under nitrogen, the reaction solution was detected by TLC, the solvent was concentrated under reduced pressure, water was added, extraction was performed twice with ethyl acetate, the ethyl acetate phases were combined, concentration was performed, and column chromatography (petroleum ether: ethyl acetate=1:1) was performed to obtain compound R39 (13 mg) as an off-white solid. 1 H NMR(400MHz,DMSO)δ11.7(s,1H),8.34(d,1H),8.30(s,1H),8.0(d,1H),7.6(t,1H),7.3(s,1H),5.4(t,1H),4.0(d,1H),3.8(d,1H),3.77(d,1H),3.74(d,1H),3.6(t,1H),2.5(s,2H),2.1(m,2H),2.0(d,2H),1.9(t,2H),1.76(d,2H),1.74(d,3H)。LC-MS[M+H] + =404.3,LC-MS[M+Na]=426.3。
EXAMPLE 20 Synthesis of Compound R44
(1) Step 1:
a50 mL round bottom flask was charged with 4, 6-dichloro-1H-pyrazolo [3,4-D ] at room temperature]Pyrimidine (500 mg), pinacol 4-pyridineborate (607 mg), copper acetate (393 mg),Triethylamine (398 mg), 4A molecular sieves (2 g) and methylene chloride (10 mL) were reacted overnight at room temperature. To the reaction solution were added water (50 mL) and ethyl acetate (50 mL), the solutions were separated, and the organic phases were combined after extraction with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:2) to give compound R44-1 (90 mg). LC-MS [ M+H ] ] + =331.21。
(2) Step 2:
the compound R44-1 (90 mg), 7-azaindole-4-boronic acid ester (80.5 mg), potassium carbonate (113.3 mg) and [1,1' -bis (diphenylphosphino) ferrocene were added at room temperature]Palladium dichloride (19.7 mg) and DMF (10 mL)/water (2 mL), nitrogen displacement 3 times, and reaction at 100deg.C for 16h. To the reaction solution were added water (50 mL) and ethyl acetate (50 mL), the mixture was separated, and the organic phases were combined after 2 times of extraction with ethyl acetate (50 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:0) to give compound R44 (31 mg). 1 H NMR(400MHz,DMSO-d 6 )δ11.79(s,1H),8.92(s,1H),8.85(d,2H),8.35(d,1H),8.24(d,2H),8.06(d,1H),7.61(t,1H),7.27(s,1H),5.56(s,1H),5.21(s,1H),4.15–3.96(m,1H),3.86(d,1H),3.82–3.71(m,1H),3.66–3.56(m,2H),1.99(s,3H)。LC-MS[M+H] + =413.31。
EXAMPLE 21 Synthesis of Compound R46
(1) Step 1:
4-bromo-7-azaindole (0.5 g), m-chloroperoxybenzoic acid (0.85 g) and methyl tert-butyl ether (40 mL) were added at room temperature and reacted for 12h, the reaction solution was filtered, and the filter cake was rinsed with methyl tert-butyl ether to give a white solid which was directly used in the next step. LC-MS [ M+H ]] + =213。
(2) Step 2:
the reaction flask was charged with compound R46-1 (0.5 g), DMF (10 mL) under nitrogen and then heated to 50deg.C. Methanesulfonyl chloride (0.64 g) was added thereto, and the temperature was raised to 75℃to effect a reaction for 1 hour. Cooling to room temperature after the reaction is finished, adding the reaction solution into ice water, cooling to 0 ℃, adjusting the pH to 7 by using a 6N sodium hydroxide solution, stirring for 3 hours at room temperature, carrying out suction filtration, washing a filter cake by using water, and drying to obtain a white solid which is directly used in the next step. LC-MS [ M+H ] ] + =231。
(3) Step 3:
into a reaction flask, under nitrogen, was charged compound R46-2 (226 mg), potassium acetate (287 mg), pinacol biborate (274 mg), pd (pddf) Cl 2 (138 mg) and 1, 4-dioxane (10 mL), warmed to 90 ℃, reacted for 16h, quenched with water and ethyl acetate after the reaction, and the organic phase was taken, dried, concentrated, purified by column chromatography (petroleum ether: ethyl acetate=5:1), and then used in the next step. LC-MS [ M+H ]] + =279。
(4) Step 4:
at room temperature4.6-dichloro-1H pyrazolo [3.4-d ] is added]Pyrimidine (1 g), (R) -3-methylmorpholine (0.6 g), dichloromethane (30 mL) and potassium carbonate (1.5 g) were reacted at 35℃for 12h, washed with water, the organic phase was concentrated and the crude product was used directly in the next step. LC-MS [ M+H ]] + =254。
(5) Step 5:
compound R46-4 (1 g), cyclopropylsulfonyl chloride (0.67 g), cesium carbonate (3.85 g) and DMF (20 mL) were added at room temperature, reacted for 12h at 60 ℃, tlc (petroleum ether: ethyl acetate=5:1), extracted with water/ethyl acetate, the organic phase concentrated, purified by column chromatography (petroleum ether: ethyl acetate=10:1), and then used in the next step. LC-MS [ M+H ]] + =358。
(6) Step 6:
under nitrogen, R46-5 (240 mg), R46-3 (238 mg), potassium carbonate (281 mg), pd (pddf) Cl were added 2 (140 mg), DME (8 mL) and H 2 O (2 mL) was reacted at 90℃for 16h under nitrogen protection, extracted with water/ethyl acetate, the organic phase concentrated and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give the desired product (13 mg). 1 H NMR (400 MHz, chloroform-d) δ9.44 (d, 1H), 8.18 (d, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 4.22 (d, 1H), 4.18-4.09 (m, 1H), 3.98 (d, 1H), 3.90 (d, 1H), 3.77 (dd, 2H), 3.13 (s, 1H), 1.53-1.40 (m, 3H), 0.09 (s, 5H). LC-MS [ M+H ]] + =474。
EXAMPLE 22 Synthesis of Compound R27
(1) Step 1:
the synthesis of R27-1 is described in R5-1.
Compound R27-1 (0.2 g), cyclopropylsulfonyl chloride (0.133 g), DMF (10 mL) and cesium carbonate (0.8 g) were added at room temperature, reacted for 5h at room temperature, ms detected the completion of the reaction, post-treated, washed with water, concentrated the organic phase, purified by column chromatography (petroleum ether: ethyl acetate=3:1), and then used for the next step.
(2) Step 2:
compound R27-2 (0.18 g), 7-azaindole-4-boronic acid pinacol ester (0.123 g), potassium carbonate (0.207 g), tetrakis triphenylphosphine palladium (0.1 g), water (10 mL) and 1, 4-dioxane (1 mL) were added at room temperature, reacted at 100℃under nitrogen for 12h, worked up, water was added, stirred, extracted with ethyl acetate, the organic phase concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R27 (55 mg, 23%). 1 H NMR (400 MHz, methanol-d) 4 )δ8.53(s,1H),8.34(d,1H),8.23(d,1H),7.76(d,1H),7.57(d,1H),4.16(d,1H),3.97–3.85(m,3H),3.74(d,2H),3.19(dt,1H),1.55(dd,4H),1.31(s,2H),1.16(d,2H)。LC-MS[M+Na]=440。
EXAMPLE 23 Synthesis of Compound R54
(1) Step 1:
(R) -4- (2-chloro-7H-pyrrole [2, 3-d) ]Pyrimidin-4-yl) -3-methylmorpholine (0.1 g), methyl iodide (0.112 g) and cesium carbonate (0.193 g) were added to DMF solution (5 mL) and reacted by heating at 60℃for 4h. TLC monitoring of the completion of the reaction, pouring the reaction solution into water (20 mL), extracting with ethyl acetate (20 mL) 3 times, and the organic phase was purified with saturated aqueous sodium chloride (20mL) was washed 3 times and the organic phase was dried to give R54-1 (94 mg, 89.5%) as a yellow oil. LC-MS [ M+H ]] + =268.1。
(2) Step 2:
the compound R54-1 (0.094 g), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-pyrazole (0.081 g), pd (dppf) Cl 2 (0.026 g) and potassium carbonate (0.092 g) were added to DCM (5 mL) and the reaction stirred at 120℃for 4h. TLC monitored completion of the reaction, the reaction mixture was added to water (20 mL), extracted 3 times with ethyl acetate (20 mL), the organic phase was washed 3 times with saturated aqueous sodium chloride (20 mL), the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give compound R54 (0.100 g, 90.9%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ7.93(s,1H),7.53(s,1H),7.05(s,1H),4.67(d,1H),4.42(s,3H),4.14(d,1H),4.08(s,3H),3.99–3.76(m,3H),3.71(t,1H),3.59(s,1H),1.49(d,3H)。LC-MS[M+H] + =314.1。
EXAMPLE 24 Synthesis of Compound R56
(1) Step 1:
LiAlH is prepared 4 Me-THF (20 mL) was added (400 mg), the temperature was lowered to about 0deg.C, N- (2-benzimidazolyl) -carbamic acid methyl ester (500 mg) was added, nitrogen was purged twice, the reaction was performed under nitrogen protection for 16h, after TLC monitoring was completed, the reaction solution was cooled to about 0deg.C, 0.4mL was slowly added, 2M NaOH aqueous solution (0.4 mL) was added, then anhydrous sodium sulfate solid (5 g) was added, ethyl acetate (20 mL) was added to dilute the reaction solution, and then suction filtration was performed, the cake was rinsed with ethyl acetate (10 mL), and the filtrate was rotary evaporated to dryness to give a yellow solid (210 mg, 55%). LC-MS [ M+H ] ] + =148.1。
(2) Step 2:
(R) -4- (2-chloro-9 h-purin-6-yl) -3-methylmorpholine (200 mg) was added to a 25mL single-necked flask at room temperature, dissolved in DMF (20 mL), cooled to about 0deg.C, then 40% NaH (63 mg) was added, and the mixture was reacted at 0deg.C for 10min, and cyclopropanesulfonyl chloride (113 mg) was added, and the reaction mixture was returned to room temperature for 30min. TLC monitored that some of the starting material was not reacted, the reaction was poured into water (50 mL), extracted 3 times with ethyl acetate (20 mL), the organic phase concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give a pale yellow solid (80 mg, yield 28%). LC-MS [ M+H ]] + =357.1。
(3) Step 3:
compound 56-2 (60 mg), snCl, was added to a 50mL pressure-resistant bottle at room temperature 2 (145 mg), trimethyl orthoformate (1 mL), absolute ethanol (5 mL) and 2 drops of concentrated hydrochloric acid, followed by heating to 90 ℃ for 5h, tlc monitoring the reaction completion, after the reaction solution cooled to room temperature, the reaction solution was poured into water (15 mL), adjusted to ph=8 with saturated aqueous solution of sodium carbonate, extracted 3 times with ethyl acetate (5 mL), the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give pale yellow solid (32 mg, yield 57%). 1 H NMR(400MHz,DMSO)δ8.87(d,1H),8.81(s,1H),8.16(d,1H),8.05(d,1H),7.29(d,1H),7.11(t,1H),7.01(t,1H),4.06(dd,1H),3.87(d,1H),3.78(d,1H),3.69–3.55(m,5H),3.08(d,3H),1.44(m,5H)。LC-MS[M+H] + =468.3。
EXAMPLE 25 Synthesis of Compound R57
(1) Step 1:
4-bromo-7-azaindole (2.0 g), m-chloroperoxybenzoic acid (3.4 g) and methyl tert-butyl ether (160 mL) were added at room temperature and reacted for 12h, the reaction solution was filtered, and the filter cake was rinsed with methyl tert-butyl ether to give a white solid which was directly used in the next step. LC-MS [ M+H ] ] + =247.1。
(2) Step 2:
the reaction flask was charged with compound R57-1 (2.04 g) and DMF (40 mL) under nitrogen and heated to 50deg.C. Methanesulfonyl chloride (2.6 g) was then added thereto, and the temperature was raised to 75℃to effect a reaction for 1 hour. Cooling to room temperature after the reaction is finished, adding the reaction solution into ice water, cooling to 0 ℃, adjusting the pH to 7 by using 6N sodium hydroxide solution, stirring for 3 hours at room temperature, carrying out suction filtration, washing a filter cake with water, and drying to obtain a white solid, and directly throwing the white solid into the next step. LC-MS [ M+H ]] + =231.1。
(3) Step 3:
to the reaction flask was added compound R57-2 (1.3 g), DMF (30 mL), cesium carbonate (4.1 g), cyclopropylsulfonyl chloride (800 mg) at room temperature, stirred at room temperature for 2h, monitored by tlc until the starting material was completely reacted, post-treated, stirred with water, extracted with ethyl acetate, concentrated by organic phase drying, purified by column chromatography (petroleum ether: ethyl acetate=10:1) to give a white solid, which was directly added to the next step. LC-MS [ M+H ]] + =335.1。
(4) Step 4:
under the protection of nitrogen, the compound R57-3 (252 mg), R-3-methylmorpholine (150 mg), potassium phosphate (480 mg) and Pd (PPh) are added 3 ) 4 (150 mg) and dioxane (6 mL) were reacted under nitrogen at 120℃for 16h, extracted with water/ethyl acetate, concentrated by organic phase drying, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give the objective product (37 mg). LC-MS [ M+H ] ] + =356.1。
(5) Step 5:
under nitrogen, R57-4 (37 mg), 7-azaindole-4-boronic acid pinacol ester (33 mg), potassium carbonate (43 mg) and PdCl were added 2 (dppf) (8 mg), DME (8 mL) and H 2 O (2 mL), 120℃for 2h, extracted with water/ethyl acetate, concentrated by organic phase drying, and purified by column chromatography (dichloromethane: methanol=100:1) to give compound R57 (18 mg). 1 H NMR(400MHz,DMSO-d 6 )δ11.75(s,1H),8.33(d,1H),7.69(d,1H),7.58(dd,2H),7.40–7.30(m,2H),6.97(d,1H),4.37(d,1H),4.04–3.96(m,1H),3.85(dd,1H),3.74(d,1H),3.71–3.58(m,2H),3.54(dd,1H),3.44(dd,1H),1.41–1.31(m,2H),1.20(d,3H),1.12(dd,2H)。LC-MS[M+H] + =438。
EXAMPLE 26 Synthesis of Compound R58
(1) Step 1:
in a 100ml single-port flask were added (R) -4- (2-chloro-9H-purin-6-yl) -3-methylmorpholine (253 mg), 4-methyl-3-boronic acid pyridine (160 mg), copper acetate (300 mg) and TEA (300 mg), followed by DCM (15 ml) and the reaction was carried out at room temperature for 36H. TLC monitoring of the product formed, direct drying, column chromatography (petroleum ether: ethyl acetate=1:2) purification, givingTo a pale yellow solid (30 mg, 8%). LC-MS [ M+H ]] + =345.1。
(2) Step 2:
in a 10mL single vial was added compound R58-1 (30 mg 0.087), 4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-pyrrole [2,3-b ]]Pyridine (21 mg), pd (dppf) Cl 2 (7 mg), potassium carbonate (24 mg) and 1, 4-dioxane/H 2 O=5:1 (4 mL/0.8 mL). The reaction was allowed to react at 100℃under nitrogen for 16h, and the completion of the reaction was detected by TLC, and the reaction liquid was purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give a pale yellow solid (7 mg). 1 H NMR(400MHz,DMSO-d 6 )δ11.72(s,1H),8.73–8.63(m,2H),8.52(s,1H),8.29(d,1H),7.93(d,1H),7.63(d,1H),7.50(t,1H),7.02(dd,1H),5.67-5.44(m,1H),5.40-5.11(m,1H),4.08(d,1H),3.90–3.77(m,2H),3.63(q,2H),2.26(s,3H),1.45(d,3H)。LC-MS[M+H] + =427.1。
EXAMPLE 27 Synthesis of Compound R59
(1) Step 1:
2-chloro-6-methylbenzoic acid (150 mg), oxalyl chloride (167 mg) and a catalytic amount of DMF were reacted in DCM under stirring at room temperature for 1h, after completion of the TLC detection the DCM was removed by rotary evaporation to give compound R59-1.
(2) Step 2:
(R) -4- (2-chloro-7H-pyrrole [2, 3-d)]Pyrimidin-4-yl) -3-methylmorpholine (222 mg), 1.0 eq of Compound R59-1, DIPEA (17)0 mg) was stirred in DCM for 2h at room temperature, after completion of the reaction by tlc, DCM was removed by swirling, diluted with water, extracted twice with ethyl acetate, separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=2:1-1:1) to give compound R59-2 as a white solid. LC-MS [ M+H ]] + =405.1。
(3) Step 3:
compound R59-2 (60 mg), 7-azaindole boronic acid pinacol ester (40 mg), potassium carbonate (41 mg) in 1, 4-dioxane (10 mL) and H 2 O (2 mL) was dissolved in a stirring manner, and Pd (dppf) Cl was added 2 (11 mg) was reacted at 100℃under nitrogen for 12 hours, after completion of the TLC detection, the solvent was concentrated under reduced pressure, and the residue was extracted twice with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4) to give compound R59 (8 mg) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ11.69(d,1H),8.16–7.93(m,2H),7.59(d,1H),7.52(m,3H),7.18(d,1H),6.93(m,2H),4.84(s,1H),4.50(s,1H),4.05(d,1H),3.77(dd,1H),3.65–3.52(m,3H),2.22(s,3H),1.39(d,3H)。LC-MS[M+H] + =487.3。
EXAMPLE 28 Synthesis of Compound R60
(1) Step 1:
(R) -4- (2-chloro-9H-purin-6-yl) -3-methylmorpholine (200 mg), 2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) pyridine (261 mg), cu (OAc) 2 (158 mg), TEA (161 mg), 4W/W4A molecular sieve in DCM at room temperature stirring reaction for 18h, after TLC detection reaction is complete, suction filtration, rotary evaporation to remove the filtrate, residueThe residue was extracted with ethyl acetate and water, the ethyl acetate layer was washed with saturated brine, dried over organic phase, and purified by column chromatography (petroleum ether: ethyl acetate=2:1-1:1) to give compound R60-1.LC-MS [ M+H ]] + =345.1。
(2) Step 2:
the compound R60-1 (80 mg), 7-azaindole boronic acid pinacol ester (56 mg) and potassium phosphate (63 mg) were dissolved in 1, 4-dioxane (5:1) with stirring, and Pd (dppf) Cl was added 2 (17 mg) was reacted at 100℃under nitrogen for 12 hours, after completion of the TLC detection, the solvent was concentrated under reduced pressure, the residue was added with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4), and the objective product was concentrated to give Compound R60 (16 mg) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ11.72(d,1H),8.75–8.68(m,1H),8.52(d,1H),8.29(dd,1H),8.02(s,1H),7.93(dd,1H),7.57–7.53(m,1H),7.50(dd,1H),7.02(dt,1H),5.56(s,1H),5.23(s,1H),4.09(s,1H),3.88(s,1H),3.80(d,1H),3.63(d,2H),2.40(d,3H),1.50–1.40(m,3H)。LC-MS[M+H] + =427.3。
EXAMPLE 29 Synthesis of Compound R62
(1) Step 1:
a50 mL round bottom flask was charged with 4-bromo-1H-pyrrole [2,3-c ] at room temperature ]Pyridine (200 mg), pinacol biborate (308 mg), potassium acetate (98 mg), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (73.2 mg) and 1, 4-dioxane (10 mL), nitrogen was replaced 3 times, and reacted at 120℃overnight. The reaction was cooled to room temperature, suction-filtered, and the filter cake was washed 2 times with ethyl acetate (50 mL), concentrated, and purified by column chromatography to give Compound R62-1 (140 mg).LC-MS[M+H] + =245.1。
(2) Step 2:
at room temperature, the compound R62-1 (68 mg), azaindole borate (50 mg), potassium carbonate (58 mg) and [1,1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride (19.7 mg) and 1, 4-dioxane (10 mL)/water (2 mL), nitrogen was replaced 3 times, and reacted at 100℃for 16 hours. To the reaction solution were added 50mL of water and 50mL of ethyl acetate, and the mixture was separated, extracted 2 times with ethyl acetate (50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:0) to give compound R62 (15 mg, 18%). 1 H NMR(400MHz,DMSO)δ11.79(s,1H),8.92(s,1H),8.85(d,1H),8.35(d,1H),8.24(d,1H),8.06(d,1H),7.61(t,1H),5.56(s,1H),5.21(s,1H),4.15–3.96(m,1H),3.86(d,1H),3.82–3.71(m,1H),3.66–3.56(m,2H),1.99(s,3H),1.44 (m,5H)。LC-MS[M+H] + =439.1。
EXAMPLE 30 Synthesis of Compound R63
(1) Step 1:
in a 100mL single vial was added (R) -4- (2-chloro-7H-pyrrole [2, 3-d)]Pyrimidin-4-yl) -3-methylmorpholine (253 mg), 3-methyl-4-boronic acid pyridine (160 mg), copper acetate (300 mg) and TEA (300 mg) were then reacted at room temperature for 36h with the addition of DCM (15 mL). TLC monitored the product formation, dried directly, and purified by column chromatography (petroleum ether: ethyl acetate=1:2) to give a pale yellow solid (30 mg, 8%). LC-MS [ M+H ] ] + =344.1。
(2) Step 2:
in a 10mL single vial was added compound R63-1 (30 mg), azaindole borate (29 mg), pd (dppf) Cl 2 (13 mg), potassium carbonate (24 mg) and 1, 4-dioxane/H 2 O5:1 (4 mL/0.8 mL). The reaction was carried out at 100℃under nitrogen for 16h, and the completion of the reaction was detected by TLC, and the reaction liquid column chromatography (petroleum ether: ethyl acetate=1:5) was purified to give compound R63 (7 mg, 18%) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ8.62(d,1H),8.26(d,1H),8.10(s,1H),7.93(d,1H),7.58(dd,2H),7.46–7.41(m,1H),6.99(d,1H),6.95(dd,1H),4.94(s,1H),4.62(d,1H),4.11–4.02(m,1H),3.88–3.75(m,2H),3.67–3.48(m,2H),2.95(s,3H),1.41(d,3H)。LC-MS[M+H] + =426.2。
EXAMPLE 31 Synthesis of Compound R64
(1) Step 1:
(R) -4- (2-chloro-7H-pyrrole [2, 3-d)]Pyrimidin-4-yl) -3-methylmorpholine (200 mg), 4-purine boronic acid (202 mg), cu (OAc) 2 (160 mg), TEA (160 mg), 4W/W of 4A molecular sieve in DCM were stirred at room temperature for 18h, after completion of TLC detection, the filtrate was removed by rotary evaporation with suction, the residue was extracted with ethyl acetate and water, the ethyl acetate layer was washed with saturated brine, the organic phase was concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=2:1-1:1) to give compound R64-1. LC-MS [ M+H ]] + =380.1。
(2) Step 2:
the compound R64-1 (30 mg), 7-azaindole boronic acid pinacol ester (21 mg), potassium phosphate (22 mg) was reacted with 1, 4-dioxane (10 mL), H 2 O(2 mL) was dissolved in a stirring medium, and Pd (dppf) Cl was added 2 (6 mg) was reacted at 100℃under nitrogen for 12 hours, after completion of the TLC detection, the solvent was concentrated under reduced pressure, and the residue was extracted 2 times with water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate: diethyl ether=1:1-1:4) to give compound R64 (8 mg, 21%) as a pale yellow solid. 1 H NMR(400MHz,CDCl 3 )δ9.15(d,1H),8.22(dd,2H),7.91–7.84(m,2H),7.79(dd,2H),7.69–7.44(m,3H),7.31–7.26(m,1H),7.12(d,1H),6.65(dd,1H),4.98(s,1H),4.65(d,1H),4.09(d,1H),3.88–3.77(m,2H),3.61(dt,2H),1.44(d,3H)。LC-MS[M+H] + =462.3。
EXAMPLE 32 Synthesis of Compound R65
(1) Step 1:
(R) -4- (2-chloro-9H-purin-6-yl) -3-methylmorpholine (300 mg), 4-pyridineboronic acid pinacol ester (365 mg), copper acetate (322 mg) and TEA (0.5 mL) were added to a 25mL single-port flask at room temperature, dissolved in DCM (15 mL), molecular sieves were added, the reaction mixture was allowed to react for 16H, and after suction filtration with celite, it was dried by spin-filtration, and column chromatography (petroleum ether: ethyl acetate=1:1 to 1:1+1% methanol) was performed to give compound R65-1 (180 mg, 45%) as a white solid. LC-MS [ M+H ]] + =331.1。
(2) Step 2:
the compound R65-1 (140 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (80 mg), pd (OAc) 2 (20mg)、BINAP(40mg)、K 2 CO 3 (116 mg) was added sequentially to a 25mL single-necked flask, 12mL of redistilled 1, 4-dioxane was added thereto, the mixture was reacted at 97℃for 5 hours, and then the mixture was cooled to room temperature and subjected to column chromatography (DCM: ethyl acetate: methanol=100:20:1 to 100:10)0:2) to give compound R65 (60 mg, 32%) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ8.87(d,2H),8.81(s,1H),8.16(d,2H),8.05(d,2H),7.29(d,1H),7.11(t,1H),7.01(t,1H),4.06(dd,1H),3.87(d,1H),3.78(d,1H),3.69–3.55(m,4H),3.08(d,3H),1.44(d,3H)。LC-MS[M+H] + =442.2。
EXAMPLE 33 Synthesis of Compound R66
(1) Step 1:
in a 100mL single-necked flask, compound (R) -4- (2-chloro-9H-purin-6-yl) -3-methylmorpholine (200 mg), 2-methyl-5-boronic acid pyridine (125 mg), copper acetate (235 mg) and TEA (300 mg) were added, followed by DCM (10 mL) and the reaction was carried out at room temperature for 16H. TLC monitored the formation of product, and the removal of copper acetate and molecular sieve by suction filtration, concentration of the reaction mixture, and purification by column chromatography (petroleum ether: ethyl acetate=2:1) gave compound R66-1 (30 mg, 15%) as a pale yellow solid. LC-MS [ M+H ] ] + =345.1。
(2) Step 2:
in a 10mL single vial was added compound R66-1 (30 mg), azaindole borate (29 mg), pd (dppf) Cl2 (13 mg), potassium carbonate (24 mg) and 1, 4-dioxane/H2O (5:1, 4mL/0.8 mL). Reacting at 100deg.C under nitrogen atmosphere for 16h, detecting completion of TLC reaction, making sand from the reaction liquid, purifying by column chromatography (petroleum ether: ethyl acetate=1:1 and 1% methanol) to remove impurity point, and then CH 2 Cl 2 Meoh=30:1 gives a second spot, which is slurried with petroleum ether: ethyl acetate=5:1, and suction filtered to give compound R66 (13 mg, 34%) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ11.76(s,1H),9.07(d,1H),8.72(s,1H),8.38–8.22(m,2H),8.01(d,1H),7.71–7.51(m,2H),7.22(s,1H),5.55(s,1H),5.34–4.95(m,1H),4.07(d,1H),3.86(d,1H),3.78(d,1H),3.61(dd,2H),2.61(s,3H),1.42(d,3H)。LC-MS[M+H] + =427.1。
EXAMPLE 34 Synthesis of Compound R67
(1) Step 1:
in a 100mL single vial was added (R) -4- (2-chloro-7- (cyclopropylsulfonyl) -7H-pyrrole [2, 3-d)]Pyrimidin-4-yl) -3-methylmorpholine (356 mg), 2-methyl-1H-benzo [ d ]]Imidazole (393 mg), pd (dppf) Cl 2 (438 mg), BINAP (746 mg), and K 2 CO 3 (414 mg) and DMF (5 mL) were added and the reaction was allowed to react under nitrogen at 100deg.C for 16h. TLC monitored the formation of product, extracted with ethyl acetate, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R67 (128 mg, 28%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.37–8.31(m,1H),7.67(d,1H),7.59(dd,1H),7.33(dd,2H),7.10(d,1H),4.84(s,1H),4.48(d,1H),4.08(d,1H),3.88–3.76(m,2H),3.63(d,2H),2.96(s,3H),1.44(d,3H),1.14-0.09(m,5H)。LC-MS[M+H] + =453.1。
EXAMPLE 35 Synthesis of Compound R68
(R) -4- (2-chloro-7- (cyclopropylsulfonyl) -7H-pyrrole [2, 3-d)]Pyrimidine-4-yl) -3-methylmorpholine (50 mg), indole-4-boronic acid pinacol ester (34 mg), potassium carbonate (39 mg) in 1, 4-dioxane (10 mL), H 2 O (2 mL) was dissolved in a stirring manner, and Pd (dppf) Cl was added 2 (10 mg) at 100deg.C under nitrogen for 12 hr, TLC detection was completed, then the solvent was concentrated under reduced pressure, the residue was taken up in water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4) to giveCompound R68 (20 mg, 32%) as a white solid. 1 H NMR(400MHz,DMSO)δ11.23(s,1H),8.16(d,1H),7.67(s,1H),7.53(d,1H),7.48(dd,2H),7.20(t,1H),6.96(d,1H),4.85(s,1H),4.52(s,1H),4.06–4.00(m,1H),3.81(d,1H),3.75(dd,1H),3.59(dd,1H),3.50(d,1H),1.40(d,2H),1.13(dd,2H),1.07(s,4H)。LC-MS[M+H] + =438.3。
EXAMPLE 36 Synthesis of Compound R71
(1) Step 1:
2, 6-dichloro-9H-purine (1.88 g), triethylamine (2.02 g) and (R) -3-methylmorpholine (1.11 g) were added to DMF (30 mL) and stirred overnight at 90 ℃. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound R71-1 (2 g, 79%) as a white solid. LC-MS [ M+H ]] + =254。
(2) Step 2:
compounds R71-1 (506 mg), cs 2 CO 3 (1.95 g) and cyclopropylsulfonyl chloride (420 mg) were added to DMF (15 mL) and stirred at 60℃for 1h. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R71-2 (500 mg, 70%) as a white solid. LC-MS [ M+H ] ] + =358。
(3) Step 3:
compound R71-2 (178 mg), 7-azaindole borate (244 mg), pd (dppf) Cl 2 (73 mg) and K 2 CO 3 (207 mg) 1, 4-dioxane H was added 2 O=5:1 (3 mL), then reacted overnight at 100 ℃ under nitrogen blanket. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R71 (10 mg, 4%) as a white solid. 1 H NMR(500MHz,DMSO)δ11.84(d,1H),8.54(s,1H),8.36(d,1H),8.03(d,1H),7.68–7.61(m,1H),7.43(dd,1H),5.46(s,1H),5.13(s,1H),4.05(d,1H),3.84(d,1H),3.76(dd,1H),3.67–3.50(m,2H),3.44(dd,1H),1.56(s,2H),1.41(d,3H),1.25(dd,2H)。LC-MS[M+H] + =440。
EXAMPLE 37 Synthesis of Compound R72
(1) Step 1:
carbendazim (1.91 g) was added to THF (100 mL), and LAH (1.9 g) was then added in portions to the above mixture at 0 ℃ under reflux with heating under nitrogen overnight. Cooling to 0 ℃, and sequentially adding H 2 O (1.9 mL), 15% aqueous NaOH (1.9 mL), and H 2 O (5.7 mL) was added at 5min intervals and stirring was continued for 2h. The resulting mixture was filtered, and the filter cake was washed twice with ethyl acetate, and the resulting filtrate was dried by spinning to give compound R72-1 (1.2 g, yield 81%) as a white solid. LC-MS [ M+H ]] + =148。
(2) Step 2:
the synthesis method of the compound R72-2 refers to the synthesis of the compound R71-2. Compound R72-1 (178 mg), compound R72-2 (220 mg), pd (AcO) 2 (22 mg), BINAP (124 mg) and K 2 CO 3 (207 mg) was added to dry DMF (3 mL) and then reacted overnight at 100deg.C under nitrogen. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R72 (10 mg, 2%) as a white solid. 1 HNMR(500MHz,DMSO)8.82(s,1H),8.57(s,1H),8.29(d,1H),7.36(d,1H),7.20(t,1H),7.17–7.09(m,1H),4.07(d,1H),3.90–3.70(m,3H),3.62(s,2H),3.42(t,2H),3.13(d,3H),1.49(q,2H),1.43(d,3H),1.28(d,2H)。LC-MS[M+H] + =469。
EXAMPLE 38 Synthesis of Compound R73
(1) Step 1:
4, 6-dichloro-1H-pyrazolo [3,4-d]Pyrimidine (1 g), (R) -3-methylmorpholine (757 mg) and triethylamine (1 g) were reacted in DCM with stirring at room temperature for 12h, after completion of tlc detection the organic phase was dried by rotary evaporation and purified by column chromatography (petroleum ether: ethyl acetate=3:1-2:1) to give compound R73-1 (600 mg, 47%) as a pale yellow solid. LC-MS [ M+H ]] + =254。
(2) Step 2:
compounds R73-1 (150 mg), cyclopropylsulfonyl chloride (108 mg), CS 2 CO 3 (385 mg) was stirred at room temperature in DMF for 3h, after completion of the TLC detection, the reaction mixture was extracted with ethyl acetate and water, the ethyl acetate layer was washed with saturated brine, the organic phase was dried by rotary evaporation, and the column chromatography (petroleum ether: ethyl acetate=2:1-1:1) was used to give compound R73-2 (150 mg, 70%) as a pale yellow solid. LC-MS [ M+H ]] + =358。
(3) Step 3:
compound R73-2 (50 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (31 mg), BINAP (17 mg), palladium acetate (7 mg), potassium carbonate (38 mg) in 1, 4-Dioxahexacyclic ring in N 2 After reaction at 100 ℃ under protection for 12h, tlc detection was complete, the solvent was concentrated under reduced pressure, the residue was taken up in water, extracted twice with ethyl acetate, the ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4) to give compound R73 (6 mg, 9%) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ8.86(s,1H),8.73(d,1H),8.29(t,1H),7.29(dd,1H),7.14(dd,1H),7.08–7.00(m,1H),4.21–3.98(m,2H),3.95–3.52(m,5H),3.15–3.06(s,3H),1.51–1.39(m,3H),1.36(s,2H),1.26–1.13(m,3H)。LC-MS[M+H] + =469。
EXAMPLE 39 Synthesis of Compound R74
(1) Step 1:
2, 4-dichloro-7H-pyrrolo [2,3-d]Pyrimidine (935 mg), pyridine (1.18 g) and N-methylpyrazole borate (1560 mg) were added to DCM (15 mL) and stirred at room temperature for 72h. The filter cake was filtered, washed with DCM and the filtrate washed with dilute hydrochloric acid. The filtrate was washed 3 times with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R74-1 (0.23 g, 17%) as a white solid. LC-MS [ M+H ]] + =268。
(2) Step 2:
compounds R74-1 (133 mg) and (R) -3-methylmorpholine (55 mg) were added to DMSO/H 2 O (10:1, 3 mL) and then stirred overnight at 60 ℃. Extraction 3 times with ethyl acetate, washing of the ethyl acetate phase with saturated brine, drying, and purification by column chromatography (petroleum ether: ethyl acetate=1:2) afforded compound R74-2 (100 mg, 60%) as a white solid. LC-MS [ M+H ]] + =333。
(3) Step 3:
the compound R74-2 (83 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (110 mg), pd (AcO) 2 (11mg)、BINAP(62mg)、K 2 CO 3 (104 mg) was added to dry DMF (3 mL) and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R74 (10 mg, 4%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.29(d,1H),8.07(d,1H),7.70(d,1H),7.56(d,1H),7.25(d,1H),7.10–7.03(m,2H),6.95–6.89(m,1H),6.59(d,1H),4.77(s,1H),4.39(d,1H),4.08(d,1H),3.87–3.74(m,3H),3.67(s,3H),3.66–3.57(m,2H),3.00(d,2H),1.42(d,3H)。LC-MS[M+H] + =444。
EXAMPLE 40 Synthesis of Compound R75
(1) Step 1:
2, 4-dichloro-7H-pyrrolo [2,3-d]Pyrimidine (1.87 g), triethylamine (2.02 g) and (R) -3-methylmorpholine (1.11 g) were added to DMF (30 mL) and stirred overnight at 90 ℃. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound R75-1 (2 g, 79%) as a white solid. LC-MS [ M+H ]] + =253。
(2) Step 2:
compounds R75-1 (1008 mg), cs 2 CO 3 (3.9) and benzenesulfonyl chloride (1056 mg) were added to ACN (15 mL), and stirred at 60℃for 3h. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R75-2 (1200 mg, 76%) as a white solid. LC-MS [ M+H ]] + =393。
(3) Step 3:
the compound R75-2 (1176 mg), N-methyl-1H-benzeneAnd [ d ]]Imidazol-2-amine (1323 mg), pd (AcO) 2 (132 mg), BINAP (747 mg) and K 2 CO 3 (1242 mg) was added to 1, 4-dioxane (15 mL) and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R75-3 (500 mg, 33%) as a white solid. LC-MS [ M+H ] ] + =503。
(4) Step 4:
compound R75-3 (252 mg), pd/C (100 mg) was added to dry EtOH (3 mL) and then reacted at 60℃for 72h under a hydrogen atmosphere. Filtration and purification by column chromatography (petroleum ether: ethyl acetate=1:3) gave compound R75-4 (150 mg, 59%) as a white solid. LC-MS [ M+H ]] + =505。
(5) Step 5:
compounds R75-4 (101 mg) and MeONa (108 mg) were added to EtOH/H 2 O (1:1, 3 mL) and then reacted at 90℃for 24h. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R75-5 (50 mg, 68%) as a white solid. LC-MS [ M+H ]] + =366。
(6) Step 6:
the compound R75-5 (36 mg) and cyclopropanesulfonyl chloride (42 mg) were added to drynessPyridine (3 mL) and then reacted overnight at 100 ℃. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase washed with dilute hydrochloric acid, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R75 (10 mg, 20%) as a white solid. 1 H NMR(400MHz,DMSO)δ12.20(s,1H),7.48(t,1H),7.38–7.30(m,1H),7.12(dd,2H),4.62–4.54(m,1H),4.21(d,1H),3.99–3.89(m,1H),3.81–3.66(m,3H),3.62–3.56(m,1H),3.52(d,3H),3.44(t,1H),3.20–3.04(m,2H),2.38(t,2H),1.22(d,3H),1.17(d,2H),1.09–1.01(m,2H)。LC-MS[M+H] + =470。
EXAMPLE 41 Synthesis of Compound R76
(1) Step 1:
(R) -3-methylmorpholine (444 mg) and triethylamine (444 mg) were added to DMF (15 mL), and then the above mixture was added dropwise to DMF (20 mL) containing 2,4, 6-trichloro-5-nitropyrimidine (1 g) dissolved therein at 0℃and stirred at room temperature for 1h. Extraction 3 times with ethyl acetate, washing of the ethyl acetate phase with saturated brine, drying, and column chromatography (petroleum ether: ethyl acetate=10:1) gave compound R76-1 (1.2 g, 93%) as a pale yellow solid. LC-MS [ M+H ] ] + =293。
(2) Step 2:
in a 100ml single vial was added compound R76-1 (292 mg), 1-methyl-1H-pyrazol-5-amine (194 mg), csCO 3 (975 mg) and ACN (3 mL). The reaction was carried out at 60℃for 4 hours. The reaction solution was subjected to sand making, column chromatography (petroleum ether)Ethyl acetate=1:2) to give compound R76-2 (180 mg, 51%) as a pale yellow solid. LC-MS [ M+H ]] + =354。
(3) Step 3:
compound R76-2 (180 mg) was dissolved in ethanol (3 mL), followed by sequential addition of SnCl 2 (385 mg), concentrated hydrochloric acid (0.5 mL), and trimethyl orthoformate (2 mL). Stirred overnight at 90 ℃ and then cooled to room temperature. Sodium bicarbonate was used to adjust the base, extraction was performed 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R76-3 (40 mg, 23%) as a pale yellow solid. LC-MS [ M+H ]] + =334。
(4) Step 4:
the compound R76-3 (40 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (53 mg), pd (AcO) 2 (5.4 mg), BINAP (30 mg) and K 2 CO 3 (50 mg) was added to dry DMF (3 mL) and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted 3 times with ethyl acetate, and the ethyl acetate phase was washed with saturated brine and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R76 (10 mg, 18%) as a dark white solid. 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.15(s,1H),8.05(d,1H),7.73(d,1H),7.26(d,1H),7.08(t,1H),6.99–6.90(m,1H),6.70(d,1H),4.09(d,1H),3.87(d,2H),3.80(d,2H),3.76(s,3H),3.64(d,2H),3.02(d,3H),1.46(d,3H)。LC-MS[M+H] + =445。
EXAMPLE 42 Synthesis of Compound R77
(1) Step 1:
the compound 2, 4-dichloro pyrrolo [2,1-f][1,2,4]Triazine (935 mg), K 2 CO 3 (2.07 g) and (R) -3-methylmorpholine (555 mg) were added to DMF (15 mL) and stirred at room temperature for 1h. Extraction 3 times with ethyl acetate, washing with saturated brine, and purification by column chromatography (petroleum ether: ethyl acetate=10:1) afforded compound R77-1 (1.2 g, 95%) as a pale yellow solid. LC-MS [ M+H ]] + =253。
(2) Step 2:
compound R77-1 (1.0 g) was added to DMF (15 mL) followed by NIS (1.8 g) and stirred overnight at room temperature. Extraction 3 times with ethyl acetate, washing of the ethyl acetate phase with saturated brine, drying, and column chromatography (petroleum ether: ethyl acetate=10:1) gave compound R77-2 (1.2 g, 79%) as a pale yellow solid. LC-MS [ M+H ]] + =379。
(3) Step 3:
the compound R77-2 (378 mg), N-methylpyrazole boric acid (150 mg), pd (dppf) Cl 2 (140 mg) and K 2 CO 3 (410 mg) 1, 4-dioxane/H was added 2 O=5:1 (3 mL), stirred for 3h at 100 ℃ under nitrogen, and then cooled to room temperature. Extraction with ethyl acetate for 3 times, washing with saturated salineThe ethyl acetate phase was dried and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R77-3 (270 mg, 78%) as a pale yellow solid. LC-MS [ M+H ] ] + =347。
(4) Step 4:
the compound R77-3 (166 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (220 mg), pd (AcO) 2 (22 mg), BINAP (124 mg) and K 2 CO 3 (207 mg) was added to anhydrous DMF (3 mL) and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R77 (10 mg, 4%) as a white solid. 1 HNMR(500MHz,DMSO)7.86(d,1H),7.65(d,1H),7.40(d,1H),7.32(d,1H),7.26(d,1H),7.12(d,1H),7.07(t,1H),6.91(dd,1H),6.75(d,1H),4.89(d,1H),4.51(d,1H),4.07(d,1H),3.87(s,3H),3.86–3.74(m,2H),3.64(t,2H),3.00(d,3H),1.47(d,3H)。LC-MS[M+H] + =444。
EXAMPLE 43 Synthesis of Compound R78
(1) Step 1:
compound R78-1 (378 mg), cuI (380 mg), sodium cyclopropanesulfinate (140 mg) were added to DMSO (3 mL), stirred for 3h at 120℃under nitrogen, and then cooled to room temperature. Extraction with ethyl acetate 3 times, washing of the ethyl acetate phase with saturated brine, drying, column chromatography (petroleum ether: ethyl acetate=)1:1) to give compound R78-2 (270 mg, 75%) as a pale yellow solid. LC-MS [ M+H ]] + =357。
(2) Step 2:
the compound R78-2 (178 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (220 mg), pd (AcO) 2 (22 mg), BINAP (124 mg) and K 2 CO 3 (207 mg) was added to anhydrous DMF (3 mL) and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted 3 times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R78 (10 mg, 2%) as a white solid. 1 HNMR(500MHz,DMSO)8.07(d,1H),7.90(s,1H),7.32–7.25(m,2H),7.12(t,1H),7.02(t,1H),4.91(s,2H),4.56(s,2H),4.07(s,1H),3.78(s,3H),3.65(t,1H),3.11–3.02(m,3H),1.48(d,3H),1.24(s,4H)。LC-MS[M+H] + =468。
EXAMPLE 44 Synthesis of Compound R80
(1) Step 1:
(R) -4- (2-chloro-7-iodopyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (378 mg), cuI (380 mg) and sodium methane sulfinate (140 mg) were added to DMSO, stirred for 3h at 120℃under nitrogen, and then cooled to room temperature. Extraction three times with ethyl acetate, washing the ethyl acetate phase with saturated brine, drying, and column chromatography (petroleum ether: ethyl acetate=1:1) purification gave the compound as a pale yellow solidR80-1(270mg,75%)。LC-MS[M+H] + =331。
(2) Step 2:
the compound R80-1 (178 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (220 mg), palladium acetate (22 mg), BINAP (124 mg) and K 2 CO 3 (207 mg) was added to ultra-dry DMF, and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted three times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R80 (10 mg, 2%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.05(d,1H),7.81(s,1H),7.30(dd,3H),7.12(dd,1H),7.05–6.98(m,1H),4.90(s,1H),4.07(s,1H),3.78(d,2H),3.65(t,3H),3.41(s,3H),3.06(d,3H),1.47(d,3H)。LC-MS[M+H] + =442。
EXAMPLE 45 Synthesis of Compound R81
(1) Step 1:
(R) -4- (6-chloro-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) -3-methylmorpholine (150 mg), 1-methylcyclopropane-1-sulfonyl chloride (118 mg) and CS 2 CO 3 (385 mg) was reacted in DMF at room temperature for 3 hours, after completion of the TLC detection, diluted with water, extracted twice with ethyl acetate, separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum) Ether ethyl acetate=1:1) to give compound R81-1 (200 mg, 91%) as a pale yellow solid. LC-MS [ M+H ]] + =372。
(2) Step 2:
compound R81-1 (100 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (84 mg), binAP (48 mg), pd (OAc) 2 (18 mg) and potassium phosphate (74 mg) were dissolved in 1, 4-dioxane with stirring, N 2 After reaction at 100 ℃ under protection for 12h, tlc detection was complete, the solvent was concentrated under reduced pressure, the residue was taken up in water, extracted twice with ethyl acetate, the ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4) to give compound R81 (26 mg, 20%) as a white solid. 1 H NMR(400MHz,DMSO)δ9.31(s,1H),8.61(s,1H),8.21(s,1H),7.27(d,1H),7.11(t,1H),7.01(t,1H),4.99–4.52(m,2H),4.17(d,2H),3.81(t,2H),3.65(t,1H),3.12(d,3H),1.72(s,2H),1.43(d,5H),1.27(s,3H)。LC-MS[M+H] + =483。
EXAMPLE 46 Synthesis of Compound R82
(1) Step 1:
(R) -4- (6-chloro-1H-pyrazolo [3, 4-d)]Pyrimidin-4-yl) -3-methylmorpholine (200 mg) and bromocyclopentane (234 mg), CS 2 CO 3 (515 mg) and KI (40 mg) were reacted in DMF under reflux with stirring overnight, after completion of the reaction by TLC, water was added for dilution, andextraction twice with ethyl acetate, separation, washing the ethyl acetate phase once with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification by column chromatography (petroleum ether: ethyl acetate=1:1) gave compound R82-1 (230 mg, 89%) as an oil. LC-MS [ M+H ] ] + =322。
(2) Step 2:
compound R82-1 (160 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (84 mg), binAP (58 mg), pd (OAc) 2 (58 mg) and potassium phosphate (129 mg) were dissolved in 1, 4-dioxane with stirring, N 2 After reaction at 100 ℃ under protection for 12h, tlc detection was complete, the solvent was concentrated under reduced pressure, the residue was taken up in water, extracted twice with ethyl acetate, the ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4) to give compound R82 (16 mg, 7.2%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.18(s,1H),7.54–7.42(m,3H),7.15–7.04(m,2H),5.34(t,1H),4.67(s,2H),4.51–4.30(m,2H),4.02(d,1H),3.81(s,3H),3.72(dd,1H),3.56(d,1H),2.13(d,2H),2.03(dd,2H),1.88(s,2H),1.77–1.65(m,2H),1.34(d,3H)。LC-MS[M+H] + =433。
EXAMPLE 47 Synthesis of Compound R83
(1) Step 1:
(R) -4- (2-chloro-7H-pyrrole [2, 3-d)]Pyrimidin-4-yl) -3-methylmorpholine(500 mg) was dissolved in DMF, naH (119 mg) was added at 0deg.C, chloromethyl sulfide (282 mg) was slowly added after 30min reaction at room temperature, and after completion of TLC detection, NH was added 4 The aqueous Cl solution was quenched, extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R83-1 (260 mg, 41%) as an oil. LC-MS [ M+H ]] + =313。
(2) Step 2:
compound R83-1 (400 mg) was reacted with mCPBA (443 mg) in DCM at room temperature for 3h, after which the reaction was complete by TLC, the compound was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R83-2 (200 mg, 45%). LC-MS [ M+H ] ] + =345。
(3) Step 3:
the compound R83-2 (50 mg) was reacted with DMF at 0℃for 30min with NaH (12 mg), then with iodomethane (63 mg), at 0℃for 1h with NaH (12 mg), at 30min with iodomethane (63 mg), at 1h with LCMS, after completion of the reaction, with NH 4 The aqueous Cl solution was quenched, extracted twice with ethyl acetate, separated, and the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R83-3 (27 mg, 51%). LC-MS [ M+H ]] + =373。
(4) Step 4:
compound R83-3 (30 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (15 mg), binAP (12 mg), pd (OAc) 2 (22 mg) and potassium phosphate (22 mg) were dissolved in 1, 4-dioxane with stirring, N 2 After reaction at 100 ℃ under protection for 12h, tlc detection was complete, the solvent was concentrated under reduced pressure, the residue was taken up in water, extracted twice with ethyl acetate, the ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4) to give compound R83 (8 mg, 20%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.13(d,1H),7.50(dd,1H),7.28(d,1H),7.09 (t,1H),7.00(t,1H),6.92(d,1H),6.29(d,1H),4.76(s,1H),4.38(d,1H),4.08–4.01(m,1H),3.82(d,1H),3.75(d,1H),3.66–3.54(m,2H),3.51(s,1H),3.07(d,3H),3.05–2.97(m,2H),1.94(d,3H),1.39(dd,3H),1.18(td,3H)。LC-MS[M+H] + =484。
EXAMPLE 48 Synthesis of Compound R84
(1) Step 1:
(R) -4- (2-chloro-7-iodopyrrole [2, 1-f) ][1,2,4]Triazin-4-yl) -3-methylmorpholine (100 mg), 5- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-pyrazole (56 mg), K 2 CO 3 (72mg)、Pd(dppf)Cl 2 (20 mg) in dioxane/H 2 Stirring in O at 100deg.C for overnight, diluting with water after TLC detection, extracting with ethyl acetate twice, separating, washing ethyl acetate phase with saturated salt water once, and anhydrous sulfurSodium acetate was dried, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:2) to give compound R84-1 (50 mg, 60%) as a pale yellow solid. LC-MS [ M+H ]] + =319。
(2) Step 2:
compounds R84-1 (60 mg), 1-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-pyrazole (59 mg), K 2 CO 3 (52mg)、Pd(dppf)Cl 2 (14 mg) in dioxane/H 2 Stirring and dissolving in O, N 2 After reaction at 110 ℃ under protection for 12h, tlc detection was complete, the solvent was concentrated under reduced pressure, the residue was taken up in water, extracted twice with ethyl acetate, the ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4) to give compound R84 (16 mg, 26%) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ13.07(s,1H),7.87(s,1H),7.53(d,2H),7.15(s,2H),6.89(s,1H),4.94(s,1H),4.57(s,1H),4.24(s,3H),4.02(d,1H),3.76(d,2H),3.58(d,2H),1.40(d,3H)。LC-MS[M+H] + =365。
EXAMPLE 49 Synthesis of Compound R86
(1) Step 1:
adding (R) -4- (2-chloro-7-iodopyrrole [2, 1-f) at room temperature][1,2,4]Triazin-4-yl) -3-methylmorpholine (0.5 g) and anhydrous tetrahydrofuran (10 mL), nitrogen protection Stirring and cooling to T<At-78 ℃, isopropyl magnesium chloride-lithium chloride complex (5 mL, 1.3M/L) is added dropwise, and the temperature T is controlled<Stirring at-75deg.C for 1 hr, adding tetrahydrofuran-3-formaldehyde dropwise, and controlling temperature T<Stirring for 1h at-75deg.C after dripping, TLC, disappearance of raw materials, dripping saturated ammonium chloride solution (5 mL), naturally heating to room temperature, adding ethyl acetate (10 mL), stirring for 30min, concentrating by organic phase drying, purifying by column chromatography (petroleum ether: ethyl acetate=1:1), and then throwing into the next step. LC-MS [ M+H ]] + =353。
(2) Step 2:
compound R86-1 (0.14 g) and DMF (3 mL) were added at room temperature and stirred down to T<NaH (0.032 g) was added, naturally warmed to room temperature and reacted for 1h, methyl iodide (0.068 g) was added, reacted for 1.5h at room temperature, TLC (petroleum ether: ethyl acetate=1:1), post-treated, water (10 mL) and ethyl acetate (20 mL) were added, stirred, concentrated by organic phase drying, and purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give compound R86-2 (90 mg, 62%). LC-MS [ M+H ]] + =367。
(3) Step 3:
compound R86-2 (0.09 g), N-methyl-1H-benzimidazol-2-amine (0.043 g), BINAP (0.06 g), palladium acetate (0.02 g), DMF (5 mL) and cesium carbonate (0.159 g) were added at room temperature, the reaction was heated to 135℃overnight under nitrogen, worked up, washed with water, extracted with ethyl acetate, concentrated by organic dryness and purified by column chromatography (DCM: meOH=100:1) to give compound R86 (10 mg, 8%). 1 H NMR(400MHz,DMSO)δ7.96(d,1H),7.66(s,1H),7.29(d,1H),7.17(d,1H),7.10(t,1H),7.00(t,1H),6.80(d,1H),4.85(s,1H),4.75(dd,1H),4.49(s,1H),4.04(d,,1H),3.84–3.49(m,8H),3.16(d,3H),3.06(d,3H), 2.97(d,1H),2.04–1.94(m,2H),1.49–1.40(m,3H)。LC-MS[M+H] + =478。
EXAMPLE 50 Synthesis of Compound R87
(1) Step 1:
(R) -4- (2-chloro-7-iodopyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (378 mg) is added to ultra-dry THF (10 mL) and cooled to-78 ℃. Then n-BuLi (THF, aq.,2.5N,0.5 mL) was added dropwise, stirring was performed at 78deg.C for 20min, then excess 2, 2-dimethyltetrahydro-4H-pyran-4-one was added dropwise, and stirring was continued for 30min. Then NH is added 4 Cl (aq.) was quenched, extracted three times with ethyl acetate, and the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R87-1 (160 mg, 42%) as a colorless oil. LC-MS [ M+H ]] + =381。
(2) Step 2:
the compound R87-1 (160 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (188 mg), palladium acetate (19 mg), BINAP (104 mg) and K 2 CO 3 (174 mg) was added to super-dry DMF (3 mL) and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted three times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R87 (10 mg, 4%) as a white solid. 1 H NMR(400MHz,DMSO)δ7.89(t,1H),7.55–7.45(m,1H),7.40–7.34(m,2H),7.32(s,1H),7.24–7.14(m,1H),6.93(s,1H),3.98(s,1H),3.83–3.47(m,4H),3.23(m,5H),3.17(s,3H),1.68(d,2H),1.48(m,6H),1.39(s,2H),1.24(m,2H),1.06(s,1H)。LC-MS[M+H] + =492。
EXAMPLE 51 Synthesis of Compound R88
(1) Step 1:
(R) -4- (2-chloro-7-iodopyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (378 mg), cuI (380 mg), isothiazolidine 1, 1-dioxide (140 mg) and trans-N, N' -dimethyl-1, 2-cyclohexanediamine (282 mg) were added to DMSO (3 mL), stirred for 3h under nitrogen at 130℃and then cooled to room temperature. Extraction three times with ethyl acetate, washing of the ethyl acetate phase with saturated brine, drying, and column chromatography (petroleum ether: ethyl acetate=1:1) purification gave compound R88-1 (200 mg, 75%) as a pale yellow solid. LC-MS [ M+H ] ] + =372。
(2) Step 2:
the compound R88-1 (178 mg), N-methyl-1H-benzo [ d ]]Imidazol-2-amine (220 mg), palladium acetate (22 mg), BINAP (124 mg) and K 2 CO 3 (207 mg) was added to ultra-dry DMF, and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted three times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and subjected to column chromatography (petroleum etherEthyl acetate=1:4) to give compound R88 (10 mg, 2%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.75(s,1H),7.91(d,1H),7.60(s,1H),7.36(s,1H),7.07(d,1H),6.95(s,1H),6.89(d,1H),4.85(s,1H),4.49(d,1H),4.09–4.03(m,2H),3.81(d,2H),3.65(s,2H),3.34(d,3H),3.00(d,3H),2.19-2.07(s,2H),1.48(d,3H)。LC-MS[M+H] + =483。
EXAMPLE 52 Synthesis of Compound R89
(1) Step 1:
adding (R) -4- (2-chloro-7-iodopyrrole [2, 1-f) at room temperature][1,2,4]Triazin-4-yl) -3-methylmorpholine (0.2 g 0.53), 3, 5-dimethylisoxazole-4-boronic acid pinacol ester (0.118 g), cesium carbonate (0.344 g), bis (triphenylphosphine) palladium dichloride (0.05 g), dioxane (5 mL) and water (0.5 mL), nitrogen protection, were added to 110 ℃ for reaction overnight, work-up, washing with water, extraction with ethyl acetate, organic phase drying concentration, column chromatography (petroleum ether: ethyl acetate=10:1) purification to give compound R89-1 (0.14 g, 76%). LC-MS [ M+H ]] + =348。
(2) Step 2:
the compound R89-1 (0.14 g), N-methyl-1H-benzimidazol-2-amine (0.071 g), BINAP (0.08 g), palladium acetate (0.03 g), DMF (5 mL) and cesium carbonate (0.262 g) were added at room temperature, and the mixture was heated to 140℃under nitrogen to react overnight, worked up, washed with water Ethyl acetate extraction, organic phase drying concentration, column chromatography (DCM: meoh=100:1) purification gave compound R89 (20 mg, 10%). 1 H NMR(400MHz,DMSO)δ7.75(d,1H),7.61(s,1H),7.30(d,1H),7.26(d,1H),7.07(t,1H),6.95(d,1H),6.89(t,1H),4.85(s,1H),4.49(d,1H),4.09–4.03(m,1H),3.81(q,2H),3.65(s,2H),3.00(d,3H),2.38(s,3H),2.19(s,3H),1.48(d,3H)。LC-MS[M+H] + =459。
EXAMPLE 53 Synthesis of Compound R90
Synthetic route reference synthesis of compound R89. 1 H NMR(400MHz,DMSO-d 6 )δ7.85(d,1H),7.64(s,1H),7.29(d,1H),7.25(d,1H),7.10(d,1H),7.04(t,1H),6.92(d,1H),6.85(t,1H),4.82(s,1H),4.43(d,1H),4.10–4.02(m,1H),3.84(q,2H),3.57(s,2H),3.05(d,3H),2.38(s,3H),2.20(s,3H),1.53(d,3H)。LC-MS[M+H] + =458。
EXAMPLE 54 Synthesis of Compound R91
(1) Step 1:
the compound (R) -4- (2-chloro-7-iodopyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (378 mg) was added to ultra-dry THF (10 mL), cooled to-78deg.C, then n-BuLi (THF, 2.5N,0.5 mL) was added dropwise, stirred at 78deg.C for 20min, then excess 3, 3-dimethylbutan-2-one was added dropwise, and stirring was continued for 30min. However, the method is thatPost-adding NH 4 Cl (aq.) was quenched, extracted three times with ethyl acetate, and the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R91-1 (150 mg, 42%) as a colorless oil. LC-MS [ M+H ]] + =353。
(2) Step 2:
compounds R91-1 (150 mg), N-methyl-1H-benzimidazol-2-amine (188 mg), palladium acetate (19 mg), BINAP (104 mg) and K 2 CO 3 (174 mg) was added to super-dry DMF (3 mL) and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted three times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R91 (10 mg, 5%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.72–8.58(m,1H),7.96(dd,1H),7.26(d,1H),7.14–7.03(m,2H),7.01–6.93(m,1H),6.68(d,1H),5.25(s,1H),4.90(s,1H),4.51(dd,1H),4.05(t,1H),3.79(p,2H),3.65(d,2H),3.05(d,3H),1.64(s,3H),1.43(dd,3H),1.25(s,2H),0.94(s,6H),0.86(d,1H)。LC-MS[M+H] + =464。
EXAMPLE 55 Synthesis of Compound R92
Synthetic route reference synthesis of compound R94. 1H NMR (400 MHz, DMSO). Delta.8.02 (dd, 1H), 7.95 (s, 1H), 7.30 (q, 2H), 7.10 (dd, 1H), 6.82 (td, 1H), 4.88 (s, 1H), 4.51 (s, 1H), 4.06 (s, 1H), 3.87-3.74 (m, 2H), 3.64 (dd, 2H), 3.41 (s, 3H), 3.07 (d, 3H), 1.46 (d, 3H). LC-MS [ m+h+ ] =460.
EXAMPLE 56 Synthesis of Compound R93
(1) Step 1:
the compound (R) -4- (2-chloro-7- (methylsulfonyl) pyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (178 mg), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis (tetrafluoroborate) (500 mg) and one drop of acetic acid were added to ultra-dry ACN (3 mL), and then reacted overnight at 80 ℃ under nitrogen. Cooled to room temperature and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give compound R93-1 (190 mg, 98%) as a white solid. LC-MS [ M+H ]] + =348。
(2) Step 2:
compounds R93-1 (190 mg), N-methyl-1H-benzimidazol-2-amine (220 mg), palladium acetate (22 mg), BINAP (124 mg), and K 2 CO 3 (207 mg) was added to ultra-dry DMF (3 mL) and then reacted overnight at 100℃under nitrogen. Cooled to room temperature, extracted three times with ethyl acetate, the ethyl acetate phase was washed with saturated brine, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:4) to give compound R93 (10 mg, 2%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.03(d,1H),7.76(d,1H),7.33–7.25(m,2H),7.12(td,1H),7.01(td,1H),4.63(s,1H),4.25(s,1H),4.07(d,1H),3.87–3.59(m,4H),3.45(d,3H),3.06(dd,3H),1.50(d,3H)。LC-MS[M+H] + =460。
EXAMPLE 57 Synthesis of Compound R94
(1) Step 1:
(R) -4- (6-chloro-1H-pyrazolo [3, 4-d) is added at room temperature]Pyrimidine-4-yl) -3-methylmorpholine (1.7 g) and DMF (15 mL), stirring at room temperature, cesium carbonate (6.55 g) was added, stirring, dropwise adding cyclopropylsulfonyl chloride (1.13 g), stirring at room temperature overnight after the addition, TLC showed the disappearance of the starting material, adding water (50 mL), stirring for 30min, filtering, oven drying the filter cake, column chromatography (petroleum ether: ethyl acetate=1:1) purification, then the next step was added. LC-MS [ M+H ]] + =358。
(2) Step 2:
compound R94-1 (0.2 g), dioxane (5 mL), 4-fluoro-2-nitroaniline (0.104 g), BINAP (0.06 g), palladium acetate (0.02 g) and cesium carbonate (0.36 g) were added at room temperature, the reaction was heated to 120℃overnight under nitrogen, post-treated, washed with water, extracted with ethyl acetate, the organic phase was concentrated by drying, and purified by column chromatography (DCM: meOH=100:1) to give compound R94-2 (0.2 g, 73%). LC-MS [ M+H ]] + =478。
(3) Step 3:
the compound R94-2 (0.2 g), ethanol (10 mL) and Pd/C (0.1 g) were added at room temperature, hydrogen was added for replacement hydrogenation, the reaction was carried out overnight at room temperature, post-treatment, filtration, and organic phase drying concentrationPurification by column chromatography (DCM: meoh=100:1) afforded compound R94-3 (50 mg, 26%). LC-MS [ M+H ] ] + =448。
(4) Step 4:
compound R94-3 (0.05 g) and pyridine (3 mL) were added at room temperature, the solution was stirred, methyl isothiocyanate (0.01 g) was added, the mixture was stirred and heated to 90℃for 30min, the reaction was cooled to room temperature, EDCI (0.032 g) was added, the mixture was heated to 90℃overnight for reaction, the post-treatment was carried out, the organic phase was concentrated by drying, and the mixture was purified by column chromatography (ethyl acetate: meOH: TEA=50:5:5) to give compound R94 (20 mg, 37%). 1 H NMR(400MHz,DMSO)δ8.17(s,1H),7.18(s,1H),7.02(s,2H),5.76(s,1H),4.67(s,1H),4.18(d,1H),3.98(d,1H),3.75(d,1H),3.71–3.65(m,1H),3.51(s,3H),3.07(d,3H),1.36(d,2H),1.24(s,2H),1.00–0.84(m,3H)。LC-MS[M+H] + =487。
EXAMPLE 58 Synthesis of Compound R96
Synthetic route reference synthesis of compound R81. 1 H NMR(400MHz,DMSO)δ7.51(d,1H),7.36(d,2H),7.27(d,1H),7.17–7.00(m,3H),4.04(d,2H),3.80(d,2H),3.61(s,2H),3.51(s,2H),3.10(d,3H),1.42–1.37(m,3H),1.27(d,6H)。LC-MS[M+H] + =470。
EXAMPLE 59 Synthesis of Compound R97
Synthetic route reference synthesis of compound R94. 1 H NMR(400MHz,DMSO)δ10.25(s,1H),9.01(s, 1H),7.99(dd,1H),7.30(dd,1H),7.07(td,1H),4.65(d,1H),4.19(d,1H),3.98(d,1H),3.76(d,1H),3.68(dd,1H),3.61–3.47(m,3H),3.04(d,3H),1.38(d,2H),1.18(t,5H)。LC-MS[M+H] + =487。
EXAMPLE 60 Synthesis of Compound R98
Synthetic route reference synthesis of compound R94. 1 H NMR(400MHz,DMSO)δ7.89(d,1H),7.75(s,1H),7.51–7.23(m,4H),7.00–6.90(m,1H),4.88(s,1H),4.52(s,1H),4.06(s,1H),3.79(s,2H),3.66(d,1H),3.05(d,3H),1.48(d,3H),1.30–0.98(m,3H)。LC-MS[M+H] + =460。
EXAMPLE 61 Synthesis of Compound R99
(1) Step 1:
(R) -N1- (1- (cyclopropylsulfonyl) -4- (3-methylmorpholine) -1H-pyrazolo [3,4-d ] is added at room temperature]Pyrimidine-6-yl) -4-fluorobenzene-1, 2-diamine (0.05 g), ethanol (4 mL), triethylamine (0.1 g) and cyanogen bromide (0.018 g), 48h at room temperature, work up, drying and concentration of the organic phase, purification by column chromatography (DCM: meOH: tea=50:5:5) afforded compound R99 (20 mg, 38%). 1 H NMR(400MHz,DMSO)δ9.02(s,3H),8.14(dd,1H),7.09–7.04(m,1H),6.95(t,1H),4.68(d,1H),4.18(d,1H),3.97(d,1H),3.75(d,1H),3.71–3.66(m,1H),3.58–3.53(m,1H),3.51(d,1H),3.47(d,1H),1.41–1.32(m,4H),1.24(s,3H)。LC-MS[M+H] + =473。
EXAMPLE 62 Synthesis of Compound R100
The steps are as follows:
(R) -N1- (1- (cyclopropylsulfonyl) -4- (3-methylmorpholine) -1H-pyrazolo [3,4-d ] is added at room temperature ]Pyrimidine-6-yl) -4-fluorobenzene-1, 2-diamine (0.1 g) and pyridine (4 mL), stirring to dissolve, adding isopropyl isothiocyanamide (0.027 g), stirring and heating to 90 ℃, reacting for 30min, cooling to room temperature, adding EDCI (0.064 g), heating to 90 ℃ overnight, reacting, post-treating, organic phase drying and concentrating, purifying by column chromatography (DCM: meOH=50:1) to obtain a compound R100 (40 mg, 35%). 1 H NMR(400MHz,DMSO-d 6 )δ8.09(s,2H),7.05(s,1H),6.82(s,2H),4.67(s,2H),4.17(d,2H),3.97(d,2H),3.52(s,3H),1.35(d,3H),1.30(d,6H),0.93–0.89(m,2H),0.75(dd,2H)。LC-MS[M+H] + =515。
EXAMPLE 63 Synthesis of Compound R101
Synthetic route reference synthesis of compound R83. 1 H NMR(400MHz,DMSO)δ8.52(s,1H),8.14(s,1H),8.03(d,1H),7.28(d,1H),7.10(s,1H),7.01(d,1H),4.63(s,1H),4.07(d,1H),3.84(d,1H),3.78(s,1H),3.61(d,1H),3.04(d,3H),2.85(s,2H),2.25(s,6H),1.41(d,3H),1.27(dd,3H)。LC-MS[M+H] + =485。
EXAMPLE 64 Synthesis of Compound R103
(1) Step 1:
to the reaction flask was added (R) -4- (2-chloro-7- (methylsulfonyl) pyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (158 mg), 4-amino-3-nitropyridine (79 mg), palladium acetate (21 mg), BINAP (58 mg), anhydrous cesium carbonate (306 mg) and anhydrous 1, 4-dioxane (10 mL), N 2 The reaction was carried out overnight at 116℃in an oil bath. TLC monitoring (petroleum ether: ethyl acetate=1:1) after completion of the reaction, column chromatography (petroleum ether: ethyl acetate=2:1) was purified to give compound R103-1 (79 mg, 38%) as a brown solid. LC-MS [ M+H ]] + =434。
(2) Step 2:
into a reaction flask were charged compound R103-1 (79 mg), iron powder (40 mg), ammonium chloride (39 mg) and 95% ethanol (10 mL), N 2 Protection, oil bath 70 ℃ reaction for 4h. TLC monitoring (DCM: meoh=50:1) after completion of the reaction, column chromatography (DCM: meoh=100:1) was purified to give compound R103-2 (45 mg, 61%) as a yellow solid. LC-MS [ M+H ] ] + =404。
(3) Step 3:
into a reaction flask were charged compound R103-2 (45 mg), methyl isothiocyanate (10 mg) and anhydrous pyridine (10 mL), and an oil bath was set at 90 DEG CThe reaction was allowed to proceed for 1h, then cooled to room temperature, EDCI (31 mg) was added and the reaction continued at 90℃overnight. TLC monitoring (DCM: meoh=10:1) after completion of the reaction, directly spin-dry, scrape the plate (DCM: meoh=50:1 spread) to give compound R103 (5 mg, 10%) as a tan solid. 1 H NMR(400MHz,DMSO)δ8.00(s,1H),7.95(s,1H),7.30(d,2H),7.12–7.04(m,1H),6.82(t,1H),4.88(s,1H),4.50(s,1H),4.06(s,1H),3.79(s,2H),3.64(t,1H),3.40(s,1H),3.07(d,3H),2.80(s,3H),1.47(d,3H)。LC-MS[M+H] + =443。
EXAMPLE 65 Synthesis of Compound R105
Synthetic route reference synthesis of compound R99. 1 H NMR(400MHz,DMSO)δ7.89(d,1H),7.75(s,1H),7.51–7.23(m,4H),7.00–6.90(m,2H),4.88(s,1H),4.52(s,1H),4.06(s,1H),3.79(s,2H),3.66(d,2H),3.05(d,3H),1.48(d,3H)。LC-MS[M+H] + =428。
EXAMPLE 66 Synthesis of Compound R106
Synthetic route reference synthesis of compound R107. 1 H NMR(400MHz,DMSO)δ8.64(s,1H),8.19(d,1H),7.66(s,1H),7.55(s,1H),7.46(s,1H),7.39(d,1H),5.19(t,1H),4.67(d,2H),4.37(t,1H),4.12–4.04(m,2H),3.88–3.75(m,4H),3.62(s,1H),1.43(d,2H),1.41(s,2H),1.24(s,3H)。LC-MS[M+H] + =469。
EXAMPLE 67 Synthesis of Compound R107
(1) Step 1:
(R) -4- (2-chloro-7- (methylsulfonyl) pyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (200 mg), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole-6-carboxylic acid methyl ester (274 mg), pd (dppf) Cl 2 (44 mg) and CS 2 CO 3 (397 mg) in dioxane/H 2 After reaction overnight at 110 ℃ in O under nitrogen protection, TLC checked that the reaction was complete, diluted with water, extracted twice with ethyl acetate, separated, the ethyl acetate phase washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=1:1 to DCM/meoh=10:1) to give compound R107-1 (170 mg, 59%) as a yellow solid. LC-MS [ M+H ] ] + =470。
(2) Step 2:
compound R107-1 (50 mg) was dissolved in THF, and LiAlH was added 4 (21 mg) under nitrogen, reaction at room temperature for 3h, after completion of tlc detection, quenched with NaOH aqueous solution, the residue was extracted twice with water, the ethyl acetate phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate=1:1-1:4 to DCM/meoh=10:1) to give compound R107 (21 mg, 8%) as a pale yellow solid. 1 H NMR(400MHz,DMSO)δ11.28(s,1H),8.03(s,1H),7.53(d,2H),7.46(d,1H),7.29(d,1H),7.17(d,1H),5.19(s,1H),5.02(s,1H),4.66(d,2H),4.06(m,2H),3.80(d,2H),3.63(s,2H),3.48(s,3H),1.45(d,3H)。LC-MS[M+H] + =442。
EXAMPLE 68 Synthesis of Compound R111
(1) Step 1:
(R) -4- (2-chloro-7- (methylsulfonyl) pyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (100 mg), 6-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-indole (118 mg), pd (dppf) Cl 2 (22 mg) and CS 2 CO 3 (202 mg) in dioxane/H 2 O is reacted at 110 ℃ overnight, N 2 After the reaction was completed by TLC, water was added to dilute, ethyl acetate was added to extract twice, the solution was separated, the ethyl acetate phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=1:1 to DCM/meoh=10:1) to give compound R111 (60 mg, 45%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ11.10(s,1H),8.16(s,1H),7.67(dd,1H),7.50(s,1H),7.41(t,1H),7.46–7.34(m,2H),4.03(d,1H),3.92–3.74(m,3H),3.64–3.51(m,3H),3.52(s,3H),1.23–1.11(m,3H)。LC-MS[M+H] + =430。
EXAMPLE 69 Synthesis of Compound R112
Synthetic route reference synthesis of compound R111. 1 H NMR(400MHz,DMSO)δ11.37(s,1H),8.66(s,1H),8.01(dd,1H),7.70(s,1H),7.51(t,1H),7.42–7.35(m,1H),4.07(d,1H),3.90–3.72(m,3H),3.67–3.57(m,2H),3.51(s,2H),1.40(d,4H),1.25–1.13(m,3H)。LC-MS[M+H] + =457。
EXAMPLE 70 Synthesis of Compound R113
(1) Step 1:
to the reaction flask was added (R) -4- (2-chloro-7- (methylsulfonyl) pyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (100 mg), 2- ((triisopropylsiloxy) methyl) -1H benzimidazole (123 mg), pd (OAc) 2 (13mg)、BINAP(37mg)、CS 2 CO 3 (195 mg) and dioxane (10 mL), N 2 Protection, reaction at 120 ℃ overnight. After completion of the TLC monitoring reaction, column chromatography (petroleum ether: ethyl acetate=3:1) gave compound R113-1 (61 mg, 33%) as a brown solid. LC-MS [ M+H ]] + =599。
(2) Step 2:
to the reaction flask were added compound R113-1 (60 mg), TBAF (52 mg) and anhydrous tetrahydrofuran (10 mL), and the mixture was reacted overnight at room temperature. After the completion of the TLC monitoring reaction, the reaction was directly dried by spin-drying with a spatula (dichloromethane: methanol=30:1) to give compound R113 (6 mg, 13%) as a yellow solid. 1 H NMR(400MHz,DMSO)δ8.15(d,1H),7.73(d,1H),7.34(d,4H),5.37(s,1H),5.06(s,2H),4.04(d,2H),3.78(d,3H),3.68–3.54(m,2H),3.51(s,1H),3.42(s,2H), 1.24(s,3H)。LC-MS[M+H] + =443。
EXAMPLE 71 Synthesis of Compound R114
Synthetic route reference synthesis of compound R106. 1 H NMR(400MHz,DMSO)δ10.17(s,1H),8.92(s,1H),8.82(s,1H),8.36(d,1H),8.15(d,1H),7.39(d,1H),7.21(s,1H),5.21(s,1H),4.58(d,2H),3.86(d,1H),3.79(d,1H),3.69–3.55(m,2H),3.08(d,3H),1.71(m,3H),1.46(m,2H),1.21(d,3H)。LC-MS[M+H] + =468。
EXAMPLE 72 Synthesis of Compound R117
(1) Step 1:
to the reaction flask was added (R) -4- (2-chloro-7- (methylsulfonyl) pyrrole [2, 1-f)][1,2,4]Triazin-4-yl) -3-methylmorpholine (83 mg), 3-aminopyrazole (25 mg), palladium acetate (12 mg), BINAP (31 mg), anhydrous cesium carbonate (163 mg) and 10mL anhydrous 1, 4-dioxane, N 2 The reaction was carried out overnight at 116℃in an oil bath. After completion of the TLC monitoring reaction, column chromatography (DCM: meoh=90:1 to 50:1) was purified to give compound R117 (9 mg, 10%) as a white solid. 1 H NMR(400MHz,DMSO)δ8.28(s,1H),7.17(d,1H),7.12(d,1H),5.83(s,1H),5.40(s,2H),4.00(d,2H),3.77–3.61(m,3H),3.57(s,2H),3.50(s,3H),1.40(s,3H)。LC-MS[M+H] + =378。
EXAMPLE 73 Synthesis of Compound R116
Synthetic route reference synthesis of compound R107. 1 H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.02(d,1H),7.61(t,1H),7.53(s,1H),7.47(t,1H),7.23(d,1H),7.15(d,1H),5.18(t,1H),5.01(s,1H), 4.66(d,2H),4.06(d,1H),3.86–3.74(m,2H),3.62(s,2H),3.24(td,1H),1.45(d,3H),1.20(q,2H),1.02(dt,3H)。LC-MS[M+H+]=468。
EXAMPLE 74 Synthesis of Compound R30
(1) Step 1:
5-nitro-2, 4, 6-trichloropyrimidine (100 mg) was dissolved in 8ml of DCM, DIPEA (85 mg) was added, the temperature was reduced to-10 ℃, (R) -3-methylmorpholine (46 mg) was added, the reaction was slowly allowed to return to room temperature for 4h, and after completion of the TLC monitoring the reaction, column chromatography (petroleum ether: ethyl acetate=3:1) was used to purify a yellow oil (95 mg). LC-MS [ m+h+ ] =293.
(2) Step 2:
compound R30-1 (95 mg) was dissolved in DMF (8 ml) at room temperature, cooled to about 0 ℃, 1-methyl-5-aminopyrazole (31 mg) was added followed by DIPEA (42 mg) and slowly returned to room temperature, the reaction was allowed to proceed for 2h, after tlc monitoring was completed, the reaction mixture was poured into 20ml of water, EA (5 ml x 3) was extracted, the organic phase was dried by filtration, and purified by spin-drying, sand making, column chromatography (petroleum ether: ethyl acetate=2:1) to give pale yellow solid (60 mg, 52%). LC-MS [ m+h+ ] =354.
(3) Step 3:
in a 50mL pressure-resistant bottle, compound R30-2 (60 mg) and SnCl were added at room temperature 2 (145 mg), trimethyl orthoformate (1 mL), 5mL of absolute ethanol and 2 drops of concentrated hydrochloric acid, then heating to 90 ℃ for reaction for 5h, TLC monitoring reaction completion, then after the reaction liquid is cooled to room temperature, pouring the reaction liquid into 15mL of water, adjusting pH to 8 with saturated aqueous solution of sodium carbonate, extracting by EA (5 mL x 3), drying the organic phase after filtration, spinning, preparing sand, purifying by column chromatography (petroleum ether: ethyl acetate=1:1) to obtain pale yellow solid (32 mg, 57%). LC-MS [ M+H ] ]=334。
(4) Step 4:
compound R30-3 (32 mg), 6-chloro-7-azaindole 4-pinacol ester (28 mg), K was reacted at room temperature 2 CO 3 (20 mg) Pd (dppf) Cl2 (8 mg) was added to a 10mL single port flask, 5mL dioxane, N 2 After the pumping and draining are carried out twice, N 2 The reaction was heated to 120 ℃ under an atmosphere for 4h, tlc monitored that the reaction was complete, then after the reaction was cooled to room temperature, the reaction was dried by spin-drying, sanded, and purified by column chromatography (dichloromethane: methanol=100:1) to give a pale yellow solid (10 mg, 25%). 1 H NMR(400MHz,DMSO)δ11.75(s,1H),8.56–8.47(m,1H),8.37–8.28(m,1H),7.97(dt,1H),7.71(dd,1H),7.58–7.52(m,1H),7.14–7.05(m,1H),6.72–6.64(m,1H),4.11–4.03(m,1H),3.90–3.84(m,1H),3.83–3.71(m,4H),3.61(m,4H),1.44(s,3H)。LC-MS[M+H+]=416。
EXAMPLE 75 Synthesis of Compound R50
(1) Step 1:
in a 25mL single vial at room temperature was added compound (R) -4- (2-chloro-9 h-purin-6-yl) -3-methylmorpholine (200 mg), 1, 4-dimethylpyrazole-5-boronic acid pinacol ester (211 mg), copper acetate (215 mg) and triethylamine (400 mg), DCM (10 mL), O 2 After the pumping and discharging are carried out twice, O 2 The reaction was carried out for 24h under an atmosphere, TLC monitored the partial reaction of the starting material, the reaction solution was filtered through celite, rinsed with DCM (5 mL), dried with dichloromethane, and purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give a yellow oil (20 mg, 7%). LC-MS [ M+H ] + ]=347。
(2) Step 2:
under room temperature conditions, the compound R50-1 (20 mg), 7-azaindole 4-pinacol ester (17 mg), KOAc (11 mg), pd (dppf) Cl 2 5mg is added to a 10ml single-necked flask, 5mL DMSO, N 2 After the pumping and draining are carried out twice, N 2 After the reaction was completed by tlc monitoring with heating to 120 ℃ under an atmosphere, and then after the reaction solution was cooled to room temperature, the reaction solution was poured into 15mL of water, extracted with EA (5 ml×3), dried by spin-drying after organic phase drying and filtration, and subjected to column chromatography (dichloromethane: methanol=100:1) to obtain pale yellow solid (11 mg, 44%). 1 H NMR(400MHz,DMSO)δ11.70(s,1H),8.29(d,1H),7.97(d,1H),7.65–7.45(m,3H),7.16–6.95(m,2H),5.00–4.86(m,1H),4.72–4.52(m,1H),4.08(dd,1H),3.81(d,2H),3.74–3.41(m,6H),3.15–3.04(m,2H),1.89(s,3H)。LC-MS[M+H + ]=429。
It should be noted that other similar compounds disclosed herein were synthesized by similar methods as in the examples described above.
Experimental example 1 ATR kinase assay
1. Preparing kinase buffer solution and stop solution which are 1 time of the preparation method
Using pH 75, 50mM HEPES, 0.0015% Brij-35 and 1M MnCl 2 Preparing a 1-time kinase buffer; stop solutions were prepared using 100mM HEPES,0.015%Brij-35, 0.2%Coating Reagent#3 and 50mM EDTA at pH 7.5.
2. Compound formulation
Compound was formulated at 1000/3 times the final concentration. 3-fold dilutions were made down in sequence from the highest concentration, 10 total concentrations, as 1000/3-fold concentration of compound. Transfer 100 μl of 100% dmso into two empty wells as Max well and Min well, respectively. Transfer 40 μl of compound to a new 384 well plate as an intermediate plate. Using Echo transfer 60nl of compound into 384 well plates.
Wherein AZ20 and BAY1895344 are yang ginseng compounds, and the structural formulas are as follows:
3. kinase reaction
Kinase was added to 1-fold kinase buffer to form a 2-fold enzyme solution. 10. Mu.L of 2-fold enzyme solution was added to 384-well reaction plates, and 10. Mu.L of kinase buffer was added to the negative control wells. Incubate for 10 minutes at room temperature. The FAM-labeled polypeptide 5-FAM-AK-17 and ATP are added to 1-fold kinase buffer to form a 2-fold substrate solution. 10. Mu.L of a 2-fold substrate solution was added to 384-well reaction plates. Incubate at 28℃for a certain period. The reaction was stopped by adding 30. Mu.IL stop solution to 384-well reaction plates. Data were read with Caliper EZ Reader II.
IC50 (nM) values are shown in Table 1.
TABLE 1
Numbering of compounds | IC 50 (nM) |
R2 | 7.1 |
R3 | 11 |
R5 | 8.9 |
R7 | 30 |
R10 | 13 |
R14 | 1.5 |
R16 | 12 |
R22 | 21 |
R23 | 6.9 |
R26 | 15 |
R27 | 2.5 |
R39 | 20 |
R50 | 2.3 |
R56 | 1.1 |
R63 | 27 |
R64 | 27 |
R65 | 11 |
R66 | 21 |
R68 | 5.1 |
R71 | 21 |
R72 | 9.2 |
R73 | 2.5 |
R75 | 2681 |
R77 | 13 |
R78 | 2.6 |
R80 | 10 |
R92 | 17 |
R105 | 11 |
R106 | 6.2 |
R107 | 2.9 |
BAY1895344 | 7 |
AZ20 | 2.8 |
Experimental example 2 LOVO in vitro cell Activity experiment
Analyzing the inhibition effect of the compound of the invention on LOVO cell proliferation, and arranging two double holes, wherein the compound concentration is as follows: 10. Mu.M starting, 5-fold dilution, 9 concentration gradients.
The LOVO cell suspension was collected, centrifuged at 1000rpm for 5 minutes, the supernatant removed and counted after resuspension with pre-warmed medium. After counting, the cell suspension was diluted to the desired densities with cell culture medium each as shown in Table 4-1, and 100. Mu.L of cell suspension was inoculated into 96-well cell culture plates per well, incubated at 37℃in a 5% CO2 incubator overnight. In the different compounds, 10 μl of compound working solution was added to the cell plate per well, 37 ℃,5% co2 incubator, and incubation continued. Wherein, the cell plating density is 5000 cells/well, and the incubation days are 3 days.
After the incubation is finished, a proper amount of CCK8 detection reagent is added into each hole of the cell plate, and the incubator is incubated for 1-4 hours. After the incubation, luminescence signal was performed using absorpiscenceAnd (5) detecting. The measured signal values of each group were normalized by subtracting the background blank control well signal value. The cell viability after compound treatment was calculated according to the following formula: inhibition ratio = 100- (RFU) Compounds of formula (I) –RFU Empty space White control )/(RFU Negative control –RFU Blank control ) X 100%. Blank control: only the cell-free treatment of the medium; negative control: cells treated with 0.5% dmso, then IC of compound was calculated using Prism mapping 50 The values are shown in table 2.
TABLE 2
Numbering of compounds | IC 50 (μM) |
R14 | 0.2638 |
R30 | 0.4776 |
R50 | 0.3545 |
R56 | 0.0812 |
R58 | 0.7654 |
R65 | 0.3131 |
R68 | 0.462 |
R72 | 0.2133 |
R73 | 0.0366 |
R75 | >10 |
R76 | 0.4429 |
R78 | 0.0892 |
R80 | 0.0426 |
R81 | 1.555 |
R83 | 0.0942 |
R88 | 0.1144 |
R92 | 0.3358 |
R93 | 0.533 |
R98 | 0.9513 |
R101 | 0.4522 |
R106 | 0.2082 |
R107 | 0.0274 |
R111 | 0.9456 |
R112 | 0.342 |
R113 | 1.971 |
R114 | 0.5232 |
R116 | 0.0315 |
R117 | 0.6167 |
BAY1895344 | 0.0342 |
The protection of the present invention is not limited to the above embodiments. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.
Claims (31)
- A compound of formula (I) or a pharmaceutically acceptable salt thereof,wherein:X 1 is NR (NR) 5 O or CR 6 Wherein R is 5 And R is 6 Independently is hydrogen, alkyl, cycloalkyl, alkoxy, hydroxyalkyl, halogen, or hydroxy, wherein the alkyl, cycloalkyl, alkoxy, and hydroxyalkyl are each independently substituted with one or more substituents selected from halogen, hydroxy, carboxyl, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl, and alkylsulfinyl;X 2 Is C or N;X 3 CH or N;X 4 CH or N;X 5 CH or N;R 1 is thatR 7 Each independently is hydrogen, alkyl, cycloalkyl, alkoxy, cyano, or halogen; wherein the alkyl, cycloalkyl and alkoxy groups are each independently selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkeneSubstituted with one or more substituents selected from the group consisting of a C2-C6 alkynyl, heterocyclic, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;R 2 selected from the group consisting ofR 8 、R 9 And R is 10 Independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano, halogen or NR 11 R 12 Wherein R is 11 And R is 12 Independently hydrogen, alkyl, cycloalkyl, alkoxy, cyano or halogen; wherein the alkyl, cycloalkyl and alkoxy groups are each independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;R 3 Is alkyl, aryl, heterocyclyl, cycloalkyl, heteroaryl, carbonyl, -S (=o) R 13 -alkyl-S (=o) R 13 -cycloalkyl-S (=o) R 13 、-S(=O) 2 R 13 -alkyl-S (=o) 2 R 13 -cycloalkyl-S (=o) 2 R 13 、-S(=O)(=NH)R 13 -alkyl-S (=o) (=nh) R 13 or-cycloalkyl-S (=o) (=nh) R 13 Wherein the alkyl, aryl, heterocyclyl, cycloalkyl and heteroaryl groups are each independently selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C1-Substituted with one or more substituents selected from the group consisting of C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;R 13 is alkyl, cycloalkyl, heteroaryl, aryl or heterocyclyl;R 4 hydrogen, alkyl, cycloalkyl, alkoxy, cyano or halogen; wherein the alkyl, cycloalkyl and alkoxy groups are each independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl;Alternatively, R 4 And X is 2 Together form a carbonyl group, or R 4 And R is 3 Together with the groups to which they are attached form a 5-7 membered ring;n, m, p represent 0, 1, 2 or 3;
- the compound of claim 1, wherein R 1 Is thatWherein R is 7 Methyl or ethyl, p is 0 or 1.
- The compound of claim 2, wherein R 1 Selected from the following groups:
- the compound of claim 1, wherein R 2 Selected from the following groups:
- the compound of claim 1, wherein R 3 Is alkyl or cycloalkyl optionally substituted with 1 to 3 substituents selected from cycloalkyl, halogen (e.g. fluorine, chlorine, bromine or iodine), cyano or pyridinyl.
- The compound of claim 5, wherein R 3 Is methyl, cyclopropyl, cyclopentyl, isopropyl, cyclopropylmethylene.
- The compound of claim 1, wherein R 3 Is an N-containing six-or five-membered unsaturated heterocyclic ring, which is optionally substituted with an alkyl group (e.g., methyl, ethyl or propyl).
- The compound of claim 7, wherein R 3 Selected from:
- the compound of claim 1, wherein R 3 Is a benzene ring, the ortho, meta or para position of the benzene ring being optionally independently selected from halogen, hydroxy, carboxyl, amino, nitro, cyano, C1-C6 amido, C1-C6 acyloxy, C1-C6 alkoxy, aryloxy, alkylthio, C1-C6 alkyl, C1-C6 acyl, C6-C10 aryl, C3-C8 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclyl, heteroaryl, methylenedioxy, isopropylcyano, ureido, mercapto, azido, carbonyl, alkylsulfonyl, sulfamoyl, dialkylsulfamoyl and alkylsulfinyl.
- The compound of claim 1, wherein R 3 is-S (=O) R 13 、-S(=O) 2 R 13 Or S (=o) (=nh) R 13 Wherein said R is 13 Is an optionally substituted alkyl group (such as methyl, ethyl or propyl), an optionally substituted cycloalkyl group (such as cyclopropyl, cyclobutyl or cyclopentyl), an optionally substituted cycloalkylalkyl group, an optionally substituted benzene ring, an optionally substituted N-containing six-membered unsaturated heterocycle or an optionally substituted N-containing six-membered saturated heterocycle.
- The compound of claim 1, wherein R 3 is-alkyl-S (=O) R 13 -cycloalkyl-S (=o) R 13 -alkyl-S (=o) 2 R 13 -cycloalkyl-S (=o) 2 R 13 -alkyl-S (=o) (=nh) R 13 or-cycloalkyl-S (=o) (=nh) R 13 Wherein the alkyl is methylene, ethylene or-CH (CH) 3 ) -said cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl, said R 13 Is an optionally substituted alkyl group (e.g., methyl, ethyl or propyl).
- The compound of claims 1-11, wherein X is 1 Is C, X 2 Is C, X 3 Is N.
- The compound of claims 1-11, wherein X is 1 Is N, X 2 Is C, X 3 Is N.
- The compound of claims 1-11, wherein R 4 And R is R 3 Together form a six membered N, O containing heterocycle.
- The compound of claims 1-11, wherein each of m and n is independently 0.
- The compound of claims 1-11, wherein R 4 And X is 2 Together forming a carbonyl group.
- The compound of claims 1-11, wherein R 5 H.
- The compound of claims 1-11, wherein R 6 H, C of a shape of H, C 1-6 Alkyl, alkoxy or halogen.
- The compound of claims 1-11, wherein R 8 Is H or halogen.
- The compound of claim 19, wherein the halogen is a chlorine atom.
- The compound of claims 1-11, wherein R 9 Is H or halogen.
- The compound of claim 21, wherein the halogen is a chlorine atom.
- The compound of claims 1-11, wherein R 10 H.
- The compound of claims 1-11, wherein R 11 And R is 12 H, C of a shape of H, C 1-6 Alkyl, halogen or substituted 1-3Alkyl substituted by halogen atom.
- The compound of claims 1-11, wherein R 13 Is cyclopropyl, isopropyl, methyl, ethyl or cyclopropylmethylene.
- The compound of claims 1-11, wherein R 13 Selected from the following groups:
- the compound of claims 1-26, the structure of the compound of formula (I) is as follows:
- the compound of claims 1-11, selected from the group consisting of:
- a pharmaceutical composition according to rules 91-corrected 15.09.2022, characterized in that it comprises a therapeutically effective amount of a compound according to any one of claims 1-27 and at least one pharmaceutically acceptable excipient.
- Use of a compound according to any one of claims 1-28 for the manufacture of a medicament for the treatment or prophylaxis of ATR kinase mediated diseases; preferably, the disease is cancer.
- The compound of any one of claims 1-28, wherein the cancer is liver cancer, melanoma, hodgkin's disease, non-hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, wilms 'tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myelogenous leukemia, primary brain cancer, malignant melanoma, small cell lung cancer, stomach cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, kaposi's sarcoma, genitourinary system tumor, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenal gland cancer, skin cancer, and prostate cancer.
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