Patent Application
20230357242
The present application belongs to the field of pharmaceutical chemistry, provides a compound as an Akt kinase inhibitor or a pharmaceutically acceptable salt thereof, a preparation method therefor and a pharmaceutical composition containing the compound, and relates to use thereof in preparing a drug for treating an Akt kinase-related disease of a patient in need thereof, such as treating cancer.
Akt, also known as Protein Kinase B (PKB) or Rac, is a serine/threonine kinase of the AGC family with high homology to Protein Kinase A (PKA) and Protein Kinase C (PKC). Akt mainly has three domains: a PH domain (which has an affinity for PIP3 and is therefore critical for binding to cell membranes), a catalytic domain and a regulatory domain. Studies have shown that Akt in humans comprises three subtypes: Akt1, Akt2 and Akt3, each of which has unique function and expression pattern. Akt1, Akt2 and Akt3 are key mediators of PI3K/AKT/mTOR signaling pathway, and can promote various physiological processes such as proliferation, migration, anti-apoptotic survival and protein synthesis. Akt1 has wide expression in tissues and is mainly involved in the survival pathway and growth control of cells; Akt2 is mainly expressed in muscle and adipocytes and involved in insulin-mediated glycometabolism and the like; Akt3 is mainly expressed in testis and brain and plays an important role in maintaining normal brain volume.
Akt is one of the most frequently activated protein kinases in human cancers. Over-activation of Akt may induce cell growth, resulting in cell proliferation and helping to resist apoptosis. In cancer, Akt activity is often elevated due to oncogenic growth factors, angiogenic factors, cytokines and genetic alterations, including mutations and/or amplification of the Akt1, Akt2 and Akt3 genes. Akt signaling can be regulated from various levels, for example several molecules upstream thereof can regulate the dephosphorylation of PIP3 that can be dephosphorylated to PIP2 by PTEN and SHIP1. Akt can also be dephosphorylated by PPA2 and PHLPP, resulting in inactivation. In addition, with phosphorylation of NFkB and IRS-1, positive and negative feedback regulation and control can be performed on Akt. Studies have shown that Akt is overexpressed in various human tumors, and the abnormal function of the Akt is closely related to the occurrence, development and tolerance of chemotherapy and radiotherapy of the tumors.
According to different binding sites, Akt inhibitors may be classified into PH domain inhibitors, ATP competitive inhibitors, allosteric inhibitors, biologics and the like. Compared with Capivasertib (AZD5363) that is developed by AstraZeneca and is a pan-Akt inhibitor, ATP competitive inhibitors and allosteric inhibitors (e.g., MK-2206) do not show monotherapy activity in many clinical trials. ARQ 092 and ARQ 751 are highly selective allosteric inhibitors, both of which show better activity in early studies.
Akt has become an anti-tumor target with a great development prospect, and an Akt inhibitor with high efficiency (activity), novelty (structure) and high selectivity (safety) is an important strategy for solving the unmet medical requirements at present.
In one aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein,
and wherein the amino or amino-C1-C6 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7-9 membered spiro-heterocyclyl, 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7-10 membered heterocycloalkenyl or 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-10 membered bridged heterocyclyl is substituted with one or more R24,
In another aspect, the present application further provides a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of the present application described above.
In another aspect, the present application further provides a method for treating a disease mediated by Akt kinase in a mammal, comprising administering to a mammal in need of such treatment a therapeutically effective amount of the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof described above.
In another aspect, the present application further provides use of the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof described above in preparing a medicament for treating a disease mediated by Akt kinase.
In another aspect, the present application further provides use of the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof described above in treating a disease mediated by Akt kinase.
In another aspect, the present application further provides the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof of the present application described above for use in treating a disease mediated by Akt kinase.
In one aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein,
wherein the amino or amino-C1-C6 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7-9 membered spiro-heterocyclyl, 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7-10 membered heterocycloalkenyl or 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-10 membered bridged heterocyclyl is substituted with one or more R24,
In some embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,
wherein the amino or amino-C1-C6 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7-9 membered spiro-heterocyclyl, 7-10 membered heterocycloalkenyl or 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-10 membered bridged heterocyclyl is substituted with one or more R24 or, R3, together with R2 or R2′ and the carbon atoms connected thereto, forms morpholinyl optionally substituted with one or more R2,
In some embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,
wherein the amino or amino-C1-C6 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7-9 membered spiro-heterocyclyl, 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7-10 membered heterocycloalkenyl or 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-10 membered bridged heterocyclyl is substituted with one or more R24,
In some embodiments, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein,
wherein the amino or amino-C1-C6 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7-9 membered spiro-heterocyclyl, 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7-10 membered heterocycloalkenyl or 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-10 membered bridged heterocyclyl is substituted with one or more R24,
In some embodiments, the 7-9 membered spiro-heterocyclyl, 7-10 membered fused-heterocyclyl and 7-10 membered bridged heterocyclyl each independently contain 1-3 heteroatoms selected from the group consisting of N, O and S.
In some embodiments, the 7-9 membered spiro-heterocyclyl, 7-10 membered fused-heterocyclyl and 7-10 membered bridged heterocyclyl each independently contain 1 or 2 heteroatoms selected from the group consisting of N, O and S.
In some embodiments, the 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom contains 1, 2, or 3 nitrogen atoms.
In some embodiments, the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom contains 1, 2, or 3 nitrogen atoms.
In some embodiments, the 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom contains 1 silicon atom or 1 phosphorus atom, and 1 or 2 heteroatoms selected from the group consisting of N, O and S.
In some embodiments, the 4-5 membered heterocyclyl and 4-12 membered heterocyclyl each independently contain 1-3 heteroatoms selected from the group consisting of N, O and S.
In some embodiments, R1 and R1′ are each independently selected from the group consisting of hydrogen and fluorine.
In some embodiments, R1 and R1′ are both selected from hydrogen.
In some embodiments, R1 is selected from hydrogen, and R1′ is selected from halogen; or R1 is selected from halogen, and R1′ is selected from hydrogen.
In some embodiments, R1 is selected from hydrogen, and R1′ is selected from fluorine; or R1 is selected from fluorine, and R1′ is selected from hydrogen.
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen, amino, amino-C1-C6 alkyl-, 7-9 membered spiro-heterocyclyl, 7-10 membered fused-heterocyclyl, 7-10 membered bridged heterocyclyl, 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom,
wherein the amino or amino-C1-C6 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7-9 membered spiro-heterocyclyl, 7-10 membered heterocycloalkenyl or 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-10 membered bridged heterocyclyl is substituted with one or more R24
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen, amino, amino-C1-C4 alkyl-, 7, 8 or 9 membered spiro-heterocyclyl, 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7, 8 or 9 membered fused-heterocyclyl, 7-8 membered bridged heterocyclyl, 5-6 membered monoheterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5-6 membered monoheterocyclyl whose ring atoms consist of a silicon atom or a phosphorus atom,
wherein the amino or amino-C1-C4 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered monoheterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7, 8 or 9 membered spiro-heterocyclyl, 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7, 8 or 9 membered fused-heterocyclyl, or 5-6 membered monoheterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-8 membered bridged heterocyclyl is substituted with one or more R24
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen, amino, amino-C1-C4 alkyl-, 7, 8 or 9 membered spiro-heterocycloalkyl, 10 membered spiro-heterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7, 8 or 9 membered fused-heterocycloalkyl, 7-8 membered bridged heterocycloalkyl, 5-6 membered monoheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5-6 membered monoheterocycloalkyl whose ring atoms contain a silicon atom or a phosphorus atom,
wherein the amino or amino-C1-C4 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered monoheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7, 8 or 9 membered spiro-heterocycloalkyl, 10 membered spiro-heterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7, 8 or 9 membered fused-heterocycloalkyl, or 5-6 membered monoheterocycloalkyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted by one or more R23, wherein the 7-8 membered bridged heterocycloalkyl is substituted by one or more R24
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen, amino, amino-C1-C4 alkyl-, 7, 8 or 9 membered spiro-heterocycloalkyl, 10 membered spiro-heterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5 membered fused 4 membered heterocycloalkyl, 5 membered fused 5 membered heterocycloalkyl, 5 membered fused 6 membered heterocycloalkyl, 7-8 membered bridged heterocycloalkyl, 5-6 membered monoheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 6 membered monoheterocycloalkyl whose ring atoms contain a silicon atom or a phosphorus atom,
wherein the amino or amino-C1-C4 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5 membered or 6 membered monoheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′ wherein the 7, 8 or 9 membered spiro-heterocycloalkyl, 10 membered spiro-heterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5 membered fused 4 membered heterocycloalkyl, 5 membered fused 5 membered heterocycloalkyl, 5 membered fused 6 membered heterocycloalkyl, or 6 membered monoheterocycloalkyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-8 membered bridged heterocycloalkyl is substituted with one or more R24
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen, amino, aminomethyl,
pyrrolidinyl, piperidinyl, piperazinyl,
wherein the amino or aminomethyl is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the pyrrolidinyl, piperidinyl or piperazinyl is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the
is substituted with one or more R23, wherein the
is substituted with one or more R24
group optionally substituted with one or more R25,
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen, amino, aminomethyl,
wherein the amino or aminomethyl is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the
is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the
is substituted
with one or more R24,
group optionally substituted with one or more R25,
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen, amino aminomethyl
pyrrolidinyl, piperidinyl, piperazinyl,
wherein the amino and aminomethyl are substituted with one or more R and optionally substituted with one or more R21′, wherein the pyrrolidinyl, piperidinyl or piperazinyl is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the
are optionally substituted with one or more R23, wherein the
is substituted with one or more R24,
group optionally substituted with one or more R2,
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen, amino, aminomethyl
wherein the amino and aminomethyl are substituted with one or more R21, and optionally substituted with one or more R21′, wherein the
are substituted with one or more R22 and optionally substituted with one or more R22′, wherein the
are optionally substituted with one or more R23, wherein the
is substituted with one or more R24,
group optionally substituted with one or more R2,
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from the group consisting of amino, amino-C1-C6 alkyl-, 7-9 membered spiro-heterocyclyl, 7-10 membered fused-heterocyclyl, 7-10 membered bridged heterocyclyl, 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom,
wherein the amino or amino-C1-C6 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7-9 membered spiro-heterocyclyl, 7-10 membered heterocycloalkenyl or 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-10 membered bridged heterocyclyl is substituted with one or more R24
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from the group consisting of amino, amino-C1-C4 alkyl-, 7, 8 or 9 membered spiro-heterocyclyl, 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7, 8 or 9 membered fused-heterocyclyl, 7-8 membered bridged heterocyclyl, 5-6 membered monoheterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5-6 membered monoheterocyclyl whose ring atoms consist of a silicon atom or a phosphorus atom,
wherein the amino or amino-C1-C4 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered monoheterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7, 8 or 9 membered spiro-heterocyclyl, 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7, 8 or 9 membered fused-heterocyclyl, or 5-6 membered monoheterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-8 membered bridged heterocyclyl is substituted with one or more R24
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from the group consisting of amino, amino-C1-C4 alkyl-, 7, 8 or 9 membered spiro-heterocycloalkyl, 10 membered spiro-heterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7, 8 or 9 membered fused-heterocycloalkyl, 7-8 membered bridged heterocycloalkyl, 5-6 membered monoheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5-6 membered monoheterocycloalkyl whose ring atoms contain a silicon atom or a phosphorus atom,
wherein the amino or amino-C1-C4 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5-6 membered monoheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the 7, 8 or 9 membered spiro-heterocycloalkyl, 10 membered spiro-heterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 7, 8 or 9 membered fused-heterocycloalkyl, or 5-6 membered monoheterocycloalkyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted by one or more R23, wherein the 7-8 membered bridged heterocycloalkyl is substituted by one or more R24
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from the group consisting of amino, amino-C1-C4 alkyl-, 7, 8 or 9 membered spiro-heterocycloalkyl, 10 membered spiro-heterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5 membered fused 4 membered heterocycloalkyl, 5 membered fused 5 membered heterocycloalkyl, 5 membered fused 6 membered heterocycloalkyl, 7-8 membered bridged heterocycloalkyl, 5-6 membered monoheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 6 membered monoheterocycloalkyl whose ring atoms contain a silicon atom or a phosphorus atom,
wherein the amino or amino-C1-C4 alkyl- is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the 5 membered or 6 membered monoheterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom is substituted with one or more R22, and optionally substituted with one or more R22′ wherein the 7, 8 or 9 membered spiro-heterocycloalkyl, 10 membered spiro-heterocycloalkyl whose ring atoms consist of a nitrogen atom and a carbon atom, 5 membered fused 4 membered heterocycloalkyl, 5 membered fused 5 membered heterocycloalkyl, 5 membered fused 6 membered heterocycloalkyl, or 6 membered monoheterocycloalkyl whose ring atoms contain a silicon atom or a phosphorus atom is optionally substituted with one or more R23, wherein the 7-8 membered bridged heterocycloalkyl is substituted with one or more R24
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from the group consisting of amino, aminomethyl,
pyrrolidinyl, piperidinyl, piperazinyl,
wherein the amino or aminomethyl is substituted with one or more R21, and optionally substituted with one or more R21′, wherein the pyrrolidinyl, piperidinyl or piperazinyl is substituted with one or more R22, and optionally substituted with one or more R22′, wherein the
is substituted with one or more R23, wherein the
is substituted with one or more R24
group optionally substituted with one or more R25.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from the group consisting of amino, aminomethyl,
wherein the amino or aminomethyl is substituted with one or more R21, and optionally substituted with one or more R21, wherein the
is substituted with one or more R22, and optionally substituted with one or more R22, wherein the
is substituted with one or more R23, wherein the
is substituted with one or more R24
group optionally substituted with one or more R25.
In some embodiments, R3 is connected to R2 or R2′, such that the structural unit
optionally substituted with one or more R25.
In some embodiments, R21 is selected from the group consisting of C2-C4 alkenyl-C(O)—, C5-C10 cycloalkyl, 4-6 membered heterocyclyl or C1-C4 alkylacylamino-C1-C4 alkyl-, wherein the C5-C10 cycloalkyl, 4-6 membered heterocyclyl or C1-C4 alkylacylamino-C1-C4 alkyl- is optionally substituted with one or more of the following groups selected from the group consisting of: hydroxy, C1-C6 alkyl and C1-C4 alkylacyl.
In some embodiments, R21 is selected from the group consisting of C2-C3 alkenyl-C(O)—, C7-C10 bridged cycloalkyl, 4-6 membered monoheterocycloalkyl and C1-C3 alkylacylamino-C1-C3 alkyl-, wherein the C7-C10 bridged cycloalkyl, 4-6 membered monoheterocycloalkyl or C1-C3 alkylacylamino-C1-C3 alkyl- is optionally substituted with one or more of the following groups selected from the group consisting of: hydroxy, C1-C4 alkyl and C1-C4 alkylacyl.
In some embodiments, R21 is selected from the group consisting of C2-C3 alkenyl-C(O)—, C10 bridged cycloalkyl, 5 membered or 6 membered monoheterocycloalkyl, or C1-C3 alkylacylamino-C1-C3 alkyl-, wherein the C10 bridged cycloalkyl, 5 membered or 6 membered monoheterocycloalkyl, or C1-C3 alkylacylamino-C1-C3 alkyl- is optionally substituted with one or more of the following groups selected from the group consisting of: hydroxy, C1-C4 alkyl and C1-C4 alkylacyl.
In some embodiments, R21 is selected from the group consisting of H2C═CHC(O)—,
and CH3C(O)N(CH3)—CH3CH2—, wherein the
is optionally substituted with one or more of the following groups selected from the group consisting of: hydroxy and C1-C4 alkylacyl.
In some embodiments, R21 is selected from the group consisting of H2C═CHC(O)—,
and CH3C(O)N(CH3)—CH3CH2—.
In some embodiments, R21 is selected from the group consisting of H2C═CHC(O)—,
and CH3C(O)N(CH3)—CH3CH2—.
In some embodiments, one of R2 and R2′ is hydrogen and the other is amino, wherein the amino is substituted with one R21, R21 being selected from the group consisting of C2-C3 alkenyl-C(O), C10 bridged cycloalkyl, 5 membered or 6 membered monoheterocycloalkyl, and C1-C3 alkylacylamino-C1-C3 alkyl-, wherein the C10 bridged cycloalkyl, 5 membered or 6 membered monoheterocycloalkyl, or C1-C3 alkylacylamino-C1-C3 alkyl- is optionally substituted with one or more of the following groups selected from the group consisting of: hydroxy, C1-C4 alkyl and C1-C4 alkylacyl; and/or R3 is hydrogen.
In some embodiments, one of R2 and R2′ is hydrogen and the other is amino, wherein the amino is substituted with one R21, R21 being selected from the group consisting of H2C═CHC(O)—,
and CH3C(O)N(CH3)—CH3CH2—; and/or R3 is hydrogen.
In some embodiments, one of R2 and R2′ is hydrogen and the other is amino-C1-C6 alkyl-, wherein the amino-C1-C6 alkyl- is substituted with C2-C3 alkenyl-C(O)—; and/or R3 is hydrogen.
In some embodiments, R22 is selected from the group consisting of C2-C6 alkynyl-C(O)— and 4-5 membered heterocyclyl, wherein the 4-5 membered heterocyclyl is optionally substituted with one or more .
In some embodiments, R22 is selected from the group consisting of C2-C3 alkynyl-C(O)—, 4 membered or 5 membered heterocyclyl and 6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a sulfur atom, wherein the 4 membered or 5 membered heterocyclyl, or 6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a sulfur atom is optionally substituted with one or more of the following groups selected from the group consisting of: , halogen, C1-C3 alkyl and C1-C6 alkylacyl.
In some embodiments, R22 is selected from the group consisting of C2-C3 alkynyl-C(O)— and 4 membered or 5 membered heterocyclyl, wherein the 4 membered or 5 membered heterocyclyl is optionally substituted with one or more .
In some embodiments, R22 is selected from the group consisting of C2-C3 alkynyl-C(O)—, 4 membered or 5 membered heterocycloalkyl and
wherein the 4 membered or 5 membered heterocycloalkyl or
is optionally substituted with one or more of the following groups selected from the group consisting of: , halogen, C1-C3 alkyl and C1-C6 alkylacyl.
In some embodiments, R22 is selected from the group consisting of C2-C3 alkynyl-C(O)— and 4 membered or 5 membered heterocycloalkyl, wherein the 4 membered or 5 membered heterocycloalkyl is optionally substituted with one or more .
In some embodiments, R22 is selected from the group consisting of H3CC≡CC(O)—,
In some embodiments, R22 is selected from the group consisting of H3CC≡CC(O)—,
In some embodiments, R21′ and R22′ are each independently selected from the group consisting of deuterium and C1-C4 alkyl.
In some embodiments, R21′ and R22′ are each independently selected from the group consisting of deuterium and methyl.
In some embodiments, R21′ and R22′ are each independently selected from C1-C4 alkyl.
In some embodiments, R21′ and R22′ are each independently selected from methyl.
In some embodiments, R23 is selected from the group consisting of , C1-C4 alkyl, C1-C4 alkylsulfonyl and C1-C4 alkylacyl.
In some embodiments, R23 is selected from the group consisting of , CH3—, CH3S(O)2— and CH3C(O)—.
In some embodiments, R24 is selected from C1-C4 alkylacyl-N(C1-C4 alkyl)-.
In some embodiments, R24 is selected from CH3C(O)N(CH3)—.
In some embodiments, R25 is selected from C1-C4 alkylacyl.
In some embodiments, R25 is selected from CH3C(O)—.
In some embodiments, R4 is selected from the group consisting of C1-C4 alkylacyl and C1-C4 alkylsulfonyl.
In some embodiments, R4 is selected from the group consisting of CH3C(O)— and CH3S(O)2—.
In some embodiments, R5 is selected from C1-C4 alkyl.
In some embodiments, R5 is selected from methyl.
In some embodiments, R4 is selected from CH3C(O)—; R5 is selected from methyl.
In some embodiments, R4 is selected from CH3S(O)2—; R5 is selected from methyl.
In some embodiments, R5′ is selected from —CD3 and —CH3, and when R5′ is —CH3, R1 or R1′ is fluorine.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from 7-9 membered spiro-heterocyclyl, wherein the 7-9 membered spiro-heterocyclyl is optionally substituted with 1 or 2 R23, R23 being selected from the group consisting of , C1-C4 alkyl, C1-C4 alkylsulfonyl and C1-C4 alkylacyl; and/or R3 is hydrogen.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from 7-9 membered spiro-heterocyclyl, wherein the 7-9 membered spiro-heterocyclyl is optionally substituted with 1 or 2 R23, R23 being selected from the group consisting of , CH3—, CH3S(O)2— and CH3C(O)—; and/or
In some embodiments, the 7-9 membered spiro-heterocyclyl is a 7, 8, or 9 membered monospiro heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S. In some embodiments, the 7-9 membered spiro-heterocyclyl is a 7, 8, or 9 membered monospiro heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N and O.
In some embodiments, one of R2 and R2′ is hydrogen and the other is 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, wherein the 10 membered spiro-heterocyclyl is optionally substituted with 1 or 2 R23, R23 being selected from the group consisting of , C1-C4 alkyl, C1-C4 alkylsulfonyl and C1-C4 alkylacyl; and/or R3 is hydrogen.
In some embodiments, one of R2 and R2′ is hydrogen and the other is 10 membered spiro-heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, wherein the 10 membered spiro-heterocyclyl is optionally substituted with 1 or 2 R23, R23 being selected from the group consisting of and C1-C4 alkyl; and/or R3 is hydrogen.
In some embodiments, the 10 membered spiro-heterocyclyl contains 1 or 2 heteroatoms selected from N.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from 7-10 membered fused-heterocyclyl, wherein the 7-10 membered fused-heterocyclyl is optionally substituted with 1 or 2 R23, R23 being selected from the group consisting of , C1-C4 alkyl, C1-C4 alkylsulfonyl and C1-C4 alkylacyl; and/or R3 is hydrogen.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from 7-9 membered fused-heterocyclyl, wherein the 7-9 membered fused-heterocyclyl is optionally substituted with 1 and C1-C4 alkylacyl; and/or R3 is hydrogen.
In some embodiments, the 7-9 membered fused-heterocyclyl contains 1 or 2 heteroatoms selected from the group consisting of N, O and S. In some embodiments, the 7-9 membered fused-heterocyclyl contains 1 or 2 heteroatoms selected from the group consisting of N and O.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom, wherein the 5-6 membered heterocyclyl is substituted with one R22 and optionally substituted with one R22′; R22 is selected from the group consisting of C2-C3 alkynyl-C(O)—, 4 membered or 5 membered heterocyclyl or 6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a sulfur atom, wherein the 4 membered or 5 membered heterocyclyl or 6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a sulfur atom is optionally substituted with 1, 2 or 3 groups selected from the group consisting of , halogen, C1-C3 alkyl and C1-C3 alkylacyl; R22′ is selected from the group consisting of deuterium and C1-C3 alkyl; and/or R3 is hydrogen.
In some embodiments, the 5-6 membered heterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom contains 1 or 2 nitrogen atoms.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from 7-10 membered bridged heterocyclyl, wherein the 7-10 membered bridged heterocyclyl is substituted with 1 or 2 R24, R24 being selected from C1-C4 alkylacyl-N(C1-C4 alkyl)-; and/or R3 is hydrogen.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from 7-10 membered bridged heterocyclyl, wherein the 7-10 membered bridged heterocyclyl is substituted with 1 CH3C(O)N(CH3)—; and/or R3 is hydrogen.
In some embodiments, the 7-10 membered bridged heterocyclyl contains 1 or 2 heteroatoms selected from the group consisting of N, O and S. In some embodiments, the 7-10 membered bridged heterocyclyl contains 1 or 2 heteroatoms selected from the group consisting of N and O.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from 5-6 membered heterocyclyl whose ring atoms contain a silicon atom and a phosphorus atom, wherein the 5-6 membered heterocyclyl is optionally substituted with 1 or 2 R23, R23 being selected from the group consisting of and C1-C4 alkyl; and/or R3 is hydrogen.
In some embodiments, the 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom contains 1 silicon atom or 1 phosphorus atom, and further contains 1 heteroatom selected from the group consisting of N, O and S. In some embodiments, the 5-6 membered heterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom contains 1 silicon atom or 1 phosphorus atom, and further contains 1 N atom.
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen,
or, R3 is connected to R2 or R2′, and together with the carbon atoms connected thereto, forms a
group, and R2, R2 and R3 are not hydrogen at the same time.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from
and R3 is hydrogen.
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen,
or, R3 is connected to R2 or R2′, and together with the carbon atoms connected thereto, forms a
group, and R2, R2′, and R3 are not hydrogen at the same time.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from the group consisting of
and R3 is hydrogen.
In some embodiments, R2, R2′ and R3 are each independently selected from the group consisting of hydrogen,
or R3 is connected to R2 or R2′ such that the structural unit
and R2, R2′ and R3 are not hydrogen at the same time.
In some embodiments, one of R2 and R2′ is hydrogen and the other is selected from the group consisting of
and R3 is hydrogen. In some embodiments, when R2, R2′ or R3 are each independently selected from the group consisting of hydrogen and
R1 or R1′ is fluorine.
In some embodiments, 2 of R2, R2′ or R3 are hydrogen.
In some embodiments, R2 and R2′ are hydrogen, and R3 is not hydrogen.
In some embodiments, R2 is not hydrogen, and R2′ and R3 are hydrogen.
In some embodiments, R2′ is not hydrogen, and R2 and R3 are hydrogen.
In some embodiments, the present application encompasses the variables defined above and embodiments thereof, as well as any combination thereof.
In another aspect, the present application provides a compound of the following formulas or a pharmaceutically acceptable salt thereof,
In another aspect, the present application further provides a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof of the present application described above. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.
In another aspect, the present application further provides a method for treating a disease mediated by Akt kinase in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof described above.
In another aspect, the present application further provides use of the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof described above in preparing a medicament for treating a disease mediated by Akt kinase.
In another aspect, the present application further provides use of the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof described above in treating a disease mediated by Akt kinase.
In another aspect, the present application further provides the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof of the present application described above for use in treating a disease mediated by Akt kinase.
In some embodiments, the disease mediated by Akt kinase is selected from a cancer, e.g., prostate cancer and endometrial cancer.
The compound of the present application has good inhibition effect on phosphorylation of LNcap cells and LNcap cells AKT1(S473), and has good cell activity, low toxicity, good pharmacokinetic property, strong in vivo tumor inhibition effect and the like.
Unless otherwise stated, the following terms used herein shall have the following meanings. A certain term, unless otherwise specifically defined, should not be considered uncertain or unclear, but construed according to its common meaning in the field. When referring to a trade name herein, it is intended to refer to its corresponding commercial product or its active ingredient.
The term “substituted” means that any one or more hydrogen atoms on a specific atom are substituted by substituents, as long as the valence of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (namely ═O), it means that two hydrogen atoms are substituted, and oxo is not available on an aromatic group. There is no keto substitution on the aromatic moiety.
The term “optional” or “optionally” means that the subsequently described event or circumstance may, but not necessarily, occur. The description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, an ethyl “optionally” substituted by halogen, means that the ethyl may be unsubstituted (CH2CH3), monosubstituted (for example, CH2CH2F), polysubstituted (for example, CHFCH2F, CH2CHF2 and the like) or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any groups comprising one or more substituents, any substitutions or substituting patterns which may not exist or cannot be synthesized spatially are not introduced.
Cm-n used herein means that the portion has an integer number of carbon atoms in the given range. For example, “C1-6” means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
When any variable (e.g., R) occurs more than once in the constitution or structure of a compound, the variable is independently defined in each case. Therefore, for example, if a group is substituted with 2 R, the definition of each R is independent.
When a bond of a substituent is cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. For example, structural unit
represents that substitution may occur in any one position of cyclohexyl or cyclohexadienyl.
The term “halo-” or “halogen” refers to fluorine, chlorine, bromine and iodine.
The term “hydroxy” refers to —OH group.
The term “amino” refers to —NH2 group.
The term “alkyl” refers to hydrocarbyl with a general formula of CnH2n+1, n being an integer from 1 to 20. The alkyl can be linear or branched. The alkyl herein may contain 1 to 10 carbon atoms (C1-C10 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), 1 to 4 carbon atoms (C1-C4 alkyl), or 1 to 3 carbon atoms (C1-C3 alkyl). For example, the term “C1-6 alkyl” refers to alkyl containing 1 to 6 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl and 2-methylpentyl). The alkyl moieties (namely alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio are similarly defined as above.
The term “alkoxyl” refers to —O-alkyl.
The term “aminoalkyl” refers to -alkyl-NH2.
The term “alkylacyl” refers to —C(O)-alkyl.
The term “alkylsulfonyl” refers to —SO2-alkyl.
The term “alkenyl” refers to linear or branched unsaturated aliphatic hydrocarbyl consisting of carbon atoms and hydrogen atoms with at least one double bond. The alkenyl herein may contain 2-10 carbon atoms (C2-C10 alkenyl), 2-6 carbon atoms (C2-C6 alkenyl), or 2-4 carbon atoms (C2-C4 alkenyl). Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
The term “alkynyl” refers to linear or branched unsaturated aliphatic hydrocarbyl consisting of carbon atoms and hydrogen atoms with at least one triple bond. The alkynyl herein may contain 2-10 carbon atoms (C2-C10 alkynyl), 2-6 carbon atoms (C2-C6 alkynyl), or 2-4 carbon atoms (C2-C4 alkynyl). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propinyl, 2-propinyl, 1,3-butadiynyl (—C≡C—C≡CH), and the like.
The term “cycloalkyl” refers to a carbon ring that is fully saturated and may exist as a monocyclic, bridged cyclic or spiro cyclic structure. The cycloalkyl herein may be 3-12 membered cycloalkyl, 3-10 membered cycloalkyl, 5-10 membered cycloalkyl, 3-8 membered cycloalkyl or 3-6 membered cycloalkyl. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.
The term “heterocyclyl” refers to a fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic group) nonaromatic ring which may exist in the form of a monocyclic, bridged cyclic, or spiro cyclic structure. The heterocyclyl herein may be a 3-7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, silicon, phosphorus, oxygen and/or nitrogen. The heterocyclyl herein may be 4-12 membered heterocyclyl, 4-8 membered heterocyclyl, 5-6 membered heterocyclyl, 4-5 membered heterocyclyl or 6 membered heterocyclyl containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen and/or nitrogen. The “5-6 membered monoheterocyclyl whose ring atoms consist of a nitrogen atom and a carbon atom” herein may contain 1 or 2 nitrogen atoms. The “5-6 membered monoheterocyclyl whose ring atoms contain a silicon atom or a phosphorus atom” herein may contain 1 silicon atom or 1 phosphorus atom and 1 or 2 heteroatoms selected from the group consisting of N, O and S. Non-limiting examples of heterocyclyl include, but are not limited to, oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, sulfomorpholinyl, tetrahydrothienyl,
and the like.
The term “heterocycloalkyl” refers to a fully saturated cyclic group that may exist in the form of a monocyclic, bridged cyclic, or spiro cyclic structure. The heterocycloalkyl herein may be a 3-7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, silicon, phosphorus, oxygen and/or nitrogen. The heterocycloalkyl herein may be 4-12 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, 5-6 membered heterocycloalkyl, 4-5 membered heterocycloalkyl or 6 membered heterocycloalkyl containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen and/or nitrogen. Examples of 3 membered heterocycloalkyl include, but are not limited to, oxiranyl, thiiranyl, and aziranyl; non-limiting examples of 4 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5 membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6 membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-oxathianyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl,
examples of 7 membered heterocycloalkyl include, but are not limited to, azacycloheptanyl, oxacycloheptanyl and thiocycloheptanyl. Preferably, the heterocycloalkyl is a monocyclic heterocycloalkyl having 5 or 6 ring atoms.
The term “monoheterocyclyl” refers to a monocyclic ring that is fully saturated or partially unsaturated (but not fully saturated aromatic) and has 3 to 10 ring atoms, or 4 to 6 ring atoms. The monoheterocyclyl herein may be a 3-10 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, silicon, phosphorus, oxygen and/or nitrogen. The monoheterocyclyl herein may be a 3-10 membered ring, a 3-8 membered ring, a 3-7 membered ring or a 4-6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen and/or nitrogen.
Non-limiting examples of the mono-heterocyclic ring include an oxirane ring, a tetrahydrofuran ring, a dihydrofuran ring, a 3,4-dihydrofuran ring, a 3,6-dihydrofuran ring, a tetrahydropyrrole ring, a dihydropyrrole ring, a piperidine ring, a piperazine ring, a morpholine ring, a tetrahydropyrazole ring, a tetrahydrothiophene ring, and the like.
The term “monoheterocycloalkyl” refers to a fully saturated monocyclic ring having 3 to 10 ring atoms, or 4 to 6 ring atoms. The monoheterocycloalkyl herein may be a 3-10 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, silicon, phosphorus, oxygen and/or nitrogen. The monoheterocycloalkyl herein may be a 3-10 membered, 3-8 membered, 3-7 membered or 4-6 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen and/or nitrogen. Non-limiting examples of monoheterocycloalkyl include an oxirane ring, a tetrahydrofuran ring, a tetrahydropyrrole ring, a piperidine ring, a piperazine ring, a morpholine ring, a tetrahydropyrazole ring, a tetrahydrothiophene ring, and the like.
The term “spirocyclyl” refers to a polycyclic ring that is fully saturated or partially unsaturated (but not fully saturated aromatic) and shares a common carbon atom (referred to as a spiro atom) between 5-20 membered monocyclic rings. The spirocyclyl is preferably 6-14 membered, more preferably 6-10 membered, 7-9 membered or 10 membered. According to the number of spiro atoms shared among the rings, the spiro cyclic ring may be a monospiro cyclic ring, a bispiro cyclic ring or a polyspiro cyclic ring, preferably a monospiro cyclic ring or a bispiro cyclic ring, and more preferably a 4 membered/4 membered, 4 membered/5 membered, 4 membered/6 membered, 5 membered/5 membered or 5 membered/6 membered monospiro cyclic ring. Non-limiting examples of spiro cyclic ring include
The term “spiro-cycloalkyl” refers to fully saturated spiro-cyclyl.
The term “spiro-heterocyclyl” refers to a spiro ring whose one or more ring atoms are heteroatoms selected from the group consisting of sulfur, silicon, phosphorus, oxygen and/or nitrogen (preferably 1 or 2 heteroatoms, preferably selected from the group consisting of N, O and/or S), the remaining ring atoms being carbon. The spiro-heterocyclyl is preferably 6-14 membered, more preferably 6-10 membered, or 7-9 membered or 10 membered. According to the number of spiro atoms shared among the rings, the spiro heterocyclic ring may be a monospiro heterocyclic ring, a bispiro heterocyclic ring or a polyspiro heterocyclic ring, preferably a monospiro heterocyclic ring or a bispiro heterocyclic ring, and more preferably a 4 membered/4 membered, 4 membered/5 membered, 4 membered/6 membered, 5 membered/5 membered or 5 membered/6 membered monospiro heterocyclic ring, preferably each ring contains 1 heteroatom selected from the group consisting of N, O and/or S. Non-limiting examples of spiro heterocyclic ring include
The term “spiro-heterocycloalkyl” refers to fully saturated spiro-heterocyclyl.
The term “bridged cyclyl” refers to an all-carbon polycyclic ring that is fully saturated or partially unsaturated (but not fully saturated aromatic) and has 5 to 20 ring atoms with the two rings sharing 3 or more ring atoms. The bridged cyclyl is preferably a 6-14 membered polycyclic ring, and more preferably a 6-10 membered polycyclic ring. According to the number of the formed rings, the bridged ring may be bicyclic, tricyclic, tetracyclic or polycyclic bridged ring, preferably bicyclic or tricyclic bridged ring, and more preferably bicyclic bridged ring. Non-limiting examples of the bridged ring include
The term “bridged cycloalkyl” refers to a fully saturated bridged cyclyl.
The term “bridged heterocyclyl” refers to a bridged ring in which one or more ring atoms are heteroatoms selected from the group consisting of sulfur, silicon, phosphorus, oxygen and/or nitrogen (preferably 1 or 2 heteroatoms, preferably selected from the group consisting of N, O and/or S), the remaining ring atoms being carbon. The bridged heterocyclyl is preferably 6-14 membered, and more preferably 6-10 membered, 7-9 membered, 7 membered or 8 membered. According to the number of the formed rings, the bridged heterocyclic ring may be bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic ring, preferably bicyclic or tricyclic bridged heterocyclic ring, and more preferably bicyclic bridged heterocyclic ring. Non-limiting examples of bridged heterocyclic ring include
The term “bridged heterocycloalkyl” refers to a fully saturated bridged heterocyclyl.
The term “fused cyclyl” refers to an all-carbon polycyclic ring that is fully saturated or partially unsaturated (but not fully saturated aromatic) and has 5 to 20 ring atoms with the two rings sharing 2 ring atoms. The fused cyclyl is preferably a 6-14 membered polycyclic ring, and more preferably a 6-10 membered polycyclic ring. According to the number of the formed rings, the fused ring may be bicyclic, tricyclic, tetracyclic or polycyclic fused ring, preferably bicyclic or tricyclic fused ring, and more preferably bicyclic fused ring. Non-limiting examples of fused ring include
The term “fused cycloalkyl” refers to a fully saturated fused cyclyl.
The term “fused-heterocyclyl” refers to a fused ring in which one or more ring atoms are heteroatoms selected from the group consisting of sulfur, silicon, phosphorus, oxygen and/or nitrogen (preferably 1 or 2 heteroatoms, preferably selected from the group consisting of N, O and/or S), the remaining ring atoms being carbon. The fused-heterocyclyl is preferably 6-14 membered, and more preferably 6-10 membered, 7-10 membered, 7 membered, 8 membered or 9 membered. According to the number of the formed rings, the bridged heterocyclic ring may be bicyclic, tricyclic or polycyclic bridged heterocyclic ring, preferably bicyclic bridged heterocyclic ring. Non-limiting examples of fused ring include
The term “fused heterocycloalkyl” refers to a fully saturated fused-heterocyclyl.
The groups described above each may be optionally substituted with one or more (e.g., 1, 2, or 3) substituents including, but not limited to, deuterium, hydroxy, halogen (F, Cl, Br, or I), , C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, and C1-C6 alkylacyl-N(C1-C6 alkyl)-.
The term “treating” or “treatment” means administering the compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
The term “therapeutically effective amount” refers to an amount of the compound disclosed herein for (i) treating a specific disease, condition, or disorder, or (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specific disease, condition, or disorder. The amount of the compound of the present application composing the “therapeutically effective amount” varies dependently on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but can be determined routinely by those skilled in the art in accordance with their knowledge and the present disclosure.
Therapeutic dosages of the compounds disclosed herein may be determined by, for example, the specific use of a treatment, the route of administration of the compound, the health and condition of a patient, and the judgment of a prescribing physician. The proportion or concentration of the compound disclosed herein in a pharmaceutical composition may not be constant and depends on a variety of factors including dosages, chemical properties (e.g., hydrophobicity), and routes of administration. For example, the compound of the present application may be provided for parenteral administration by a physiological buffered aqueous solution containing about 0.1-10% w/v of the compound. Certain typical dosage ranges from about 1 μg/kg body weight/day to about 1 g/body weight/day. In certain embodiments, the dosage ranges from about 0.01 mg/kg body weight/day to about 100 mg/kg body weight/day. The dosage is likely to depend on such variables as the type and degree of progression of the disease or disorder, the general health condition of the particular patient, the relative biological potency of the compound selected, the excipient formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
The term “pharmaceutically acceptable” is used herein for those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt, for example, may be a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, and the like.
The term “pharmaceutical composition” refers to a mixture consisting of one or more of the compounds or the salts thereof disclosed herein and a pharmaceutically acceptable excipient. The pharmaceutical composition is intended to facilitate the administration of the compound to an organic entity. The pharmaceutical compositions of the present invention may be prepared by conventional methods in the art, for example, by mixing the compound of the present application or a salt thereof with one or more pharmaceutically acceptable excipients.
The term “pharmaceutically acceptable excipients” refers to those which do not have a significant irritating effect on an organic entity and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrate, wax, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic material, gelatin, oil, solvent and water.
The word “comprise” and variations thereof such as “comprises” or “comprising” will be understood in an open, non-exclusive sense, i.e., “including but not limited to”.
The compounds and intermediates disclosed herein may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, a proton tautomer (also referred to as prototropic tautomer) includes interconversion via proton transfer, such as keto-enol isomerism and imine-enamine isomerism. A specific example of a proton tautomer is an imidazole moiety where a proton can transfer between two ring nitrogens. A valence tautomer includes the interconversion via recombination of some bonding electrons.
The present application also comprises isotopically labeled compounds which are identical to those recited herein but have one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 35S, 31P, 32P, 35S, 18F, 123I, 125I and 36Cl.
Certain isotopically labeled compounds disclosed herein (e.g., those labeled with 3H and 14C) can be used to analyze compounds and/or substrate tissue distribution. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15O, 13N, 11C and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds disclosed herein can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below while substituting a non-isotopically labeled reagent with an isotopically-labeled reagent.
Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage) resulting from greater metabolic stability and hence may be preferred in some circumstances in which deuterium substitution may be partial or complete, wherein partial deuterium substitution refers to substitution of at least one hydrogen with at least one deuterium. The hydrogens in the exemplary methyl are all deuterated to form methyl-d3, but not limited thereto.
The compound disclosed herein can be asymmetrical, for example, has one or more stereoisomers.
Unless otherwise stated, all stereoisomers are included, for example, enantiomers and diastereoisomers. The compound with asymmetric carbon atoms disclosed herein can be separated in an optically pure form or in a racemic form. The optically pure form can be separated from a racemic mixture or can be synthesized using a chiral raw material or a chiral reagent. For example, the
contained in the structure of the compound is the (R)-and (S)-enantiomers.
Unless otherwise stated, the absolute configuration of a stereogenic center is represented by a wedged solid bond () and a wedged dashed bond (
), and the relative configuration of a stereogenic center is represented by a straight solid bond (
) and a straight dashed bond (
). A wavy line (
) represents a wedged solid bond (
) or a wedged dashed bond (
), or a wavy line (
) represents a straight solid bond (
) and a straight dashed bond (
).
Unless otherwise stated, when a double bond structure such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond is present in the compound, and each atom on the double bond is linked to two different substituents (in the double bond including a nitrogen atom, a lone pair of electrons on the nitrogen atom is regarded as a substituent to which the nitrogen atom is linked), if the atom on the double bond of the compound and its substituents are linked using a wavy line (), means that the compound exists in the form of a (Z)-type isomer, an (E)-type isomer, or a mixture of the two isomers.
The pharmaceutical composition disclosed herein can be prepared by combining the compound disclosed herein with a suitable pharmaceutically acceptable excipient, and can be formulated, for example, into a solid, semisolid, liquid, or gaseous formulation such as tablet, pill, capsule, powder, granule, ointment, emulsion, suspension, suppository, injection, inhalant, gel, microsphere and aerosol.
Typical routes of administration of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof of the present application include, but are not limited to, oral, rectal, local, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous and intravenous administration.
The pharmaceutical composition disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, and lyophilizing.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound disclosed herein to be formulated into tablets, pills, pastilles, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to a patient.
A solid oral composition can be prepared by conventional mixing, filling or tableting. For example, it can be obtained by the following method: mixing the active compounds with solid excipients, optionally grinding the resulting mixture, adding additional suitable excipients if desired, and processing the mixture into granules to get the core parts of tablets or dragees. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents and the like.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
The compounds of the present application can be prepared using a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art. The preferred embodiments include, but are not limited to, the examples of the present application.
The chemical reactions of the embodiments disclosed herein are carried out in a proper solvent that must be suitable for the chemical changes in the present application and the reagents and materials required. In order to acquire the compounds disclosed herein, it is sometimes necessary for those skilled in the art to modify or select a synthesis procedure or a reaction scheme based on the existing embodiments.
An important consideration in synthesis route planning in the art is the selection of suitable protecting groups for reactive functional groups (e.g., amino in the present application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc. All references cited herein are incorporated by reference in their entirety. In some embodiments, the compound of formula (I) disclosed herein may be prepared by one skilled in the art of organic synthesis using standard methods in the art by the following routes:
wherein,
R1, R1′, R2, R2′ and R3 are defined as above.
For clarity, the present application is further described with the following examples, which are, however, not intended to limit the scope of the invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific examples of the present invention without departing from the spirit and scope of the present invention. All reagents are commercially available and can be used without further purification.
N,N-diisopropylethylamine (13.4 g) was added slowly dropwise to a solution of 2,6-dichloro-3-nitropyridine (20.0 g) and tert-butyl (1-(4-aminophenyl)cyclobutyl)carbamate (25.5 g) in tetrahydrofuran at −30° C. under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 1A (43.4 g).
MS (ESI, [M+Na]+) m/z: 441.5.
To a reaction flask were added compound 1A (40.0 g), zinc powder (31.2 g), ammonium chloride (5.1 g), ethanol (400 mL) and water (40 mL) successively at room temperature. After the addition was completed, the reaction solution was reacted at 90° C. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1B (41.0 g).
MS (ESI, [M+H]+) m/z: 389.3.
To a reaction flask were added compound 1B (34.0 g), 2-aminonicotinaldehyde (11.2 g), sodium perborate (14.3 g), acetic acid (250 mL) and methanol (30 mL) successively at room temperature. After the addition was completed, the reaction solution was stirred at 55° C. After the reaction was completed, the reaction solution was concentrated, and added with ethyl acetate and water; then the pH of the reaction solution was adjusted to 11-12 with an aqueous sodium hydroxide solution. The reaction solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=50/1) to give compound 1C (16.0 g).
MS (ESI, [M+H]+) m/z: 491.3.
2-butynoic acid (1.00 g), 2-(7-azabenzotriazole)-0′-tetramethyluronium hexafluorophosphate (4.97 g) and dichloromethane (50 mL) were added to a reaction flask successively, and a solution of N,N-diisopropylethylamine (3.07 g) and 2-(3-bromophenyl)-pyrrolidine (2.96 g) in dichloromethane (30 mL) was slowly added dropwise to the reaction flask at 0° C. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, a saturated aqueous ammonium chloride solution was added to the reaction solution, the phases were separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 1D (3.92 g).
MS (ESI, [M+H]+) m/z: 292.0.
To a reaction flask were added compound 1D (0.92 g), bis(pinacolato)diboron (1.20 g), potassium acetate (0.93 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.13 g) and 1,4-dioxane (15 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (petroleum ether/ethyl acetate=2/1) to give compound 1E (0.38 g).
MS (ESI, [M+H]+) m/z: 340.2.
To a microwave tube were added compound 1E (0.17 g), compound 1C (0.12 g), potassium carbonate (0.11 g), tetrakis(triphenylphosphine)palladium (0.03 g), 1,4-dioxane (3 mL) and water (0.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. in microwave reactor for 2 h. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 1F (68 mg).
MS (ESI, [M+Na]+) m/z: 690.6.
Compound 1F (68 mg), methanesulfonic acid (0.1 mL) and dichloromethane (4 mL) were added successively to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 1 (18 mg).
HRMS (ESI, [M+H]+) m/z: 568.2823.
1H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J=8.3 Hz, 1H), 8.05-7.95 (m, 2H), 7.94-7.79 (m, 2H), 7.71-7.63 (m, 2H), 7.58-7.50 (m, 2H), 7.46-7.38 (m, 1H), 7.31-7.16 (m, 2H), 6.93 (d, J=8.5 Hz, 2H), 6.46-6.42 (m, 1H), 5.24-5.02 (m, 1H), 3.83 (t, J=6.9 Hz, 1H), 3.65-3.54 (m, 1H), 2.62-2.52 (m, 2H), 2.45-2.30 (m, 3H), 2.18-2.09 (m, 1H), 1.94-1.73 (m, 4H), 1.87 (s, 3H).
A solution of acryloyl chloride (1.08 g) in tetrahydrofuran (10 mL) was slowly added to a reaction solution of 3-bromobenzylamine (2.00 g) and N,N-diisopropylethylamine (1.63 g) in tetrahydrofuran (90 mL) in a reaction flask at −10° C. under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at room temperature until the reaction was completed. The reaction solution was added with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate; the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 2A (2.58 g).
MS (ESI, [M+H]+) m/z: 240.1.
To a reaction flask were added compound 2A (2.00 g), bis(pinacolato)diboron (3.17 g), potassium acetate (2.45 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.68 g) and 1,4-dioxane (30 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 2B (1.89 g).
MS (ESI, [M+H]+) m/z: 288.1.
To a microwave tube were added compound 2B (0.14 g), compound 1C (0.12 g), potassium carbonate (0.11 g), tetrakis(triphenylphosphine)palladium (0.028 g), 1,4-dioxane (3 mL) and water (0.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 2C (85 mg).
MS (ESI, [M+H]+) m/z: 616.5.
1H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J=8.3 Hz, 1H), 8.05-7.95 (m, 2H), 7.94-7.79 (m, 2H), 7.71-7.63 (m, 2H), 7.58-7.50 (m, 2H), 7.42 (dt, J=26.0, 7.7 Hz, 1H), 7.31-7.16 (m, 2H), 6.93 (d, J=8.5 Hz, 2H), 6.46-6.42 (m, 1H), 5.24-5.02 (m, 1H), 3.83 (t, J=6.9 Hz, 1H), 3.65-3.54 (m, 1H), 2.62-2.52 (m, 2H), 2.45-2.30 (m, 3H), 2.18-2.09 (m, 1H), 1.94-1.73 (m, 4H), 1.87 (s, 3H).
Compound 2C (80 mg), methanesulfonic acid (0.1 mL) and dichloromethane (4 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 2 (45 mg).
HRMS (ESI, [M+H]+) m/z: 516.2516.
1H NMR (500 MHz, DMSO-d6) δ 8.67 (t, J=6.0 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.01 (dd, J=4.8, 1.8 Hz, 1H), 7.98-7.88 (m, 3H), 7.67-7.59 (m, 2H), 7.50-7.40 (m, 3H), 7.30 (dt, J=7.6, 1.3 Hz, 1H), 7.21 (dd, J=7.6, 1.9 Hz, 1H), 6.94 (s, 2H), 6.42 (dd, J=7.7, 4.9 Hz, 1H), 6.31 (dd, J=17.1, 10.2 Hz, 1H), 6.15 (dd, J=17.1, 2.2 Hz, 1H), 5.65 (dd, J=10.2, 2.2 Hz, 1H), 4.43 (d, J=5.9 Hz, 2H), 2.49-2.43 (m, 2H), 2.23-2.13 (m, 2H), 2.11-2.00 (m, 1H), 1.77-1.69 (m, 1H).
A solution of acryloyl chloride (2.98 g) in tetrahydrofuran (10 mL) was slowly added to a stirred solution of p-bromophenylamine (5.00 g) and N,N-diisopropylethylamine (4.51 g) in tetrahydrofuran (90 mL) in a reaction flask at −10° C. under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at room temperature until the reaction was completed. The reaction solution was added with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate; the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 3A (5.90 g).
MS (ESI, [M+H]+) m/z: 226.1.
To a reaction flask were added compound 3A (0.5 g), bis(pinacolato)diboron (0.84 g), potassium acetate (0.65 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.18 g) and 1,4-dioxane (20 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (petroleum ether/ethyl acetate=2/1) to give compound 3B (0.26 g).
MS (ESI, [M+H]+) m/z: 274.5.
To a microwave tube were added compound 3B (0.13 g), compound 1C (0.12 g), potassium carbonate (0.11 g), tetrakis(triphenylphosphine)palladium (0.028 g), 1,4-dioxane (3 mL) and water (0.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. in microwave reactor for 2 h. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 3C (78 mg).
MS (ESI, [M+H]+) m/z: 602.4.
Compound 3C (70 mg), methanesulfonic acid (0.1 mL) and dichloromethane (4 mL) were added successively to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 3 (34 mg).
HRMS (ESI, [M+H]+) m/z: 502.2343.
1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.99-7.91 (m, 3H), 7.88 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.12 (dd, J=7.7, 1.8 Hz, 1H), 6.90 (s, 2H), 6.45-6.30 (m, 2H), 6.21 (dd, J=16.9, 2.0 Hz, 1H), 5.70 (dd, J=10.0, 2.0 Hz, 1H), 2.42-2.36 (m, 2H), 2.15-2.07 (m, 2H), 2.05-1.95 (m, 1H), 1.71-1.62 (m, 1H).
2-Chloroacetyl chloride (3.24 g) was added dropwise to a reaction solution of 2-amino-4-bromophenol (3.60 g) and sodium carbonate (3.22 g) in tetrahydrofuran (60 mL) in an ice-water bath under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=3/1) to give compound 4A (3.60 g).
MS (ESI, [M−H]−) m/z: 226.1; MS (ESI, [M+H]+) m/z: 228.0.
A solution of 1 M borane in tetrahydrofuran (516 mg) was added slowly to a solution of compound 4A (452 mg) in tetrahydrofuran (10 mL) in an ice-water bath under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 70° C. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate, and the reaction solution was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to give compound 4B (380 mg).
MS (ESI, [M+H]+) m/z: 214.3.
To a reaction flask were added [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (123 mg), compound 4B (320 mg), bis(pinacolato)diboron (508 mg), potassium carbonate (294 mg) and dioxane (5 mL) successively. The reaction solution was reacted at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=3/1) to give compound 4C (242 mg).
MS (ESI, [M+H]+) m/z: 262.4.
To a reaction flask were added compound 4C (200 mg), potassium carbonate (270 mg), tetrakis(triphenylphosphine)palladium (47 mg), compound 1C (320 mg), water (0.5 mL), and dioxane (5 mL) successively. After the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=98/2) to give compound 4D (260 mg).
To the reaction flask were added compound 4D (260 mg), methanesulfonic acid (0.5 mL), and dichloromethane (5 mL) successively. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 7 to 9 with saturated aqueous sodium bicarbonate, the reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=95/5) to give compound 4 (135 mg).
HRMS (ESI, [M+H]+) m/z: 490.2360.
1H NMR (500 MHz, DMSO-d6): δ 8.16 (d, J=5.0 Hz, 1H), 7.99 (dd, J=5.0 Hz, 10.0 Hz, 1H), 7.75 (d, J=10.0 Hz, 1H), 7.61 (d, J=10.0 Hz, 1H), 7.41 (d, J=10.0 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H), 7.16-7.14 (m, 2H), 6.94 (s, 2H), 6.71 (d, J=5.0 Hz, 1H), 6.39 (q, J=5.0 Hz, 1H), 5.88 (s, 1H), 4.14 (t, J=5.0 Hz, 2H), 3.30 (d, J=10.0 Hz, 2H), 2.46-2.14 (m, 2H), 2.13 (br, 2H), 2.12-2.03 (m, 3H), 1.78-1.72 (m, 1H).
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (279 mg), tris(dibenzylideneacetone)dipalladium (274 mg), 1,3-dibromobenzene (705 mg), 4,4-dimethyl-1,4-silapiperidine (386 mg), sodium tert-butoxide (431 mg) and toluene (10 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 115° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=95/5) to give compound 5A (475 mg). The compound was directly used in the next step without purification.
To a reaction flask were added [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (63.9 mg), compound 5A (475 mg), bis(pinacolato)diboron (795 mg), potassium acetate (461 mg) and dioxane (8 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 5B (450 mg).
MS (ESI, [M+H]+) m/z: 332.5.
To a reaction flask were added compound 5B (311 mg), potassium carbonate (287 mg), compound 1C (340 mg), water (1 mL), and dioxane (10 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=96/4) to give compound 5C (280 mg).
MS (ESI, [M+H]+) m/z: 660.7.
In a reaction flask, methanesulfonic acid (200 mg) was slowly added to a solution of compound 5C (280 mg) in dichloromethane (5 mL). After the addition was completed, the reaction solution was reacted at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 7 to 9 with saturated aqueous sodium bicarbonate, the reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=95/5) to give compound 5 (120 mg).
MS (ESI, [M+H]+) m/z: 560.6.
1H NMR (500 MHz, DMSO-d6): δ 8.16 (d, J=10.0 Hz, 1H), 7.96-7.95 (m, 1H), 7.85 (d, J=5.0 Hz, 1H), 7.54 (d, J=10.0 Hz, 1H), 7.47 (s, 1H), 7.38 (d, J=5.0 Hz, 1H), 7.21-7.17 (m, 3H), 6.97 (br, 2H), 6.82 (q, J=5.0 Hz, 1H), 6.37 (q, J=5.0 Hz, 1H), 3.63-3.61 (m, 4H), 2.38-2.32 (m, 2H), 2.17 (br, 2H), 2.09-2.03 (m, 2H), 2.00-1.93 (m, 1H), 1.64-1.61 (m, 1H), 0.67-0.65 (m, 4H), 0.001 (s, 6H).
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.475 g), tris(dibenzylideneacetone)dipalladium (0.466 g), 1,3-dibromobenzene (1.200 g), 7-oxa-2-azaspiro[3.5]nonane (0.647 g), sodium tert-butoxide (0.733 g) and toluene (10 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 115° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=85/15) to give compound 6A (780 mg).
To a reaction flask were added [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (339 mg), compound 6A (780 mg), bis(pinacolato)diboron (1404 mg), potassium acetate (814 mg) and dioxane (8 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 6B (520 mg).
MS (ESI, [M+H]+) m/z: 330.5.
To a reaction flask were added compound 6B (520 mg), potassium carbonate (220 mg), tetratriphenylphosphine (36 mg), compound 1C (260 mg), water (0.50 mL), and dioxane (10 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=98/2) to give compound 6C (240 mg).
MS (ESI, [M+H]+) m/z: 658.7.
To a reaction flask were added methanesulfonic acid (331 mg), compound 6C (240 mg), and dichloromethane (5 mL) successively, and after the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to 7 to 9 with saturated aqueous sodium bicarbonate, the reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=95/5) to give compound 6 (140 mg).
MS (ESI, [M+H]+) m/z: 558.6.
1H NMR (500 MHz, DMSO-d6): δ 8.45 (d, J=5.0 Hz, 1H), 8.22 (t, J=5.0 Hz, 2H), 8.11-8.10 (m, 1H), 8.08 (d, J=10.0 Hz, 1H), 8.01 (dd, J=5.0 Hz, 10.0 Hz, 1H), 7.82-7.78 (m, 2H), 7.72-7.70 (m, 2H), 7.65 (t, J=10.0 Hz, 1H), 7.55 (dd, J=5.0 Hz, 10.0 Hz, 1H), 6.98 (t, J=10.0 Hz, 1H), 4.34 (s, 4H), 3.59-3.57 (m, 4H), 2.66 (t, J=5.0 Hz, 4H), 2.55 (t, J=5.0 Hz, 4H), 1.97 (t, J=5.0 Hz, 4H).
1,1′-binaphthyl-2,2′-diphenyl phosphine (367 mg), bis(dibenzylideneacetone)palladium (270 mg), 1,3-dibromobenzene (695 mg), tert-butyl (R)-3-(methylamine)pyrrole-1-carboxylate (590 mg), sodium tert-butoxide (566 mg) and dioxane (15 mL) were successively added to a reaction flask under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=95/5) to give compound 7A (642 mg).
MS (ESI, [M-55+H]+) m/z: 299.1.
To a reaction flask were added compound 7A (640 mg), dichloromethane (5 mL) and a solution of 4 M hydrogen chloride in dioxane (3 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at room temperature until the reaction was completed, and the solvent was removed by distillation under the reduced pressure to give compound 7B (680 mg).
To a reaction flask were added compound 7B (680 mg), tetrahydrofuran (20 mL), N-diisopropylethylamine (581 mg), and acetyl chloride (300 mg) separately. After the addition was completed, the reaction solution was reacted at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 7C (430 mg).
MS (ESI, [M+H]+) m/z: 297.4.
To a reaction flask were added [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (154 mg), compound 7C (360 mg), bis(pinacolato)diboron (478 mg), potassium acetate (370 mg) and dioxane (8 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 110° C. The reaction was completed, the reaction was quenched by saturated brine, the reaction solution was extracted by ethyl acetate, organic phases were combined, the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=90/10) to give compound 7D (440 mg).
MS (ESI, [M+H]+) m/z: 345.6.
To a reaction flask were added tetrakis(triphenylphosphine)palladium (99 mg), compound 1C (420 mg), compound 7D (294 mg), potassium carbonate (236 mg), dioxane (5 mL), and water (0.5 mL) successively. After the addition was completed, the reaction solution was heated and reacted at 120° C. After the starting materials were reacted completely, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=98/2) to give compound 7E (540 mg).
MS (ESI, [M+H]+) m/z: 673.7.
To the reaction flask were added compound 7E (490 mg), dichloromethane (6 mL) and methanesulfonic acid (420 mg) successively. After the addition was completed, the reaction solution was reacted at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to be neutral by using sodium bicarbonate, the reaction solution was extracted with dichloromethane, and the organic phase were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=96/4) to give compound 7 (30 mg).
MS (ESI, [M+H]+) m/z: 573.4.
1H NMR (500 MHz, DMSO-d6): δ 8.23 (d, J=3.5 Hz, 1H), 8.01-7.96 (m, 2H), 7.62-7.60 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 7.45 (d, J=6.5 Hz, 1H), 7.29-7.22 (m, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.42 (t, J=6.5 Hz, 1H), 4.58-4.47 (m, 1H), 3.69-3.40 (m, 3H), 3.28-3.25 (m, 2H), 2.83-2.80 (m, 3H), 2.50 (s, 3H), 2.15-2.08 (m, 3H), 2.06-2.00 (m, 2H), 1.96-1.85 (m, 3H).
A solution of N,N-diethyl-1,1,1-trifluoro-14-thiamine (20.890 g) in 1,2-dichloroethane (25 mL) was slowly added dropwise to a reaction flask containing tert-butyl 3-oxopyrrolidine-1-carboxylate (4.000 g) under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to give compound 8A (2.510 g).
MS (ESI, [M+H]+) m/z: 208.0.
To a reaction flask were added compound 8A (1.000 g), a solution of 1,4-dioxane (2 mL), and a solution of 4 M hydrochloric acid in 1,4-dioxane (9.50 mL) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 8B (0.512 g).
To a reaction flask were added sodium tert-butoxide (0.928 g), tris(dibenzylideneacetone)dipalladium (0.442 g), 3,3-difluoropyrrolidine (0.517 g), 1,3-dibromobenzene (2.279 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.451 g) and toluene (30 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=95/5) to give compound 8C (1.199 g).
To a reaction flask were added compound 8C (1.150 g), potassium carbonate (1.227 g), bis(pinacolato)diboron (1.587 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.170 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.451 g), and N,N-dimethylformamide (30 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=90/10) to give compound 8D (0.779 g).
MS (ESI, [M+H]+) m/z: 310.2.
To a reaction flask were added compound 8D (0.307 g), potassium carbonate (0.115 g), compound 1C (0.210 g), tetrakis(triphenylphosphine)palladium (0.048 g), 1,4-dioxane (16.00 mL), and water (4.00 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 140° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=98/3) to give compound 8E (0.140 g).
MS (ESI, [M+H]+) m/z: 638.4.
To a reaction flask were added compound 8E (0.140 g), dichloromethane (10 mL) and methanesulfonic acid (0.160 g) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=93/7) to give compound 8 (98 mg).
MS (ESI, [M+H]+) m/z: 538.6.
1H NMR (500 MHz, DMSO-d6) δ 8.24 (d, J=8.4 Hz, 1H), 8.00 (t, J=7.6 Hz, 2H), 7.64 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.40 (d, J=7.7 Hz, 1H), 7.27 (dq, J=13.3, 7.8 Hz, 3H), 7.02 (s, 2H), 6.66 (d, J=8.1 Hz, 1H), 6.43 (dd, J=7.7, 4.7 Hz, 1H), 3.74 (t, J=13.3 Hz, 2H), 3.53 (t, J=7.2 Hz, 2H), 2.55 (dd, J=1.6, 10.3 Hz, 2H), 2.44 (t, J=8.6 Hz, 2H), 2.24-2.10 (m, 2H), 2.11-2.00 (m, 1H), 1.72 (dd, J=11.4, 6.5 Hz, 1H).
Hexahydropyrrolo[1,2-A]pyrazin-6-one hydrochloride (0.230 g), 1,3-dibromobenzene (0.774 g), tris(dibenzylideneacetone)dipalladium (0.150 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.153 g), sodium tert-butoxide (0.552 g) and toluene (7.5 mL) were added successively to a reaction flask under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=4/6) to give compound 9A (0.100 g).
MS (ESI, [M+H]+) m/z: 295.4296.3.
To a reaction flask were added potassium carbonate (0.249 g), bis(pinacolato)diboron (0.332 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.027 g), compound 9A (0.260 g), and N,N-dimethylformamide (20.00 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 70° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 9B (0.112 g).
MS (ESI, [M+H]+) m/z: 343.5.
To a reaction flask were added compound 9B (0.268 g), compound 1C (0.145 g), potassium carbonate (0.079 g), tetrakis(triphenylphosphine)palladium (0.033 g), 1,4-dioxane (4 mL), and water (7.5 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=93/7) to give compound 9C (0.130 g).
MS (ESI, [M+H]+) m/z: 671.7.
To the reaction flask were added compound 9C (0.130 g), dichloromethane (10 mL) and methanesulfonic acid (0.149 g) successively. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=93/7) to give compound 9 (0.047 g).
MS (ESI, [M+H]+) m/z: 571.5.
1H NMR (500 MHz, DMSO-d6) δ 8.25 (d, J=8.4 Hz, 1H), 8.09-7.95 (m, 2H), 7.74-7.60 (m, 3H), 7.53-7.41 (m, 3H), 7.31 (t, J=7.9 Hz, 1H), 7.24 (dd, J=7.6, 1.9 Hz, 1H), 7.14-7.02 (m, 1H), 6.98 (s, 2H), 6.43 (dd, J=7.7, 4.8 Hz, 1H), 4.55 (s, 2H), 3.95-3.85 (m, 2H), 3.81-3.73 (m, 1H), 3.69 (dtd, J=10.8, 7.1, 3.7 Hz, 1H), 2.93 (td, J=12.6, 3.8 Hz, 1H), 2.61 (td, J=12.2, 3.6 Hz, 1H), 2.49-2.42 (m, 2H), 2.35-2.21 (m, 4H), 2.16 (tdd, J=13.9, 7.7, 3.8 Hz, 1H), 2.09 (ddd, J=11.1, 5.2, 2.4 Hz, 1H), 1.75 (dtt, J=11.0, 9.0, 6.2 Hz, 1H), 1.69-1.59 (m, 1H), 0.90-0.80 (m, 1H).
To a reaction flask were added 1,3-dibromobenzene (2.356 g), tert-butyl 3-methylpiperazine-1-carboxylate (1.000 g), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.280 g), tris(dibenzylideneacetone)dipalladium (0.320 g), sodium tert-butoxide (1.440 g) and toluene (30 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 70° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=10/1) to give compound 10A (0.927 g).
MS (ESI, [M+H]+) m/z: 355.3.
To a reaction flask were added compound 10A (0.494 g), trifluoroacetic acid (6.440 g), 3-oxetanone (0.150 g), sodium cyanoborohydride (0.175 g), dichloromethane (2 mL) and methanol (2 mL) successively at room temperature. After the addition was completed, the reaction solution was stirred for reaction. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=9/1) to give compound 10B (0.300 g).
To a reaction flask were added compound 10B (0.300 g), potassium carbonate (0.275 g), bis(pinacolato)diboron (0.356 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.035 g) and N,N-dimethylformamide (34.00 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 70° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 10C (0.403 g).
MS (ESI, [M+H]+) m/z: 359.5.
To a reaction flask were added compound 10C (0.394 g), tert-butyl (1-(4-(((6-chloro-3-nitropyridin-2-yl)amino)phenyl)cyclobutyl)carbamate (0.522 g), tetrakis(triphenylphosphine)palladium (0.059 g), saturated sodium bicarbonate solution (2.50 mL), ethanol (20 mL) and toluene (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 10D (0.579 g).
MS (ESI, [M+H]+) m/z: 615.6.
To a reaction flask were added compound 10D (0.579 g), palladium/carbon (0.022 g), and tetrahydrofuran (15 mL) successively under hydrogen protection. After the addition was completed, the reaction solution was stirred for reaction at 30° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/2) to give compound 10E (0.401 g).
MS (ESI, [M+H]+) m/z: 585.6.
To a reaction flask were added compound 10E (0.100 g), 2-aminonicotine (0.021 g), sodium perborate tetrahydrate (0.014 g), methanol (5 mL) and acetic acid (2 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 50° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=96/4) to give compound 10F (0.078 g).
MS (ESI, [M+H]+) m/z: 687.5.
To a reaction flask were added compound 10F (0.050 g), methanesulfonic acid (0.035 g), and dichloromethane (5 mL) successively at room temperature. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=99/1) to give compound 10 (33 mg).
MS (ESI, [M+H]+) m/z: 587.5.
1H NMR (500 MHz, CDCl3) δ 8.07 (dd, J=32.5, 6.3 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.64-7.47 (m, 4H), 7.38-7.28 (m, 2H), 7.20 (d, J=7.8 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H), 6.63 (s, 2H), 6.41 (t, J=6.5 Hz, 1H), 4.70 (dd, J=15.0, 7.8 Hz, 2H), 4.62 (d, J=6.7 Hz, 1H), 3.86 (s, 2H), 3.60-3.41 (m, 2H), 3.28 (d, J=11.6 Hz, 1H), 3.18 (t, J=10.8 Hz, 1H), 2.63 (dt, J=18.5, 8.5 Hz, 3H), 2.43 (s, 2H), 2.30 (d, J=10.9 Hz, 3H), 2.15 (p, J=9.1, 8.7 Hz, 1H), 1.88-1.78 (m, 1H), 1.11 (d, J=6.4 Hz, 4H).
To a reaction flask were added 1,3-dibromobenzene (4.240 g), 1-(oxetan-3-yl)piperazine (1.278 g), 1,1′-binaphthyl-2,2′-bis-diphenylphosphine (0.420 g), sodium tert-butoxide (2.590 g), tris(dibenzylideneacetone)dipalladium (0.411 g) and toluene (22 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 70° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 11A (2.032 g).
MS (ESI, [M+K]+) m/z: 335.4.
To a reaction flask were added compound 11A (2.032 g), potassium tert-butoxide (2.010 g), bis(pinacolato)diboron (2.600 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.223 g) and N,N-dimethylformamide (34 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 70° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 11B (2.016 g).
MS (ESI, [M+H]+) m/z: 345.4.
To a reaction flask were added tert-butyl (1-(4-(((6-chloro-3-nitropyridin-2-yl)amino)phenyl)cyclobutyl)carbamate (0.568 g), compound 11B (0.576 g), tetrakis(triphenylphosphine)palladium (0.078 g), ethanol (15 mL), saturated sodium bicarbonate (3 mL) and toluene (15 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 11C (0.732 g).
MS (ESI, [M+H]+) m/z: 601.3.
Compound 11C (0.037 g) and palladium/carbon (0.001 g) were added to the reaction flask successively under hydrogen protection. After the addition was completed, the reaction solution was stirred for reaction at 30° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=2/1) to give compound 11D (0.013 g).
MS (ESI, [M+H]+) m/z: 571.5.
To a reaction flask were added compound 11D (0.100 g), 2-aminonicotine (0.022 g), sodium perborate tetrahydrate (0.014 g), methanol (5 mL) and acetic acid (2 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 50° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=99/1) to give compound 11E (50 mg).
MS (ESI, [M+H]+) m/z: 673.6.
To a reaction flask were added compound 11E (50 mg), methanesulfonic acid (35 mg), and dichloromethane (3 mL) successively at room temperature, and the mixture was stirred for reaction. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=99/1) to give compound 11 (28 mg).
MS (ESI, [M+H]+) m/z: 573.5.
1H NMR (500 MHz, CDCl3) δ 8.11 (d, J=8.3 Hz, 1H), 8.07 (tt, J=5.9, 3.2 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.61 (t, J=2.0 Hz, 1H), 7.59-7.54 (m, 2H), 7.54-7.46 (m, 2H), 7.45-7.41 (m, 2H), 7.34 (t, J=7.8 Hz, 2H), 7.20-7.13 (m, 1H), 6.96 (dd, J=8.3, 2.5 Hz, 1H), 6.63 (s, 2H), 6.45-6.36 (m, 1H), 4.69 (dt, J=19.8, 6.4 Hz, 4H), 3.57 (p, J=6.5 Hz, 1H), 3.29 (t, J=5.0 Hz, 4H), 2.62 (ddd, J=11.9, 8.9, 6.2 Hz, 2H), 2.52 (t, J=4.9 Hz, 4H), 2.25 (q, J=10.5, 9.1 Hz, 2H), 2.18-2.00 (m, 2H).
7-Oxa-2-azaspiro[3.5]nonane (0.809 g), 1,4-dibromobenzene (1.500 g), tris(dibenzylideneacetone)dipalladium (0.582 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.594 g), sodium tert-butoxide (0.917 g) and toluene (20 mL) were added to a reaction flask successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=17/3) to give compound 12A (1.257 g).
1H NMR (500 MHz, DMSO-d6) δ 7.27-7.29 (m, 2H), 6.35-6.37 (m, 2H), 3.56 (s, 4H), 3.53 (t, J=5.2 Hz, 4H), 1.71 (t, J=5.2 Hz, 4H).
To a reaction flask were added potassium acetate (1.263 g), bis(pinacolato)diboron (2.178 g), [1,1′-bis (diphenylphosphino)ferrocene]palladium dichloride (0.525 g), compound 12A (0.452 g) and dioxane (15 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 12B (1.500 g).
MS (ESI, [M+H]+) m/z: 330.5.
To a reaction flask were added compound 12B (0.419 g), compound 1C (0.500 g), potassium carbonate (0.422 g), tetrakis(triphenylphosphine)palladium (0.058 g), 1,4-dioxane (10 mL), and water (5 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=98:2) to give compound 12C (0.114 g).
MS (ESI, [M+H]+) m/z: 658.7.
To a reaction flask were added compound 12C (0.114 g), dichloromethane (10 mL) and methanesulfonic acid (0.081 g) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 20% aqueous sodium hydroxide solution was added, and the reaction solution was stirred under an ice bath. The pH of the reaction solution was adjusted to 12, the phases were separated, the aqueous phase was extracted by dichloromethane, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=90/10) to give compound 12 (28 mg).
MS (ESI, [M+H]+) m/z: 558.6.
1H NMR (500 MHz, DMSO-d6) δ7.96-7.98 (m, 2H), 7.83-7.85 (m, 2H), 7.61-7.62 (m, 1H), 7.47-7.48 (m, 2H), 7.33-7.35 (m, 2H), 7.02-7.04 (m, 1H), 6.49 (s, 2H), 6.40-6.42 (m, 2H), 6.30-6.32 (m, 1H), 3.61 (s, 4H), 3.59 (t, J=5.2 Hz, 4H), 3.59 (q, J=9.25 Hz, 2H), 2.18 (q, J=10.5 Hz, 2H), 2.03-2.11 (m, 2H), 1.76 (t, J=5.2 Hz, 4H).
To a reaction flask were added 2-oxa-6-azaspiro[3,3]heptane (1.00 g), m-dibromobenzene (2.49 g), (tris(dibenzylideneacetone)dipalladium (0.24 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.16 g), tetrahydrofuran (50 mL) and sodium tert-butoxide (2.03 g) successively, and the reaction solution was stirred at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=10/1) to give compound 13A (1.24 g).
MS (ESI, [M+H]+) m/z: 254.3.
1H NMR (500 MHz, DMSO-d6): δ 7.09 (t, J=8.0 Hz, 1H), 6.81 (dd, J=1.0, 8.0 Hz, 1H), 6.56 (t, J=2.0 Hz, 1H), 6.40 (dd, J=2.0, 8.0 Hz, 1H), 4.70 (s, 4H), 3.97 (m, 4H).
To a reaction flask containing compound 13A (1.13 g) were added bis(pinacolato)diboron (1.69 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.18 g), 1,4-dioxane (50 mL) and potassium acetate (1.30 g) successively, and after the addition was completed, the reaction solution was stirred for reaction at 120° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 13B (1.22 g).
MS (ESI, [M+H]+) m/z: 302.2.
1H NMR (500 MHz, DMSO-d6): δ 7.18 (t, J=7.5 Hz, 1H), 7.01 (d, J=7.0 Hz, 1H), 6.69 (d, J=2.5 Hz, 1H), 6.55 (d, J=2.0, 8.0 Hz, 1H), 4.70 (s, 4H), 3.95 (s, 4H), 1.28 (s, 12H).
13C NMR (125 MHz, DMSO-d6): δ 151.34, 128.76, 123.98, 117.41, 115.17, 83.97, 80.38, 61.48, 38.96, 25.12.
To a reaction flask containing compound 1C (0.495 g) were added methylene chloride (20 mL) and methanesulfonic acid (1.480 g) successively, and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was poured into water, the pH of the reaction solution was adjusted to 9 with an aqueous sodium hydroxide solution (20% w/w), and the reaction solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 13C (0.393 g).
MS (ESI, [M+H]+) m/z: 391.2.
To a microwave tube were added compound 13B (0.20 g), compound 13C (0.30 g), potassium carbonate (0.28 g), tetrakis(triphenylphosphine)palladium (0.16 g), 1,4-dioxane (10 mL), and water (1 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 120° C. in microwave reactor for 2 h. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 13 (135 mg).
MS (ESI, [M+H]+) m/z: 530.7.
1H NMR (500 MHz, DMSO-d6): δ 8.09 (d, J=8.0 Hz, 1H), 7.96 (d, J=4.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.36 (d, J=7.5 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.12 (d, J=7.5 Hz, 1H), 7.01 (s, 1H), 6.46-6.44 (m, 1H), 6.39-6.36 (m, 1H), 4.81 (s, 4H), 4.02 (s, 4H), 3.43-3.33 (m, 4H), 2.66-2.60 (m, 2H), 2.41-2.36 (m, 2H), 2.22-2.13 (m, 1H), 1.88-1.80 (m, 1H).
To a reaction flask were added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.10 g), m-dibromobenzene (0.45 g), tris(dibenzylideneacetone)dipalladium (32 mg), 1,1′-binaphthyl-2,2′-diphenyl phosphine (21 mg), tetrahydrofuran (20 mL) and sodium tert-butoxide (0.20 g) successively, and the reaction solution was stirred for reaction at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=10/1) to give compound 14A (108 mg).
1H NMR (500 MHz, DMSO-d6): δ 7.09 (t, J=8.0 Hz, 1H), 6.81 (dd, J=1.0, 8.0 Hz, 1H), 6.55 (t, J=2.0 Hz, 1H), 6.39 (dd, J=2.0, 8.0 Hz, 1H), 4.01 (s, 4H), 3.93 (s, 4H), 1.38 (s, 9H).
To a reaction flask containing compound 14A (152 mg) were added bis(pinacolato)diboron (164 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (50 mg), 1,4-dioxane (5 mL) and potassium acetate (127 mg) successively, and after the addition was completed, the reaction solution was stirred for reaction at 120° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 14B (53 mg).
MS (ESI, [M+H]+) m/z: 401.5.
To a microwave tube were added compound 14B (50 mg), compound 1C (67 mg), potassium carbonate (70 mg), tetrakis(triphenylphosphine)palladium (40 mg), 1,4-dioxane (4 mL), and water (0.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 120° C. in microwave reactor for 2 h. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 14C (80 mg).
MS (ESI, [M+H]+) m/z: 729.7.
1H NMR (500 MHz, DMSO-d6): δ 8.23 (d, J=8.5 Hz, 1H), 8.00 (dd, J=1.5, 5.0 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.69-7.54 (m, 3H), 7.46-7.34 (m, 3H), 7.24-7.17 (m, 2H), 7.10-7.07 (m, 3H), 6.46 (dd, J=1.5, 7.5 Hz, 1H), 6.33 (dd, J=5.0, 7.5 Hz, 1H), 4.03 (s, 4H), 3.95 (s, 4H), 2.46-2.41 (m, 4H), 2.02 (brs, 1H), 1.83 (brs, 1H), 1.39 (s, 9H), 1.36 (s, 9H).
To a reaction flask were added compound 14C (69 mg), methanesulfonic acid (0.1 mL) and dichloromethane (10 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 14 (25 mg).
HRMS (ESI, [M+H]+) m/z: 529.2814.
1H NMR (500 MHz, DMSO-d6): δ 8.23 (d, J=8.0 Hz, 1H), 8.01 (dd, J=2.0, 5.0 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.0 Hz, 1H), 7.25-7.21 (m, 2H), 7.06-7.02 (m, 3H), 6.46-6.44 (m, 1H), 6.43-6.41 (m, 1H), 3.90 (s, 4H), 3.64 (s, 4H), 3.43-3.33 (m, 3H), 2.46-2.41 (m, 2H), 2.16-2.11 (m, 2H), 2.07-2.01 (m, 1H), 1.76-1.67 (m, 1H).
To a reaction flask were added (5S,7S)-2-aminoadamantan-1-ol (1.17 g), 1,3-dibromobenzene (1.65 g), tris(dibenzylideneacetone)dipalladium (0.64 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.65 g), sodium tert-butoxide (1.00 g) and toluene (10 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to give compound 15A (1.15 g).
MS (ESI, [M+H]+) m/z: 322.2.
To a reaction flask were added potassium acetate (0.795 g), bis(pinacolato)diboron (1.372 g), [1,1′-bis (diphenylphosphino)ferrocene]palladium dichloride (0.331 g), compound 15A (1.154 g) and dioxane (30 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to give compound 15B (0.750 g).
MS (ESI, [M+H]+) m/z: 370.6.
To a reaction flask were added compound 15B (0.750 g), compound 1C (0.612 g), potassium carbonate (0.495 g), tetrakis(triphenylphosphine)palladium (0.069 g), 1,4-dioxane (20 mL), and water (10 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=3/2) to give compound 15C (1.215 g).
MS (ESI, [M+H]+) m/z: 698.8.
To a reaction flask were added compound 15C (1.215 g), dichloromethane (20 mL) and methanesulfonic acid (0.694 g) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 20% aqueous sodium hydroxide solution was added, and the reaction solution was stirred under an ice bath. The pH of the reaction solution was adjusted to 12, the phases were separated, the aqueous phase was extracted by dichloromethane, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=4/1) to give compound 15 (0.388 g).
MS (ESI, [M+H]+) m/z: 598.7.
1H NMR (500 MHz, DMSO-d6) δ 8.21 (d, 1H), 7.99-8.00 (m, 1H), 7.83 (d, 1H), 7.62 (d, 2H), 7.43 (d, 2H), 7.28 (s, 1H), 7.19-7.20 (m, 1H), 7.12-7.13 (m, 2H), 6.96 (s, 2H), 6.69 (d, 1H), 6.39-6.42 (s, 1H), 5.61 (d, 1H), 2.41-2.46 (m, 3H), 1.93-2.16 (m, 9H), 1.63-1.77 (m, 7H), 1.30 (d, 2H).
Compound 14A (1.00 g) was weighed out and added to a reaction flask, methylene chloride (100 mL) was added, the mixture was stirred and dissolved, followed by addition of methanesulfonic acid (0.82 g), and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, triethylamine (2.5 mL) was added to terminate the reaction. Dichloromethane was added to adjust the volume of the reaction solution to 120 mL to obtain a solution of compound 16A. The reaction solution was not concentrated and was directly fed for the next step.
A solution of compound 16A (35 mL) was added to the acetic anhydride (169 mg), and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=96/4) to give compound 16B (219 mg).
MS (ESI, [M+H]+) m/z: 295.1.
1H NMR (500 MHz, CDCl3): δ 7.06 (t, J=8.0 Hz, 1H), 6.90-6.88 (m, 1H), 6.57 (d, J=4.0 Hz, 1H), 6.37-6.34 (m, 1H), 4.29 (s, 2H), 4.16 (s, 2H), 3.99 (s, 4H), 1.88 (s, 3H).
To a reaction flask containing compound 16B (210 mg) were added bis(pinacolato)diboron (271 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (29 mg), 1,4-dioxane (20 mL) and potassium acetate (209 mg) successively, and after the addition was completed, the reaction solution was stirred for reaction at 120° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (dichloromethane/methanol=98/2) to give compound 16C (185 mg).
MS (ESI, [M+H]+) m/z: 343.3.
To a microwave tube were added compound 16C (140 mg), compound 1C (276 mg), potassium carbonate (239 mg), tetrakis(triphenylphosphine)palladium (75 mg), 1,4-dioxane (10 mL), and water (1 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 120° C. in microwave reactor for 2 h. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=96/4) to give compound 16D (280 mg).
MS (ESI, [M+H]+) m/z: 671.7.
To a reaction flask were added compound 16D (260 mg), methanesulfonic acid (0.25 mL) and dichloromethane (20 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 16 (125 mg).
MS (ESI, [M+H]+) m/z: 571.6.
1H NMR (500 MHz, CDCl3): 8.11-8.04 (d, J=8.5 Hz, 1H), 8.06-7.96 (dd, J=1.0, 4.5 Hz, 1H), 7.76-7.67 (d, J=8.5 Hz, 1H), 7.65-7.48 (d, J=8.5 Hz, 2H), 7.43-7.35 (m, 3H), 7.26-7.25 (m, 1H), 7.15-6.98 (m, 2H), 6.61-6.57 (m, 2H), 6.44-6.32 (m, 1H), 6.39-6.25 (m, 1H), 4.29-4.26 (m, 2H), 4.20-4.16 (m, 2H), 4.05-3.92 (m, 4H), 2.69-2.64 (m, 2H), 2.58-2.52 (m, 2H), 2.46-2.26 (m, 3H), 1.90-1.86 (m, 4H).
A solution of compound 16A (35 mL) was added to the methanesulfonyl chloride (189 mg), after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=3/1) to give compound 17A (227 mg).
MS (ESI, [M+H]+) m/z: 331.1.
1H NMR (500 MHz, CDCl3): δ 7.06 (t, J=3.0 Hz, 1H), 6.90-6.88 (m, 1H), 6.57 (t, J=2.0 Hz, 1H), 6.36-6.34 (m, 1H), 4.10 (s, 4H), 3.98 (s, 4H), 2.88 (s, 3H).
To a reaction flask containing compound 17A (220 mg) were added bis(pinacolato)diboron (253 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (27 mg), 1,4-dioxane (20 mL) and potassium acetate (196 mg) successively, and after the addition was completed, the reaction solution was stirred for reaction at 120° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 17B (157 mg).
MS (ESI, [M+H]+) m/z: 379.3.
To a microwave tube were added compound 17B (132 mg), compound 1C (223 mg), potassium carbonate (193 mg), tetrakis(triphenylphosphine)palladium (81 mg), 1,4-dioxane (10 mL), and water (1 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 120° C. in microwave reactor for 2 h. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (dichloromethane/methanol=98/2) to give compound 17C (146 mg).
MS (ESI, [M+H]+) m/z: 707.7.
To a reaction flask were added compound 17C (150 mg), methanesulfonic acid (0.15 mL) and dichloromethane (15 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=95/5) to give compound 17 (47 mg).
HRMS (ESI, [M+H]+) m/z: 607.2606.
1H NMR (500 MHz, CDCl3): 8.05-7.91 (m, 2H), 7.69-7.60 (m, 1H), 7.52-7.41 (m, 2H), 7.37-7.26 (m, 3H), 7.23-7.20 (m, 1H), 7.09-6.93 (m, 2H), 6.53, 6.44 (s, 2H), 6.42-6.18 (m, 2H), 4.04, 4.02 (s, 4H), 3.96, 3.85 (s, 4H), 2.81, 2.80 (s, 3H), 2.58-2.36 (m, 3H), 2.22-2.02 (m, 3H).
To a reaction flask were added hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (0.824 g), 1,3-dibromobenzene (1.300 g), tris(dibenzylideneacetone)dipalladium (0.505 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.515 g), sodium tert-butoxide (0.794 g) and toluene (10 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=19/1) to give compound 18A (0.452 g).
MS (ESI, [M+H]+) m/z: 268.4.
To a reaction flask were added potassium acetate (0.496 g), bis(pinacolato)diboron (0.809 g), [1,1′-bis (diphenylphosphino)ferrocene]palladium dichloride (0.206 g), compound 18A (0.452 g) and dioxane (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=19/1) to give compound 18B (0.490 g).
MS (ESI, [M+H]+) m/z: 316.5.
To a reaction flask were added compound 18B (0.210 g), compound 1C (0.327 g), potassium carbonate (0.276 g), tetrakis(triphenylphosphine)palladium (0.038 g), 1,4-dioxane (15 mL), and water (7.5 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=1/1) to give compound 18C (0.400 g).
MS (ESI, [M+H]+) m/z: 644.8.
To the reaction flask were added compound 18C (0.400 g), dichloromethane (10 mL) and methanesulfonic acid (0.149 g) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 20% aqueous sodium hydroxide solution was added, and the reaction solution was stirred under an ice bath. The pH of the reaction solution was adjusted to 12, the phases were separated, the aqueous phase was extracted by dichloromethane, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=7/3) to give compound 18 (0.285 g).
MS (ESI, [M+H]+) m/z: 544.7.
1H NMR (500 MHz, DMSO-d6) δ 8.43 (d, 1H), 8.11-8.21 (m, 3H), 8.00 (d, 1H), 7.92 (d, 1H), 7.80 (d, 2H), 7.71 (d, 2H), 7.48-7.58 (m, 2H), 6.98 (t, 1H), 3.70-3.88 (m, 6H), 3.21 (s, 2H), 2.65-2.68 (m, 4H), 2.21-2.28 (m, 1H), 1.82-1.90 (m, 1H), 1.17-1.29 (m, 2H).
In a reaction flask, a solution of 2-chloroacetyl chloride (3.24 g) in tetrahydrofuran (10 mL) was slowly added dropwise to a reaction solution of 2-amino-4-bromophenol (3.60 g) and sodium carbonate (3.22 g) in tetrahydrofuran (60 mL) under nitrogen atmosphere at 0° C. After the addition was completed, the reaction solution was stirred at room temperature. Potassium carbonate (5.29 g) was added to the reaction solution, and the reaction solution was stirred for reaction at 66° C., filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=3/1) to give compound 19A (3.4 g).
MS (ESI, [M−H]−) m/z: 226.4.
In a reaction flask, a solution (15 mL) of 2 M borane in toluene-dimethylsulfide was added slowly under nitrogen atmosphere at 0° C. to a solution of compound 19A (2.28 g) in tetrahydrofuran (10 mL). After the addition was completed, the mixture was stirred at room temperature and reacted at 66° C. After the reaction was completed, the reaction was quenched with a saturated aqueous sodium hydroxide solution, the reaction solution was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to give compound 19B (2.10 g). The reaction product from this step was used directly in the next step.
In a reaction flask, acetyl chloride (0.733 g) was slowly added to a solution of compound 19B (2.000 g), N,N-diisopropylethylamine (1.208 g) in tetrahydrofuran (12 mL) under nitrogen atmosphere a 0° C. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction was quenched with saturated sodium carbonate solution, the reaction solution was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=95/5) to give compound 19C (2.200 g). The reaction product from this step was used directly in the next step.
To a reaction flask were added [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.702 g), compound 19C (2.200 g), bis(pinacolato)diboron (4.360 g), potassium acetate (1.686 g) and dioxane (8 mL) successively under nitrogen atmosphere; after the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was extracted with ethyl acetate, and organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=90/10) to give compound 19D (2.410 g).
MS (ESI, [M+H]+) m/z: 304.5.
To a reaction flask were added compound 19D (324 mg), compound 1C (350 mg), potassium carbonate (197 mg), tetrakis(triphenylphosphine)palladium (82 mg), and dioxane (10 mL) successively under nitrogen atmosphere, and after the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=95/5) to give compound 19E (320 mg).
MS (ESI, [M+H]+) m/z: 632.7.
To the reaction flask were added compound 19E (320 mg), dichloromethane (10 mL) and methanesulfonic acid (48.7 mg) successively, and the reaction solution was stirred for reaction at room temperature. The raw materials were reacted completely. The reaction was quenched with saturated aqueous sodium carbonate (30 mL), the reaction solution was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=94/6) to give compound 19 (120 mg).
MS (ESI, [M+H]+) m/z: 532.7.
1H NMR (500 MHz, DMSO-d6): δ 8.22 (d, J=8.0 Hz, 1H), 8.00 (s, 1H), 7.87 (br, 1H), 7.63-7.62 (m, 2H), 7.45-7.44 (m, 2H), 7.21 (d, J=7.5 Hz, 1H), 7.00-7.69 (m, 3H), 6.41 (t, J=5.0 Hz, 1H), 4.29 (s, 2H), 3.88 (s, 2H), 2.50-2.43 (m, 2H), 2.24 (s, 3H), 2.19-2.15 (m, 2H), 2.06-2.04 (m, 1H), 1.75-1.72 (m, 1H).
To a reaction flask were added 1-bromo-3-iodobenzene (1.180 g), isothiazole-1,1-dioxide (0.720 g), cuprous iodide (0.159 g), potassium carbonate (1.153 g), (1S,2S)-N1,N2-dimethylcyclohexyl-1,2-diamine (0.119 g), and dimethyl sulfoxide (10 mL) successively under nitrogen atmosphere, and the reaction solution was reacted at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=90/10) to give compound 20A (640 mg).
MS(ESI, [M+H]+) m/z: 276.2.
To a reaction flask were added [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (151 mg), compound 20A (640 mg), bis(pinacolato)diboron (1177 mg), potassium acetate (455 mg) and dioxane (8 mL) successively under nitrogen atmosphere; after the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=80/20) to give compound 20B (620 mg).
MS(ESI, [M+H]+) m/z: 324.5.
To a reaction flask were added tetrakis(triphenylphosphine)palladium (99 mg), compound 1C (420 mg), compound 20B (415 mg), potassium carbonate (236 mg), dioxane (5 mL) and water (0.5 mL) successively, and the reaction solution was heated at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=60/40) to give compound 20C (380 mg).
MS(ESI, [M+H]+) m/z: 652.5.
To the reaction flask were added compound 20C (150 mg), dichloromethane (6 mL) and methanesulfonic acid (133 mg) successively. After the addition was completed, the reaction solution was reacted at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to be neutral with saturated aqueous sodium bicarbonate, the reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=97/3) to give compound 20 (27 mg).
MS(ESI, [M+H]+) m/z: 552.5.
1H NMR (500 MHz, DMSO-d6): δ 8.29 (d, J=8.0 Hz, 1H), 8.01 (dd, J=3.0 Hz, 6.0 Hz, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.50-7.45 (m, 3H), 7.28-7.23 (m, 2H), 6.96 (br, 2H), 6.44 (q, J=7.5 Hz, 1H), 3.81 (t, J=7.5 Hz, 2H), 3.54 (t, J=7.5 Hz, 2H), 2.43 (t, J=7.5 Hz, 1H), 2.34 (s, 2H), 2.26-2.21 (m, 2H), 2.09 (m, 1H), 1.77-1.75 (m, 1H).
To a reaction flask were added sodium tert-butoxide (0.179 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.040 g), tris(dibenzylideneacetone)dipalladium (0.039 g), 1,3-dibromobenzene (0.200 g), 1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (0.174 g) and toluene (10 mL) successively, and the reaction solution was stirred for reaction at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, added with 5 mL of saturated brine and extracted with ethyl acetate (10 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=60/1) to give compound 21A (0.270 g).
MS (ESI, [M+H]+) m/z: 323.4.
To a reaction flask were added compound 21A (0.270 g), potassium acetate (0.270 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.037 g), bis(pinacolato)diboron (0.280 g), 1,4-dioxane (25 mL) and water (5 mL) successively, and the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, added with saturated brine and extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=60/1) to give compound 21B (0.300 g).
MS (ESI, [M+H]+) m/z: 371.6.
To a reaction flask were added compound 1C (2.40 g), compound 21B (0.30 g), potassium carbonate (0.17 g), tetrakis(triphenylphosphine)palladium (0.057 g), 1,4-dioxane (25 mL) and water (5 mL) successively, and the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, added with saturated brine and extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=65/1) to give compound 21C (0.25 g).
MS (ESI, [M+H]+) m/z: 699.8.
To a reaction flask were added compound 21C (0.25 g), dichloromethane (25 mL) and methanesulfonic acid (0.30 g) successively. The reaction solution was stirred at 30° C. for reaction; after the reaction was completed, the pH of the reaction solution was adjusted to be alkaline, the reaction solution was added with saturated brine and extracted with dichloromethane, and the organic phases were combined, and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 21 (0.19 g).
HRMS (ESI, [M+H]+) m/z: 599.3237.
1H NMR (500 MHz, CDCl3) δ 7.99 (dd, J=11.1, 8.5 Hz, 1H), 7.90 (t, J=4.6 Hz, 1H), 7.64 (t, J=8.2 Hz, 1H), 7.57 (d, J=8.2 Hz, 2H), 7.48 (s, 1H), 7.47-7.22 (m, 4H), 7.01 (t, J=7.6 Hz, 1H), 6.80 (dd, J=28.6, 9.7 Hz, 1H), 6.55 (d, J=15.2 Hz, 2H), 6.27 (ddd, J=58.5, 7.7, 5.0 Hz, 1H), 4.05 (ddd, J=16.5, 10.7, 3.8 Hz, 1H), 3.65 (t, J=16.0 Hz, 2H), 3.28 (dt, J=14.1, 6.9 Hz, 2H), 2.76 (dt, J=24.5, 12.3 Hz, 2H), 2.62-2.46 (m, 4H), 2.44-2.22 (m, 4H), 1.99-1.86 (m, 3H), 1.83-1.65 (m, 5H).
To a reaction flask were added sodium tert-butoxide (0.180 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.040 g), tris(dibenzylideneacetone)dipalladium (0.039 g), 1,3-dibromobenzene (0.200 g), 4-methyl-4-oxo-1,4-azaphosphine (0.11 g) and toluene (10 mL) successively. The reaction solution was stirred for reaction at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, added with saturated brine and extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=60/1) to give compound 22A (0.230 g).
MS (ESI, [M+H]+) m/z: 288.4.
To a reaction flask were added compound 22A (0.23 g), potassium acetate (0.28 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (39 mg), bis(pinacolato)diboron (0.29 g), 1,4-dioxane (25 mL) and water (5 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, condition with saturated brine and extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=60/1) to give compound 22B (0.28 g).
MS (ESI, [M+H]+) m/z: 336.6.
To a reaction flask were added compound 1C (2.30 g), compound 22B (0.28 g), potassium carbonate (0.16 g), tetrakis(triphenylphosphine)palladium (55 mg), 1,4-dioxane (25 mL) and water (5 mL) successively, and the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated, added with saturated brine and extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=65/1) to give compound 22C (0.24 g).
MS (ESI, [M+H]+) m/z: 664.7.
To a reaction flask were added compound 22C (0.24 g), dichloromethane (25 mL) and methanesulfonic acid (0.30 g) successively. The reaction solution was stirred at 30° C. for reaction; after the reaction was completed, the pH of the reaction solution was adjusted to be alkaline, the reaction solution was added with saturated brine and extracted with dichloromethane, and the organic phases were combined, and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 22 (0.16 g).
HRMS (ESI, [M+H]+) m/z: 564.2634.
1H NMR (500 MHz, DMSO-d6) δ 8.24 (d, J=8.3 Hz, 1H), 8.02 (dd, J=4.7, 1.6 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.61 (s, 1H), 7.49 (d, J=8.5 Hz, 2H), 7.38 (d, J=7.6 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.26 (dd, J=7.6, 1.6 Hz, 1H), 7.06-6.96 (m, 3H), 6.43 (dd, J=7.6, 4.8 Hz, 1H), 4.48 (s, 2H), 4.03-3.85 (m, 2H), 3.57-3.46 (m, 2H), 2.49-2.43 (m, 2H), 2.28-2.20 (m, 2H), 2.13-2.03 (m, 1H), 1.88 (t, J=13.6 Hz, 2H), 1.75 (ddt, J=20.2, 14.2, 6.4 Hz, 3H), 1.53 (d, J=13.0 Hz, 3H).
In a reaction flask, methanesulfonyl chloride (0.572 g) was added at 0° C. to a solution of tert-butyl (R)-3-(methylamine)pyrrole-1-carboxylate (1.000 g) and N,N-diisopropylethylamine (0.645 g) in dichloromethane (15 mL) under nitrogen atmosphere, and the reaction solution was stirred at room temperature overnight. After the reaction was completed, the reaction was quenched by saturated aqueous sodium carbonate solution, the reaction solution was extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 23A (1.160 g).
In a reaction flask, a solution of 4 M hydrogen chloride in dioxane (4 mL) was added slowly to a solution of compound 23A (590 mg) in dichloromethane (10 mL) under an ice-water bath. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was directly distilled under reduced pressure to remove the solvent to obtain compound 23B, which was used directly in the next step.
1,1′-binaphthyl-2,2′-diphenyl phosphine (1320 mg), sodium tert-butoxide (204 mg), 1,3-dibromobenzene (500 mg) and dioxane (10 mL) were added successively to a reaction flask containing compound 23B. After the addition was completed, the reaction solution was stirred for reaction at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=80/20) to give compound 23C (380 mg).
MS (ESI, [M+H]+) m/z: 333.3.
To a reaction flask were added [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (93 mg), compound 23C (380 mg), bis(pinacolato)diboron (434 mg), potassium acetate (336 mg) and dioxane (8 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=80/20) to give compound 23D (280 mg).
MS (ESI, [M+H]+) m/z: 381.3.
To a reaction flask were added tetrakis(triphenylphosphine)palladium (99 mg), compound 1C (420 mg), compound 23D (325 mg), potassium acetate (236 mg), dioxane (5 mL), and water (0.5 mL) successively. After the addition was completed, the reaction solution was stirred for reaction at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=60/40) to give compound 23E (154 mg).
MS (ESI, [M+H]+) m/z: 709.8.
To the reaction flask were added compound 23E (100 mg), dichloromethane (6 mL) and methanesulfonic acid (600 mg) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to be neutral by sodium bicarbonate, the reaction solution was extracted with dichloromethane, and the organic phase were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=97/3) to give compound 23 (60 mg).
MS (ESI, [M+H]+) m/z: 609.6.
1H NMR (500 MHz, DMSO-d6): δ 8.23 (d, J=3.5 Hz, 1H), 8.01-7.96 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.32 (d, J=7.0 Hz, 2H), 7.27-7.22 (m, 3H), 7.01 (s, 1H), 6.43 (d, J=7.0 Hz, 2H), 6.42-6.41 (m, 1H), 4.54 (t, J=7.5 Hz, 1H), 3.47 (q, J=7.5 Hz, 1H), 3.24 (t, J=7.5 Hz, 1H), 2.99 (s, 3H), 2.78 (s, 3H), 2.44-2.42 (m, 2H), 2.22-2.20 (s, 6H).
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (349 mg), bis(dibenzylideneacetone)palladium (256 mg), (R)-N-methyl-N-(pyrrol-3-yl)acetamide hydrochloride (500 mg), 1,3-dibromobenzene (660 mg), sodium tert-butoxide (807 mg) and dioxane (15 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was heated and reacted at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=60/40) to give compound 24A (740 mg).
MS (ESI, [M+H]+) m/z: 297.4.
To a reaction flask [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (179 mg), compound 24A (650 mg), bis(pinacolato)diboron (1111 mg), potassium acetate (644 mg) and dioxane (15 mL) successively under nitrogen atmosphere; after the addition was completed, the reaction solution was reacted at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=80/20) to give compound 24B (740 mg).
MS (ESI, [M+H]+) m/z: 345.6.
To a reaction flask were added tetrakis(triphenylphosphine)palladium (208 mg), compound 1C, compound 24B (620 mg), potassium carbonate (498 mg), dioxane (15 mL), and water (0.5 mL) successively. After the addition was completed, the reaction solution was heated and reacted at 120° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=98/2) to give compound 24C (470 mg).
MS (ESI, [M+H]+) m/z: 673.6.
To the reaction flask were added compound 24C (420 mg), dichloromethane (6 mL) and methanesulfonic acid (360 mg) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to be neutral with saturated aqueous sodium bicarbonate, the reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=96/4) to give compound 24 (140 mg).
MS (ESI, [M+H]+) m/z: 573.7.
1H NMR (500 MHz, DMSO-d6): δ 8.22 (d, J=8.0 Hz, 1H), 8.00 (dd, J=3.5 Hz, 7.0 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.30-7.14 (m, 4H), 7.02 (s, 2H), 6.61 (br, 1H), 6.43-6.41 (m, 1H), 5.20 (t, J=7.5 Hz, 1H), 4.68 (t, J=7.5 Hz, 1H), 3.49-3.48 (m, 1H), 3.37-3.23 (m, 6H), 2.89 (s, 2H), 2.43-2.42 (m, 2H), 2.15-2.12 (m, 4H), 2.03 (s, 2H).
To a reaction flask were added tert-butyl (S′)-3-(methylamino)pyrrolidine-1-carboxylate (1.60 g), N-diisopropylethylamine (1.24 g), and methanesulfonyl chloride (0.91 g) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 25A (2.53 g).
To a reaction flask were added a solution (6 mL) of hydrochloric acid in dioxane, compound 25A (2.53 g), and dichloromethane (20 mL) successively. The reaction solution was reacted at room temperature; after the reaction was completed, the reaction solution was concentrated to give compound 25B (1.58 g).
To a reaction flask were added compound 25B (0.700 g), 1,3-dibromobenzene (0.949 g), tris(dibenzylideneacetone)dipalladium (0.368 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.500 g), sodium tert-butoxide (1.500 g), and toluene (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 120′° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=4/1) to give compound 25C (0.456 g).
MS (ESI, [M+H]+) m/z: 333.3.
To a reaction flask were added potassium acetate (0.385 g), bis(pinacolato)diboron (0.627 g), [1,1′-bis (diphenylphosphino)ferrocene]palladium dichloride (0.160 g), compound 25C (0.430 g) and dioxane (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the starting materials were reacted completely, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=7/3) to give compound 25D (0.166 g).
MS (ESI, [M+H]+) m/z: 381.6.
To a reaction flask were added compound 25D (0.165 g), compound 1C (0.213 g), potassium carbonate (0.180 g), tetrakis(triphenylphosphine)palladium (0.025 g), 1,4-dioxane (10 mL), and water (5 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=17/3) to give compound 25E (0.075 g).
MS (ESI, [M+H]+) m/z: 709.7.
To a reaction flask were added compound 25E (0.075 g), dichloromethane (10 mL) and methanesulfonic acid (0.050 g) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 20% aqueous sodium hydroxide solution was added, and the reaction solution was stirred under an ice bath. The pH of the reaction solution was adjusted to 12, the phases were separated, the aqueous phase was extracted by dichloromethane, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=3/7) to give compound 25 (0.040 g).
MS (ESI, [M+H]+) m/z: 609.7.
1H NMR (500 MHz, DMSO-d6) δ8.41 (d, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.84 (d, 1H), 7.75 (d, 2H), 7.67 (d, 2H), 7.41-7.45 (m, 2H), 7.29 (m, 1H), 6.96 (m, 1H), 4.26 (s, 4H), 4.00 (m, 1H), 3.53 (d, 2H), 3.08 (t, 2H), 2.63 (s, 4H), 2.25 (t, 3H), 1.71-2.01 (m, 7H).
To a reaction flask were added 1,3-dibromobenzene (0.54 g), tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (0.30 g), sodium tert-butoxide (0.29 g), tris(dibenzylideneacetone)dipalladium (0.14 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.09 g) and 1,4-dioxane (12 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 26A (0.51 g).
MS (ESI, [M-Boc+H]+) m/z: 253.4.
To a reaction flask were added compound 26A (0.46 g) and a solution of 4 M hydrogen chloride in dioxane (8 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 26B (0.43 g).
MS (ESI, [M+H]+) m/z: 253.4.
Acetyl chloride (2.98 g) was slowly added to a solution of compound 26B (0.43 g) and triethylamine (0.69 g) in dichloromethane (20 mL) in a reaction flask at 0° C. under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was added with a saturated aqueous sodium bicarbonate solution (75 mL) and extracted with dichloromethane (50 mL×3), and the organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=1/4) to give compound 26C (0.25 g).
MS (ESI, [M+H]+) m/z: 295.4.
To a 100 mL reaction flask were added compound 26C (0.25 g), bis(pinacolato)diboron (0.32 g), potassium acetate (0.25 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.069 g) and 1,4-dioxane (15 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=1/4) to give compound 26D (0.22 g).
MS (ESI, [M+H]+) m/z: 343.6.
To a 25 mL microwave tube were added compound 26D (0.21 g), compound 1C (0.20 g), potassium carbonate (0.17 g), tetrakis(triphenylphosphine)palladium (0.047 g), 1,4-dioxane (10 mL) and water (1.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 140° C. in microwave reactor for 2 h. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 26E (0.22 g).
MS (ESI, [M+H]+) m/z: 671.7.
To a 50 mL reaction flask were added compound 26E (183 mg), methanesulfonic acid (0.2 mL), and dichloromethane (10 mL) successively. The reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 26 (106 mg).
HRMS (ESI, [M+H]+) m/z: 571.2924.
1H NMR (500 MHz, CDCl3) δ 8.11 (dd, J=8.3, 5.2 Hz, 1H), 8.07 (dt, J=4.9, 1.7 Hz, 1H), 7.79 (dd, J=8.4, 3.6 Hz, 1H), 7.60-7.54 (m, 2H), 7.53-7.41 (m, 4H), 7.36-7.30 (m, 1H), 7.16 (ddd, J=14.3, 7.8, 1.8 Hz, 1H), 6.82-6.76 (m, 1H), 6.62 (s, 2H), 6.40 (dt, J=7.8, 5.3 Hz, 1H), 4.94 (dd, J=6.9, 4.5 Hz, 1H), 4.30-4.10 (m, 2H), 3.98-3.83 (m, 1H), 3.76 (dd, J=22.2, 10.2 Hz, 1H), 3.29-3.18 (m, 1H), 3.08-2.88 (m, 2H), 2.68-2.56 (m, 2H), 2.32-2.05 (m, 4H), 1.84 (s, 3H).
To a reaction flask were added 1,3-dibromobenzene (4.98 g), tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate (2.00 g), sodium tert-butoxide (2.70 g), tris(dibenzylideneacetone)dipalladium (0.64 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.66 g) and 1,4-dioxane (100 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere; after the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 27A (2.78 g).
MS (ESI, [M+H]+) m/z: 297.4.
Sodium hydride (1.87 g) was slowly added to a solution of compound 27A (2.78 g) in tetrahydrofuran (60 mL) at 0° C. under nitrogen atmosphere. After the addition was completed, the mixture was stirred at room temperature for 0.5 h, and methyl iodide (6.64 g) was added thereto for reaction. After the reaction was completed, a saturated aqueous ammonium chloride solution was added to the reaction solution in an ice bath, followed by extraction with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=1/2) to give compound 27B (1.91 g).
MS (ESI, [M+H]+) m/z: 311.4.
To a reaction flask were added compound 27B (1.91 g), bis(pinacolato)diboron (2.34 g), potassium acetate (1.81 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.50 g) and 1,4-dioxane (120 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 27C (2.11 g).
MS (ESI, [M+H]+) m/z: 359.6.
To a microwave tube were added compound 27C (0.33 g), compound 1C (0.30 g), potassium carbonate (0.25 g), tetrakis(triphenylphosphine)palladium (71 mg), 1,4-dioxane (14 mL), and water (2 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 140° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 27D (0.38 g).
MS (ESI, [M+H]+) m/z: 687.8.
Compound 27D (370 mg), methanesulfonic acid (0.3 mL) and dichloromethane (16 mL) were added successively to a reaction flask. The reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 27 (157 mg).
HRMS (ESI, [M+H]+) m/z: 587.3278.
1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J=9.5, 8.3 Hz, 1H), 8.06 (dd, J=4.8, 1.8 Hz, 1H), 7.79 (dd, J=8.4, 1.3 Hz, 1H), 7.67-7.57 (m, 3H), 7.48 (dt, J=7.8, 1.0 Hz, 1H), 7.46-7.41 (m, 2H), 7.31 (dt, J=18.8, 7.9 Hz, 1H), 7.12 (ddd, J=29.3, 7.8, 1.8 Hz, 1H), 6.93 (td, J=7.6, 2.4 Hz, 1H), 6.60 (s, 2H), 6.39 (ddd, J=7.8, 5.9, 4.8 Hz, 1H), 4.77-4.68 (m, 1H), 3.86-3.72 (m, 1H), 3.72-3.56 (m, 1H), 2.91 (d, J=18.3 Hz, 3H), 2.75-2.56 (m, 4H), 2.47-2.35 (m, 2H), 2.26-2.18 (m, 1H), 2.15 (s, 3H), 1.92-1.70 (m, 5H).
To a reaction flask were added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.50 g), 1,3-dibromofluorobenzene (0.66 g), tris(dibenzylideneacetone)dipalladium (80 mg), 1,1′-binaphthyl-2,2′-diphenyl phosphine (60 mg), tetrahydrofuran (50 mL) and sodium tert-butoxide (1.00 g) successively. After the addition was completed, the reaction solution was stirred for reaction at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=10/1) to give compound 28A (0.51 g).
Compound 28A (0.50 g) was weighed out and added to a reaction flask, methylene chloride (10 mL) was added, the mixture was stirred and dissolved, followed by addition of methanesulfonic acid (0.39 g), and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, triethylamine (2 mL) was added to terminate the reaction to give a solution of compound 28B. The reaction solution was not concentrated and was directly fed for the next step.
Acetic anhydride (206 mg) was added to the above solution of compound 28B, and the mixture was stirred at room temperature for reaction. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=96:4) to give compound 28C (313 mg).
MS (ESI, [M+H]+) m/z: 313.79.
To a reaction flask containing compound 28C (300 mg) were added bis(pinacolato)diboronate (365 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (39 mg), 1,4-dioxane (30 ml) and potassium acetate (282 mg) successively. After the addition was completed, the reaction solution was stirred for reaction at 120° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (dichloromethane/methanol=98/2) to give compound 28D (278 mg).
MS (ESI, [M+H]+) m/z: 361.04.
To a microwave tube were added compound 28D (300 mg), compound 1C (409 mg), potassium carbonate (460 mg), tetrakis(triphenylphosphine)palladium (48 mg), 1,4-dioxane (10 mL), and water (1 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 120° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (dichloromethane/methanol=96/4) to give compound 28E (252 mg).
MS (ESI, [M+H]+) m/z: 689.5.
Compound 28E (250 mg), methanesulfonic acid (349 mg) and dichloromethane (30 mL) were added successively to a reaction flask. The reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 28 (70 mg).
MS (ESI, [M+H]+) m/z: 589.5.
1H NMR (500 MHz, CDCl3): 8.25 (d, J=8.5 Hz, 1H), 8.00 (dd, J=2.0, 5.0 Hz, 1H), 7.68 (dd, J=2.0, 8.0 Hz, 1H), 7.60 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.20 (dd, J=2.0, 8.0 Hz, 1H), 7.10-7.44 (m, 2H), 6.94 (m, 2H), 6.61-6.57 (m, 1H), 6.42-6.40 (m, 1H), 4.29 (s, 2H), 4.08 (s, 4H), 4.02 (s, 2H), 2.44-2.37 (m, 2H), 2.13-2.06 (m, 2H), 2.06-1.98 (m, 1H), 1.75 (s, 3H), 1.73-1.65 (m, 1H).
N-tert-butoxycarbonyl-N-methylethylenediamine (1.00 g), methylene chloride (30 mL), anhydrous potassium carbonate (1.59 g) and acetic anhydride (0.64 g) were added to the reaction flask successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, The reaction solution was washed with water and saturated brine successively, and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 29A (1.13 g).
To a reaction flask containing compound 29A (1.13 g) was added a solution of hydrogen chloride (4 M) in 1,4-dioxane (20 mL), and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 29B (0.87 g).
To a reaction flask were added compound 29B (0.87 g), 1,3-dibromofluorobenzene (5.42 g), tris(dibenzylideneacetone)dipalladium (263 mg), 1,1′-binaphthyl-2,2′-diphenyl phosphine (179 mg), tetrahydrofuran (50 mL) and sodium tert-butoxide (3.31 g) successively. After the addition was completed, the reaction solution was stirred for reaction at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (ethyl acetate) to give compound 29C (0.48 g).
MS (ESI, [M+H]+) m/z: 271.1.
Tetrahydrofuran (10 mL) was added to a reaction flask containing compound 29C (0.48 g), and after the mixture was dissolved with stirring, sodium hydride (0.28 g) was added after the reaction solution was cooled with ice/ethanol. After the addition was completed, the reaction solution was stirred for 10 min, methyl iodide (0.76 g) was added, and after the addition was completed, the reaction solution was stirred for reaction at room temperature. The reaction was completed. The reaction solution was poured into aqueous saturated ammonium chloride solution, stirred, and extracted with dichloromethane, and the organic phases were combined. The reaction solution was dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 29D (0.64 g).
MS (ESI, [M+H]+) m/z: 285.1.
To a reaction flask containing compound 29D (509 mg) were added bis(pinacolato)diboron (680 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (73 mg), 1,4-dioxane (20 mL) and potassium acetate (525 mg) successively. After the addition was completed, the reaction solution was stirred for reaction at 120° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/2) to give compound 29E (441 mg).
MS (ESI, [M+H]+) m/z: 333.3.
To a microwave tube were added compound 29E (440 mg), compound 1C (716 mg), potassium carbonate (550 mg), tetrakis(triphenylphosphine)palladium (77 mg), 1,4-dioxane (10 mL), and water (1 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 120° C. in microwave reactor for 2 h. After the reaction was completed, the reaction solution was filtered, concentrated and subjected to column chromatography (dichloromethane/methanol=96/4) to give compound 29F (400 mg).
MS (ESI, [M+H]+) m/z: 661.39.
To a reaction flask were added compound 29F (400 mg), methanesulfonic acid (582 mg) and dichloromethane (30 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 29 (387 mg).
MS (ESI, [M+H]+) m/z: 561.34.
1H NMR (500 MHz, CDCl3): 8.29 (d, J=8.5 Hz, 1H), 8.01 (dd, J=1.5, 5.0 Hz, 1H), 7.96 (t, J=8.5 Hz, 1H), 7.62 (d, J=8.0 Hz, 2H), 7.47-7.40 (m, 3H), 7.31-7.22 (m, 2H), 7.01 (s, 2H), 6.79-6.74 (m, 1H), 6.43-6.41 (m, 1H), 3.56-3.54 (m, 1H), 3.49-3.46 (m, 1H), 3.43-3.33 (m, 6H), 2.94 (s, 2H), 2.90 (s, 1H), 2.78 (s, 1H), 2.46-2.41 (m, 2H), 2.18-2.13 (m, 2H), 2.08-2.02 (m, 1H), 1.88 (s, 2H), 1.79 (s, 2H), 1.75-1.66 (m, 1H).
1-(Piperidin-4-yl)pyrrolidin-2-one hydrochloride (0.32 g), 1,3-dibromofluorobenzene (0.40 g), tris(dibenzylideneacetone)dipalladium (0.07 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.10 g), sodium tert-butoxide (0.33 g) and toluene (20 mL) were added to a reaction flask successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 120° C. After the starting materials were reacted completely, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=65/1) to give compound 30A (0.20 g).
To a reaction flask were added potassium acetate (0.06 g), bis(pinacolato)diboron (0.10 g), [1,1′-bis (diphenylphosphino)ferrocene]palladium dichloride (25 mg), compound 30A (0.20 g) and dioxane (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the starting materials were reacted completely, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=65/1) to give compound 30B (0.21 g).
To a reaction flask were added compound 30B (0.21 g), compound 1C (0.11 g), potassium carbonate (0.06 g), tetrakis(triphenylphosphine)palladium (13 mg), 1,4-dioxane (15 mL), and water (7.5 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=3/7) to give compound 30C (0.16 g).
MS (ESI, [M+H]+) m/z: 717.8.
To a reaction flask were added compound 30C (0.16 g), dichloromethane (10 mL) and methanesulfonic acid (0.21 g) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 20% aqueous sodium hydroxide solution was added, and the reaction solution was stirred under an ice bath. The pH of the reaction solution was adjusted to 12, the phases were separated, the aqueous phase was extracted by dichloromethane, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=2/3) to give compound 30 (0.08 g).
MS (ESI, [M+H]+) m/z: 617.7.
1H NMR (500 MHz, DMSO-d6) δ 8.23 (d, 1H), 7.96-8.02 (m, 2H), 7.63 (d, 2H), 7.47 (d, 2H), 7.22-7.33 (m, 3H), 6.98 (s, 2H), 6.62-6.64 (m, 1H), 6.41-6.43 (m, 1H), 4.51-4.57 (m, 1H), 3.47 (q, 2H), 3.24 (q, 2H), 2.99 (s, 3H), 2.78 (s, 3H), 2.44-2.48 (m, 2H), 2.02-2.25 (m, 5H), 1.69-1.77 (m, 1H), 1.23 (s, 2H).
1-(Piperidin-4-yl)pyrrolidin-2-one hydrochloride (0.61 g), 1,3-dibromobenzene (0.80 g), tris(dibenzylideneacetone)dipalladium (0.31 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.32 g), sodium tert-butoxide (0.49 g) and toluene (10 mL) were added to a reaction flask successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 120° C. After the starting materials were reacted completely, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=2/3) to give compound 31A (0.50 g). MS (ESI, [M+H]+) m/z: 297.1.
To a reaction flask were added potassium acetate (0.489 g), bis(pinacolato)diboron (0.811 g), [1,1′-bis (diphenylphosphino)ferrocene]palladium dichloride (0.207 g), compound 31A (0.502 g) and dioxane (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the starting materials were reacted completely, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=7/3) to give compound 31B (0.293 g).
MS (ESI, [M+H]+) m/z: 345.6.
To a reaction flask were added compound 31B (0.293 g), compound 1C (0.320 g), potassium carbonate (0.270 g), tetrakis(triphenylphosphine)palladium (0.040 g), 1,4-dioxane (15 mL), and water (7.5 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred for reaction at 110° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=7/3) to give compound 31C (0.294 g).
MS (ESI, [M+H]+) m/z: 673.4.
To a reaction flask were added compound 31C (0.294 g), dichloromethane (10 mL) and methanesulfonic acid (0.210 g) successively. After the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 20% aqueous sodium hydroxide solution was added, and the reaction solution was stirred under an ice bath. The pH of the reaction solution was adjusted to 12, the phases were separated, the aqueous phase was extracted by dichloromethane, and the organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=2/3) to give compound 31 (0.183 g).
MS (ESI, [M+H]+) m/z: 573.7.
1H NMR (500 MHz, DMSO-d6) δ 8.21 (d, 1H), 7.95-8.01 (m, 2H), 7.62 (d, 2H), 7.44 (d, 2H), 7.23-7.32 (m, 4H), 7.02 (s, 2H), 6.60 (d, 1H), 6.41-6.43 (m, 1H), 3.36-3.49 (m, 1H), 3.21-3.35 (m, 4H), 2.89 (s, 3H), 2.42-2.43 (m, 2H), 2.03-2.20 (m, 8H), 1.7 (m, 1H).
To a 100 mL single-neck flask were added tert-butyl 4-(N-methylmethanesulfonamide)piperidine-1-carbamate (1.8 g), methylene chloride (5 mL), and a solution of 4 M hydrogen chloride (2 mL) in dioxane successively, and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was distilled under reduced pressure to give compound 32A (1.26 g), which was used directly in the next step.
To a 100 mL single-neck flask were added 2,2′-(3,3′-dichloro-1,1′-biphenyl-4,4′-bisazo)bis(N-phenyl-3-oxo-butyramide) (0.491 g), bis(dibenzylideneacetone)palladium (0.361 g), 1,3-dibromo-2-fluorobenzene (1 g), compound 32A (1.2 g), sodium tert-butoxide (0.757 g), and dioxane (15 mL) successively under nitrogen atmosphere, and the mixture was heated to 120° C. for reaction. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent, concentrated, and then subjected to column chromatography (petroleum ether:ethyl acetate=85:15) to give compound 32B (680 mg).
MS (ESI, [M+H]+) m/z: 365.1.
To a 100 mL one-neck flask were added [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (139 mg), compound 32B (620 mg), bis(pinacolato)diboron (862 mg), potassium acetate (333 mg), and dioxane (15 mL) successively, and the mixture was heated to 120° C. under nitrogen atmosphere for reaction. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate=75:25) to give compound 32C (420 mg).
MS (ESI, [M+H]+) m/z: 413.3.
To a 100 mL single-neck flask were added tetrakis(triphenylphosphine)palladium (51.8 mg), compound 32C (220 mg), compound 1C (220 mg), potassium carbonate (124 mg), dioxane (5 mL) and water (0.5 mL) successively, and the mixture was transferred to a 100° C. oil bath and heated for reaction. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane:methanol=94:6) to give 32D (180 mg).
MS (ESI, [M+H]+) m/z: 741.4.
To a 50 mL single-necked flask were added compound 32D (180 mg), dichloromethane (10 mL) and methanesulfonic acid (46.7 mg) successively, and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the pH of the reaction solution was adjusted to be neutral with a saturated aqueous sodium carbonate solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane:methanol=96:4) to give compound 32 (120 mg).
MS (ESI, [M+H]+) m/z: 641.7.
1H NMR (500 MHz, CDCl3): δ 8.12 (d, J=7.5 Hz, 1H), 8.07 (dd, J=5.0, 10.0 Hz, 1H), 7.80 (dd, J=5.0, 10.0 Hz, 1H), 7.56-7.51 (m, 3H), 7.40 (d, J=10.0 Hz, 1H), 7.12 (q, J=10.0 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 6.59 (br, 2H), 6.39 (q, J=8.0 Hz, 1H), 3.93-3.91 (m, 1H), 3.51 (d, J=10.0 Hz, 2H), 2.88-2.87 (m, 6H), 2.81 (t, J=10.0 Hz, 2H), 2.63-2.58 (m, 2H), 2.24-2.19 (m, 1H), 2.12-2.06 (m, 2H), 1.83 (br, 6H).
Trifluoroacetic acid (2 mL) was slowly added dropwise to a reaction solution of tert-butyl 7-oxo-2,6-diazaspiro[3,4]octane-2-carboxylate (0.5 g) in dichloromethane (10 mL) at 0° C. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 33A (0.78 g).
MS (ESI, [M+H]+) m/z: 127.4.
To a reaction flask were added compound 33A (0.5 g), 1,3-dibromobenzene (0.74 g), (tris(dibenzylideneacetone)dipalladium (0.19 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.13 g), sodium tert-butoxide (1 g) and 1,4-dioxane (30 mL) successively. After the addition was completed, the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=50/1) to give compound 33B (0.54 g).
MS (ESI, [M+H]+) m/z: 281.4.
Sodium hydride (0.37 g) was slowly added to a solution of compound 33B (0.52 g) in tetrahydrofuran (30 mL) at 0° C. under nitrogen atmosphere, and after the addition was completed, the reaction solution was transferred to the room temperature condition and stirred for 0.5 h, and further added with methyl iodide (1.32 g) for reaction. After the reaction was completed, a saturated aqueous ammonium chloride solution (75 mL) was added to the reaction solution in an ice bath, and the mixture was extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with a saturated aqueous sodium chloride solution (100 mL), dried, filtered, and concentrated to give compound 33C (0.50 g).
MS (ESI, [M+H]+) m/z: 295.4.
To a reaction flask were added compound 33C (0.50 g), bis(pinacolato)diboron (0.65 g), potassium acetate (0.50 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.14 g) and 1,4-dioxane (30 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 33D (0.12 g).
MS (ESI, [M+H]+) m/z: 343.5.
To a microwave tube were added compound 33D (0.12 g), compound 1C (0.14 g), potassium carbonate (0.12 g), tetrakis(triphenylphosphine)palladium (0.03 g), 1,4-dioxane (4 mL) and water (0.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 33E (0.18 g).
MS (ESI, [M+H]+) m/z: 671.4.
Compound 33E (176 mg), methanesulfonic acid (0.15 mL) and dichloromethane (10 mL) were added successively to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 33 (69 mg).
MS (ESI, [M+H]+) m/z: 571.6.
1H NMR (500 MHz, CDCl3) δ 8.14 (dd, J=8.4, 2.8 Hz, 1H), 8.02 (dd, J=5.0, 1.9 Hz, 1H), 7.78 (dd, J=8.5, 2.7 Hz, 1H), 7.60-7.55 (m, 2H), 7.48-7.42 (m, 3H), 7.30 (t, J=7.9 Hz, 1H), 7.17 (dt, J=7.8, 1.8 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.52 (dd, J=7.9, 2.4 Hz, 1H), 6.42 (dd, J=7.7, 4.8 Hz, 1H), 3.91 (s, 4H), 3.69 (d, J=2.6 Hz, 2H), 2.89 (s, 3H), 2.72 (s, 2H), 2.68-2.61 (m, 2H), 2.35-2.28 (m, 2H), 2.20-2.02 (m, 1H), 1.90-1.80 (m, 1H).
To the reaction flask were added ethyl 2,2-difluoro-2-iodoacetate (10 g), vinyltrimethylsilane (8.9 g), copper powder (0.13 g) and acetonitrile (50 mL) successively. After the addition was completed, the reaction solution was stirred at 65° C. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent and concentrated to give compound 34A (8.34 g).
MS (ESI, [M+H]+) m/z: 351.0.
To a reaction flask were added compound 34A (3.0 g), tert-butyl 4-aminopiperidine-1-carboxylate (1.1 g) and ethanol (20 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=8/2) to give compound 34B (1.0 g).
MS (ESI, [M+K]+) m/z: 415.4.
To a reaction flask were added compound 34B (1.0 g), potassium fluoride (1.0 g) and dimethyl sulfoxide (20 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 34C (0.76 g).
MS (ESI, [M+H]+) m/z: 305.4.
To the reaction flask were added compound 34C (3.0 g), a solution of 4 M hydrochloric acid in dioxane (6.2 mL), and dichloromethane (20 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 34D (0.63 g).
MS (ESI, [M+H]+) m/z: 205.4.
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.33 g), tris(dibenzylideneacetone)dipalladium (0.37 g), 1,3-dibromo-2-fluorobenzene (4.5 g), compound 34D (0.63 g), sodium tert-butoxide (0.28 g) and dioxane (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 34E (0.23 g).
MS (ESI, [M+H]+) m/z: 359.0.
To a reaction flask were added compound 34E (0.43 g), bis(pinacolato)diboron (0.25 g), potassium acetate (0.19 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.10 g) and 1,4-dioxane (10 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 34F (0.17 g).
MS (ESI, [M+H]+) m/z: 407.12.
To a reaction flask were added compound 34F (0.17 g), compound 1C (0.12 g), potassium carbonate (0.090 g), tetrakis(triphenylphosphine)palladium (0.077 g), 1,4-dioxane (10 mL), and water (10 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 34G (0.20 g).
MS (ESI, [M+H]+) m/z: 735.7.
Compound 34G (0.21 g), methanesulfonic acid (0.13 g) and dichloromethane (15 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 34 (0.041 g).
MS (ESI, [M+H]+) m/z: 635.5.
1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=8.6 Hz, 1H), 8.31 (d, J=5.1 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.97 (d, J=8.2 Hz, 2H), 7.92-7.83 (m, 3H), 7.80 (d, J=7.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.77 (t, J=6.4 Hz, 1H), 4.46-4.33 (m, 1H), 4.14 (d, J=12.3 Hz, 2H), 3.82 (t, J=6.7 Hz, 2H), 3.21 (t, J=12.2 Hz, 2H), 3.13-3.02 (m, 2H), 2.94 (q, J=10.3, 9.6 Hz, 2H), 2.86 (dd, J=14.7, 7.7 Hz, 2H), 2.32-2.24 (m, 2H), 2.18 (d, J=13.6 Hz, 2H), 1.59 (d, J=17.5 Hz, 2H).
To a reaction flask were added 1,1′-binaphthyl-2,2′-bis-diphenylphosphine (0.21 g), tris(dibenzylideneacetone)dipalladium (0.20 g), 1,3-dibromo-2-fluorobenzene (1.68 g), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carbonate (1.00 g), sodium tert-butoxide (1.70 g), and tetrahydrofuran (25 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 85° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 35A (1.51 g).
MS (ESI, [M-100+H]+) m/z: 299.4.
Compound 35A (1.51 g), methanesulfonic acid (3.62 g) and dichloromethane (60 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 35B (1.32 g).
MS (ESI, [M+H]+) m/z: 299.4.
To a reaction flask were added compound 35B (1.32 g), acetic anhydride (0.67 g), triethylamine (1.32 g) and dichloromethane (50 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 35C (1.32 g).
MS (ESI, [M+H]+) m/z: 341.4.
To a reaction flask were added compound 35C (1.32 g), bis(pinacolato)diboron (1.47 g), potassium acetate (1.14 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.32 g) and 1,4-dioxane (50 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 35D (1.27 g).
MS (ESI, [M+H]+) m/z: 389.6.
To a reaction flask were added compound 35D (0.59 g), compound 1C (0.5 g), potassium carbonate (0.42 g), tetrakis(triphenylphosphine)palladium (0.12 g), 1,4-dioxane (25 mL), and water (5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 35E (0.64 g).
MS (ESI, [M+H]+) m/z: 717.8.
Compound 35E (0.63 g), methanesulfonic acid (0.84 g) and dichloromethane (30 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 35 (0.32 g).
MS (ESI, [M+H]+) m/z: 617.7.
1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.3 Hz, 1H), 8.05 (dd, J=4.8, 1.5 Hz, 1H), 7.76 (dd, J=8.3, 2.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.24 (t, J=6.7 Hz, 1H), 7.09 (dd, J=7.8, 1.6 Hz, 1H), 7.03 (t, J=7.8 Hz, 1H), 6.59 (s, 2H), 6.46 (t, J=8.1 Hz, 1H), 6.36 (dd, J=7.8, 4.9 Hz, 1H), 3.77 (s, 4H), 3.60-3.54 (m, 2H), 3.44-3.38 (m, 2H), 2.59 (ddd, J=11.8, 8.9, 6.6 Hz, 2H), 2.19 (ddd, J=11.5, 9.1, 6.0 Hz, 2H), 2.09 (s, 4H), 2.03 (s, 1H), 1.92 (s, 2H), 1.87-1.83 (m, 2H), 1.81-1.77 (m, 2H).
To a reaction flask were added 1,1′-binaphthyl-2,2′-bis-diphenylphosphine (0.088 g), tris(dibenzylideneacetone)dipalladium (0.086 g), 1,3-dibromo-2-fluorobenzene (0.72 g), tert-butyl 2,6-diaza-spiro[3.4]octane-2-carbonate (0.40 g), sodium tert-butoxide (0.72 g), and tetrahydrofuran (25 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 85° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 36A (620 mg).
MS (ESI, [M+H]+) m/z: 385.4.
Compound 36A (600 mg), methanesulfonic acid (1.55 g) and dichloromethane (30 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 36B (420 mg).
MS (ESI, [M+H]+) m/z: 285.3.
To a reaction flask were added compound 36B (0.42 g), acetic anhydride (0.23 g), triethylamine (0.45 g) and dichloromethane (20 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 36C (440 mg).
MS (ESI, [M+H]+) m/z: 327.4.
To a reaction flask were added compound 36C (0.44 g), bis(pinacolato)diboron (0.51 g), potassium acetate (0.40 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.11 g) and 1,4-dioxane (30 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=40/1) to give compound 36D (0.63 g).
MS (ESI, [M+H]+) m/z: 375.5.
To a reaction flask were added compound 36D (0.74 g), compound 1C (0.5 g), potassium carbonate (0.42 g), tetrakis(triphenylphosphine)palladium (0.12 g), 1,4-dioxane (25 mL), and water (5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 36E (500 mg).
MS (ESI, [M+H]+) m/z: 703.4.
Compound 36E (500 mg), methanesulfonic acid (0.7 g) and dichloromethane (20 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 36 (190 mg).
MS (ESI, [M+H]+) m/z: 603.6.
1H NMR (500 MHz, CDCl3) δ 8.12 (d, J=8.3 Hz, 1H), 8.06 (dd, J=4.8, 1.7 Hz, 1H), 7.76 (dd, J=8.3, 2.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.27-7.18 (m, 1H), 7.10 (dd, J=7.8, 1.6 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H), 6.78-6.64 (m, 1H), 6.59 (s, 2H), 6.38 (dd, J=7.8, 4.9 Hz, 1H), 4.11 (d, J=8.4 Hz, 1H), 4.05 (d, J=8.4 Hz, 1H), 4.01 (d, J=9.9 Hz, 1H), 3.96 (d, J=9.9 Hz, 1H), 3.60 (qd, J=9.8, 2.0 Hz, 2H), 3.49 (ddq, J=14.4, 9.5, 7.3 Hz, 2H), 2.66-2.54 (m, 2H), 2.27-2.17 (m, 4H), 2.16-1.94 (m, 4H), 1.89 (s, 3H).
To a reaction flask were added tert-butyl 2,6-diaza-spiro[3.4]octane-2-carbonate (0.60 g), acetic anhydride (0.44 g), triethylamine (0.86 g) and methylene chloride (40 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 37A (0.82 g).
MS (ESI, [M+H]+) m/z: 255.4.
To a reaction flask were added compound 37A (0.82 g), trifluoroacetic acid (6.14 g), and dichloromethane (50 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 37B (1.68 g).
MS (ESI, [M+H]+) m/z: 155.4.
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.22 g), tris(dibenzylideneacetone)dipalladium (0.22 g), 1,3-dibromo-2-fluorobenzene (1.68 g), compound 37B (1.20 g), sodium tert-butoxide (0.88 g) and tetrahydrofuran (100 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 85° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 37C (960 mg).
MS (ESI, [M+H]+) m/z: 327.4.
To a reaction flask were added compound 37C (0.78 g), bis(pinacolato)diboron (0.92 g), potassium acetate (0.80 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.19 g) and 1,4-dioxane (60 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 37D (0.64 g).
MS (ESI, [M+H]+) m/z: 375.5.
To a reaction flask were added compound 37D (0.53 g), compound 1C (0.32 g), potassium carbonate (0.27 g), tetrakis(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (25 mL), and water (5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 37E (0.43 g).
MS (ESI, [M+H]+) m/z: 703.7.
Compound 37E (0.43 g), methanesulfonic acid (0.58 g) and dichloromethane (25 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 37 (0.10 g).
MS (ESI, [M+H]+) m/z: 603.6.
1H NMR (500 MHz, CDCl3) δ 8.26-7.99 (m, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.54 (d, J=6.2 Hz, 2H), 7.39 (d, J=7.5 Hz, 2H), 7.33-7.26 (m, 1H), 7.22-6.93 (m, 2H), 6.59 (s, 2H), 6.48 (dd, J=13.6, 6.9 Hz, 1H), 6.38 (dd, J=7.1, 5.1 Hz, 1H), 3.93 (s, 3H), 3.66 (d, J=10.6 Hz, 2H), 3.54 (dt, J=10.4, 6.9 Hz, 2H), 2.60 (dd, J=17.4, 8.9 Hz, 2H), 2.27 (t, J=6.7 Hz, 1H), 2.21 (dd, J=15.6, 10.0 Hz, 2H), 2.12 (dd, J=14.1, 7.5 Hz, 2H), 2.05 (t, J=6.6 Hz, 3H), 1.98 (s, 3H), 1.87-1.75 (m, 1H).
Diluted hydrochloric acid (0.433 g) was added dropwise to 1-(piperidin-4-yl)pyrrolidin-2-one (1 g) and water (10 mL) at 0° C., and after the addition was completed, an aqueous sodium nitrite solution (0.533 g) was slowly added dropwise and stirred at room temperature. After the reaction was completed, the reaction solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 38A (0.7 g).
MS (ESI, [M+H]+) m/z: 198.4.
Heavy water (8 mL) was slowly added to compound 38A (0.7 g) and sodium methoxide (0.553 g) under nitrogen atmosphere, and after the addition was completed, the mixture was stirred at 80° C. Deuterated ethanol (5 mL) was added slowly to the reaction flask, and then the reaction solution was stirred at 80° C. After the reaction was completed, the reaction solution was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered under vacuum and concentrated to give compound 38B (0.45 g).
1H NMR (500 MHz, CDCl3) δ 4.40-4.29 (m, 1H), 3.33-3.21 (m, 2H), 2.00 (t, J=7.0 Hz, 2H), 1.97-1.92 (m, 1H), 1.82-1.71 (m, 2H), 1.44 (tt, J=14.8, 7.3 Hz, 1H), 1.23 (s, 1H), 0.92-0.75 (in, 1H).
Sodium methoxide (0.362 g) was added to a solution of compound 38B (0.45 g) in deuterated ethanol (2.5 mL) and heavy water (5.00 mL) at room temperature, and after the addition was completed, nickel-aluminum alloy (1.35 g) was added to the reaction flask, and the temperature was controlled at 30-40° C. After the addition was completed, the reaction solution was stirred at 35° C. After the reaction was completed, the reaction solution was filtered and concentrated, and the residue was extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 38C (0.23 g).
MS (ESI, [M+H]+) m/z: 173.5.
To a microwave tube were added sodium tert-butoxide (0.352 g), 1,1′-binaphthyl-2,2′-bis-diphenylphosphine (0.152 g), tris(dibenzylideneacetone)dipalladium (0.224 g), 1,3-dibromo-2-fluorobenzene (0.31 g), compound 38C and 1,4-dioxane (10 mL) successively, and the reaction solution was stirred for reaction under nitrogen atmosphere at 100° C. After the reaction solution was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=40/1) to give compound 38D (0.14 g).
MS (ESI, [M+H]+) m/z: 345.3.
To a reaction flask were added compound 38D (0.14 g), bis(pinacolato)diboron (0.21 g), potassium acetate (0.12 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.066 g) and 1,4-dioxane (15 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=40/1) to give compound 38E (0.13 g).
MS (ESI, [M+H]+) m/z: 393.4.
To a reaction flask were added compound 38E (0.13 g), compound 1C (0.1 g), potassium carbonate (0.056 g), tetrakis(triphenylphosphine)palladium (0.047 g), 1,4-dioxane (10 mL), and water (2 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and stirred for reaction at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=30/1) to give compound 38F (0.03 g).
MS (ESI, [M+H]+) m/z: 721.4.
To a reaction flask were added compound 38F (0.028 g), methanesulfonic acid (0.019 g) and dichloromethane (20 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 38 (0.013 g).
MS (ESI, [M+H]+) m/z: 621.5.
1H NMR (500 MHz, CDCl3) δ 8.11 (d, J=8.3 Hz, 1H), 8.06 (d, J=3.6 Hz, 1H), 7.81 (d, J=6.9 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.51 (t, J=7.1 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.12 (dd, J=12.9, 7.2 Hz, 2H), 7.00 (t, J=7.6 Hz, 1H), 6.57 (s, 2H), 6.39 (dd, J=7.5, 4.9 Hz, 1H), 4.15 (t, J=12.1 Hz, 1H), 3.48 (s, 1H), 3.41 (t, J=6.9 Hz, 2H), 2.65-2.57 (m, 2H), 2.41 (dd, J=16.7, 8.4 Hz, 1H), 2.28-2.21 (m, 2H), 2.20-2.09 (m, 2H), 2.03 (dd, J=13.9, 7.0 Hz, 2H), 1.93 (dd, J=16.1, 7.5 Hz, 2H), 1.78 (d, J=12.3 Hz, 2H).
Diluted hydrochloric acid (0.914 g) was slowly added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1 g) in methylene chloride (20 mL) at room temperature, and after the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 39A (0.7 g).
MS (ESI, [M+H]+) m/z: 100.1.
To a reaction flask were added compound 39A (0.7 g), 1-bromo-3-iodobenzene (1.461 g), potassium carbonate (2.85 g), cuprous iodide (0.098 g), L-alanine (0.119 g), and dimethyl sulfoxide (10 mL) successively, and the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere.
After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 39B (0.088 g).
MS (ESI, [M+H]+) m/z: 254.1.
To a reaction flask were added compound 39B (0.3 g), 2-aminopropan-1-ol (0.177 g), acetic acid (0.142 g) and methanol (10 mL) successively, and the reaction solution was stirred for 1 h at room temperature under nitrogen atmosphere. Sodium cyanoborohydride (0.148 g) was added to the reaction flask, and the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=25/1) to give compound 39C (0.23 g) MS (ESI, [M+H]+) m/z: 313.4.
To a reaction flask were added N,N-carbonyldiimidazole (0.179 g), compound 39C (0.23 g), toluene (10 mL) successively, and the reaction solution was stirred at room temperature for 1 h under nitrogen atmosphere and then stirred at 110° C. After the reaction was completed, the reaction solution was concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 39D (0.16 g).
MS (ESI, [M+H]+) m/z: 339.1.
To a reaction flask were added compound 39D (0.16 g), bis(pinacolato)diboron (0.24 g), potassium acetate (0.14 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.039 g) and 1,4-dioxane (20 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=50/1) to give compound 39E (0.06 g).
MS (ESI, [M+H]+) m/z: 387.6.
To a reaction flask were added compound 39E (0.06 g), compound 1C (0.08 g), potassium carbonate (0.045 g), tetrakis(triphenylphosphine)palladium (0.038 g), 1,4-dioxane (10 mL), and water (2 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and stirred for reaction at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=30/1) to give compound 39F (65 mg).
MS (ESI, [M+H]+) m/z: 715.5.
To a reaction flask were added compound 39F (0.065 g), methanesulfonic acid (0.051 g) and dichloromethane (20 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 39 (0.032 g).
MS (ESI, [M+H]+) m/z: 615.7.
1H NMR (500 MHz, CDCl3) δ 8.05 (d, J=8.3 Hz, 1H), 7.91 (d, J=4.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.2 Hz, 2H), 7.49 (s, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.24 (d, J=7.9 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.88 (d, J=7.9 Hz, 3H), 6.41 (dd, J=7.2, 5.3 Hz, 1H), 4.35 (t, J=8.3 Hz, 1H), 4.00-3.90 (m, 1H), 3.82 (dd, J=8.2, 5.6 Hz, 1H), 3.77-3.65 (m, 3H), 2.86-2.72 (m, 4H), 2.68 (s, 4H), 2.37 (d, J=7.5 Hz, 1H), 2.07 (qd, J=12.1, 3.7 Hz, 1H), 1.99-1.92 (m, 2H), 1.88 (d, J=7.1 Hz, 1H), 1.81 (d, J=10.8 Hz, 1H), 1.32 (d, J=6.1 Hz, 3H).
To a reaction flask were added Cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (250 mg), 1,3-dibromo-2-fluorobenzene (448 mg), tris(dibenzylideneacetone)dipalladium (55 mg), 1,1′-binaphthyl-2,2′-diphenyl phosphine (40 mg), tetrahydrofuran (30 mL) and sodium tert-butoxide (509 mg) successively, and the reaction solution was stirred for reaction at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 40A (164 mg).
MS (ESI, [M+H]+) m/z: 385.0.
To a reaction flask containing compound 40A (164 mg) were added dichloromethane (15 mL) and methanesulfonic acid (130 mg) successively, and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, and the reaction solution was directly used in the next step without treatment.
To the reaction solution containing compound 40B were added triethylamine (42.9 mg) and acetic anhydride (43.3 mg), and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was washed with water 2 times and dried over anhydrous sodium sulfate. The reaction solution was filtered, and the filtrate was concentrated to give compound 40C (142 mg).
MS (ESI, [M+H]+) m/z: 327.4.
To a reaction flask were added compound 40C (142 mg), bis(pinacolato)diboron (164 mg), potassium acetate (127 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (50 mg) and 1,4-dioxane (10 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 40D (101 mg).
MS (ESI, [M+H]+) m/z: 375.4.
To a microwave tube were added compound 40D (100 mg), compound 1C (135 mg), potassium carbonate (150 mg), tetrakis(triphenylphosphine)palladium (20 mg), 1,4-dioxane (3 mL) and water (0.3 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 120° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 40E (101 mg).
MS (ESI, [M+H]+) m/z: 703.5.
To a reaction flask were added compound 40E (101 mg), methanesulfonic acid (138 mg) and dichloromethane (10 mL) successively, and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, a saturated aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to 9, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 40 (42 mg).
MS (ESI, [M+H]+) m/z: 603.7.
1H NMR (500 MHz, CDCl3) δ 8.12 (d, J=8.5 Hz, 1H), 8.05 (d, J=1.0 Hz, 1H), 7.76 (d, J=7.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.26-7.24 (m, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.06 (t, J=8.0 Hz, 1H), 6.71 (t, J=8.0 Hz, 1H), 6.58 (s, 2H), 6.39 (dd, J=5.0, 7.5 Hz, 1H), 3.80-3.75 (m, 2H), 3.61-3.56 (m, 2H), 3.54-3.51 (m, 1H), 3.43-3.40 (m, 1H), 3.37-3.32 (m, 2H), 3.10-3.04 (m, 1H), 3.02-2.96 (m, 1H), 2.63-2.58 (m, 2H), 2.27-2.24 (m, 2H), 2.17-2.12 (m, 2H), 2.06 (s, 3H), 2.06-2.04 (m, 1H), 1.86-1.78 (m, 1H).
To a reaction flask were added 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.94 g), bis(benzhydrylacetylene)palladium (2.164 g), 1,3-dibromo-2-fluorobenzene (6 g), tert-butylpiperidin-4-ylcarbamate (4.73 g), sodium tert-butoxide (4.54 g), dioxane (20 mL) successively, and the mixture was stirred overnight at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=50/1) to give compound 41A (2.6 g).
MS (ESI, [M+H]+) m/z: 373.2.
To a reaction flask were added compound 41A (2.6 g), dichloromethane (30 mL) and a solution (7.37 mL) of hydrochloric acid in dioxane successively, and the mixture was stirred at room temperature for 1 h. 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 41B (2 g).
MS (ESI, [M+H]+) m/z: 273.3.
In an ice-water bath, 4-chlorobutane-1-sulfonyl chloride (0.611 g) was slowly added to a solution of compound 41B (0.873 g) in N,N-dimethylformamide (15 mL), and after the addition was completed, the reaction solution was slowly warmed to room temperature and stirred. After the reaction was completed, the reaction solution was added to 30 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=2/1) to give compound 41C (0.826 g).
MS (ESI, [M+H]+) m/z: 427.4.
After compound 41C (0.826 g) was dissolved in N,N-dimethylformamide (15 mL), sodium hydrogen (153 mg) was added under an ice-bath condition, and after the addition was completed, the reaction solution was refluxed at 80° C. overnight. After the reaction was completed, the reaction solution was poured into 30 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=2/3) to give compound 41D (0.3 g).
MS (ESI, [M+H]+) m/z: 391.6.
To a reaction flask were added compound 41D (0.3 g), bis(pinacolato)diboron (0.389 g), potassium acetate (0.15 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.125 g) and 1,4-dioxane (15 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (petroleum ether/ethyl acetate=7/3) to give compound 41E (0.265 g).
MS (ESI, [M+H]+) m/z: 439.5.
To a reaction flask were added compound 41E (0.265 g), compound 1C (0.187 g), potassium carbonate (0.105 g), tetrakis(triphenylphosphine)palladium (0.088 g), 1,4-dioxane (10 mL), and water (2 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and stirred for reaction at 110° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/10% methanol=4/1) to give compound 41F (184 mg).
MS (ESI, [M+H]+) m/z: 767.7.
Compound 41F (171 mg), methanesulfonic acid (0.142 mL) and dichloromethane (10 mL) were added successively to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/10% methanol=1/1) to give compound 41 (80 mg).
MS (ESI, [M+H]+) m/z: 667.6.
1H NMR (500 MHz, DMSO-d6) δ 8.26 (d, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.60 (s, 2H), 7.44 (s, 2H), 7.29 (s, 1H), 7.09-7.19 (m, 3H), 6.94 (s, 2H), 6.41 (s, 1H), 3.86 (s, 1H), 3.56 (s, 2H), 3.42 (s, 2H), 3.06 (s, 2H), 2.77 (s, 2H), 2.43 (s, 2H), 2.17 (s, 2H), 2.04 (s, 3H), 1.89 (d, 2H), 1.72 (s, 2H), 1.60 (s, 2H).
In an ice-water bath, 3-chloropropane-1-sulfonyl chloride (0.538 g) was slowly added to a solution of compound 41B (0.83 g) in N,N-dimethylformamide (15 mL), and after the addition was completed, the reaction solution was slowly warmed to room temperature and stirred. After the reaction was completed, the reaction solution was added to 30 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=13/7) to give compound 42A (0.212 g).
MS (ESI, [M+H]+) m/z: 413.4.
After compound 42A (0.212 g) was dissolved in N,N-dimethylformamide (15 mL), sodium hydrogen (146 mg) was added under an ice-bath condition, and after the addition was completed, the reaction solution was refluxed at 80° C. overnight. After the reaction was completed, the reaction solution was poured into 30 mL of ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=2/3) to give compound 42B (0.249 g).
MS (ESI, [M+H]+) m/z: 377.3.
To a reaction flask were added compound 42B (0.249 g), bis(pinacolato)diboron (0.335 g), potassium acetate (0.13 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.054 g) and 1,4-dioxane (15 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (petroleum ether/ethyl acetate=1/1) to give compound 42C (0.21 g).
MS (ESI, [M+H]+) m/z: 425.3.
To a reaction flask were added compound 42C (0.21 g), compound 1C (0.243 g), potassium carbonate (0.137 g), tetrakis(triphenylphosphine)palladium (0.057 g), 1,4-dioxane (10 mL), and water (2 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and stirred for reaction at 110° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/10% methanol=3/7) to give compound 42D (185 mg).
MS (ESI) m/z: 753.7 [M+H]+.
Compound 42D (185 mg), methanesulfonic acid (0.16 mL) and dichloromethane (10 mL) were added successively to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/10% methanol=2/3) to give compound 42 (40 mg).
MS (ESI, [M+H]+) m/z: 653.6.
1H NMR (500 MHz, DMSO-d6) δ 8.26 (d, 1H), 8.00 (d, 1H), 7.7 (d, 1H), 7.59 (d, 2H), 7.42 (d, 2H), 7.28 (t, 1H), 7.08-7.20 (m, 3H), 6.90 (s, 2H), 6.41 (t, 1H), 3.4 (d, 2H), 3.28 (t, 3H), 3.19 (t, 2H), 2.8 (m, 2H), 2.42 (q, 2H), 2.2 (m, 2H), 2.02-2.13 (m, 3H), 1.88 (s, 4H), 1.70 (m, 1H).
To a reaction flask were added tert-butyl exo-8-azabicyclo[3.2.1]octan-3-carbamate (0.5 g), 1-bromo-3-iodobenzene (0.75 g), potassium carbonate (0.92 g), cuprous iodide (0.05 g), L-proline (0.02 g), and dimethyl sulfoxide (10 mL) successively. After the addition was completed, the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 43A (0.14 g).
MS (ESI, [M+H]+) m/z: 381.5.
To a reaction flask were added compound 43A (0.14 g) and a solution of 4 M dioxane in hydrogen chloride (4 mL) successively, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 43B (0.15 g).
MS (ESI, [M+H]+) m/z: 281.8.
Acetic anhydride (0.07 g) was slowly added to a reaction solution of compound 43B (0.15 g) and triethylamine (0.24 g) in dichloromethane (6 mL) at 0° C., and after the addition was completed, the reaction solution was transferred to the room temperature condition and stirred for reaction. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction solution, and the reaction solution was extracted with methylene chloride (30 mL×3), and the organic phases were combined, washed with a saturated aqueous sodium chloride solution (50 mL) and dried. The reaction solution was filtered and concentrated to give compound 43C (0.11 g).
MS (ESI, [M+H]+) m/z: 323.4.
Sodium hydride (0.07 g) was slowly added to a solution of compound 43C (0.22 g) in tetrahydrofuran (12 mL) at 0° C. under nitrogen atmosphere, and after the addition was completed, the reaction solution was transferred to the room temperature condition and stirred for 0.5 h, and further added with methyl iodide (0.48 g) for reaction. After the reaction was completed, a saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution in an ice bath, and the reaction solution was extracted with ethyl acetate (50 mL×3), and the organic phases were combined, washed with a saturated aqueous sodium chloride solution (100 mL), and dried. The reaction solution was filtered and concentrated to give compound 43D (0.22 g).
MS (ESI, [M+H]+) m/z: 336.8.
To a reaction flask were added compound 43D (0.22 g), bis(pinacolato)diboron (0.25 g), potassium acetate (0.20 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.05 g) and 1,4-dioxane (10 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 43E (0.1 g).
MS (ESI, [M+H]+) m/z: 385.6.
To a microwave tube were added compound 43E (0.10 g), compound 1C (0.11 g), potassium carbonate (0.09 g), tetrakis(triphenylphosphine)palladium (0.03 g), 1,4-dioxane (4 mL) and water (0.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 43F (0.10 g).
MS (ESI, [M+H]+) m/z: 713.7.
Compound 43F (100 mg), methanesulfonic acid (0.10 mL) and dichloromethane (6 mL) were added successively to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 43 (26 mg).
MS (ESI, [M+H]+) m/z: 613.7.
1H NMR (500 MHz, CDCl3) δ 8.06 (dt, J=36.6, 6.5 Hz, 2H), 7.76 (q, J=6.6, 5.8 Hz, 1H), 7.58 (t, J=7.4 Hz, 2H), 7.53-7.39 (m, 3H), 7.39-7.24 (m, 2H), 7.15 (q, J=6.9 Hz, 1H), 6.79 (t, J=7.5 Hz, 1H), 6.61 (s, 2H), 6.39 (q, J=6.4 Hz, 1H), 5.18 (dq, J=12.7, 6.5 Hz, 1H), 4.35 (d, J=14.0 Hz, 2H), 2.61 (q, J=9.4, 8.6 Hz, 3H), 2.55-2.30 (m, 6H), 2.25-2.05 (m, 4H), 2.05-1.77 (m, 6H), 1.53-1.20 (m, 3H).
Acetic anhydride (0.68 g) was slowly added to a reaction solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1 g) and triethylamine (2.24 g) in methylene chloride (20 mL) at 0° C., and after the addition was completed, the reaction solution was transferred to the room temperature condition and stirred for reaction. After the reaction was completed, the reaction solution was extracted with saturated aqueous sodium bicarbonate and dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 44A (1.18 g).
MS (ESI, [M+H]+) m/z: 269.5.
Trifluoroacetic acid (2 mL) was added dropwise slowly to a reaction solution of compound 44A (0.5 g) in dichloromethane (10 mL) at 0° C. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 44B (0.85 g).
MS (ESI, [M+H]+) m/z: 169.4.
To a reaction flask were added compound 44B (0.5 g), 1,3-dibromofluorobenzene (0.68 g), (tris(dibenzylideneacetone)dipalladium (0.16 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.11 g), sodium tert-butoxide (0.85 g) and 1,4-dioxane (25 mL) successively. After the addition was completed, the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=50/1) to give compound 44C (0.22 g).
MS (ESI, [M+H]+) m/z: 341.4.
To a reaction flask were added compound 44C (0.22 g), bis(pinacolato)diboron (0.24 g), potassium acetate (0.19 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.05 g) and 1,4-dioxane (20 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 44D (98 mg).
MS (ESI, [M+H]+) m/z: 389.5.
To a microwave tube were added compound 44D (98 mg), compound 1C (103 mg), potassium carbonate (87 mg), tetrakis(triphenylphosphine)palladium (24 mg), 1,4-dioxane (4 mL) and water (0.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 44E (84 mg).
MS (ESI, [M+H]+) m/z: 717.4.
Compound 44E (84 mg), methanesulfonic acid (0.10 mL) and dichloromethane (6 mL) were added successively to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 44 (37 mg).
MS (ESI, [M+H]+) m/z: 617.6.
1H NMR (500 MHz, CDCl3) δ 8.11 (d, J=8.3 Hz, 1H), 8.05-7.99 (m, 1H), 7.79 (dd, J=8.4, 2.1 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.49 (t, J=7.3 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.14-7.06 (m, 2H), 6.95 (t, J=7.9 Hz, 1H), 6.59 (s, 2H), 6.39 (dd, J=7.7, 4.8 Hz, 1H), 3.80 (d, J=49.5 Hz, 4H), 3.06-2.92 (m, 4H), 2.64-2.58 (m, 2H), 2.40-2.32 (m, 2H), 2.24-2.14 (m, 1H), 1.98-1.92 (m, 4H), 1.89 (s, 3H), 1.85-1.80 (m, 1H).
Sodium hydride (7.9 g) was slowly added to a solution of tert-butyl 3-oxo-2,8-diazospiro[4.5]decane-8-carboxylate (10 g) in tetrahydrofuran at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 1 h. Methyl iodide (27.9 g) was added dropwise to the reaction flask at 0° C. and then stirred at room temperature. After the reaction was completed, the reaction was quenched with aqueous ammonium chloride solution, and the reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 45A (13.0 g).
MS (ESI, [M+H]+) m/z: 269.5.
To a reaction flask were added compound 45A (13.0 g), dichloromethane (260 mL) and diluted hydrochloric acid (12.4 g) successively, and the mixture was stirred at room temperature. After the reaction was completed, the reaction solution was filtered and dried to give compound 45B (8.9 g).
MS (ESI, [M+H]+) m/z: 169.4.
To a reaction flask were added sodium tert-butoxide (11.3 g), 1,1′-binaphthyl-2,2′-bis-diphenylphosphine (1.8 g), tris(dibenzylideneacetone)dipalladium (2.7 g), 1,3-dibromo-2-fluorobenzene (11.2 g), compound 45B (8.9 g) and 1,4-dioxane (100 mL) successively, and the reaction solution was stirred for reaction under nitrogen atmosphere at 100° C. After the reaction solution was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=100/1) to give compound 45C (4.8 g).
MS (ESI, [M+H]+) m/z: 341.4.
To a reaction flask were added compound 45C (3.0 g), bis(pinacolato)diboron (3.4 g), potassium acetate (2.6 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.4 g) and 1,4-dioxane (100 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=100/1) to give compound 45D (3.0 g).
MS (ESI, [M+H]+) m/z: 389.5.
To a reaction flask were added compound 45D (2.8 g), compound 1C (2.3 g), potassium carbonate (1.3 g), tetrakis(triphenylphosphine)palladium (1.1 g), 1,4-dioxane (50 mL), and water (10 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and stirred for reaction at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 45E (2.1 g).
MS (ESI, [M+H]+) m/z: 717.5.
To a reaction flask were added compound 45E (2.1 g), methanesulfonic acid (2.3 g) and dichloromethane (80 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 45 (0.43 g).
MS (ESI, [M+H]+) m/z: 617.6.
1H NMR (500 MHz, CDCl3) δ 8.19-7.88 (m, 2H), 7.73 (d, J=8.5 Hz, 1H), 7.60-7.26 (m, 5H), 7.05 (s, 2H), 6.94 (d, J=8.8 Hz, 1H), 6.53 (d, J=10.6 Hz, 1H), 6.33 (s, 1H), 3.19 (s, 2H), 3.02 (s, 4H), 2.94 (d, J=9.5 Hz, 2H), 2.79 (s, 3H), 2.60-2.52 (m, 1H), 2.27 (d, J=14.2 Hz, 3H), 2.10 (s, 1H), 1.75 (s, 4H), 1.19 (d, J=14.4 Hz, 1H).
To a reaction flask were added tert-butyl 4-amino-3-methylpiperidine-1-carboxylate oxalate (1.4 g), triethylamine (0.93 g), 4-bromobutyryl chloride (0.93 g) and tetrahydrofuran (25 mL) successively. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent and concentrated to give compound 46A (0.84 g).
MS (ESI, [M+H]+) m/z: 363.1.
To a reaction flask were added compound 46A (3.0 g), sodium hydride (0.088 g), and tetrahydrofuran (25 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 46B (0.18 g).
MS (ESI, [M+H]+) m/z: 283.5.
To a reaction flask were added compound 46B (1.0 g), a solution of 4 M hydrochloric acid in 1,4-dioxane (3.7 mL), and a solution of 1,4-dioxane (20 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 46C (0.83 g).
MS (ESI, [M+H]+) m/z: 183.5.
To a reaction flask were added compound 46C (3.0 g), cesium carbonate (2.3 g), tris(dibenzylideneacetone)dipalladium-chloroform adduct (0.21 g), 1-(3-methylpiperidin-4-yl)pyrrolidin-2-one hydrochloride (0.51 g), 1,3-dibromom-fluorobenzene (0.89 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.14 g), and dioxane (10 mL) successively. The reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 46D (0.38 g).
MS (ESI, [M+H]+) m/z: 355.4.
To a reaction flask were added 46D (0.38 g), potassium carbonate (0.21 g), bis(pinacolato)diboron (0.41 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.17 g) and dioxane (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 46E (0.16 g).
MS (ESI, [M+H]+) m/z: 403.6.
To a reaction flask were added compound 46E (0.16 g), compound 1C (0.18 g), potassium carbonate (0.087 g), tetrakis(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (10 mL), and water (2.0 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 46F (0.20 g).
MS (ESI, [M+H]+) m/z: 731.8.
Compound 46F (0.20 g), methanesulfonic acid (0.16 g) and dichloromethane (15 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 46 (0.078 g).
MS (ESI, [M+H]+) m/z: 631.7.
1H NMR (500 MHz, CDCl3) δ 8.10-8.04 (m, 1H), 7.94 (dd, J=5.0, 2.3 Hz, 1H), 7.74 (dq, J=8.1, 2.7 Hz, 1H), 7.56-7.47 (m, 2H), 7.43-7.33 (m, 3H), 7.05 (tt, J=11.9, 3.0 Hz, 2H), 6.95 (t, J=8.0 Hz, 1H), 6.34 (ddd, J=7.4, 4.9, 2.1 Hz, 1H), 3.71 (td, J=12.1, 4.2 Hz, 1H), 3.46-3.32 (m, 3H), 3.32-3.26 (m, 1H), 2.76 (td, J=11.9, 2.9 Hz, 1H), 2.59 (dddd, J=11.9, 9.0, 6.3, 2.3 Hz, 2H), 2.47-2.41 (m, 1H), 2.37 (dtt, J=11.7, 5.8, 2.6 Hz, 4H), 2.15 (ddtt, J=15.9, 9.6, 6.7, 3.4 Hz, 1H), 1.98 (dp, J=12.3, 5.2, 4.0 Hz, 3H), 1.81 (ddtq, J=12.4, 9.3, 6.3, 3.7, 2.9 Hz, 1H), 1.72-1.60 (m, 1H), 1.34 (d, J=2.3 Hz, 1H), 1.26-1.14 (m, 3H).
To a reaction flask were added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (2.5 g), acetic anhydride (1.93 g), triethylamine (6.3 g), and dichloromethane (40 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 47A (3.0 g).
MS (ESI, [M+Na]+) m/z: 241.1.
To a reaction flask were added compound 47A (3.01 g), trifluoroacetic acid (2.2 g), and dichloromethane (50 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 47B (2.3 g).
MS (ESI, [M+H]+) m/z: 141.1.
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.73 g), tris(dibenzylideneacetone)dipalladium (0.26 g), 1,3-dibromo-2-fluorobenzene (4.5 g), compound 47B (1.6 g), sodium tert-butoxide (11 g) and dioxane (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 85° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 47C (0.43 g).
MS (ESI, [M+H]+) m/z: 312.9.
To a reaction flask were added compound 47C (0.43 g), bis(pinacolato)diboron (0.52 g), potassium acetate (0.22 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.270 g) and 1,4-dioxane (60 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 47D (0.13 g).
MS (ESI, [M+H]+) m/z: 361.6.
To a reaction flask were added compound 47D (0.13 g), compound 1C (0.12 g), potassium carbonate (0.068 g), tetrakis(triphenylphosphine)palladium (0.057 g), 1,4-dioxane (25 mL), and water (5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 47E (0.21 g).
MS (ESI, [M+H]+) m/z: 689.44.
Compound 47E (0.21 g), methanesulfonic acid (0.58 g) and dichloromethane (25 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 47 (0.11 g).
MS (ESI, [M+H]+) m/z: 589.6.
1H NMR (500 MHz, CDCl3) δ 8.07-7.89 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.46 (dd, J=17.7, 8.1 Hz, 2H), 7.28 (t, J=12.7 Hz, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 6.97 (q, J=7.7 Hz, 1H), 6.48 (dt, J=26.1, 8.2 Hz, 2H), 6.33 (dd, J=7.8, 4.8 Hz, 1H), 4.46-4.25 (m, 2H), 3.86 (dd, J=18.6, 12.8 Hz, 2H), 3.53 (d, J=13.7 Hz, 1H), 3.47-3.28 (m, 1H), 2.78 (q, J=6.9 Hz, 1H), 2.48 (dq, J=53.9, 11.6, 10.3 Hz, 4H), 2.28-2.09 (m, 1H), 1.91-1.79 (m, 3H), 1.54 (d, J=8.6 Hz, 1H), 1.35 (s, 1H).
To a reaction flask were added tert-butyl 4-amino-3-methylpiperidine-1-carboxylate oxalate (3.5 g), triethylamine (2.9 g), 4-bromobutyryl chloride (3.3 g) and tetrahydrofuran (25 mL) successively. After the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the solvent and concentrated to give compound 48A (0.78 g).
MS (ESI, [M+H]+) m/z: 363.1.
To a reaction flask were added compound 48A (1.4 g), sodium hydride (0.088 g), and tetrahydrofuran (25 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 48B (0.52 g).
MS (ESI, [M+H]+) m/z: 283.5.
To a reaction flask were added compound 48B (0.52 g), a solution of 4 M hydrochloric acid in 1,4-dioxane (0.34 mL), and a solution of 1,4-dioxane (20 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 48C (0.41 g).
MS (ESI, [M+H]+) m/z: 183.5.
To a reaction flask were added compound 48C (0.41 g), cesium carbonate (2.2 g), tris(dibenzylideneacetone)dipalladium-chloroform adduct (0.21 g), 1-(3-methylpiperidin-4-yl)pyrrolidin-2-one hydrochloride (0.51 g), 1,3-dibromom-fluorobenzene (0.89 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.14 g), and dioxane (10 mL) successively. The reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 48D (0.28 g).
MS (ESI, [M+H]+) m/z: 337.1.
To a reaction flask were added 48D (0.28 g), potassium carbonate (0.24 g), bis(pinacolato)diboron (0.32 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.138 g) and dioxane (20 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=9/1) to give compound 48E (0.087 g).
MS (ESI, [M+H]+) m/z: 385.3.
To a reaction flask were added compound 48E (0.087 g), compound 1C (0.075 g), potassium carbonate (0.087 g), tetrakis(triphenylphosphine)palladium (0.075 g), 1,4-dioxane (10 mL), and water (2 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 48F (0.080 g).
MS (ESI, [M+H]+) m/z: 713.1.
Compound 48F (0.080 g), methanesulfonic acid (0.16 g) and dichloromethane (15 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 48 (0.021 g).
MS (ESI, [M+H]+) m/z: 613.1.
1H NMR (500 MHz, CDCl3) δ 8.09-7.94 (m, 2H), 7.70 (d, J=8.5 Hz, 1H), 7.48 (h, J=9.0, 8.5 Hz, 3H), 7.36 (d, J=7.8 Hz, 2H), 7.23 (t, J=7.9 Hz, 1H), 7.09 (d, J=7.7 Hz, 1H), 6.84 (dd, J=8.2, 2.4 Hz, 1H), 6.59 (d, J=20.1 Hz, 2H), 6.33 (dd, J=7.8, 4.8 Hz, 1H), 4.39 (ddt, J=12.9, 9.3, 4.6 Hz, 1H), 4.26 (dt, J=22.0, 11.0 Hz, 1H), 3.47 (dt, J=12.6, 3.7 Hz, 1H), 3.29 (t, J=7.0 Hz, 2H), 3.16-3.03 (m, 1H), 2.54 (dt, J=12.0, 8.5 Hz, 3H), 2.35 (t, J=8.1 Hz, 3H), 2.16 (tt, J=9.0, 4.5 Hz, 3H), 1.72 (dtd, J=24.1, 12.1, 11.6, 6.7 Hz, 4H), 1.60 (d, J=12.3 Hz, 2H), 1.07 (d, J=6.9 Hz, 3H).
To a reaction flask were added 33A (0.52 g), 1,3-dibromofluorobenzene (0.83 g), (tris(dibenzylideneacetone)dipalladium (0.20 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.14 g), sodium tert-butoxide (1.04 g) and 1,4-dioxane (30 mL) successively. After the addition was completed, the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=50/1) to give compound 49A (0.22 g).
MS (ESI, [M+H]+) m/z: 299.3.
Sodium hydride (0.11 g) was slowly added to a solution of compound 49A (0.16 g) in tetrahydrofuran (10 mL) at 0° C. under nitrogen atmosphere, and after the addition was completed, the reaction solution was transferred to the room temperature condition and stirred for 0.5 h, and further added with methyl iodide (0.23 g) for reaction. After the reaction was completed, a saturated aqueous ammonium chloride solution was added to the reaction solution in an ice bath, followed by extraction with ethyl acetate, and the reaction solution was washed with saturated brine, and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 49B (0.18 g).
MS (ESI, [M+H]+) m/z: 313.3.
To a reaction flask were added compound 49B (0.17 g), bis(pinacolato)diboron (0.20 g), potassium acetate (0.16 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.04 g) and 1,4-dioxane (10 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 49C (0.19 g).
MS (ESI, [M+H]+) m/z: 361.5.
To a microwave tube were added compound 49C (0.14 g), compound 1C (0.16 g), potassium carbonate (0.14 g), tetrakis(triphenylphosphine)palladium (0.04 g), 1,4-dioxane (4 mL) and water (0.5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 49D (0.14 g).
MS (ESI, [M+H]+) m/z: 689.7.
Compound 49D (135 mg), methanesulfonic acid (0.10 mL) and dichloromethane (6 mL) were added successively to a reaction flask, and the mixture was stirred at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 49 (49 mg).
MS (ESI, [M+H]+) m/z: 589.4.
1H NMR (500 MHz, CDCl3) δ 8.14 (dd, J=8.5, 3.4 Hz, 1H), 8.02 (dt, J=4.9, 2.5 Hz, 1H), 7.83-7.75 (m, 1H), 7.55 (dt, J=8.4, 2.4 Hz, 2H), 7.42 (dt, J=8.3, 2.4 Hz, 2H), 7.32-7.26 (m, 1H), 7.17-7.13 (m, 1H), 7.07 (dd, J=9.5, 6.0 Hz, 1H), 6.57-6.49 (m, 1H), 6.45-6.39 (m, 1H), 4.10-3.96 (m, 4H), 3.71 (d, J=3.3 Hz, 2H), 2.89 (d, J=3.5 Hz, 3H), 2.72 (d, J=3.5 Hz, 2H), 2.70-2.60 (m, 2H), 2.37-2.22 (m, 2H), 2.20-2.08 (m, 1H), 1.90-1.80 (m, 1H).
To a reaction flask were added compound 39B (1.7 g), L-proline benzyl hydrochloride (2.4 g), acetic acid (0.8 g) and methanol (20 mL) successively, and the mixture was stirred at room temperature under nitrogen atmosphere. Sodium cyanoborohydride (0.84 g) was added thereto, and after the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution (50 mL) was added to the reaction solution, and the mixture was concentrated; the residue was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 50A (1.3 g).
MS (ESI, [M+H]+) m/z: 443.4.
To a reaction flask were added compound 50A (1.3 g), sodium hydroxide (0.35 g), tetrahydrofuran (30 mL) and water (10 mL) successively, and the reaction solution was stirred for reaction at 70° C.
After the reaction was completed, the reaction solution was concentrated, the residue was extracted with ethyl acetate, and the pH of the aqueous phase was adjusted to 4-5 with 1 M diluted hydrochloric acid. The aqueous phase was then concentrated, dissolved in methanol (30 mL), filtered through an organic membrane, and further concentrated to give compound 50B (1.0 g).
To a reaction flask were added compound 50B (1.0 g), 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.2 g) and dichloromethane (20 mL) successively, and the mixture was stirred at room temperature under nitrogen atmosphere. N,N-diisopropylethylamine (1.5 g) and N,O-dimethylhydroxylamine hydrochloride (0.4 g) were added to the reaction solution, and after the addition was completed, the reaction solution was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=100/1) to give compound 50C (1.0 g).
MS (ESI, [M+H]+) m/z: 396.2.
Methylmagnesium bromide (1.5 g) was added dropwise to a solution of compound 50C (1.0 g) in tetrahydrofuran (20 mL) at −15° C. under nitrogen atmosphere, and after the addition was completed, the mixture was stirred at room temperature. After the reaction was completed, 50 mL of a saturated aqueous ammonium chloride solution was added to the reaction flask, and the reaction solution was extracted with ethyl acetate and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=40/1) to give compound 50D (0.23 g).
MS (ESI, [M+H]+) m/z: 351.1.
To a reaction flask were added compound 50D (0.23 g), bis(pinacolato)diboron (0.33 g), potassium acetate (0.2 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.053 g) and 1,4-dioxane (20 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=40/1) to give compound 50E (0.054 g).
MS (ESI, [M+H]+) m/z: 399.4.
To a reaction flask were added compound 50E (0.054 g), compound 1C (0.06 g), potassium carbonate (0.051 g), tetrakis(triphenylphosphine)palladium (0.014 g), 1,4-dioxane (5 mL), and water (1 mL) successively. After the addition was completed, the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 50F (0.050 g).
MS (ESI, [M+H]+) m/z: 727.4.
To a reaction flask were added compound 50F (0.05 g), methanesulfonic acid (0.066 g) and dichloromethane (6 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, 10% aqueous sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 50 (0.0050 g).
MS (ESI, [M+H]+) m/z: 627.7.
1H NMR (500 MHz, DMSO) δ 9.36 (d, J=41.5 Hz, 1H), 8.99 (s, 1H), 8.34-8.26 (m, 1H), 8.08 (d, J=6.1 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.74 (dd, J=33.2, 8.5 Hz, 2H), 7.66-7.57 (m, 3H), 7.48 (d, J=7.1 Hz, 3H), 7.31 (t, J=7.9 Hz, 1H), 7.02 (d, J=6.5 Hz, 1H), 6.61 (s, 1H), 4.88 (d, J=26.5 Hz, 1H), 3.90 (dd, J=20.9, 9.0 Hz, 2H), 3.55 (d, J=34.7 Hz, 2H), 2.72 (s, 3H), 2.63 (t, J=7.8 Hz, 4H), 2.37 (d, J=9.4 Hz, 3H), 2.28-2.09 (m, 3H), 2.07-1.96 (m, 3H), 1.88-1.80 (m, 2H), 1.62 (dd, J=71.1, 14.4 Hz, 3H).
To a reaction flask were added 1,1′-binaphthyl-2,2′-bis-diphenylphosphine (0.22 g), tris(dibenzylideneacetone)dipalladium (0.32 g), 1,3-dibromo-2-fluorobenzene (0.89 g), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carbonate (0.70 g), sodium tert-butoxide (1.0 g), and tetrahydrofuran (25 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 85° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 51A (0.37 g).
MS (ESI, [M+H]+) m/z: 371.3.
Compound 51A (0.37 g), methanesulfonic acid (0.28 g) and dichloromethane (10 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 51B (0.23 g).
MS (ESI, [M+H]+) m/z: 271.3.
To a reaction flask were added compound 51B (0.23 g), acetic anhydride (0.13 g), triethylamine (0.87 g) and dichloromethane (50 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 51C (0.34 g).
MS (ESI, [M+H]+) m/z: 313.0.
To a reaction flask were added compound 51C (0.34 g), bis(pinacolato)diboron (0.42 g), potassium acetate (0.21 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.18 g) and 1,4-dioxane (50 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 51D (0.17 g).
MS (ESI, [M+H]+) m/z: 361.5.
To a reaction flask were added compound 51D (0.17 g), compound 1C (0.16 g), potassium carbonate (0.89 g), tetrakis(triphenylphosphine)palladium (0.74 g), 1,4-dioxane (25 mL), and water (5 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 51E (0.15 g).
MS (ESI, [M+H]+) m/z: 689.6.
Compound 51E (0.15 g), methanesulfonic acid (0.21 g) and dichloromethane (10 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 51 (0.089 g).
HRMS (ESI, [M+H]+) m/z: 589.2825.
1H NMR (500 MHz, CDCl3) δ 8.09-7.94 (m, 2H), 7.66 (d, J=8.5 Hz, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H), 7.09-7.02 (m, 1H), 6.98 (t, J=7.8 Hz, 1H), 6.59-6.47 (m, 2H), 6.32 (m, 1H), 4.39 (d, J=6.0 Hz, 2H), 3.88 (dd, J=20.6, 12.8 Hz, 2H), 3.54 (d, J=13.7 Hz, 1H), 3.41 (d, J=11.6 Hz, 1H), 2.80 (q, J=7.0 Hz, 1H), 2.54 (q, J=9.1 Hz, 3H), 2.21 (m, 2H), 2.10 (dt, J=19.0, 9.3 Hz, 1H), 1.89 (s, 3H), 1.82-1.70 (m, 1H).
To a reaction flask were added 1-tert-butoxycarbonyl-4-methylaminopiperidine (2.00 g), 1,3-dibromobenzene (3.30 g), tris(dibenzylideneacetone)dipalladium (0.43 g), 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.44 g), 1,4-dioxane (100 mL) and sodium tert-butoxide (1.79 g) successively, and after the addition was completed, the reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 52A (1.16 g).
MS (ESI, [M-t-Bu+H]+) m/z: 313.4.
To a reaction flask containing compound 52A (1.15 g) were added methylene chloride (10 mL) and a solution (15 mL) of 4 M hydrogen chloride in dioxane successively, and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 52B (1.17 g).
MS (ESI, [M+H]+) m/z: 269.5.
To a reaction flask containing compound 52B (1.17 g) were added triethylamine (1.16 g), acetic anhydride (0.78 g) and methylene chloride (40 mL) successively, and after the addition was completed, the reaction solution was stirred for reaction at room temperature. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=1/2) to give compound 52C (0.90 g).
MS (ESI, [M+H]+) m/z: 311.4.
To a reaction flask were added compound 52C (0.88 g), bis(pinacolato)diboron (1.08 g), potassium acetate (0.83 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.23 g) and 1,4-dioxane (50 mL) successively. The reaction solution was stirred for reaction at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (petroleum ether/ethyl acetate=1/2) to give compound 52D (0.90 g).
MS (ESI, [M+H]+) m/z: 359.6.
To a microwave tube were added compound 52D (200 mg), compound 1C (219 mg), potassium carbonate (169 mg), tetrakis(triphenylphosphine)palladium (47 mg), 1,4-dioxane (10 mL) and water (2 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 140° C. in microwave reactor. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 52E (216 mg).
MS (ESI, [M+H]+) m/z: 687.8.
To a reaction flask were added compound 52E (206 mg), methanesulfonic acid (0.2 mL) and dichloromethane (10 mL) successively, and the reaction solution was stirred for reaction at room temperature. After the reaction was completed, a saturated aqueous sodium carbonate solution was added to the reaction solution to adjust the pH to 9, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 52 (145 mg).
MS (ESI, [M+H]+) m/z: 587.7.
1H NMR (500 MHz, CDCl3) δ 8.07 (d, J=8.4 Hz, 1H), 7.90 (dd, J=5.2, 1.7 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.68-7.62 (m, 2H), 7.48-7.43 (m, 2H), 7.39 (s, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.26-7.21 (m, 1H), 7.15 (dd, J=7.8, 1.7 Hz, 1H), 6.82 (dd, J=8.1, 2.5 Hz, 1H), 6.44 (dd, J=7.7, 5.2 Hz, 1H), 4.65-4.57 (m, 1H), 3.89-3.81 (m, 1H), 3.78-3.70 (m, 1H), 3.10-3.02 (m, 1H), 2.81-2.71 (m, 5H), 2.70-2.59 (m, 2H), 2.55-2.47 (m, 1H), 2.38-2.29 (m, 1H), 2.04 (s, 3H), 1.93-1.84 (m, 1H), 1.81-1.71 (m, 2H), 1.66-1.51 (m, 2H).
To a reaction flask were added tert-butyl 3,6-diazacyclo[3.2.0]heptane-6-carboxylate (0.35 g), acetyl chloride (0.28 g), triethylamine (0.54 g) and dichloromethane (15 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 53A (0.45 g).
MS (ESI, [M+H]+) m/z: 241.1.
To a reaction flask were added compound 53A (0.42 g), hydrochloric acid (3.06 g) and dichloromethane (10 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to give compound 53B (0.4 g).
MS (ESI, [M+H]+) m/z: 141.1.
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (0.20 g), tris(dibenzylideneacetone)dipalladium (0.30 g), 1,3-dibromobenzene (0.43 g), compound 53B (0.29 g), sodium tert-butoxide (0.47 g) and dioxane (30 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (dichloromethane/methanol=50/1) to give compound 53C (0.07 g).
MS (ESI, [M+H]+) m/z: 295.4.
To a reaction flask were added compound 53C (0.12 g), bis(pinacolato)diboron (0.21 g), potassium acetate (0.12 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.066 g) and 1,4-dioxane (20 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=40/1) to give compound 53D (0.09 g).
MS (ESI, [M+H]+) m/z: 343.6.
To a reaction flask were added compound 53D (0.088 g), compound 1C (0.075 g), potassium carbonate (0.042 g), tetrakis(triphenylphosphine)palladium (0.035 g), 1,4-dioxane (10 mL), and water (2 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=40/1) to give compound 53E (0.054 g).
MS (ESI, [M+H]+) m/z: 671.8.
Compound 53E (0.050 g), methanesulfonic acid (0.072 g) and dichloromethane (10 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=40/1) to give compound 53 (0.020 g).
HRMS (ESI, [M+H]+) m/z: 571.2924.
1H NMR (500 MHz, CDCl3) δ 8.08 (t, J=8.4 Hz, 1H), 8.02 (dd, J=8.7, 4.4 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.41 (t, J=8.5 Hz, 2H), 7.34 (d, J=7.7 Hz, 1H), 7.23 (dd, J=14.2, 7.0 Hz, 2H), 7.13-7.07 (m, 1H), 6.62 (d, J=9.8 Hz, 2H), 6.37 (dd, J=14.0, 8.0 Hz, 2H), 4.67-4.50 (m, 1H), 4.18 (dd, J=19.0, 11.7 Hz, 1H), 3.95-3.76 (m, 3H), 3.67-3.60 (m, 1H), 3.58 (d, J=6.1 Hz, 1H), 3.34 (dd, J=14.7, 6.2 Hz, 1H), 3.31-3.23 (m, 1H), 3.17 (s, 1H), 2.65 (dd, J=39.8, 30.3 Hz, 4H), 2.45 (d, J=39.0 Hz, 2H), 2.12 (s, 1H), 2.00 (s, 1H), 1.85 (s, 1H).
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (3.3 g), tris(dibenzylideneacetone)dipalladium (4.9 g), 1,3-dibromo-2-fluorobenzene (2.6 g), 4-acetylaminopiperidine hydrochloride (3.0 g), sodium tert-butoxide (3.6 g) and dioxane (30 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 54A (0.90 g).
MS (ESI, [M+H]+) m/z: 297.1.
To a reaction flask were added compound 54A (0.90 g), sodium hydride (1.2 g), deuterated iodomethane (3.1 g), and tetrahydrofuran (20 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction solution, and water and ethyl acetate were added to extract the reaction solution; the reaction solution was then washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 54B (1.5 g).
MS (ESI, [M+H]+) m/z: 314.5.
To a reaction flask were added compound 54B (1.5 g), bis(pinacolato)diboron (2.4 g), potassium acetate (1.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.57 g) and 1,4-dioxane (50 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 54C (0.62 g).
MS (ESI, [M+H]+) m/z: 362.1.
To a reaction flask were added compound 54C (0.33 g), compound 1C (0.30 g), potassium carbonate (0.17 g), tetrakis(triphenylphosphine)palladium (0.21 g), 1,4-dioxane (30 mL), and water (6 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 54D (0.28 g).
MS (ESI, [M+H]+) m/z: 690.8.
Compound 54D (0.28 g), methanesulfonic acid (0.19 g) and dichloromethane (10 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 54 (0.14 g).
HRMS (ESI, [M+H]+) m/z: 590.3460.
1H NMR (500 MHz, CDCl3) δ 8.08-7.96 (m, 2H), 7.70 (dd, J=8.4, 2.1 Hz, 1H), 7.55 (m, 1H), 7.49 (dd, J=8.2, 5.9 Hz, 2H), 7.43 (dd, J=15.3, 7.7 Hz, 1H), 7.40-7.32 (m, 2H), 7.25 (q, J=8.1 Hz, 1H), 7.08 (dd, J=7.8, 1.8 Hz, 1H), 6.89 (dd, J=8.2, 2.6 Hz, 1H), 6.56 (s, 2H), 6.32 (dd, J=7.8, 4.8 Hz, 1H), 4.59 (tt, J=12.2, 4.1 Hz, 1H), 3.84-3.66 (m, 2H), 2.80 (m, 2H), 2.54 (m, 2H), 2.17 (m, 2H), 2.10 (s, 1H), 2.04 (s, 2H), 1.97 (s, 3H), 1.75 (m, 2H), 1.66-1.59 (m, 1H).
To a reaction flask were added 1,1′-binaphthyl-2,2′-diphenyl phosphine (3.1 g), tris(dibenzylideneacetone)dipalladium (2.3 g), 1,3-dibromo-2-fluorobenzene (5.1 g), 4-acetylaminopiperidine hydrochloride (3.0 g), sodium tert-butoxide (3.6 g) and tetrahydrofuran (30 mL) successively under nitrogen atmosphere. After the addition was completed, the reaction solution was stirred at 100° C. After the reaction was completed, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 55A (1.0 g).
MS (ESI, [M+H]+) m/z: 315.4.
To a reaction flask were added compound 55A (1.0 g), sodium hydride (1.1 g), deuterated iodomethane (1.1 g), and tetrahydrofuran (10 mL) successively. The mixture was stirred at room temperature. After the reaction was completed, a saturated ammonium chloride solution was added to the reaction solution, and water and ethyl acetate were added to extract the reaction solution; the reaction solution was then washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered and concentrated to give compound 55B (1.4 g).
MS (ESI, [M+H]+) m/z: 332.4.
To a reaction flask were added compound 55B (1.4 g), bis(pinacolato)diboron (2.0 g), potassium acetate (1.2 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.5 g) and 1,4-dioxane (50 mL) successively. The reaction solution was stirred at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 55C (0.75 g).
MS (ESI, [M+H]+) m/z: 380.1.
To a reaction flask were added compound 55C (0.35 g), compound 1C (0.30 g), potassium carbonate (0.17 g), tetrakis(triphenylphosphine)palladium (0.21 g), 1,4-dioxane (30 mL), and water (6 mL) successively. After the addition was completed, the reaction solution was purged with nitrogen gas, and reacted at 100° C. After the reaction was completed, the reaction solution was filtered and concentrated. The reaction solution was subjected to column chromatography (dichloromethane/methanol=20/1) to give compound 55D (0.28 g).
MS (ESI, [M+H]+) m/z: 708.5.
Compound 55D (0.28 g), methanesulfonic acid (0.19 g) and dichloromethane (10 mL) were added successively to a reaction flask. The mixture was stirred at room temperature. After the reaction was completed, 10% sodium hydroxide solution was added to the reaction solution to adjust the pH to 13, water and dichloromethane were added to extract the reaction solution, and the reaction solution was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction solution was filtered, concentrated, and subjected to column chromatography (dichloromethane/methanol=10/1) to give compound 55 (0.11 g).
HRMS (ESI, [M+H]+) m/z: 608.3345.
1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J=8.3, 5.6 Hz, 1H), 7.99 (dd, J=4.8, 1.9 Hz, 1H), 7.74 (dd, J=8.4, 2.3 Hz, 1H), 7.48 (dd, J=8.5, 2.5 Hz, 2H), 7.46-7.40 (m, 1H), 7.33 (dd, J=8.4, 2.2 Hz, 2H), 7.09-7.00 (m, 2H), 6.98-6.89 (m, 1H), 6.54 (s, 2H), 6.31 (dd, J=7.8, 4.9 Hz, 1H), 4.57 (tt, J=12.3, 4.2 Hz, 1H), 3.53-3.36 (m, 2H), 2.86-2.66 (m, 2H), 2.53 (dddd, J=12.1, 9.5, 6.2, 2.9 Hz, 2H), 2.20-2.14 (m, 3H), 2.09 (s, 2H), 2.04 (s, 3H), 1.86 (m, 2H), 1.74 (m, 1H), 1.66 (m, 2H).
A dish of LNcap cells (human prostate cancer cells with PTEN deficiency) growing at log phase and in good conditions were taken and digested for 3 min by using 1 mL of pancreatin, then the mixture was added with 4 mL of complete culture medium to terminate digestion, and the cells were added to a centrifuge tube. 20 μL of cells were taken and counted, the required number of cells (mL) was pipetted and centrifuged at 1200 rpm for 5 min, the supernatant was discarded, and an appropriate amount of plating medium (RPMI medium+5% FBS+1% sodium pyruvate+1% glutamine) was added to adjust the cell density to 3×104 cells/mL. The cells were seeded on a 96-well plate at 100 μL/well using a multi-channel pipette and cultured in a cell incubator at 37° C., 5% CO2 and saturated humidity. After incubation overnight, compounds were loaded using a nanoliter pipettor, 2 duplicate wells were set for each concentration, and cells without compound were used as negative controls. After 72 h, CCK-8 was added at 10 μL/well for incubation for 4 h, then absorbance was measured at 450 nm with an Envision plate reader, and inhibition rate was calculated. Inhibition rate (%)=(mean value of negative control group−mean value of experimental group)/(mean value of negative control group−mean value of blank group)×100%. A dose-response curve was fitted by four-parameter analysis, with the logarithm of compound concentration as abscissa and inhibition rate as ordinate, so that IC50 was calculated. The experimental results are shown in Table 1.
LNcap cells AKT1 (S473) growing at log phase were taken, digested with 1 mL of pancreatin for 3 min, and added with 4 mL of complete medium to terminate digestion. The cells were added to a centrifuge tube. 20 μL of cells were taken and counted, the required number of cells (mL) was taken and centrifuged at 1200 rpm for 5 min, and a plating medium (2% FBS+phenol-free red 1640 base medium+1% sodium pyruvate+1% glutamine) was added to adjust the cell density to about 1×10E6 cells/mL. The cells were plated (96 wells) at the above cell density (100 μL/well), and cultured in a cell incubator at 37° C., 5% CO2 overnight; the next day, according to the plate distribution, the corresponding compound was sprayed using a nanoliter pipettor and incubated for 1 h at 37° C. in a cell incubator containing 5% CO2; the supernatant was discarded, and the plate was added with 40 μL of lysis buffer (1×) containing blocking buffer and incubated by shaking at room temperature for 30 min. After the mixture was mixed, 16 μL of lysate was transferred to another 384-well small-volume white plate. The plate was added with 4 μL of pre-mixed antibody (v/v) in assay buffer, covered, centrifuged to mix well, and incubated overnight at room temperature. The 665 nm/620 nm signal value was detected using a PE Envision multi-functional microplate reader, and IC50 was calculated by four-parameter fitting.
The results of the inhibitory effect of the compound on the phosphorylation of LNcap cells AKT1 (S473) are shown in table 2.
ICR mice, weight 18-22 g, after adaption for 3-5 days, were randomly divided into 4 groups of 9 mice, each group was intragastrically (IG) administered with compound 28 or compound 30 at a dose of 10 mg/kg, or intravenously (IV) administered with compound 28 or compound 30 at a dose of 1 mg/kg.
The animals to be tested (ICR mice) were fasted for 12 h before administration and food was provided 4 h after administration, and water was freely drunk before and after the experiment and during the experiment.
After intragastric administration, about 0.1 mL of blood was taken from eye sockets at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h; after intravenous injection, about 0.1 mL of blood was taken from eye sockets at 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h; each mouse was collected at 3-4 time points and 3 mice were collected at each time point, whole blood was collected, placed in centrifuge tubes containing EDTA-K2, and stored at 4° C. within 1 h, and the plasma was separated off by centrifugation at 4° C. and 4000 rpm for 10 min. All the plasma samples were collected and immediately stored at −20° C. for testing. 30 μL of the plasma sample to be tested and a standard curve sample were pipetted and added with 300 μL of acetonitrile solution containing an internal standard (20 ng/mL diazepam), shaken and mixed well for 5 min, and centrifuged at 13,000 rpm for 10 min. 80 μL of supernatant was taken and diluted with 80 μL of ultrapure water. After being mixed well, 2 μL of the resulting sample was taken for liquid chromatography-mass determination, and a chromatogram was recorded.
Oral and intravenous exposure of the compound of the present application was evaluated by in vivo pharmacokinetic experiment in mice. The results are shown in the table 3 below.
SD rats, weight 180-220 g, after adaption for 7 days, were randomly divided into 4 groups of 3 mice, each group was intragastrically (IG) administered with compound 28 or compound 30 at a dose of 10 mg/kg, or intravenously (IV) administered with compound 28 or compound 30 at a dose of 1 mg/kg. The animals to be tested (SD rats) were fasted for 12 h before administration and food was provided 4 h after administration, and water was freely drunk before and after the experiment and during the experiment.
After intragastric administration, about 0.1 mL of blood was taken from eye sockets at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, and 24 h; after intravenous injection, about 0.1 mL of blood was taken from eye sockets at 5 min, 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h; 3 rats were collected at each time point, whole blood was collected, placed in centrifuge tubes containing EDTA-K2, and stored at 4° C. within 1 h, and the plasma was separated off by centrifugation at 4° C. and 4000 rpm for 10 min. All the plasma samples were collected and immediately stored at −20° C. for testing. 30 μL of the plasma sample to be tested and a standard curve sample were pipetted and added with 300 μL of acetonitrile solution containing an internal standard (20 ng/mL diazepam), shaken and mixed well for 5 min, and centrifuged at 13,000 rpm for 10 min. 80 μL of supernatant was taken and diluted with 80 μL of ultrapure water. After being mixed well, 2 μL of the resulting sample was taken for liquid chromatography-mass determination, and a chromatogram was recorded.
Oral and intravenous exposure of the compound of the present application was evaluated by in vivo pharmacokinetic experiment in rats. The results are shown in the table 4 below.
SPF-grade female BALB/C nude mice (from Changzhou Cavens Laboratory Animal Ltd.) were inoculated subcutaneously at the right side armpit with 5×106 AN3CA cells (sourec: Nanjing Cobioer Biosciences Co., Ltd.). When the mean tumor volume reached about 130 mm3, the animals were divided into 3 groups of 6 and dosed as shown in table 5:
The day of grouping was determined as do, and the intragastric administration was started on the grouping day, and the administration volume was 10 mL/kg. The solvent was: D5W (5% glucose solution). The tumor volume was measured 2-3 times a week, meanwhile, the mice were weighed and the data were recorded; the general behavior of the mice was observed and recorded every day. After the experiment was completed, the tumors were removed, weighed and photographed.
Calculation formula for tumor volume: Tumor volume (mm3)=½×(a×b2) (where a represents long diameter and b represents short diameter).
Relative tumor proliferation rate (T/C %) refers to the percentage of the relative tumor volume of the treatment and control groups at a certain time point. The calculation formula is as follows: T/C %=TRTV/CRTV×100% (TRTv: mean relative tumor volume (RTV) for treatment group; CRTV: mean RTV for vehicle control group; RTV=TVt/TV0, where TV0 is the tumor volume at grouping, TVt is the tumor volume after treatment).
Tumor growth inhibition rate (TGI %) was calculated according to the following formula: TGI %=(1−tumor weight in treatment group/tumor weight in control group)×100%.
The calculation formula for weight change rate (WCR) (%) is: WCR=(Wtt−Wt0)/Wt0×100%, where Wt0 is the body weight of the animal at grouping (i.e., d0), Wtt is the body weight of the animal at each measurement.
All experimental results are expressed as mean±SD (mean±standard deviation). The relative tumor volume of the treatment group was compared with that of the control group for any significant difference by T tests, wherein p<0.01 indicates a very significant difference.
The results are shown in table 6, and the in vivo efficacy results show that both compound 28 and compound 30 have strong in vivo tumor inhibition effects.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202011057860.0 | Sep 2020 | CN | national |
| 202110261605.6 | Mar 2021 | CN | national |
The present application is a National Stage Application of International Application No. PCT/CN2021/122040, filed Sep. 30, 2021, which claims priority to and benefit of the Chinese Patent Application No. 202011057860.0 filed with China National Intellectual Property Administration on Sep. 30, 2020 and the Chinese Patent Application No. 202110261605.6 filed with China National Intellectual Property Administration on Mar. 10, 2021, the disclosure of each of which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/122040 | 9/30/2021 | WO |
