CN113620931A - Androgen receptor inhibitor and application thereof - Google Patents

Androgen receptor inhibitor and application thereof Download PDF

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CN113620931A
CN113620931A CN202111067653.8A CN202111067653A CN113620931A CN 113620931 A CN113620931 A CN 113620931A CN 202111067653 A CN202111067653 A CN 202111067653A CN 113620931 A CN113620931 A CN 113620931A
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秦冲
陈怡铭
钟腾江
张赛
葛玲
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Abstract

The invention relates to the field of pharmacy, and particularly discloses an Androgen Receptor (AR) regulator combined with an E3 ubiquitin ligase ligand, or a salt and a stereoisomer thereof, and a pharmaceutical composition containing the same.

Description

Androgen receptor inhibitor and application thereof
Technical Field
The invention relates to the field of pharmacy, and particularly discloses an Androgen Receptor (AR) regulator combined with an E3 ubiquitin ligase ligand, or a salt and a stereoisomer thereof, and a pharmaceutical composition containing the same.
Background
Protein-targeting chimera (PROTAC) is a novel strategy for the selective knock-down of target proteins by small molecules (Sakamoto KM et al, Proc Natl Acad Sci 2001,98: 8554-9.; Sakamoto KM et al, Methods enzymol.2005; 399: 833-. ProTAC uses the ubiquitin-protease system to target specific proteins and induce their degradation in cells (Zhou P.et al, Mol cell.2000; 6(3): 751-756; Neklesa TK et al, Pharmacol Ther.2017; 174: 138-144; Lu M.et al, Eur J Med chem.2018; 146: 251-259). The normal physiological function of the ubiquitin protease system is responsible for the clearance of denatured, mutated or harmful proteins in cells. The normal physiological function of the ubiquitin protease system is responsible for the clearance of denatured, mutated or harmful proteins in cells. The ubiquitin-proteasome system (UPS), also known as the ubiquitin-proteasome pathway (UPP), is a common post-translational regulatory mechanism responsible for protein degradation in normal and pathological states (Ardley H. et al, Essays biochem.2005,41, 15-30; Komanger D. et al, biochem.2012,81, 203-. Ubiquitin is highly conserved in eukaryotic cells, is a modified molecule consisting of 76 amino acids, covalently binds and labels target substrates through a cascade of enzymatic reactions involving the enzymes E1, E2 and E3. Subsequently, the modified substrate is recognized by the 26S proteasome complex for ubiquitination-mediated degradation. To date, two E1 enzymes have been discovered, referred to as UBA1 and UBA6, respectively. On the other hand, approximately 40E 2 enzymes and over 600E 3 enzymes provide functional diversity to control the activity of many downstream protein substrates. However, only a limited number of E3 ubiquitin ligases were successfully hijacked for use by small molecule PROTAC technology: von Hippel-Lindau disease tumor suppressor protein (VHL), mouse two minute 2 homolog (MDM2), apoptosis inhibitor (cIAP) and cereblon (Philipp o et al, chem. biol.2017,12, 2570-.
Bifunctional compounds consisting of a target protein binding moiety and an E3 ubiquitin ligase binding moiety have been shown to induce proteasome-mediated degradation of selected proteins. Such drug molecules offer the possibility of temporal control of protein expression and are useful in the treatment of related diseases. In recent years, this newly developed method has been widely used in antitumor studies (Lu J. et al., Chem biol. 2015; 22(6):755- > 763; Ottis P. et al, Chem biol. 2017; 12 (4): 892-; and have been disclosed or discussed in patent publications, for example US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016149989, WO 2016032, WO 2016197197114, WO2017011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, WO2017211924, WO2018033556, WO 20180717171606.
Prostate cancer (PCa) remains the leading cause of cancer-related death in north american men (s.m.green, mol.cell.endocrinol.360(2012) 3-13). The major driver of this disease is the Androgen Receptor (AR), a steroid-induced transcription factor, which regulates many genes that promote tumor growth (n.lallous, int.j.mol.sci.14(2013), 12496-. AR is a part of the nuclear receptor family, consisting of an N-terminal domain (NTD), followed by a DNA Binding Domain (DBD) and a C-terminal Ligand Binding Domain (LBD) (g. jenster, mol. endocrinol.5(1991) 1396-. Steroid binding to LBD signals nuclear localization followed by DBD-mediated AR dimerization and activated receptor dimer binding to Androgen Response Element (ARE) on target genes. Currently used AR antagonists, such as enzalutamide, block AR activation by interfering with steroid binding to the androgen binding pocket on LBD (c.e. bohl, j.biol. chem.280(2005) 37747-37754). Resistance occurs when mutations in the binding pocket render these drugs ineffective, or by expression of constitutively active splice variants completely lacking LBD (e.g., AR-V7, 6-9). Despite the improvements in medical treatment over the last 30 years, prostate cancer (PCa) remains a significant cause of cancer-related death, second only to lung cancer in men in developed countries (Hamdy, f.c.; n.engl.j.med.2016,375, 1415-1424; Litwin, m.s.; j.am.med.assoc.2017,317, 2532-2542). In addition to surgery and radiation therapy, Androgen Deprivation Therapy (ADTs) is a first line treatment for patients with high risk localized prostate cancer, and second generation antiandrogens such as abiraterone and enzalutamide have been shown to be beneficial in patients with advanced prostate cancer (Karantans, T.; Oncogene 2013,32, 5501-. However, patients who progress to metastatic castration resistant prostate cancer (mCRPC), a hormone resistant disease, face a high mortality rate and currently have no cure (Narayanan, R.; Oncococience 2017,4, 175-. Androgen Receptor (AR) and its downstream signaling play a key role in the development and progression of localized and metastatic prostate cancer. (Sund ren, H.; J.Med.Chem.2015,58, 1569-Asca 1574) previously successful strategies to target AR signaling have mainly focused on blocking androgen synthesis by drugs (such as Abiraterone) and on AR antagonists (such as Enzalutamide and Apragylamine (ARN-509)) (Oksala, R.; J.Steroid Biochem.mol.biol.2018; Watson, PA; Nat.Rev.Cancer 2015,15, 701-containing 711; Guo, C.; J.Med.Chem.2011,54, 93-Asca 7704.; Guerrii, A.; J.Med.Chem.2014,57,7263-7279.Jung, M.E, J.Med.2010, Chem.2010,53, 2796, Yamamoto, S.; J.2017678-7279. Jung, M.E, J.Med.1697, J.Pat.J.J.Pat.J.J.Pat.2. Patch.23598; McAb.3, J.J.J.Pat.J.J.Pat.Pat.J.Pat.J.J.Pat.Pat.J.J.2. Pat.J.Pat No. 3,2359-No. 3,2359,2359,2359,120,120, R.S.; chem.biol.2014,21, 1476-.
The compounds of the invention are new AR antagonists that are more potent than known AR antagonists and antagonize AR by alternative strategies, for example by degradation of AR. The present application addresses this need.
Disclosure of Invention
It is an object of the present invention to provide a proteolysis targeting chimera (PROTAC) compound, which functions to recruit a target protein to E3 ubiquitin ligase for degradation, by combining an AR antagonist with an E3 ligase ligand, a preparation method and uses thereof. In particular, the present disclosure provides PROTAC compounds having formula I.
A compound shown in a general formula (I) or pharmaceutically acceptable salt and stereoisomer thereof,
Figure BDA0003259005860000031
wherein Q is Linker, A is E3 ubiquitin ligase part;
r1, R3 and R4 are independently selected from H, halogen, -C1-8 alkyl, -C1-8 alkenyl, -C1-8 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the-C1-8 alkyl, -C1-8 alkenyl, -C1-8 alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by halogen, hydroxy, -C1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;
r2 is selected from C, O, S;
R5-R8 are each independently selected from CRd, N, O, S;
q is a bond or a divalent linking group;
a is a ligand of E3 ubiquitin ligase.
R1, R3, R4 are further selected from-C1-8 alkyl.
A is selected from
Figure BDA0003259005860000041
Figure BDA0003259005860000042
Wherein R9 is independently selected from hydrogen, halogen, -C1-8 alkyl, -C1-8 alkenyl, -C1-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR5a, -SO2R5a, -COR5a, -CO2R5a, -CONR5aR5b, -C (═ NR5a) NR5bR5C, -NR5aR5b, -NR5aCOR5b, -NR5aCONR5bR5C, -NR5aCO2R5b, -NR5 aonr 5bR5C, -NR5 aoo 2NR5bR5C, -NR5 ao 2R5b, said-C1-8 alkyl, -C1-8 alkenyl, -C1-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, each of which is substituted by a halogen, hydroxy, -C1-8 alkoxy, cycloalkyl, heterocyclyl, heteroaryl;
r5a, R5b, R5C are each independently selected from hydroxy, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
n is 0, 1, 2;
and the junction of Q and A.
Wherein A is further selected from
Figure BDA0003259005860000051
Q is selected from- (L1) z- (L2) r- (L3) Q-;
wherein L1 is selected from
Figure BDA0003259005860000052
L2 is selected from
Figure BDA0003259005860000053
Figure BDA0003259005860000054
L3 is selected from
Figure BDA0003259005860000055
Figure BDA0003259005860000056
z is 1;
r is 0 or 1;
q is 0 or 1
The left and right sides of the junction.
In particular Q is
Figure BDA0003259005860000061
A compound represented by general formula (I) or a pharmaceutically acceptable salt, stereoisomer thereof, wherein the compound represented by general formula (I) is selected from Table 1:
table 1:
Figure BDA0003259005860000062
Figure BDA0003259005860000071
Figure BDA0003259005860000081
Figure BDA0003259005860000091
Figure BDA0003259005860000101
Figure BDA0003259005860000111
Figure BDA0003259005860000121
Figure BDA0003259005860000131
Figure BDA0003259005860000141
Figure BDA0003259005860000151
Figure BDA0003259005860000161
on the other hand, the invention also discloses a pharmaceutical composition which contains the compound shown in the general formula (I) or pharmaceutically acceptable salt and stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
The dosage form of the medicine can be oral preparation and injection preparation.
In another aspect, the present invention discloses methods of inhibiting AR activity comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof, including a compound of general formula (I) or a particular compound exemplified herein.
In another aspect, the invention features a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, as an AR antagonist, wherein the compound "disclosed herein includes a compound of formula (I) or a specific compound exemplified herein. In some embodiments, the disease or condition is associated with antagonism of the AR such as the disease or disorder is cancer, metastatic bone disease, prostatic hypertrophy, acne vulgaris, seborrhea, hirsutism, androgenic alopecia, precocious puberty, or androsaemization. Preferably the cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, pancreatic cancer or hepatocellular cancer. Preferably, the disease or disorder is cancer. More preferably, the disease or condition is prostate cancer. Even more preferably, the disease or disorder is castration-resistant prostate cancer (CRPC). Even more preferably, the disease or disorder is metastatic castration resistant prostate cancer (mCRPC).
On the other hand, the invention discloses the application of the compound in the general formula 1 or pharmaceutically acceptable salts and stereoisomers thereof, or a pharmaceutical composition containing the compound in preparing a medicament of an antiandrogen agent.
Unless specifically defined, the compounds and salts provided herein may also contain all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers.
One skilled in the art will appreciate that the methods described are not exclusive means by which the compounds provided herein may be synthesized, and that a wide collection of synthetic organic reactions may be obtained for potential use in synthesizing the compounds provided herein. The skilled person knows how to select and implement an appropriate synthetic route. Suitable synthetic methods for starting materials, intermediates and products can be determined by reference to documents including, for example, the following references: advances in heterocyclic chemistry, Vol.1-107 (Elsevier, 1963-; journal of heterocyclic chemistry, Vol.1-49 (journal of heterocyclic chemistry, 1964-; carreira et al, (ed.), science of Synthesis, Vol.1-48 (2001-; katritzky et al (eds.), integrated organofunctional group transformations (Pergamon Press, 1996); katritzky et al (eds); integration of organofunctional group transformations II (Elsevier, 2 nd edition, 2004); katritzky et al (eds.), general heterocyclic chemistry (Pergamon Press, 1984); smith et al, advanced organic chemistry: reactions, mechanisms and structures, 6 th edition (Wiley, 2007); trost et al (eds.), in combination with organic synthesis (Pergamon Press, 1991).
The preparation of the compounds described herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the choice of an appropriate protecting group can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in t.w.greene and p.g.m.wuts, protecting groups in organic synthesis, 3 rd edition, Wiley & Sons, inc., New York (1999).
The reaction may be monitored according to any suitable method known in the art. For example, product formation can be monitored by: spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,1h or13C) Infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or chromatographic methods such as High Performance Liquid Chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or Thin Layer Chromatography (TLC). The compounds can be purified by a wide variety of methods including High Performance Liquid Chromatography (HPLC) and normal phase silica gel chromatography by those skilled in the art.
As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced with a substituent. It is understood that substitution on a given atom is limited by valence.
Throughout all definitions, the term "Cn-m"denotes a range including endpoints, where n and m are integers and represent a carbon number. Examples include C1-14And C2-14And the like.
The term "alkyl" refers to a hydrocarbon group selected from straight and branched chain saturated hydrocarbon groups containing from 1 to 18, such as from 1 to 12, further such as from 1 to 10, still further such as from 1 to 8, or from 1 to 6, or from 1 to 4 carbon atoms. Examples of alkyl groups containing 1 to 6 carbon atoms (i.e., C1-6 alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-propyl or n-butyl ("n-Bu"), 1-pentyl, 2-pentyl, 3-2-butyl, 2-methyl-2-butyl, 2-methyl-1-butyl, and, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl.
As used herein, the term "C" used alone or in combination with other termsn-mAlkyl "refers to a saturated hydrocarbon group having n to m carbons that may be straight or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1 butyl, n-pentyl, 3-pentyl, n-hexyl and 1,2, 2-trimethylpropyl and the like. In some embodiments, the alkyl group comprises 1 to 14 carbon atoms, 1 to 13 carbon atoms, 1 to 12 carbon atoms, 1 to 11 carbon atoms, 1 to 10 carbon atoms, 1 to 9 carbon atoms, 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, 1 to 2 carbon atoms.
The term "C" as used herein alone or in combination with other termsn-mAlkoxy "refers to a group of the formula-O-alkyl, wherein the alkyl group has n to m carbons. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
"halogen" as used herein refers to F, Cl, Br or I. In some embodiments, the halogen is F, Cl or Br. In some embodiments, halogen is F. In some embodiments, the halogen is Cl. In some embodiments, the halogen is Br. In some embodiments, halogen is I.
The term "haloalkyl" as used herein refers to an alkyl group wherein one or more hydrogens are replaced with one or more halogen atoms such as fluorine, chlorine, bromine and iodine. Examples of haloalkyl include, but are not limited to, haloC 1-8 alkyl, haloC 1-6 alkyl, or haloC 1-4 alkyl, such as-CF 3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, and the like.
The term "alkenyl" refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups comprising at least one C ═ C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6 carbon atoms. Examples of alkenyl groups such as C2-6 alkenyl include, but are not limited to, vinyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methylbut-1, 3-diene, 1-hexene, 2-hexene, 3-hexene, 4-hexene, and 1, 3-dihexene.
The term "alkynyl" refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups comprising at least one C ≡ C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6 carbon atoms. Examples of alkynyl groups such as C2-6 alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.
The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyl groups.
For example, a cycloalkyl group may comprise 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6,3 to 5 or 3 to 4 carbon atoms. For further example, cycloalkyl groups may be selected from monocyclic groups comprising 3 to 12, such as 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In particular, saturated monocyclic cycloalkyl radicals such as C3-8Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred insertion, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (abbreviated as C)3-6Cycloalkyl) including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4]、[4,5]、[5,5]、[5,6]And [6,6 ]]Ring systems, or as selected from bicyclo [2.2.1 ]]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Bridged bicyclic rings of nonanes. Other examples of bicyclic cycloalkyl groups include those arranged as selected from [5,6 ]]And [6,6 ]]Those of the bicyclic ring of the ring system.
The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed by at least two rings sharing an atom. The term "7 to 12 membered spirocycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and formed by at least two rings sharing one atom.
The term "fused cycloalkyl" refers to a bicyclic cycloalkyl group, as defined herein, which is saturated and formed from two or more rings that share two adjacent atoms.
The term "bridged cycloalkyl" refers to a cyclic structure comprising carbon atoms and formed from two rings that share two atoms that are not adjacent to each other. The term "7-to 10-membered bridged cycloalkyl" refers to a cyclic structure containing 7 to 12 carbon atoms and formed from two rings sharing two atoms not adjacent to each other.
The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a single or multiple ring and having at least one double bond, preferably 1 to 2 double bonds. In one embodiment cycloalkenyl is cyclopentenyl or cyclohexenyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, preferably cyclohexenyl.
The term "fused cycloalkenyl" refers to a bicyclic cycloalkyl group, as defined herein, which contains at least one double bond and is formed from two or more rings that share two adjacent atoms.
The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of 5 to 10 carbon atoms having a single ring or multiple rings and having at least one triple bond.
The term "fused cycloalkynyl" refers to a bicyclic cycloalkyl group, as defined herein, which contains at least one triple bond and is formed from two or more rings that share two adjacent atoms.
The term "benzofused cycloalkyl" is a bicyclic fused cycloalkyl in which a 4 to 8 membered monocyclic cycloalkyl ring is fused to a benzene ring. For example, a benzofused cycloalkyl is where the wavy line indicates the point of attachment.
The term "benzofused cycloalkenyl" is a bicyclic fused cycloalkenyl group in which a 4-to 8-membered monocyclic cycloalkenyl ring is fused to a benzene ring.
The term "benzofused cycloalkynyl" is a bicyclic fused cycloalkynyl in which a 4-to 8-membered monocyclic cycloalkynyl ring is fused to a benzene ring.
Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include, but are not limited to, bicyclo [1.1.0] butyl, bicyclo [2.1.0] pentyl, bicyclo [3.1.0] hexyl, bicyclo [4.1.0] heptyl, bicyclo [3.3.0] octyl, bicyclo [4.2.0] octyl, decahydronaphthalene, and benzo 3 to 8 membered cycloalkyl, benzo C4-6 cycloalkenyl, 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetraaryl, 1, 4-dihydronaphthyl, and the like. Preferred embodiments are 8 to 9 membered fused rings, which in the above examples refer to cyclic structures containing 8 to 9 ring atoms.
As used herein, the term "aryl" refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings). The term "Cn-mAryl "refers to an aryl group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, and the like. In some embodiments, aryl has 6 to 10 carbon atoms. In some embodiments, aryl is substituted or unsubstituted phenyl.
As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon that includes cyclized alkyl and/or alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2 fused rings) groups. Cycloalkyl groups can have 3, 4,5, 6 ring-forming carbons (i.e., C)3-6Cycloalkyl groups). The ring-forming carbon atoms of the cycloalkyl group may be optionally substituted with an oxy group (oxo) or a thio group (sulfido) (e.g., C (═ O) or C (═ S)). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, or cyclohexadienyl and the like. In some embodiments, the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In some embodiments, cycloalkyl has 3-6 ring-forming carbon atoms (i.e., C)3-6Cycloalkyl groups).
As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N or S. Included among the heterocycloalkyl groups are monocyclic 4-, 5-, and 6-membered heterocycloalkyl groups. Examples of heterocycloalkyl groups include pyrrolidin-2-one, 1, 3-isoxazolidin-2-one, pyranyl, tetrahydropyranyl, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and azanyl, and the like. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted with oxy (═ O). The heterocycloalkyl group may be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.
The compounds disclosed herein may contain asymmetric centers and thus may exist as enantiomers. "enantiomers" refers to two stereoisomers of a compound that are mirror images of each other that are not superimposable. When the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended to include all such possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any possible isomer. When the isomeric composition is not specified, all possible isomers are included.
As used herein, the term "substantially pure" means that the stereoisomer of interest contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, by weight of any other stereoisomer. In some embodiments, the term "substantially pure" means that the target stereoisomer comprises no more than 10% by weight, such as no more than 5% by weight, for example no more than 1% by weight, of any other stereoisomer.
When the compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers, unless otherwise specified.
When the compounds disclosed herein comprise disubstituted ring systems, the substituents found on such ring systems may adopt cis and trans structures. Cis formation means that both substituents are located on the carbon at the upper side of the 2 substituent positions, while trans means that they are located on opposite sides. For example, the disubstituted ring system may be a cyclohexyl or cyclobutyl ring.
It may be advantageous to separate the reaction products from each other and/or from the starting materials. The desired product of each step or series of steps is isolated and/or purified (hereinafter isolated) by techniques commonly used in the art to the desired degree of homogeneity. Typically, such separations involve heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography may involve a variety of methods, for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques. Those skilled in the art will apply the techniques most likely to achieve the desired separation.
"diastereomer" refers to a stereoisomer of a compound having two or more chiral centers that are not mirror images of each other. Mixtures of diastereomers may be separated into their individual diastereomers on the basis of their physical or chemical differences by methods well known to those skilled in the art, e.g., by chromatography and/or fractional crystallization. Enantiomers can be separated into the corresponding pure enantiomers by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers. Enantiomers and diastereomers may also be separated by use of a chiral HPLC column.
Single stereoisomers, e.g. substantially pure enantiomers, may be obtained by resolving a racemic mixture using methods such as diastereomer formation using optical resolving agents (Eliel, E. and Wilen, S. stereospecificity of Organic Compounds, New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al "chromatographic resolution of enantiomers: Selectivity review". J.Chromatogr.,113(3) (1975): pp 283- "302) the racemic mixture of chiral compounds of the invention may be separated and isolated by any suitable method, including: (1) formation of ions, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compound derivative reagents with chiral compounds, separation of diastereomers and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See: verner, owen w., ed. Stereochemistry of drug: analytical methods and pharmacology. New York: marcel Dekker, inc., 1993. All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (e.g. hydrates and solvates) or may be isolated.
In some embodiments, preparation of the compounds may involve the addition of an acid or base to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.
Examples of acids may be inorganic or organic acids and include, but are not limited to, strong and weak acids. Some examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, pyroglutamic acid, tartaric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid and capric acid (which may be added further as development progresses).
Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium hydrogencarbonate. Some examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, wherein alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and tert-butyl oxides; metal amino compounds include sodium amide, potassium amide, and lithium amide; metal hydrides including sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include lithium, sodium and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.
The phrase "pharmaceutically acceptable" is employed herein to refer to 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 problem or complication, commensurate with a reasonable benefit/risk ratio.
The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by conversion of an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali metal salts or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids, including primarily salts of inorganic acids such as sulfuric, nitric, hydrobromic, phosphoric, hydrochloric, boric, sulfamic and the like; or organic acids such as acetic acid, propionic acid, butyric acid, camphoric acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, glycolic acid, trifluoroacetic acid, adipic acid, alginic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, stearic acid, lactic acid, citric acid, oxalic acid, malonic acid, succinic acid, pyroglutamic acid, ascorbic acid, aspartic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, hydroxymaleic acid, palmitic acid, cinnamic acid, isobutyric acid, lauric acid, mandelic acid, maleic acid, fumaric acid, malic acid, tartaric acid, sulfanilic acid, 2-acetoxy-benzoic acid, 2-hydroxy-1, 2, 3-propanetricarboxylic acid, suberic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, formic acid, fumaric acid, mucic acid, gentisic acid, pyruvic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, Phenylmethanesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfinic acid, isethionic acid, ethanedisulfonic acid, 4- (fluorenyl-methoxycarbonylamino) butyric acid, dichloroacetic acid, 1, 2-ethanedisulfonic acid, camphor-10-sulfonic acid, 2, 4-dihydroxybenzoic acid, α -ketoglutaric acid, 1-hydroxy-2-naphthoic acid, p-acetamidobenzoic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, all-trans retinoic acid, valproic acid, and the like. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred.
In some embodiments, the compounds and salts provided herein are substantially isolated. By "substantially separated" is meant that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions enriched for the compounds provided herein. Substantially isolating may include compositions comprising at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound provided herein, or a salt thereof. Methods for isolating compounds and their salts are conventional in the art.
Pharmaceutical compositions comprising the compounds disclosed herein can be administered to a subject in need thereof by oral, inhalation, rectal, parenteral, or topical routes. For oral administration, the pharmaceutical composition may be a conventional solid preparation such as tablets, powders, granules, capsules and the like, a liquid preparation such as aqueous or oily suspensions or other liquid preparations such as syrups, solutions, suspensions and the like; for parenteral administration, the pharmaceutical composition may be: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Preferably, the pharmaceutical composition is formulated as a tablet, a coated tablet, a capsule, a suppository, a nasal spray or an injection, more preferably a tablet or a capsule. The pharmaceutical composition may be administered as a single unit with the correct dosage. In preparing the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. In addition, the pharmaceutical composition may further comprise additional active ingredients.
All formulations of the pharmaceutical compositions disclosed herein can be manufactured by methods conventional in the pharmaceutical arts. For example, the active ingredient may be mixed with one or more excipients and then formulated into the desired formulation. By "pharmaceutically acceptable excipient" is meant a conventional pharmaceutical carrier suitable for use in the desired pharmaceutical formulation, for example: diluents, carriers such as water, various organic solvents and the like, fillers such as starch, sucrose and the like, binders such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); humectants such as glycerin; disintegrating agents such as agar, calcium carbonate and sodium hydrogen carbonate; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin, bentonite, etc.; talc powder, calcium stearate, magnesium stearate, polyethylene glycol and other lubricating agents. In addition, the pharmaceutical composition also comprises other pharmaceutically acceptable excipients such as a dispersing agent, a stabilizing agent, a thickening agent, a complexing agent, a buffering agent, an osmotic agent and the like. Enhancers, polymers, fragrances, sweeteners, dyes, and the like.
The term "disease" refers to any disease, disorder, condition, symptom, or indication, and may be interchangeable with the terms "disorder" or "condition.
The disease or condition is associated with antagonism of the AR, e.g. the disease or disorder is cancer, metastatic bone disease, prostatic hypertrophy, acne vulgaris, seborrhea, hirsutism, androgenic alopecia, precocious puberty or andrology. Preferably the cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, pancreatic cancer or hepatocellular cancer. Preferably, the disease or disorder is cancer. More preferably, the disease or condition is prostate cancer. Even more preferably, the disease or disorder is castration-resistant prostate cancer (CRPC). Even more preferably, the disease or disorder is metastatic castration resistant prostate cancer (mCRPC).
The compounds of the present invention may be used alone or in combination with other therapeutic agents for the treatment of the diseases or conditions described herein. The compounds of the invention are combined with other antineoplastic agents. Such antineoplastic agents include, but are not limited to: cyclophosphamide, mechlorethamine, mazuran, meclizine, carmustine, platinoids such as carboplatin, cisplatin, oxaliplatin, camptothecin, irinotecan, daunorubicin, doxorubicin, bleomycin, plicamycin, paclitaxel, vinorelbine, docetaxel, doxorubicin, fluorouracil, methotrexate, cytarabine, gemcitabine, EGFR inhibitors, VEGFR inhibitors, ALK inhibitors, BTK inhibitors, mTOR inhibitors, HDAC inhibitors.
The active ingredient may be administered in an effective and generally pharmaceutically effective amount over a wide dosage range. However, it will be understood that the amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, and the severity of the subject's symptoms, etc.
The invention has the beneficial effects that by combining the AR antagonist and the E3 ligase ligand, a proteolysis targeting chimera (PROTAC) compound is provided, and a new chemical entity is provided for the treatment of various cancers related to AR, so that the current cancer treatment method is changed.
Drawings
FIG. 1 shows the effect of the compound on the reduction of the expression level of Androgen Receptor (AR) in LNCaP cells.
FIG. 2, effect of the compounds on the reduction of Androgen Receptor (AR) expression in VCaP cells.
FIG. 3, effect of compound on reduction of Androgen Receptor (AR) expression level in 22RV1 cells.
FIG. 4 proliferation assay of LNCaP cells.
Detailed Description
The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a wide variety of non-critical parameters that may be varied or modified to achieve substantially the same results.
The examples provided below further illustrate and exemplify the compounds of the present invention and methods for their preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes describe the preparation of the compounds of the present invention, all starting materials being prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these routes are as defined below or in the claims.
The present invention is described in detail below with reference to specific examples, but the use and purpose of these exemplary embodiments are merely to exemplify the present invention, and do not set forth any limitation on the actual scope of the present invention in any form, and the scope of the present invention is not limited thereto.
Example 1:
Figure BDA0003259005860000251
Figure BDA0003259005860000261
dissolving raw materials 1(1.5g, 1.0eq.) and 2(1.8g, 1.2eq.) in 40mL of methanol, adding 1 drop of concentrated hydrochloric acid, heating to 90 deg.C, reacting for 6 hr, detecting by TLC that the raw materials are completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 2.3g of a white solid in 85% yield. UPLC-MS calculated for C16H24N4O4[M+H]+:337.18,found:337.19.UPLC-retention time:6.9min.1H NMR(400MHz,Chloroform-d)δ8.84(s,2H),4.34(q,J＝7.1Hz,2H),4.11(s,2H),3.92(s,4H),2.71(t,J＝13.1Hz,2H),2.47(s,3H),2.22(s,1H),1.71(dd,J＝50.0,18.9Hz,4H),1.46(s,9H),1.41–1.26(m,4H),1.11(d,J＝11.7Hz,2H).
Figure BDA0003259005860000262
Dissolving the intermediate 3(2.3g, 1.0eq.) in 60mL of dichloromethane, adding 15mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 30mL of water, adjusting the pH to 8-9 by using ammonia water, extracting by dichloromethane, adding anhydrous magnesium sulfate, drying, filtering and concentrating to obtain 1.5g of white solid with the yield of 95%. UPLC-MS calculated for C11H16N4O2[M+H]+:237.13,found:237.14.UPLC-retention time:4.2min.
Figure BDA0003259005860000263
Dissolving the intermediate 4(1.7g, 1.0eq.) and the intermediate 5(1.9g, 1.2eq.) in 50mL of 1, 2-dichloroethane, adding 2 drops of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (3.0g, 2.0eq.), reacting at room temperature overnight, detecting that the raw material is completely reacted by TLC, adding 20mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol20/1) gave 2.7g of a white solid in 86% yield. UPLC-MS calculated for C22H35N5O4[M+H]+:434.27,found:434.28.UPLC-retention time:6.1min.1H NMR(400MHz,CDCl3)δ8.84(s,2H),4.34(q,J＝7.1Hz,2H),4.11(s,2H),3.92(s,4H),2.71(t,J＝13.1Hz,2H),2.47(s,3H),2.22(s,1H),1.71(dd,J＝50.0,18.9Hz,4H),1.46(s,9H),1.41–1.33(m,3H),1.26(s,1H),1.11(d,J＝11.7Hz,2H).
Figure BDA0003259005860000271
Intermediate 6(300mg, 1.0eq.) was dissolved in 20mL of a mixed solution of tetrahydrofuran and water (V)Tetrahydrofuran (THF)/VWater (W)3/1), heating to 35 ℃, reacting overnight, detecting by TLC that the raw material is completely reacted, adjusting the pH of the reaction solution to about 5.0 by 1M HCl, extracting by dichloromethane, drying and concentrating the organic phase to obtain white solid 270mg, and the yield is 96%. UPLC-MS calculated for C20H31N5O4[M+H]+:406.24,found:406.25.UPLC-retention time:3.7min.
Figure BDA0003259005860000272
Dissolving intermediate 7(170mg, 1.0eq.), raw material 8(102mg, 1.2eq.), HATU (316mg, 1.2eq.), raw material 8(102mg, 1.2eq.) in 10mL of anhydrous N, N-dimethylformamide, protecting with argon, adding N, N-diisopropylethylamine (360 uL, 3.0eq.), reacting overnight at room temperature, detecting by TLC, allowing the raw material to react completely, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 190mg of a white solid in 89% yield. UPLC-MS calculated for C27H38N6O4[M+H]+:511.30,found:511.31.UPLC-retention time:5.5min.
Figure BDA0003259005860000273
Dissolving intermediate 9(190mg, 1.0eq.) in 8mL of anhydrous N, N-dimethylformamide, adding 60% NaH (23mg, 1.5eq.) under ice bath condition, stirring for 0.5h, adding raw material 10(70mg, 1.2eq.) to react at room temperature overnight, detecting by TLC until the raw material is completely reacted, adding 20mL of water to the reaction solution, extracting with ethyl acetate, adding organic phase into anhydrous sodium sulfate, drying, concentrating, and purifying by column chromatography (V)Methylene dichloride/VMethanol40/1-20/1) gave 180mg of a white solid in 75% yield. UPLC-MS calculated for C34H40ClN7O4[M+H]+:646.28,found:646.00.UPLC-retention time:5.2min.1H NMR(400MHz,CDCl3)δ8.80(s,2H),8.23(d,J＝22.4Hz,1H),7.64–7.44(m,3H),6.93(d,J＝13.4Hz,2H),6.74(dd,J＝58.9,8.5Hz,1H),4.07(d,J＝12.7Hz,2H),3.90(s,4H),2.70(d,J＝13.2Hz,2H),2.45(s,4H),2.20(d,J＝6.9Hz,2H),2.11(s,3H),1.79–1.57(m,3H),1.43(s,9H),,1.07(q,J＝12.1Hz,2H).
Figure BDA0003259005860000281
Dissolving the intermediate 11(180mg, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting by TLC that the raw materials completely react, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate for drying, filtering and concentrating to obtain 146mg of white solid with the yield of 96%. UPLC-MS calculated for C29H32ClN7O2[M+H]+:546.23,found:545.92.UPLC-retention time:4.4min.
Figure BDA0003259005860000282
Dissolving the intermediate 12(66mg, 1.0eq.) and the intermediate 15(40mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (40 mu L, 2.0eq.) into the mixture, heating the mixture to 90 ℃ for reaction for 8 hours, detecting that the raw materials completely react by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 63mg of a fluorescent green solid in 65% yield. UPLC-MS calculated for C42H40ClN9O6[M+H]+:802.28found:802.05.
UPLC-retention time:5.9min.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.23(s,1H),8.95(s,2H),7.91(d,J＝8.6Hz,1H),7.73(d,J＝1.8Hz,2H),7.65(d,J＝8.8Hz,1H),7.34(s,1H),7.16(s,1H),7.10(d,J＝8.6Hz,1H),6.91(dd,J＝8.4,2.2Hz,1H),5.09(d,J＝11.7Hz,1H),4.09(d,J＝12.8Hz,2H),3.04(m,8H),2.97(m,1H),2.58-2.47(m,5H),1.97(m,2H),1.82(d,J＝12.8Hz,2H),1.26(m,2H),1.20(m,4H).
Figure BDA0003259005860000283
Dissolving a raw material 13(3.0g, 1.0eq.) in 60mL of acetic acid, sequentially adding a raw material 14(3.27g, 1.1eq.) and potassium acetate (5.5g, 3.1eq.), heating to 90 ℃, stirring for 14h, detecting complete consumption of the raw material by TLC, cooling a reaction solution to room temperature, pouring the reaction solution into water, extracting with dichloromethane, drying, concentrating, and purifying by column chromatography (V)Methylene dichloride/VMethanol40/1-20/1) gave 4.5g of a white solid in 95% yield. UPLC-MS calculated for C13H9FN2O4[M+H]+:277.05found:277.15.UPLC-retention time:5.0min.1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.98(dd,J＝8.3,4.5Hz,1H),7.82(dd,J＝7.0,1.7Hz,1H),7.69(td,J＝9.3,8.6,2.2Hz,1H),5.17–5.08(m,1H),2.94–2.78(m,1H),2.67–2.46(m,2H),2.09–1.96(m,1H).
Example 2:
Figure BDA0003259005860000291
dissolving the intermediate 12(66mg, 1.0eq.) and the intermediate 16(43mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (44 mu L, 2.0eq.) into the mixture, heating the mixture to 90 ℃ for reaction for 5 hours, detecting that the raw materials completely react by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to give 79mg of a fluorescent green solid in 80% yield. UPLC-MS calculated for C42H39ClFN9O6[M+H]+:820.27found:819.93.
UPLC-retention time:5.8min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.23(s,1H),8.95(s,2H),7.91(dd,J＝8.7,1.3Hz,2H),7.72(d,J＝11.3Hz,2H),7.46(s,1H),7.16(s,1H),6.91(d,J＝11.1Hz,1H),4.93(dd,J＝121.4,13.3Hz,2H),3.63(d,J＝12.0Hz,4H),3.10(m,4H),2.96–2.83(m,2H),2.56(d,J＝18.2Hz,1H),2.08(s,3H),2.11-1.86(m,8H),1.38(d,J＝13.0Hz,2H),1.20(m,1H).
Figure BDA0003259005860000292
Dissolving a raw material 15(3.3g, 1.0eq.) in 60mL of acetic acid, sequentially adding a raw material 14(3.27g, 1.1eq.) and potassium acetate (5.5g, 3.1eq.), heating to 90 ℃, stirring for 14h, detecting complete consumption of the raw material by TLC, cooling a reaction solution to room temperature, pouring the reaction solution into water, extracting with dichloromethane, drying, concentrating, and purifying by column chromatography (V)Methylene dichloride/VMethanol40/1-20/1) to yield 5.0g of a white solid with a yield of 95%. UPLC-MS calculated for C13H8F2N2O4[M+H]+:295.05found:295.06.UPLC-retention time:5.0min.1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.13(t,J＝7.8Hz,2H),5.19–5.09(m,1H),2.85(t,J＝13.7Hz,1H),2.62–2.47(m,2H),2.07–1.99(m,1H).
Example 3:
Figure BDA0003259005860000301
dissolving the raw material 18(5.0g, 1.0eq.) and the intermediate 2(3.8g, 1.0eq.) in 15mL of 1, 2-dichloroethane, adding 2 drops of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (8.6g, 2.0eq.), reacting at room temperature overnight, detecting that the raw material is completely reacted by TLC, adding 10mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol30/1) gave 7.5g of a white solid in 89% yield. UPLC-MS calculated for C23H35N3O4[M+H]+:418.27,found:418.15.UPLC-retention time:2.5min.1H NMR(400MHz,DMSO-d6)δ7.31(s,5H),6.02(s,2H),3.96(d,J＝12.0Hz,2H),2.22(t,J＝4.0Hz,4H),2.07(t,J＝4.0Hz,2H),1.66(s,1H),1.63(s,2H),1.36(s,9H),0.97-0.87(m,2H).
Figure BDA0003259005860000311
Dissolving the intermediate 19(7.5g) in 150mL of methanol, adding 10% Pd (0.75g), replacing with hydrogen for 3 times, heating to 50 ℃, reacting for 4 hours, monitoring by TLC that the raw materials are completely reacted, filtering to remove 10% Pd, and concentrating the filtrate to obtain 4.9g of white solid with the yield of 100%. UPLC-MS calculated for C15H29N3O2[M+H]+:284.22,found:284.02.UPLC-retention time:1.8min.
Figure BDA0003259005860000312
Dissolving intermediate 20(1.3g, 1.2eq.) and raw material 21(0.7g, 1.0eq.) in 40mL isopropanol, adding 1 drop of concentrated hydrochloric acid, heating to 90 deg.C, reacting for 6h, detecting by TLC that the raw material has reacted completely, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 1.5g of a white solid in 89% yield. UPLC-MS calculated for C22H35N5O4[M+H]+:434.27,found:434.10.UPLC-retention time:6.2min.1H NMR(400MHz,DMSO-d6)δ7.88(s,2H),4.50(q,J＝8.0Hz,2H),4.23(d,J＝8.0Hz,1H),3.63(d,J＝8.0Hz,1H),2.82(t,J＝8.0Hz,3H),2.79(t,J＝8.0Hz,1H),2.59(d,J＝8.0Hz,1H),2.29-2.26(m,4H),1.98-1.1.91(m,2H),1.39(dd,J＝8.0Hz,4.0,2H),1.37(s,2H),1.36(s,9H),1.19(m,2H),0.97-0.87(m,2H).
Figure BDA0003259005860000313
Intermediate 22(500mg, 1.0eq.) was dissolved in 20mL of a mixed solution of tetrahydrofuran and water (V)Tetrahydrofuran (THF)/VWater (W)3/1), heating to 35 deg.C for reaction overnight, detecting by TLC that the raw material is completely reacted, adjusting pH of the reaction solution to about 5.0 with 1M HCl, extracting with dichloromethane, drying and concentrating organic phase to obtain white solid 420mg, yield 90%. UPLC-MS calculated for C20H31N5O4[M+H]+:406.24,found:406.10.UPLC-retention time:1.8min.
Figure BDA0003259005860000314
Dissolving intermediate 23(270mg, 1.0eq.) and HATU (304mg, 1.2eq.) in 10mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (350 uL, 2.0eq.), stirring at room temperature for 0.5h, adding intermediate 26(216mg, 1.1eq.), reacting at room temperature for 6h, detecting by TLC, completely reacting the raw materials, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding an organic phase into sodium sulfate, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 357mg of white solid in 83% yield. UPLC-MS calculated for C34H40ClN7O4[M+H]+:646.28,found:646.29.UPLC-retention time:6.7min.1H NMR(400MHz,Chloroform-d)δ8.78(s,2H),7.72(s,1H),7.61(s,1H),7.56(d,J＝8.8Hz,1H),7.47(d,J＝10.9Hz,1H),6.99–6.91(m,2H),6.82(dd,J＝8.7,2.4Hz,1H).4.87(d,J＝13.1Hz,2H),3.44-3.48(m，4H),2.94(t,J＝12.8Hz,2H),2.40-2.31(m,4H),2.14(s,3H),1.90-1.88(m,4H),1.45(s,9H),1.33–1.06(m,4H).
Figure BDA0003259005860000321
Dissolving the intermediate 27(200mg, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting by TLC that the raw materials are completely reacted, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate for drying, filtering and concentrating to obtain a white solid, wherein the yield is 96%. UPLC-MS calculated for C29H32ClN7O2[M+H]+:546.23,found:545.95.UPLC-retention time:4.5min.
Figure BDA0003259005860000322
Dissolving intermediate 28(162mg, 1.0eq.) and intermediate 15(98mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (104 μ L, 2.0eq.), heating to 90 ℃ for reaction overnight, detecting by TLC, completely reacting raw materials, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 169mg of fluorescent green solid in 71% yield. UPLC-MS calculated for C42H40ClN9O6[M+H]+:802.28found:802.03.UPLC-retention time:5.6min.1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.18(s,1H),8.90(s,2H),7.94(d,J＝9.0Hz,1H),7.78(d,J＝10.4Hz,2H),7.68(d,J＝10.0Hz,1H),7.51(s,1H),7.39(t,J＝9.6Hz,1H),7.20(s,1H),7.12(d,J＝8.6Hz,1H),6.97–6.91(m,1H),4.78(d,J＝13.0Hz,2H),4.23(d,J＝13.5Hz,2H),3.64(d,J＝12.0Hz,2H),3.35(t,J＝13.0Hz,2H),3.25–3.01(m,4H),2.93-8.84(m,2H),2.34-2.17(m,2H),2.11(s,3H),2.03(d,J＝12.1Hz,1H),1.89(d,J＝12.7Hz,2H),1.26-1.12(m,4H).
Figure BDA0003259005860000323
Dissolving the intermediate 24(1.8g, 1.0eq.) in 40mL of anhydrous N, N-dimethylformamide, adding 60% NaH (0.5g, 1.5eq.) under ice bath condition, stirring for 0.5h, adding the raw material 10(1.5g, 1.2eq.), reacting overnight at room temperature, detecting by TLC until the raw material is completely reacted, adding 60mL of water into the reaction solution, extracting with ethyl acetate, adding the organic phase into anhydrous sodium sulfate, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate10/1-3/1) gave 2.7g of a white solid in 94% yield. UPLC-MS calculated for C19H19ClN2O3[M+H]+:359.11,found:359.12.UPLC-retention time:6.9min.1H NMR(400MHz,CDCl3)δ7.56(t,J＝8.7Hz,1H),7.38(s,1H),7.18(d,J＝8.5Hz,1H),6.91(d,J＝7.5Hz,2H),6.80(d,J＝9.1Hz,1H),2.11(s,3H)1.52(s,9H).
Figure BDA0003259005860000331
Intermediate 25(2.7g, 1.0eq.) was dissolved in 60mL of dichloromethane, 20mL of dioxane hydrochloride was added, the mixture was stirred overnight at room temperature, the starting material was reacted completely by TLC, and the mixture was filtered to give 2.2g of a white solid with a yield of 97%. UPLC-MS calculated for C14H11ClN2O[M+H]+:259.06,found:258.95.UPLC-retention time:3.5min.
Example 4:
Figure BDA0003259005860000332
dissolving intermediate 28(66mg, 1.0eq.) and intermediate 16(43mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (44 μ L, 2.0eq.), heating to 90 deg.C for reaction for 5h, detecting by TLC that the raw materials are completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to give 79mg of a fluorescent green solid in 80% yield. UPLC-MS calculated for C42H39ClFN9O6[M+H]+:820.27found:819.99.UPLC-retention time:5.6min.1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.14(s,1H),8.87(s,2H),7.90(d,J＝9.9Hz,1H),7.80(d,J＝11.0Hz,1H),7.72(s,1H),7.64(d,J＝9.3Hz,1H),7.58(d,J＝7.8Hz,1H),7.16(s,1H),7.08(d,J＝8.7Hz,1H),6.91(d,J＝10.2Hz,1H),5.09(d,J＝11.7Hz,1H),4.75(d,J＝13.2Hz,2H),3.76(d,J＝13.2Hz,2H),3.61(d,J＝10.9Hz,2H),3.38–3.19(m,4H),3.10(s,2H),3.02(t,J＝12.5Hz,2H),2.86(s,1H),2.57(dd,J＝34.6,17.0Hz,2H),2.19(s,1H),2.07(s,3H),2.03(s,1H),1.85(d,J＝12.7Hz,2H),1.18(d,J＝12.4Hz,2H).
Example 5:
Figure BDA0003259005860000341
mixing raw material 29 (12)Dissolving 7mg, 1.2eq.), HATU (340mg, 1.2eq.) in 15mL of anhydrous N, N-dimethylformamide, protecting with argon, adding N, N-diisopropylethylamine (390 mu L, 3.0eq.), stirring at room temperature for 0.5h, adding intermediate 26(220mg, 1.0eq.), reacting for 6h, detecting by TLC, allowing the raw materials to react completely, adding 20mL of water to the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate to the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 250mg of a white solid in 87% yield. UPLC-MS calculated for C20H13ClFN3O2[M+H]+:382.07,found:381.89.UPLC-retention time:5.8min.1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.78(s,1H),8.46(t,J＝9.3Hz,1H),7.90(d,J＝9.1Hz,1H),7.76(s,1H),7.66(d,J＝9.0Hz,1H),7.35(d,J＝8.6Hz,1H),7.18(s,1H),7.11(d,J＝8.8Hz,1H),6.91(d,J＝8.7Hz,1H),2.09(s,3H).
Figure BDA0003259005860000342
Dissolving intermediate 30(236mg, 1.0eq.), raw material 2(127mg, 1.1eq.), and potassium carbonate (171mg, 2.0eq.) in 10mL of anhydrous N, N-dimethylformamide, heating to 85 deg.C under protection of argon gas for overnight reaction, detecting by TLC until the raw material is completely reacted, adding 20mL of water to the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate to the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 250mg of a white solid in 87% yield. UPLC-MS calculated for C29H30ClN5O4[M+H]+:548.20,found:547.87.UPLC-retention time:6.9min.1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.71(s,1H),8.06(dd,J＝9.0,2.4Hz,1H),7.90(d,J＝8.7Hz,1H),7.76(d,J＝2.2Hz,1H),7.66(dd,J＝8.8,2.4Hz,1H),7.17(d,J＝2.4Hz,1H),7.07(d,J＝8.7Hz,1H),6.90(dd,J＝8.8,2.6Hz,2H),3.66–3.58(m,4H),3.45–3.36(m,4H),2.07(s,3H),1.39(s,9H).
Figure BDA0003259005860000351
Dissolving the intermediate 31(200mg, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting by TLC that the raw materials completely react, filtering, dissolving the solid in 10mL of water, adjusting the pH value to 8-9 by using ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate for drying, filtering and concentrating to obtain a white solid 157mg with the yield of 96%. UPLC-MS calculated for C24H22ClN5O2[M+H]+:448.15,found:447.97.UPLC-retention time:4.9min.
Figure BDA0003259005860000352
Dissolving the intermediate 32(100mg, 1.0eq.) and the intermediate 5(57mg, 1.2eq.) in 10mL of 1, 2-dichloroethane, adding 1 drop of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (95mg, 2.0eq.) to react at room temperature overnight, detecting by TLC that the raw materials completely react, adding 5mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol20/1) gave 122mg of a white solid in 85% yield. UPLC-MS calculated for C35H41ClN6O4[M+H]+:645.29,found:644.95.UPLC-retention time:6.0min.
Figure BDA0003259005860000353
Dissolving the intermediate 33(100mg, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting by TLC that the raw materials completely react, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 by using ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate for drying, filtering and concentrating to obtain a white solid 82mg with the yield of 97%. UPLC-MS calculated for C30H33ClN6O2[M+H]+:545.24,found:545.25.UPLC-retention time:3.8min.
Figure BDA0003259005860000354
Dissolving intermediate 28(66mg, 1.0eq.) and intermediate 15(40mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (42 uL, 2.0eq.), heating to 90 ℃ for reaction for 5h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 68mg of a fluorescent green solid in 70% yield. UPLC-MS calculated for C43H41ClN8O6[M+H]+:801.28found:801.29.UPLC-retention time:5.2min.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.14(s,1H),8.77(s,1H),8.21–8.05(m,1H),7.91(d,J＝9.1Hz,1H),7.79–7.62(m,3H),7.36–6.88(m,5H),5.05(s,1H),4.51(d,J＝14.0Hz,2H),4.08(d,J＝13.1Hz,2H),3.61(d,J＝11.9Hz,2H),3.36(s,2H),3.02(d,J＝34.8Hz,5H),2.71–2.50(m,4H),2.07(m,8H),1.27–1.25(m,2H).
Example 6:
Figure BDA0003259005860000361
dissolving intermediate 28(66mg, 1.0eq.) and intermediate 17(39mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (42 uL, 2.0eq.), heating to 90 ℃ for reaction for 5h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 82mg of a fluorescent green solid in 83% yield. UPLC-MS calculated for C42H39ClFN9O6[M+H]+:819.27found:819.15.UPLC-retention time:5.4min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.13(s,1H),8.83–8.70(m,1H),8.21–8.08(m,1H),7.91(d,J＝8.7Hz,1H),7.77–7.64(m,3H),7.45(d,J＝7.4Hz,1H),7.16(d,J＝2.4Hz,1H),7.07(dd,J＝13.7,8.9Hz,2H),6.91(dd,J＝8.8,2.4Hz,1H),5.08(dd,J＝12.8,5.4Hz,1H),4.52(d,J＝13.4Hz,3H),3.62(d,J＝10.7Hz,5H),3.33(t,J＝13.0Hz,2H),2.97–2.53(m,6H),2.14–1.81(m,8H),1.40–1.38(m,2H).
Example 7:
Figure BDA0003259005860000362
Figure BDA0003259005860000371
dissolving raw material 35(150mg, 1.0eq.), intermediate 20(386mg, 1.1eq.), potassium carbonate (340mg, 2.0eq.) in 12mL of anhydrous N, N-dimethylformamide, heating to 85 deg.C under the protection of argon gas for overnight reaction, detecting by TLC to ensure that the raw material is completely reacted, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1-1/1) gave 429mg of a white solid in 91% yield. UPLC-MS calculated for C22H32N4O2[M+H]+:385.25,found:385.05.UPLC-retention time:3.5min.1H NMR(400MHz,Chloroform-d)δ7.47(d,J＝8.7Hz,2H),6.84(d,J＝8.8Hz,2H),3.85(m,2H),3.42(m,4H),2.85(m,2H),2.35(m,4H),2.20(m,2H),1.91–1.67(m,3H),1.46(s,9H),1.31–1.19(m,2H).
Figure BDA0003259005860000372
Intermediate 36(200mg, 1.0eq.) was dissolved in 10mL ethanol/water (V)Ethanol/VWater (W)5/1), the mixture was refluxed overnight at elevated temperature, TLC detection showed complete reaction of the starting materials, the reaction solution was concentrated, 5mL of water was added to dissolve the solid, the pH was adjusted to about 4.5 with 1M hydrochloric acid, extraction was performed with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 195mg of a white solid with a yield of 93%. UPLC-MS calculated for C22H33N3O4[M+H]+:404.25,found:404.26.UPLC-retention time:4.0min.
Figure BDA0003259005860000381
Dissolving intermediate 37(100mg, 1.0eq.) and HATU (113mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (130. mu.L, 2.0eq.), stirring at room temperature for 0.5h, adding intermediate 26(81mg, 1.1eq.), reacting for 6h, detecting by TLC, allowing the raw materials to react completely, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding sodium sulfate into the anhydrous phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 136mg of a white solid in 85% yield. UPLC-MS calculated for C36H42ClN5O4[M+H]+:644.29,found:644.30.UPLC-retention time:6.7min.
Figure BDA0003259005860000382
Dissolving the intermediate 38(100mg, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting by TLC that the raw materials are completely reacted, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate for drying, filtering and concentrating to obtain a white solid 81mg, wherein the yield is 96%. UPLC-MS calculated for C31H34ClN5O2[M+H]+:544.24,found:544.25.UPLC-retention time:4.0min.
Figure BDA0003259005860000383
Dissolving intermediate 39(50mg, 1.0eq.) and intermediate 17(30mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (32 muL, 2.0eq.), heating to 90 ℃ for reaction for 5h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to give 54mg of a fluorescent green solid in 73% yield. UPLC-MS calculated for C44H42ClN7O6[M+H]+:800.29found:800.30.UPLC-retention time:5.3min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.06(s,1H),7.91(d,J＝8.0Hz,3H),7.79(s,1H),7.72-7.68(m,2H),7.45(d,J＝8.0Hz,1H),7.16(s,1H),7.11-7.06(m,3H),6.91(d,J＝8.0Hz,1H),5.08(dd,J＝8.0Hz,4Hz,1H),3.99(s,2H),3.61(s,6H),3.16-3.13(m,6H),2.96-2.83(m,3H),2.07(s,3H),2.01(s,2H),1.88(d,J＝8.0Hz,2H),1.43-1.35(m,2H).
Example 8:
Figure BDA0003259005860000391
dissolving intermediate 39(50mg, 1.0eq.) and intermediate 17(30mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (32 muL, 2.0eq.), heating to 90 ℃ for reaction for 5h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 64mg of a fluorescent green solid in 85% yield. UPLC-MS calculated for C44H41ClFN7O6[M+H]+:818.28found:818.29.UPLC-retention time:5.3min.UPLC-MS calculated for C42H39ClFN9O6[M+H]+:819.27found:819.15.UPLC-retention time:5.4min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.06(s,1H),7.94-7.90(m,3H),7.79(s,1H),7.72-7.68(m,2H),7.45(d,J＝8.0Hz,1H),7.16(s,1H),7.11-7.06(m,3H),6.91(d,J＝8.0Hz,1H),5.08(dd,J＝8.0Hz,4Hz,1H),3.99(s,2H),3.61(s,6H),3.16-3.13(m,6H),2.96-2.83(m,3H),2.07-2.01(m,4H),1.96(d,J＝8.0Hz,2H),1.40-1.35(m,2H).
Example 9:
Figure BDA0003259005860000392
Figure BDA0003259005860000401
dissolving a raw material 40(1.0g, 1.0eq.) in 20mL of anhydrous N, N-dimethylformamide, adding 60% NaH (0.3g, 1.5eq.) under an ice bath condition, stirring for 0.5h, adding a raw material 10(0.9g, 1.2eq.) to react at room temperature overnight, detecting by TLC until the raw material completely reacts, adding 30mL of water to the reaction solution, extracting with ethyl acetate, adding an organic phase into anhydrous sodium sulfate, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate10/1-3/1) gave 1.5g of a white solid in 94% yield. UPLC-MS calculated for C18H23ClN2O3[M+H]+:351.14,found:351.15.UPLC-retention time:6.9min.
Figure BDA0003259005860000402
Intermediate 41(1.5g, 1.0eq.) was dissolved in 30mL of dichloromethane, 10mL of dioxane hydrochloride was added, the mixture was stirred overnight at room temperature, the starting material was reacted completely by TLC, and the mixture was filtered to give 146mg of a white solid with a yield of 96%. UPLC-MS calculated for C13H15ClN2O[M+H]+:251.09,found:250.94.UPLC-retention time:2.0min.
Figure BDA0003259005860000403
Dissolving intermediate 23(140mg, 1.0eq.) and HATU (158mg, 1.2eq.) in 10mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (270. mu.L, 3.0eq.), stirring at room temperature for 0.5h, adding intermediate 42(109mg, 1.0eq.), reacting for 6h, detecting by TLC, allowing the raw materials to react completely, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding sodium sulfate into the anhydrous phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 185mg of white solid in 84% yield. UPLC-MS calculated for C33H44ClN7O4[M+H]+:638.31,found:638.10.UPLC-retention time:4.2min.1H NMR(400MHz,DMSO-d6)δ8.70(s,2H),8.08(d,J＝7.4Hz,1H),7.83(d,J＝8.8Hz,1H),7.36(d,J＝2.3Hz,1H),7.11(dd,J＝8.8,2.3Hz,1H),4.72–4.62(m,2H),4.56–4.47(m,1H),3.76(s,1H),2.89(t,J＝11.8Hz,2H),2.27(m,5H),2.14–2.00(m,4H),1.90–1.73(m,4H),1.46(t,J＝9.8Hz,4H),1.35(s,9H),1.22-1.20(m,4H),1.07–0.94(m,2H).
Figure BDA0003259005860000411
Dissolving the intermediate 43(126mg, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting by TLC that the raw materials are completely reacted, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate for drying, filtering and concentrating to obtain a white solid, namely 102mg, and obtaining the yield of 96%. UPLC-MS calculated for C28H36ClN7O2[M+H]+:538.26,found:537.96.UPLC-retention time:5.2min.
Figure BDA0003259005860000412
Dissolving intermediate 44(50mg, 1.0eq.) and intermediate 17(30mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (32 muL, 2.0eq.), heating to 90 ℃ for reaction for 5h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 63mg of a fluorescent green solid in 84% yield. UPLC-MS calculated for C41H43ClFN9O6[M+H]+:812.30found:812.28.UPLC-retention time:4.5min.1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.73(s,2H),8.13(d,J＝7.4Hz,1H),7.89–7.74(m,2H),7.58(d,J＝7.3Hz,1H),7.35(d,J＝2.3Hz,1H),7.11(dd,J＝8.8,2.4Hz,1H),5.10(dd,J＝12.8,5.3Hz,1H),4.70(d,J＝12.9Hz,2H),4.51(s,2H),3.68(m,6H),3.34(t,J＝11.9Hz,2H),3.04–2.76(m,4H),1.94(m,8H),1.47(t,J＝10.3Hz,5H),1.23–1.09(m,2H).
Example 10:
Figure BDA0003259005860000421
dissolving intermediate 45(200mg, 1.0eq.) and HATU (575mg, 1.2eq.) in 15mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (660 μ L, 3.0eq.), stirring at room temperature for 0.5h, adding intermediate 42(399mg, 1.1eq.), reacting for 6h, detecting by TLC, allowing the raw materials to react completely, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding sodium sulfate into the anhydrous phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 419mg of a white solid in 85% yield. UPLC-MS calculated for C18H16Cl2N4O2[M+H]+:391.07,found:390.87.UPLC-retention time:4.9min.1H NMR(400MHz,Chloroform-d)δ8.29(d,J＝8.6Hz,1H),7.98(d,J＝8.4Hz,1H),7.71(d,J＝8.9Hz,1H),7.58(d,J＝8.7Hz,1H),7.01(s,1H),6.86(d,J＝10.5Hz,1H),4.35(s,1H),4.10(d,J＝11.3Hz,1H),2.32–2.13(m,4H),1.79–1.48(m,4H).
Figure BDA0003259005860000431
Dissolving intermediate 46(340mg, 1.0eq.), intermediate 20(295mg, 1.2eq.), and potassium carbonate (240mg, 2.0eq.) in 10mL of anhydrous N, N-dimethylformamide, heating to 85 deg.C under protection of argon gas for overnight reaction, detecting by TLC until the raw materials react completely, adding 20mL of water to the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate to the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1-1/1) gave 429mg of a white solid in 91% yield. UPLC-MS calculated for C33H44ClN7O4[M+H]+:638.31,found:638.04.UPLC-retention time:4.3min.1H NMR(400MHz,DMSO-d6)δ8.57(d,J＝8.2Hz,1H),7.82(d,J＝8.8Hz,1H),7.76(d,J＝9.6Hz,1H),7.35(d,J＝2.3Hz,1H),7.29(d,J＝9.7Hz,1H),7.10(dd,J＝8.8,2.4Hz,1H),4.55–4.33(m,3H),3.81(tt,J＝11.1,8.2,5.8Hz,1H),2.95(t,J＝11.9Hz,2H),2.33–2.18(m,4H),2.15–2.00(m,4H),2.00–1.71(m,6H),1.53(dq,J＝51.3,11.9Hz,5H),1.35(s,9H),1.25–0.99(m,4H).
Figure BDA0003259005860000432
Dissolving the intermediate 11(200mg, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting by TLC that the raw materials completely react, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate for drying, filtering and concentrating to obtain a white solid, wherein the yield is 96%. UPLC-MS calculated for C28H36ClN7O2[M+H]+:538.26,found:538.27.UPLC-retention time:4.0min.
Figure BDA0003259005860000433
Dissolving intermediate 48(90mg, 1.0eq.) and intermediate 17(55mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (60 muL, 2.0eq.), heating to 90 ℃ for reaction for 5h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 82mg of a fluorescent green solid in 83% yield. UPLC-MS calculated for C41H44ClN9O6[M+H]+:794.31found:794.17.
UPLC-retention time:4.6min.1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),8.58(d,J＝8.2Hz,1H),7.85–7.70(m,3H),7.50–7.29(m,4H),7.10(d,J＝11.2Hz,1H),5.06(dd,J＝12.8,5.4Hz,1H),4.49(t,J＝12.3Hz,3H),4.19(dd,J＝8.9,5.6Hz,2H),3.89–3.78(m,1H),3.66–3.53(m,2H),3.22–2.77(m,8H),2.34–1.78(m,10H),1.67–1.39(m,5H),1.27–1.14(m,2H).
Example 11:
Figure BDA0003259005860000441
dissolving raw materials 10(5.0g, 1.0eq.), 48(5.5g, 1.0eq.), and potassium carbonate (6.7g, 1.5eq.) in 10mL of anhydrous N, N-dimethylformamide under the protection of argon, heating to 90 ℃ for reaction overnight, detecting by TLC that the raw materials are completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate10/1) gave 4.7g of a white solid in 48% yield. UPLC-MS calculated for C15H11ClN2O3[M+H]+:304.04,found:303.95.UPLC-retention time:6.3min.1H NMR(400MHz,DMSO-d6)δ8.13(s,2H),7.91(d,J＝8.0Hz,1H),7.26(s,1H),6.90(dd,J＝8.0Hz,2.4Hz,1H),2.13(s,6H).
Figure BDA0003259005860000442
Dissolving intermediate 49(4.7g, 1.0eq.) in 50mL of methanol, adding reduced iron powder (2.6g, 3.0eq.) and 10mL of HCl, heating to 50 ℃ to react for 4h, detecting by TLC that the raw materials are completely reacted, filtering with diatomite, concentrating the filtrate, adjusting the pH to be neutral by using 3N NaOH, spin-drying the solvent, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate4/1) gave 4.7g of an off-white solid in 48% yield. UPLC-MS calculated for C15H13ClN2O[M+H]+:273.08,found:272.95.UPLC-retention time:3.0min.1H NMR(400MHz,DMSO-d6)δ7.85(d,J＝8.0Hz,1H),7.03(s,1H),6.80(d,J＝8.0Hz,1H),6.47(s,1H),6.31(s,1H),4.99(s,2H),2.13(s,6H).
Figure BDA0003259005860000451
Dissolving intermediate 7(400mg, 1.0eq.), intermediate 50(324mg, 1.2eq.), HATU (375mg, 1.2eq.) in 10mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (520. mu.L, 3.0eq.), reacting at room temperature overnight, detecting by TLC, and completely reacting the raw materials,adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate2/1) gave 550mg of a white solid in 84% yield. UPLC-MS calculated for C35H42ClN7O4[M+H]+:660.30,found:660.09.UPLC-retention time:5.7min.1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.84(s,2H),7.88(d,J＝8.0Hz,2H),7.83(s,2H),7.12(s,1H),6.82(d,J＝8.0Hz,4H),3.90(d,J＝8.0Hz,2H),3.80(s,4H),2.37(s,4H),2.13(d,J＝4.0Hz,2H),2.01(s,6H),1.88-1.85(s,3H),1.35(s,2H),1.19(s,9H),0.95-0.88(m,2H).
Figure BDA0003259005860000452
Dissolving the intermediate 51(460mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, allowing the raw materials to react completely, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 355mg with a yield of 91%. UPLC-MS calculated for C30H34ClN7O2[M+H]+:560.25,found:560.02.UPLC-retention time:3.1min.
Figure BDA0003259005860000453
Dissolving intermediate 90(100mg, 1.0eq.) and intermediate 15(60mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (62 mu L, 2.0eq.), heating to 90 ℃ for reaction for 8 hours, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 90mg of a fluorescent green solid in 62% yield. UPLC-MS calculated for C43H42ClN9O6[M+H]+:816.30,found:815.99.UPLC-retention time:5.0min.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.18(s,1H),8.96(s,2H),7.89(d,J＝8.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.67(s,2H),7.34(s,1H),7.25(d,J＝8.0Hz,1H),7.11(s,1H),6.83(dd,J＝8.0Hz,4.0Hz,1H),5.06-5.02(m,1H),4.79-4.76(m,2H),4.10-4.07(m,2H),3.60(s,4H),3.49-3.43(m,2H),3.06(s,4H),3.00-2.94(m,2H),2.89-2.82(m,1H),2.15(s,1H),2.02(s,6H),1.83(d,J＝12.0Hz,2H),1.27(d,J＝8.0Hz,2H),1.19(s,1H).
Example 12:
Figure BDA0003259005860000461
dissolving intermediate 90(50mg, 1.0eq.) and intermediate 15(32mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (31 muL, 2.0eq.), heating to 90 ℃ for reaction for 4 hours, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 59mg of a fluorescent green solid in 79% yield. UPLC-MS calculated for C43H41ClFN9O6[M+H]+:834.29,found:834.06.UPLC-retention time:6.5min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.20(s,1H),8.96(s,2H),7.89(d,J＝8.0Hz,1H),7.70(d,J＝8.0Hz,1H),7.67(s,2H),7.34(s,1H),7.11(d,J＝2.0Hz,1H),6.83(dd,J＝8.0Hz,4.0Hz,1H),5.10-5.06(m,1H),4.80-4.76(m,2H),4.09(m,6H),3.64-3.61(m,4H),3.09(s,4H),2.93-2.85(m,3H),2.01(s,6H),1.89-1.86(m,2H),1.39(q,J＝12.0Hz,2H).
Example 13:
Figure BDA0003259005860000462
Figure BDA0003259005860000471
intermediate 23(400mg, 1.0eq.), intermediate 50(323mg, 1.2eq.), and HATU (560mg, 1.2eq.) were dissolved in 10mL of anhydrous N, N-dimethyl formamideAdding N, N-diisopropylethylamine (515 mu L, 3.0eq.) into amide under the protection of argon, reacting at room temperature overnight, detecting by TLC, completely reacting the raw materials, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 550mg of white solid in 85% yield. UPLC-MS calculated for C35H42ClN7O4[M+H]+:660.30,found:660.09.UPLC-retention time:5.7min.1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.83(s,2H),7.88(d,J＝8.0Hz,1H),7.54(s,2H),7.11(s,1H),6.82(d,J＝8.0Hz,1H),4.92(d,J＝12.0Hz,2H),3.29(s,2H),2.27(s,2H),2.12(d,J＝8.0Hz,2H),2.01(s,6H),1.81-1.75(m,3H),1.35(s,9H),1.18(m,2H),1.01-0.98(m,2H).
Figure BDA0003259005860000472
Dissolving the intermediate 53(500mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 400mg with a yield of 94%. UPLC-MS calculated for C30H34ClN7O2[M+H]+:560.25,found:560.02.UPLC-retention time:3.2min.
Figure BDA0003259005860000481
Dissolving intermediate 90(100mg, 1.0eq.) and intermediate 15(60mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (62 mu L, 2.0eq.), heating to 90 ℃ for reaction for 8 hours, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 85mg of a fluorescent green solid in 58% yield. UPLC-MS calculated for C43H42ClN9O6[M+H]+:816.30,found:816.07.UPLC-retention time:5.0min.1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.12(s,1H),8.87(s,2H),7.89(d,J＝8.0Hz,1H),7.73(d,J＝8.0Hz,1H),7.67(s,2H),7.46(s,1H),7.33(d,J＝8.0Hz,1H),7.12(d,J＝4.0Hz,1H),6.83(dd,J＝6.4Hz,2.0Hz,1H),5.10-5.04(m,1H),4.76-4.72(m,2H),4.19-4.16(m,2H),3.66-3.42(m,8H),3.13-2.99(m,4H),2.89-2.81(m,1H),2.20(s,1H),2.01(s,6H),1.92-1.89(m,2H),1.39(m,3H).
Example 14:
Figure BDA0003259005860000482
dissolving intermediate 90(50mg, 1.0eq.) and intermediate 15(32mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (31 muL, 2.0eq.), heating to 90 ℃ for reaction for 4 hours, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 55mg of a fluorescent green solid in 74% yield. UPLC-MS calculated for C43H41ClFN9O6[M+H]+:834.29,found:834.09.UPLC-retention time:5.5min.1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.08(s,1H),8.86(s,2H),7.89(d,J＝8.0Hz,1H),7.80(d,J＝12.0Hz,1H),7.68(s,1H),7.66(s,2H),7.11(d,J＝2.0Hz,1H),6.83(q,J＝4.0Hz,1H),5.11-5.08(m,1H),4.76-4.73(m,2H),4.09(s,6H),3.64-3.61(m,4H),3.09(s,4H),2.93-2.85(m,3H),2.01(s,6H),1.89-1.86(m,2H),1.39(m,2H).
Example 15:
Figure BDA0003259005860000491
dissolving 29(200mg, 1.0eq.), 50(465mg, 1.2eq.), HATU (650mg, 1.2eq.) in 10mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (740 mu L, 3.0eq.), reacting at room temperature overnight, detecting by TLC, and reacting the raw materialsCompletely, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate2/1) gave 490mg of a white solid in 87% yield. UPLC-MS calculated for C21H15ClFN3O2[M+H]+:396.09,found:395.96.UPLC-retention time:6.8min.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.78(s,1H),8.78-8.43(s,1H),7.88(d,J＝8.0Hz,1H),7.08(s,2H),7.36-7.33(m,1H),7.12(d,J＝4.0Hz,1H),6.83(q,J＝4.0Hz,1H),2.02(s,6H).
Figure BDA0003259005860000492
Dissolving intermediate 55(490mg, 1.0eq.), raw material 2(230mg, 1.0eq.), and potassium carbonate (256mg, 1.5eq.) in 10mL of anhydrous N, N-dimethylformamide, heating to 90 deg.C under argon protection for overnight reaction, detecting by TLC that the raw material is completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate4/1) gave 542mg of a white solid in 78% yield. UPLC-MS calculated for C30H32ClN5O4[M+H]+:562.22,found:561.90.UPLC-retention time:6.5min.1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.71(s,1H),8.08-8.06(s,1H),7.88(d,J＝8.0Hz,1H),7.68(s,2H),7.12(d,J＝4.0Hz,1H),6.89(d,J＝8.0Hz,1H),6.83(q,J＝4.0Hz,1H),3.62-3.60(m,4H),3.41-3.39(s,1H),2.01(s,6H),1.39(s,9H).
Figure BDA0003259005860000501
Dissolving the intermediate 56(500mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain 375mg of white solid with the yield of 91%. UPLC-MS calculated for C25H24ClN5O2[M+H]+:462.17,found:462.05.UPLC-retention time:3.2min.
Figure BDA0003259005860000502
Dissolving intermediate 57(300mg, 1.0eq.) and intermediate 5(165mg, 1.2eq.) in 15mL of 1, 2-dichloroethane, adding 2 drops of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (275mg, 2.0eq.), reacting at room temperature overnight, detecting by TLC that the raw materials completely react, adding 10mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol20/1) gave 380mg of white solid in 89% yield. UPLC-MS calculated for C36H43ClN6O4[M+H]+:659.31,found:659.06.UPLC-retention time:5.1min.1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.03(d,J＝12Hz,2H),7.67(s,2H),7.16(s,1H),6.87-6.80(m,2H),4.45(d,J＝12.0Hz,2H),3.92(s,4H),3.69(s,4H),2.38(s,1H),2.12(d,J＝4.0,2H),2.00(s,6H),1.65(d,J＝8.0,2H),1.57(d,J＝12.0Hz,2H),1.34(s,9H),1.17(s,1H),0.96-0.89(m,2H).
Figure BDA0003259005860000503
Dissolving the intermediate 58(350mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 280mg with the yield of 95%. UPLC-MS calculated for C31H35ClN6O2[M+H]+:559.25,found:560.02.UPLC-retention time:2.9min.
Figure BDA0003259005860000504
Intermediate 59(100mg, 1.0eq.), intermediateDissolving 15(60mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide, adding N, N-diisopropylethylamine (62 μ L, 2.0eq.) under the protection of argon, heating to 90 deg.C, reacting for 8 hr, detecting by TLC that the raw materials are completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 99mg of a fluorescent green solid in 68% yield. UPLC-MS calculated for C44H43ClN8O6[M+H]+:815.30,found:815.11.UPLC-retention time:6.0min.1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),9.60(s,1H),8.30(s,1H),7.68(dd,J＝8.0Hz,1.6Hz,1H),7.43(d,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.13(s,2H),6.88(s,2H),6.79(d,J＝8.0Hz,1H),6.65(d,J＝2.0Hz,1H),6.58(d,J＝8.0Hz,1H),6.37(dd,J＝4.0Hz,2.4Hz,1H),4.58(dd,J＝8.0Hz,5.6Hz,1H),4.05(d,J＝12.0Hz,2H),3.62(d,J＝16.0Hz,1H),3.15(d,J＝12.0Hz,2H),2.97(s,10H),2.54(t,J＝8.0Hz,2H),2.54-2.48(m,1H),1.35(t,J＝16Hz,2H),0.83-0.73(m,2H).
Example 16:
Figure BDA0003259005860000511
dissolving intermediate 90(50mg, 1.0eq.) and intermediate 15(32mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (31 muL, 2.0eq.), heating to 90 ℃ for reaction for 4 hours, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 59mg of a fluorescent green solid in 79% yield. UPLC-MS calculated for C44H42ClFN8O6[M+H]+:833.29,found:833.02.UPLC-retention time:6.2min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.06(s,1H),8.76(d,J＝4.0Hz,1H),8.15(dd,J＝8.0Hz,2.4Hz,1H),7.89(d,J＝8.0Hz,1H),7.71(d,J＝12.0Hz,1H),7.59(s,2H),7.45(d,J＝4.0Hz,1H),7.12(d,J＝4.0Hz,1H),7.05(d,J＝12.0Hz,1H),7.83(dd,J＝8.0Hz,2.4Hz,1H),5.08(dd,J＝18.0Hz,5.2Hz,1H),4.53(d,J＝16.0Hz,2H),3.62(d,J＝8.0Hz,8H),3.11(s,2H),2.91(t,J＝12.0Hz,2H),2.56(d,J＝16.0Hz,2H),2.07(t,J＝8.0Hz,1H),1.88(d,J＝12.0Hz,2H),1.42-1.34(m,2H).
Example 17:
Figure BDA0003259005860000521
dissolving intermediate 55(400mg, 1.0eq.), raw material 2(287mg, 1.0eq.), and potassium carbonate (210mg, 1.5eq.) in 10mL of anhydrous N, N-dimethylformamide, heating to 90 ℃ for reaction overnight under the protection of argon, detecting by TLC that the raw material is completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate4/1) gave 500mg of a white solid in 75% yield. UPLC-MS calculated for C36H43ClN6O4[M+H]+:659.31,found:659.03.UPLC-retention time:5.3min.1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.68(s,1H),8.00(dd,J＝8.0Hz,4.0Hz,1H),7.89(d,J＝12.0Hz,1H),7.69(s,2H),7.12(d,J＝2.0Hz,1H),6.86(d,J＝8.0Hz,1H),6.83(q,J＝4.0Hz,1H),4.40(d,J＝12.0Hz,2H),3.27(s,4H),2.86(t,J＝12.0Hz,2H),2.26(s,4H),2.11(d,J＝4.0,2H),2.01(s,6H),1.75(d,J＝8.0Hz,2H),1.36(s,9H),1.19(s,1H),1.03(q,J＝12.0Hz,2H).
Figure BDA0003259005860000522
Dissolving the intermediate 60(400mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain 320mg of white solid with the yield of 95%. UPLC-MS calculated for C31H35ClN6O2[M+H]+:559.25,found:559.09.UPLC-retention time:3.8min.
Figure BDA0003259005860000523
Dissolving the intermediate 61(100mg, 1.0eq.) and the intermediate 15(60mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (62 mu L, 2.0eq.) into the mixture, heating the mixture to 90 ℃ for reaction for 8 hours, detecting that the raw materials completely react by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 92mg of a fluorescent green solid in 63% yield. UPLC-MS calculated for C44H43ClN8O6[M+H]+:815.30,found:815.11.UPLC-retention time:5.6min.1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.97(s,1H),8.07(s,2H),8.05(dd,J＝8.0Hz,2.4Hz,1H),7.89(d,J＝8.0Hz,1H),7.75(d,J＝12.0Hz,1H),7.68(s,2H),7.47(s,1H),7.35(dd,J＝8.0Hz,2.0Hz,1H),7.12(d,J＝4.0Hz,1H),6.95(d,J＝12.0Hz,1H),6.83(d,J＝12.0Hz,1H),5.09-5.04(m,1H),4.45(d,J＝12.0Hz,2H),4.19(d,J＝12.0Hz,2H),3.80(s,6H),3.61(s,2H),3.15(s,2H),3.09(s,2H),2.98-2.92(m,1H),2.16(s,1H),2.01(s,6H),1.83(d,J＝12.0Hz,2H),1.22-1.16(m,3H).
Example 18:
Figure BDA0003259005860000531
dissolving intermediate 90(50mg, 1.0eq.) and intermediate 15(32mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (31 muL, 2.0eq.), heating to 90 ℃ for reaction for 4 hours, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 57mg of a fluorescent green solid in 76% yield. UPLC-MS calculated for C44H42ClFN8O6[M+H]+:833.29,found:833.05.UPLC-retention time:4.7min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.99(s,1H),8.69(s,2H),8.05(d,J＝16Hz,1H),7.89(d,J＝8.0Hz,1H),7.80(d,J＝12.0Hz,1H),7.58(s,3H),7.11(s,1H),7.97-6.94(m,1H),6.83(d,J＝12.0Hz,1H),5.12-5.09(m,1H),4.45(d,J＝12.0Hz,2H),4.19(d,J＝12.0Hz,2H),3.89(s,8H),3.15(s,2H),3.09(s,2H),2.98-2.92(m,1H),2.16(s,1H),2.01(s,6H),1.83(d,J＝12.0Hz,2H),1.22-1.16(m,3H).
Example 19:
Figure BDA0003259005860000541
dissolving the raw material 62(200mg, 1.0eq.), the intermediate 50(213mg, 1.2eq.), HATU (300mg, 1.2eq.), and the intermediate in 10mL of anhydrous N, N-dimethylformamide, protecting with argon, adding N, N-diisopropylethylamine (340 uL, 3.0eq.), reacting overnight at room temperature, detecting by TLC, completely reacting the raw material, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding the organic phase into anhydrous sodium sulfate, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate2/1) gave 265mg of white solid in 72% yield. UPLC-MS calculated for C31H33ClFN4O4[M+H]+:561.22,found:561.02.UPLC-retention time:7.6min.
Figure BDA0003259005860000542
Dissolving the intermediate 63(200mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid of 142mg with the yield of 87%. UPLC-MS calculated for C26H25ClN4O2[M+H]+:461.17,found:460.98.UPLC-retention time:2.9min。
Figure BDA0003259005860000543
Dissolving intermediate 64(120mg, 1.0eq.) and intermediate 5(67mg, 1.2eq.) in 15mL of 1, 2-dichloroethane, adding 2 drops of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (275mg, 2.0eq.), reacting at room temperature overnight, TLCDetecting the reaction of the raw materials, adding 10mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol20/1) gave 150mg of a white solid in 86% yield. UPLC-MS calculated for C37H44ClN5O4[M+H]+:658.31,found:658.13.UPLC-retention time:7.0min.1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),7.88(d,J＝8.0Hz,2H),7.83(d,J＝8.0Hz,2H),7.60(s,2H),7.12-7.11(m,2H),6.98-6.96(m,1H),6.83(dd,J＝8.0Hz,2.4Hz,1H),3.87(s,6H),2.37(s,4H),2.13(d,J＝4.0Hz,2H),2.01(s,6H),1.79-1.64(m,3H),1.35(s,9H),1.19(s,2H),0.93-0.90(m,2H)
Figure BDA0003259005860000551
Dissolving the intermediate 65(100mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 80mg with a yield of 93%. UPLC-MS calculated for C32H36ClN5O2[M+H]+:558.26,found:558.03.UPLC-retention time:3.9min.
Figure BDA0003259005860000552
Dissolving intermediate 66(50mg, 1.0eq.) and intermediate 15(30mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (30 muL, 2.0eq.), heating to 90 ℃ for reaction for 8h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 43mg of a fluorescent green solid in 59% yield. UPLC-MS calculated for C45H44ClN7O6[M+H]+:814.31,found:814.21.UPLC-retention time:6.7min.1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),9.98(s,1H),7.90(dd,J＝8.0Hz,2.0Hz,4H),7.65(d,J＝8.0Hz,1H),7.61(s,2H),7.34(s,1H),7.25(d,J＝8.0Hz,1H),7.12(d,J＝4.0Hz,1H),7.09(d,J＝8.0Hz,2H),6.83(dd,J＝8.0Hz,4.0Hz,1H),5.04(dd,J＝8.0Hz,1.2Hz,1H),4.09(d,J＝16.0Hz,2H),4.01(d,J＝16.0Hz,2H),3.61(d,J＝8.0Hz,2H),3.48(s,8H),3.20-3.11(m,3H),2.99(t,J＝8.0Hz,2H),1.83(d,J＝8.0Hz,2H),1.29-1.20(m,2H).
Example 20:
Figure BDA0003259005860000561
dissolving intermediate 66(30mg, 1.0eq.) and intermediate 15(20mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (20 muL, 2.0eq.), heating to 90 ℃ for reaction for 4 hours, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 27mg of a fluorescent green solid in 61% yield. UPLC-MS calculated for C45H43ClFN7O6[M+H]+:832.29,found:832.17.UPLC-retention time:5.7min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.92(s,1H),8.12(s,1H),7.86(dd,J＝18.0,8.8Hz,3H),7.71–7.59(m,3H),7.41(d,J＝7.3Hz,1H),7.15–6.78(m,3H),5.07(dd,J＝12.8,5.3Hz,1H),3.58(d,J＝11.8Hz,4H),2.99–2.51(m,6H),2.33–1.62(m,13H),1.27–1.25(m,2H).
Example 21:
Figure BDA0003259005860000562
Figure BDA0003259005860000571
dissolving raw material 67(2.0g) in 40mL of methanol, heating to 75 ℃, refluxing for reaction for 6h, detecting the completion of the reaction of the raw material by TLC (thin layer chromatography), removing the solvent from the reaction solution by spin drying, extracting with ethyl acetate and saturated aqueous solution of sodium bicarbonateThe organic layer was dried and the solvent removed by rotary evaporation to give 2.0g of a white oily product in 95% yield. UPLC-MS calculated for C8H7FO2[M+H]+:155.04,found:154.85.UPLC-retention time:3.9min.1H NMR(400MHz,DMSO-d6)δ8.00-7.97(m,2H),7.34-7.29(m,2H),3.81(s,3H).
Figure BDA0003259005860000572
Dissolving the intermediate 68(1.0g, 1.0eq.), the intermediate 20(1.8g, 1.0eq.), and potassium carbonate (1.3g, 1.5eq.) in 10mL of anhydrous N, N-dimethylformamide under the protection of argon, heating to 90 ℃ for reaction overnight, detecting by TLC that the raw materials are completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate4/1) gave 1.1g of a white solid in 39% yield. UPLC-MS calculated for C23H35N3O4[M+H]+:418.26,found:418.08.UPLC-retention time:6.3min.
Figure BDA0003259005860000573
Intermediate 69(1.0g, 1.0eq.) was dissolved in 20mL of a mixed solution of tetrahydrofuran and water (V)Tetrahydrofuran (THF)/VWater (W)3/1), heating to 35 deg.C for overnight reaction, detecting by TLC that the raw material is completely reacted, adjusting pH of the reaction solution to about 5.0 with 1M HCl, extracting with dichloromethane, drying and concentrating organic phase to obtain white solid 950mg, and obtaining yield 98%. UPLC-MS calculated for C22H33N3O4[M+H]+:405.25,found:405.21.UPLC-retention time:3.5min.
Figure BDA0003259005860000574
Intermediate 70(500mg, 1.0eq.), intermediate 50(400mg, 1.2eq.), and HATU (560mg, 1.2eq.) were dissolved in 10mL of anhydrous N, N-dimethylformamide under argon, and N, N-diisopropyl addedReacting phenylethylamine (650 μ L, 3.0eq.) at room temperature overnight, detecting by TLC, reacting the raw materials completely, adding 20mL water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 550mg of a white solid in 68% yield. UPLC-MS calculated for C35H42ClN7O4[M+H]+:658.31,found:658.21.UPLC-retention time:5.5min.1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.99(d,J＝8.0Hz,1H),7.92-7.87(m,1H),7.82(d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,2H),7.12(d,J＝4.0Hz,1H),7.07(d,J＝8.0Hz,1H),6.96(d,J＝8.0Hz,1H),6.83(dd,J＝8.0Hz,2.4Hz,1H),4.06-3.84(m,2H),2.85(s,2H),2.69(s,2H),2.26(m,4H),2.13(d,J＝8.0Hz,2H),2.01(s,6H),1.95(s,1H),1.76(d,J＝12.0Hz,2H),1.36(s,9H),1.19(s,2H),1.14(t,J＝4.0Hz,2H).
Figure BDA0003259005860000581
Dissolving the intermediate 71(500mg, 1.0eq.) in 60mL of dichloromethane, adding 15mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 30mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 400mg with the yield of 95%. UPLC-MS calculated for C32H36ClN5O2[M+H]+:558.26,found:558.07.UPLC-retention time:4.2min.
Figure BDA0003259005860000582
Dissolving intermediate 72(100mg, 1.0eq.) and intermediate 15(60mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (60 muL, 2.0eq.), heating to 90 ℃ for reaction for 8h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to obtain fluorescent green101mg of a colored solid, yield 69%. UPLC-MS calculated for C45H44ClN7O6[M+H]+:814.31,found:814.11.UPLC-retention time:5.3min.1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.90(s,1H),7.89(d,J＝8.0Hz,2H),7.85(d,J＝8.0Hz,2H),7.75(d,J＝12.0Hz,1H),7.61(s,2H),7.48(s,1H),7.35(d,J＝12Hz,1H),7.12(s,1H),7.02-6.99(m,1H),6.86-6.82(m,1H),5.07(dd,J＝7.6Hz,5.2Hz,1H),4.19(d,J＝16.0Hz,2H),3.92(d,J＝16.0Hz,1H),3.58(s,8H),3.15-3.09(s,4H),2.84(t,J＝8.0Hz,2H),2.08(s,1H),2.01(s,6H),1.82(d,J＝12.0Hz,2H),1.22-1.16(m,2H).
Example 22:
Figure BDA0003259005860000583
dissolving intermediate 72(50mg, 1.0eq.) and intermediate 17(30mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (30 muL, 2.0eq.), heating to 90 ℃ for reaction for 4 hours, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 48mg of a fluorescent green solid in 65% yield. UPLC-MS calculated for C45H43ClFN7O6[M+H]+:832.30,found:832.16.UPLC-retention time:5.8min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.89(s,1H),7.85(dd,J＝24.8,8.8Hz,3H),7.74–7.58(m,3H),7.42(d,J＝7.4Hz,1H),7.12(d,J＝2.3Hz,1H),6.97(d,J＝9.0Hz,2H),6.83(dd,J＝8.7,2.4Hz,1H),5.08(dd,J＝12.8,5.3Hz,1H),3.87(d,J＝12.5Hz,2H),2.93–2.49(m,10H),2.31–1.68(m,15H),1.20–1.16(m,2H).
Summary of YMA327 experiments
Figure BDA0003259005860000591
Dissolving raw material 73(600mg, 1.0eq.) and intermediate 20(1.2g, 1.2eq.) in 40mL of isopropanol, adding 1 drop of concentrated hydrochloric acid, heating to 90 deg.CReacting for 6h, detecting by TLC that the raw materials are completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 1.2g of a white solid in 80% yield. UPLC-MS calculated for C21H33N5O4[M+H]+:420.03,found:420.26.UPLC-retention time:5.7min.1H NMR(400MHz,DMSO-d6)δ7.77(d,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),4.48(d,J＝8.0Hz,2H),3.93(s,1H),3.82(s,3H),2.97(t,J＝12.0Hz,1H),2.63(d,J＝8.0Hz,1H),2.29-2.26(m,4H),2.11(d,J＝8.0Hz,1H),1.84-1.76(m,4.0Hz,2H),1.37(s,2H),1.36(s,9H),1.20(m,2H),1.09-1.00(m,2H).
Figure BDA0003259005860000601
Intermediate 74(1.0g, 1.0eq.) was dissolved in 20mL of a mixed solution of tetrahydrofuran and water (V)Tetrahydrofuran (THF)/VWater (W)3/1), heating to 35 deg.C for reaction overnight, detecting by TLC that the raw material is completely reacted, adjusting pH of the reaction solution to about 5.0 with 1M HCl, extracting with dichloromethane, drying and concentrating organic phase to obtain white solid 820mg, yield 85%. UPLC-MS calculated for C20H31N5O4[M+H]+:406.24,found:406.25.UPLC-retention time:2.5min.
Figure BDA0003259005860000602
Dissolving intermediate 75(800mg, 1.0eq.), intermediate 50(650mg, 1.2eq.), HATU (900mg, 1.2eq.), argon shielding, adding N, N-diisopropylethylamine (1000. mu.L, 3.0eq.), reacting overnight at room temperature, detecting by TLC, allowing the raw materials to react completely, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 1.1g of a white solid in 86% yield. UPLC-MS calculated for C35H42ClN7O4[M+H]+:660.30,found:660.27.UPLC-retention time:5.5min.
Figure BDA0003259005860000603
Dissolving the intermediate 76(1.0g, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting the complete reaction of the raw materials by TLC, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 by using ammonia water, extracting the dichloromethane, adding anhydrous magnesium sulfate, drying, filtering and concentrating to obtain a white solid 790mg, wherein the yield is 93%. UPLC-MS calculated for C30H34ClN7O2[M+H]+:560.25,found:560.24.UPLC-retention time:4.0min.
Figure BDA0003259005860000604
Dissolving intermediate 77(100mg, 1.0eq.) and intermediate 15(60mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (60 muL, 2.0eq.), heating to 90 ℃ for reaction for 8h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 82mg of a fluorescent green solid in 56% yield. UPLC-MS calculated for C43H42ClN9O5[M+H]+:816.30,found:815.96.UPLC-retention time:5.9min.1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.66(s,1H),7.93-7.88(m,2H),7.74(d,J＝4.0Hz,1H),7.46(t,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,1H),7.14-.7.13(m,2H),6.84(q,J＝4.0Hz,2H),5.07(q,J＝8.0Hz,1H),4.53(d,J＝20.0Hz,2H),4.18(d,J＝16.0Hz,2H),3.62(d,J＝16.0Hz,4H),3.36-3.28(m,2H),3.12-3.09(m,4H),3.00-2.94(m,2H),2.89-2.82(m,1H),2.15(s,1H),2.02(s,6H),1.86(d,J＝8.0Hz,2H),1.23(d,J＝12.0Hz,2H),1.19(s,1H).
Example 23:
Figure BDA0003259005860000611
dissolving intermediate 77(50mg, 1.0eq.) and intermediate 17(30mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (30 μ L, 2.0eq.), heating to 90 deg.C for 4h, detecting by TLC that the raw materials completely react, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to give 52mg of a fluorescent green solid in 70% yield. UPLC-MS calculated for C43H41ClFN9O6[M+H]+:834.29,found:834.14.UPLC-retention time:6.0min.1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),10.66(s,1H),7.93-7.88(m,2H),7.81(d,J＝8.0Hz,1H),7.76(s,2H),7.69(d,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.14-.7.13(m,1H),6.84(q,J＝4.0Hz,1H),5.10(dd,J＝8.0Hz,4.0Hz,1H),4.53(d,J＝8.0Hz,2H),3.78(d,J＝16.0Hz,4H),3.64(m,6H),3.24(m,2H),3.00-2.94(m,2H),2.89-2.82(m,1H),2.15(s,1H),2.02(s,6H),1.87(d,J＝8.0Hz,2H),1.25(d,J＝12.0Hz,2H),1.19(s,1H).
Summary of YMA329 experiments
Figure BDA0003259005860000612
Figure BDA0003259005860000621
Dissolving 73(600mg, 1.0eq.) and 2(780mg, 1.2eq.) in 40mL isopropanol, adding 1 drop of concentrated hydrochloric acid, heating to 90 deg.C, reacting for 6h, detecting by TLC that the reaction of the raw materials is complete, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 850mg of a white solid in 76% yield. UPLC-MS calculated for C15H22N4O4[M+H]+:323.17,found:322.96.UPLC-retention time:3.5min.1H NMR(400MHz,DMSO-d6)δ7.83(d,J＝8.0Hz,1H),7.25(d,J＝4.0Hz,1H),3.84(m,3H),3.73(t,J＝2.4Hz,4H),3.45(t,J＝2.4Hz,4H),1.38(s,9H).
Figure BDA0003259005860000622
Intermediate 74(800mg, 1.0eq.) was dissolved in 20mL of a mixed solution of tetrahydrofuran and water (V)Tetrahydrofuran (THF)/VWater (W)3/1), heating to 35 deg.C for overnight reaction, detecting by TLC that the raw material is completely reacted, adjusting pH of the reaction solution to about 5.0 with 1M HCl, extracting with dichloromethane, drying and concentrating organic phase to obtain 790mg of white solid with 79% yield. UPLC-MS calculated for C14H20N4O4[M+H]+:406.24,found:406.25.UPLC-retention time:2.5min.
Figure BDA0003259005860000623
Dissolving the intermediate 79(700mg, 1.0eq.), the intermediate 50(560mg, 1.2eq.), and the HATU (790mg, 1.2eq.) in 10mL of anhydrous N, N-dimethylformamide, protecting with argon, adding N, N-diisopropylethylamine (900 μ L, 3.0eq.), reacting overnight at room temperature, detecting by TLC, allowing the raw materials to react completely, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding the organic phase into anhydrous sodium sulfate, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 800mg of a white solid in 82% yield. UPLC-MS calculated for C29H31ClN6O4[M+H]+:563.21,found:562.98.UPLC-retention time:7.6min.UPLC-MS calculated for C35H42ClN7O4[M+H]+:660.30,found:660.29.UPLC-retention time:5.7min.1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.94(d,J＝16.0Hz,1H),7.88(d,J＝16.0Hz,1H),7.74(s,2H),7.39(d,J＝12.0Hz,1H),7.14(d,J＝4.0Hz,1H),6.83(d,J＝4.0Hz,1H),3.73(t,J＝4.0Hz,4H),3.46(s,4H),2.01(s,6H),1.40(s,9H).
Figure BDA0003259005860000631
The intermediate is reacted with a catalyst80(700mg, 1.0eq.) is dissolved in 5mL of dichloromethane, 1mL of dioxane hydrochloride is added, the mixture is stirred at room temperature overnight, TLC detects that the raw materials completely react, the mixture is filtered, the solid is dissolved in 10mL of water, the pH value is adjusted to 8-9 by ammonia water, dichloromethane is extracted, anhydrous magnesium sulfate is added for drying, and the mixture is filtered and concentrated to obtain 510mg of white solid with the yield of 89%. UPLC-MS calculated for C24H23ClN6O2[M+H]+:463.16,found:462.95.UPLC-retention time:5.4min.
Figure BDA0003259005860000632
Dissolving the intermediate 81(500mg, 1.0eq.) and the raw material 5(280mg, 1.2eq.) in 10mL of 1, 2-dichloroethane, adding 1 drop of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (95mg, 2.0eq.) to react at room temperature overnight, detecting the completion of the reaction of the raw materials by TLC, adding 5mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol20/1) gave 584mg of a white solid in 82% yield. UPLC-MS calculated for C35H42ClN7O4[M+H]+:660.30,found:660.29.UPLC-retention time:5.7min.1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),7.89(t,J＝8.0Hz,2H),7.74(s,2H),7.37(d,J＝12.0Hz,1H),7.12(s,1H),6.82(d,J＝8.0Hz,1H),3.90(s,2H),3.70(s,4H),3.12(s,2H),2.42(s,4H),2.01(s,6H),1.69-1.60(m,3H),1.35(s,9H),0.97-0.91(m,4H).
Figure BDA0003259005860000633
Dissolving the intermediate 82(500mg, 1.0eq.) in 5mL of dichloromethane, adding 1mL of dioxane hydrochloride, stirring overnight at room temperature, detecting by TLC that the raw materials completely react, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate for drying, filtering and concentrating to obtain a white solid 360mg with the yield of 84%. UPLC-MS calculated for C30H34ClN7O2[M+H]+:560.25,found:560.24.UPLC-retention time:3.2min.
Figure BDA0003259005860000641
Dissolving the intermediate 83(100mg, 1.0eq.) and the intermediate 15(60mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (60 mu L, 2.0eq.) into the mixture, heating the mixture to 90 ℃ for reaction for 8 hours, detecting that the raw materials completely react by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 86mg of a fluorescent green solid in 59% yield. UPLC-MS calculated for C43H42ClN9O6[M+H]+:816.30,found:816.15.UPLC-retention time:5.6min.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.72(s,1H),7.96(dd,J＝53.9,8.9Hz,2H),7.69(d,J＝44.9Hz,4H),7.37–7.12(m,3H),6.86–6.81(m,1H),5.04(d,J＝18.2Hz,1H),4.59(d,J＝9.9Hz,1H),4.08(d,J＝12.8Hz,2H),3.78–3.43(m,4H),3.24–2.54(m,8H),2.02(s,12H),1.31–1.16(m,2H).
Example 24:
Figure BDA0003259005860000642
dissolving the intermediate 83(50mg, 1.0eq.) and the intermediate 17(30mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (30 mu L, 2.0eq.) into the mixture, heating the mixture to 90 ℃ for reaction for 4 hours, detecting that the raw materials completely react by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 54mg of a fluorescent green solid in 72% yield. UPLC-MS calculated for C43H41ClFN9O6[M+H]+:834.29,found:834.14.UPLC-retention time:5.5min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.67(s,1H),7.90(t,J＝9.5Hz,2H),7.70(d,J＝31.5Hz,3H),7.40(t,J＝8.5Hz,2H),7.14(s,1H),6.83(d,J＝8.7Hz,1H),5.07(dd,J＝12.8,5.4Hz,1H),3.79–3.55(m,8H),2.92–2.79(m,4H),2.26–1.71(m,15H),1.29–1.26(m,2H).
Example 25:
Figure BDA0003259005860000651
dissolving raw materials 10(500mg, 1.0eq.), 84(670mg, 1.0eq.), and potassium carbonate (670mg, 1.5eq.) in 10mL of anhydrous N, N-dimethylformamide, heating to 90 ℃ under the protection of argon gas for reaction overnight, detecting by TLC that the raw materials are completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 710mg of a white solid in 64% yield. UPLC-MS calculated for C18H17ClN2O3[M+H]+:345.10,found:344,96.UPLC-retention time:6.3min.1H NMR(400MHz,DMSO-d6)δ7.93(d,J＝12.0Hz,1H),7.47(d,J＝8.0Hz,2H),7.31(d,J＝4.0Hz,1H),7.26(d,J＝8.0Hz,1H),7.03(q,J＝4.0Hz,1H),1.35(s,9H).
Figure BDA0003259005860000652
Dissolving the intermediate 85(710mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 by using ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid, wherein the yield is 96%. UPLC-MS calculated for C13H9ClN2O[M+H]+:245.04,found:244.92.UPLC-retention time:3.1min.1H NMR(400MHz,DMSO-d6)δ7.93(d,J＝12.0Hz,1H),7.47(d,J＝8.0Hz,2H),7.31(d,J＝4.0Hz,1H),7.26(d,J＝8.0Hz,1H),7.03(q,J＝4.0Hz,1H),5.71(s,2H).
Figure BDA0003259005860000661
Mixing the intermediate 86(485mg, 1.2eq.), the raw material 62(505mg, 1.0eq.), and,Dissolving HATU (753mg, 1.2eq.) in 10mL of anhydrous N, N-dimethylformamide, adding N, N-diisopropylethylamine (863 mu L, 3.0eq.) under the protection of argon, reacting at room temperature overnight, detecting by TLC, completely reacting raw materials, adding 20mL of water into reaction liquid, extracting with ethyl acetate, adding an organic phase into anhydrous sodium sulfate, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 712mg of a white solid in 81% yield. UPLC-MS calculated for C29H29ClN4O4[M+H]+:533.19,found:533.31.UPLC-retention time:6.6min.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.91(d,J＝8.0Hz,1H),7.85(d,J＝12.0Hz,1H),7.24(s,1H),7.16-7.13(m,2H),7.00(d,J＝12.0Hz,3H),3.43(s,4H),3.26(s,4H),1.39(s,9H).
Figure BDA0003259005860000662
Dissolving the intermediate 87(712mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, allowing the raw materials to react completely, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 554mg with a yield of 96%. UPLC-MS calculated for C24H21ClN4O2[M+H]+:432.90,found:432.95.UPLC-retention time:3.1min.
Figure BDA0003259005860000663
Dissolving intermediate 88(554mg, 1.0eq.) and intermediate 5(327mg, 1.2eq.) in 15mL of 1, 2-dichloroethane, adding 2 drops of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (542mg, 2.0eq.), reacting at room temperature overnight, detecting by TLC that the raw materials completely react, adding 10mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol20/1) gave 660mg of a white solid in 82% yield. UPLC-MS calculated for C35H40ClN5O4[M+H]+:630.28,found:630.15.UPLC-retention time:5.9min.
Figure BDA0003259005860000664
Dissolving the intermediate 89(660mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 10mL of water, adjusting the pH to 8-9 by using ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering and concentrating to obtain a white solid 511mg, wherein the yield is 92%. UPLC-MS calculated for C24H21ClN4O2[M+H]+:530.23,found:529.92.UPLC-retention time:4.0min.
Figure BDA0003259005860000671
Dissolving intermediate 90(50mg, 1.0eq.) and intermediate 15(31mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (33 muL, 2.0eq.), heating to 90 ℃ for reaction for 8h, detecting complete reaction of raw materials by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 46mg of a fluorescent green solid in 62% yield. UPLC-MS calculated for C43H40ClN7O6[M+H]+:786.27found:786.00.UPLC-retention time:5.8min.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.06(s,1H),7.92(d,J＝12.0Hz,1H),7.86(d,J＝8.0Hz,4H),7.62(d,J＝8.0Hz,1H),7.29(s,1H),7.25(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.15(d,J＝12.0Hz,3H),7.02(d,J＝2.0Hz,1H),6.99(d,J＝2.0Hz,1H),5.03(dd,J＝8.0Hz,4.0Hz,1H),4.03(d,J＝16.0Hz,6H),3.36-3.29(m,3H),2.95(t,J＝12.0Hz,2H),2.63-2.59(m,4H),2.93(s,2H),1.99-1.96(m,2H),1.81(d,J＝12.0Hz,2H),1.20-1.13(m,2H).
Example 26:
Figure BDA0003259005860000672
dissolving 91(500mg, 1.0eq.), 84(690mg, 1.0eq.), and potassium carbonate (685mg, 1.5eq.) in 10mL of anhydrous N, N-dimethylformamide, under the protection of argon, heating to 90 deg.C for overnight reaction, detecting by TLC that the raw materials are completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 788mg of a white solid in 70% yield. UPLC-MS calculated for C19H20N2O4[M+H]+:341.15,found:340.94.UPLC-retention time:5.7min.1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝12.0Hz,1H),7.47(d,J＝8.0Hz,2H),7.31(d,J＝4.0Hz,1H),7.26(d,J＝8.0Hz,1H),7.03(q,J＝4.0Hz,1H),3.83(s,9H),1.35(s,9H).
Figure BDA0003259005860000681
Dissolving the intermediate 92(788mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 534mg with the yield of 96%. UPLC-MS calculated for C12H12N2O2[M+H]+:241.09,found:241.13.UPLC-retention time:3.0min.1H NMR(400MHz,DMSO-d6)δ7.96(d,J＝12.0Hz,1H),7.47(d,J＝8.0Hz,2H),7.31(d,J＝4.0Hz,1H),7.26(d,J＝8.0Hz,1H),7.03(q,J＝4.0Hz,1H),4.78(s,9H),3.83(s,9H).
Figure BDA0003259005860000682
Intermediate 93(378mg, 1.2eq.), starting material 62(400mg, 1.0eq.), HATU (596mg, 1.2eq.), was dissolved in 10mL of anhydrous N, N-dimethylformamide under argon and N, N-diisopropylethylamine (810 μ L, 3) was added.0eq.), reacting at room temperature overnight, detecting by TLC, completely reacting the raw materials, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate2/1) gave 580mg of white solid in 84% yield. UPLC-MS calculated for C30H32N4O5[M+H]+:529.24,found:592.31.UPLC-retention time:6.2min.
Figure BDA0003259005860000683
Dissolving the intermediate 94(580mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 451mg with a yield of 96%. UPLC-MS calculated for C25H24N4O3[M+H]+:429.18,found:428.98.UPLC-retention time:3.8min.
Figure BDA0003259005860000691
Dissolving intermediate 95(451mg, 1.0eq.) and intermediate 5(268mg, 1.2eq.) in 15mL of 1, 2-dichloroethane, adding 2 drops of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (446mg, 2.0eq.), reacting at room temperature overnight, detecting by TLC that the raw materials completely react, adding 10mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol20/1) gave 552mg of white solid in 84% yield. UPLC-MS calculated for C36H43N5O5[M+H]+:626.33,found:626.28.UPLC-retention time:5.9min.
Figure BDA0003259005860000692
Dissolving the intermediate 95(552mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, allowing the raw materials to react completely, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 445mg with a yield of 96%. UPLC-MS calculated for C31H35N5O3[M+H]+:526.27,found:526.28.UPLC-retention time:3.8min.
Figure BDA0003259005860000693
Dissolving the intermediate 97(50mg, 1.0eq.) and the intermediate 15(31mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (33 mu L, 2.0eq.) into the mixture, heating the mixture to 90 ℃ for reaction for 8 hours, detecting that the raw materials completely react by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 48mg of a fluorescent green solid in 65% yield. UPLC-MS calculated for C44H43N7O7[M+H]+:782.32,found:782.00.UPLC-retention time:5.9min.1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.12(s,1H),7.91(d,J＝8.0Hz,2H),7.84(d,J＝8.0Hz,2H),7.65(d,J＝8.0Hz,2H),7.33(s,1H),7.24(d,J＝8.0Hz,1H),7.13-7.07(m,4H),6.83(d,J＝4.0Hz,1H),6.46(dd,J＝8.0Hz,2.0Hz,1H),6.46(dd,J＝8.0Hz,2.0Hz,1H),5.04(dd,J＝8.0Hz,5.4Hz,1H),4.07(d,J＝8.0Hz,2H),3.99(d,J＝8.0Hz,2H),3.87(s,3H),3.66-3.64(m,4H),3.25(t,J＝12.0Hz,2H),3.14-3.08(m,4H),2.98(t,J＝12.0Hz,2H),2.85(s,1H),2.17(s,1H),1.99-1.96(m,1H),1.87(d,J＝12.0Hz,2H),1.30-1.19(m,2H).
Example 27:
Figure BDA0003259005860000701
dissolving raw material 8(240mg, 1.2eq.), raw material 62(500mg, 1.0eq.), and HATU (750mg, 1.2eq.) in 10mLAdding N, N-diisopropylethylamine (860 mu L and 3.0eq.) into water N, N-dimethylformamide under the protection of argon, reacting at room temperature overnight, detecting by TLC, completely reacting the raw materials, adding 20mL of water into the reaction solution, extracting with ethyl acetate, adding anhydrous sodium sulfate into the organic phase, drying, concentrating, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 500mg of a white solid in 75% yield. UPLC-MS calculated for C23H29N3O4[M+H]+:412.22,found:412.01.UPLC-retention time:4.8min.
Figure BDA0003259005860000702
Dissolving intermediate 98(500mg, 1.0eq.), raw material 10(190mg, 1.0eq.), potassium carbonate (250mg, 1.5eq.) in 10mL of anhydrous N, N-dimethylformamide, under the protection of argon, heating to 90 ℃ for reaction overnight, detecting by TLC that the raw material is completely reacted, concentrating the reaction solution, and purifying by column chromatography (V)Petroleum ether/VEthyl acetate3/1) gave 553mg of white solid in 83% yield. UPLC-MS calculated for C30H21ClN4O4[M+H]+:547.21,found:547.02.UPLC-retention time:7.2min.
Figure BDA0003259005860000703
Dissolving the intermediate 99(553mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, allowing the raw materials to react completely, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid of 434mg with a yield of 96%. UPLC-MS calculated for C25H23ClN4O2[M+H]+:448.15,found:448.02.UPLC-retention time:3.8min.
Figure BDA0003259005860000711
Dissolving the intermediate 100(400mg, 1.0eq.) and the raw material 5(230mg, 1.2eq.) in 15mL of 1, 2-dichloroethane, adding 2 drops of acetic acid, stirring at room temperature for 0.5h, adding sodium triacetyl borohydride (380mg, 2.0eq.), reacting at room temperature overnight, detecting the completion of the reaction of the raw materials by TLC, adding 10mL of methanol to quench the reaction, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol20/1) gave 420mg of a white solid in 73% yield. UPLC-MS calculated for C36H42ClN5O4[M+H]+:644.30found:644.00.UPLC-retention time:5.3min.
Figure BDA0003259005860000712
Dissolving the intermediate 101(420mg, 1.0eq.) in 20mL of dichloromethane, adding 5mL of 4M dioxane hydrochloride solution, stirring overnight at room temperature, detecting by TLC, completely reacting the raw materials, filtering, dissolving the solid in 5mL of water, adjusting the pH to 8-9 with ammonia water, extracting with dichloromethane, adding anhydrous magnesium sulfate, drying, filtering, and concentrating to obtain a white solid 337mg with a yield of 95%. UPLC-MS calculated for C31H34ClN5O2[M+H]+:543.97,found:544.24.UPLC-retention time:2.6min.
Figure BDA0003259005860000713
Dissolving the intermediate 102(100mg, 1.0eq.) and the intermediate 15(61mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (65 muL, 2.0eq.) into the mixture, heating the mixture to 90 ℃ for reaction for 8 hours, detecting that the raw materials completely react by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) gave 89mg of a fluorescent green solid in 61% yield. UPLC-MS calculated for C44H43ClN7O6[M+H]+:800.29,found:800.04.UPLC-retention time:5.9min.1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.12(s,1H),7.90(d,J＝8.0Hz,2H),7.80(d,J＝8.0Hz,2H),7.70(d,J＝12.0Hz,1H),7.63(d,J＝12.0Hz,2H),7.31(s,1H),7.23(d,J＝12.0Hz,1H),7.16(s,1H),7.07(d,J＝4.0Hz,2H),6.92-6.89(m,1H),5.04(dd,J＝8.0Hz,5.4Hz,1H),4.05(d,J＝8.0Hz,2H),3.93(s,2H),3.66-3.64(m,4H),3.25(t,J＝12.0Hz,2H),3.14-3.08(m,4H),2.97(t,J＝12.0Hz,2H),2.63-2.57(m,2H),2.06(s,3H),1.99-1.95(m,1H),1.90(d,J＝4.0Hz,2H),1.24-1.19(m,2H).
Example 28:
Figure BDA0003259005860000721
dissolving the intermediate 102(50mg, 1.0eq.) and the intermediate 17(32mg, 1.2eq.) in 5mL of anhydrous N, N-dimethylformamide under the protection of argon, adding N, N-diisopropylethylamine (33 mu L, 2.0eq.) into the mixture, heating the mixture to 90 ℃ for reaction for 4 hours, detecting that the raw materials completely react by TLC, concentrating the reaction solution, and purifying by column chromatography (V)Methylene dichloride/VMethanol80/1-30/1) to yield 60mg of a fluorescent green solid in 80% yield. UPLC-MS calculated for C44H41ClFN7O6[M+H]+:818.28,found:818.14.UPLC-retention time:5.3min.1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.06(s,1H),7.91(d,J＝8.0Hz,3H),7.79(s,1H),7.72-7.68(m,2H),7.45(d,J＝8.0Hz,1H),7.16(s,1H),7.11-7.06(m,3H),6.91(d,J＝8.0Hz,1H),5.08(dd,J＝8.0Hz,4Hz,1H),3.99(s,2H),3.61(s,6H),3.16-3.13(m,6H),2.96-2.83(m,3H),2.07(s,3H),2.01(s,2H),1.88(d,J＝8.0Hz,2H),1.43-1.35(m,2H).
< bioassay >
Example 29: evaluation of Androgen Receptor (AR) expression level lowering Effect
AR-positive human prostate cancer cells LNCaP, 22RV1 and VCaP were each placed in RPMI 1640 or DMEM (hereinafter referred to as evaluation medium) containing 10% FBS to reach 3X 105The amount per well was inoculated into a 6-well microplate (Corning), and cultured overnight. The evaluation medium containing the example compound was added to the culture so that the final concentrations of the example compound reached 0.1 and 1. mu. mol/L, and the culture was incubated for 24 hours. In-line with the aboveThen removing the culture medium, washing cells by using PBS, adding RIPA lysate containing 1% Protease Inhibitor Cocktail, obtaining total protein extract after lysis and centrifugation, and detecting the protein concentration in the extract by using BCA method; protein electrophoresis was performed by SDS-PAGE, followed by 200mA constant current electrophoresis for 90min to transfer proteins to PVDF (Millipore Sigma IPVH00010) membranes; placing the PVDF membrane in skim milk containing 5%, and sealing for 1h at room temperature; using Anti-Androgen Receptor antibody [ EPR1535(2)](HRP) (abcam) to perform an immune reaction; and (4) washing the membrane, then dropwise adding ECL luminescent liquid, and exposing. The strip was grey scale analyzed using software Image J. GAPDH, alpha-tublin or beta-Actin protein bands were detected simultaneously for each sample as internal controls. The degradation rate of the compound of the example on AR protein was calculated according to the gray scale of the protein band, as shown in FIGS. 1-3
The results for LNCaP, VCaP and 22RV1 cells are shown in table 2 below. A decrease in AR expression of 50% or more is indicated as "decrease". Among the compounds of the present invention, the example compounds YMA-301, YMA-302, YMA-303, YMA-304, YMA-305, YMA-306, YMA-307, YMA-308, TJA-309, TJA-310, YMA-315, YMA-316, TJA-317, TJA-318, YMA-323, YMA-324 and YMA-325 exhibited a certain AR expression-reducing effect on all of the three prostate cancer cells LNCaP, VCaP and 22RV 1.
TABLE 2 reduction of Androgen Receptor (AR) expression by Compounds
Figure BDA0003259005860000731
Example 30 androgen-dependent prostate cancer cell proliferation inhibitory Activity
Androgen receptor positive human prostate cancer cells LNCaP were cultured in RPMI 1640 medium (hereinafter referred to as evaluation medium) containing 5% carbon adsorption serum (CCS) to 5X 103The amount per well was inoculated into a 96-well microplate with a transparent bottom (Corning), and cultured for 48 hours. To this culture were added an evaluation medium containing R1881 (final concentration of R1881: 0.1nmo1/L) and an evaluation medium containing the compound of example or comparative example (Enzalutamide). (Final of the Compounds of this example or comparative example)Concentrations of 3.810395, 11.43, 34.29, 102.88, 308.64, 925.9, 2777.78, 8333.33 and 25000nmo1/L), and the number of viable cells was determined after 96 hours of culture. The number of viable cells was determined using WST-1 (Roche). The cell growth activity value of R1881 was set to 100% at 0.1nmol/L, the cell growth activity of only the evaluation medium was set to 0%, and the 50% growth Inhibitory Concentration (IC) was calculated from the number of viable cells measured by logistic regression50Value).
The cell proliferation inhibitory results are shown in FIG. 4, which shows that Compound YMA-325 exhibits androgen-dependent cell proliferation inhibitory activity of prostate cancer, maximum median Inhibitory Concentration (IC)50) It was 106.9 nmol/L. Enzalutamide as a positive control, IC50It was 36.6nmo 1/L.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims (11)

1. A compound shown in a general formula (I) or pharmaceutically acceptable salt and stereoisomer thereof,
Figure FDA0003259005850000011
wherein Q is Linker, A is E3 ubiquitin ligase part;
r1, R3 and R4 are independently selected from H, halogen and-C1－8Alkyl radical, -C1－8Alkenyl, -C1－8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said-C1－8Alkyl radical, -C1－8Alkenyl, -C1－8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said heteroaryl being optionally substituted by halogen, hydroxy, -C1－8Alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl substituted;
r2 is selected from C, O, S;
R5-R8 are each independently selected from CRd，N，O，S；
Q is a bond or a divalent linking group;
a is a ligand of E3 ubiquitin ligase.
2. The compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, R1, R3, R4 according to claim 1 further selected from-C1－8An alkyl group.
3. The compound of the general formula (I) according to claims 1-2 or a pharmaceutically acceptable salt, stereoisomer thereof,
a is selected from
Figure FDA0003259005850000012
Figure FDA0003259005850000013
Figure FDA0003259005850000021
Wherein R9 is independently selected from hydrogen, halogen, -C1－8Alkyl radical, -C1－8Alkenyl, -C1－8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2，-OR5a，-SO2R5a，-COR5a，-CO2R5a，-CONR5aR5b，-C(＝NR5a)NR5bR5c，-NR5aR5b，-NR5aCOR5b，-NR5aCONR5bR5c，-NR5aCO2R5b，-NR5aSONR5bR5c，-NR5aSO2NR5bR5c，-NR5aSO2R5bsaid-C1－8Alkyl radical, -C1－8Alkenyl, -C1－8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, each independently selected from halogen, hydroxy, -C1－8Alkoxy, cycloalkyl, heterocyclyl, arylAryl, heteroaryl substituted;
R5a，R5b，R5ceach independently selected from hydroxy, -C1－8Alkyl radical, -C2－8Alkenyl, -C2－8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; n is 0, 1, 2;
and the junction of Q and A.
4. A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer thereof, wherein a is further selected from
Figure FDA0003259005850000022
5. The compound of formula (I) according to any one of claims 1 to 4, wherein Q is selected from- (L)1)z-(L2)r-(L3)q-；
Wherein L1 is selected from
Figure FDA0003259005850000023
L2 is selected from
Figure FDA0003259005850000031
Figure FDA0003259005850000032
L3 is selected from
Figure FDA0003259005850000033
Figure FDA0003259005850000034
z is 1;
r is 0 or 1;
q is 0 or 1
The left and right sides of the junction.
6. The compound of formula (I) according to any one of claims 1 to 5, wherein Q is
Figure FDA0003259005850000035
7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer thereof, selected from:
Figure FDA0003259005850000041
Figure FDA0003259005850000051
Figure FDA0003259005850000061
Figure FDA0003259005850000071
Figure FDA0003259005850000081
8. a pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical dosage form is oral preparation or injection preparation.
10. A compound shown in a general formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 7, and a use of the pharmaceutical composition according to claim 8 in preparing an antiandrogen agent.
11. Use of a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for a disease or condition associated with Androgen Receptor (AR) expression, preferably said disease or condition is cancer, metastatic bone disease, prostatic hypertrophy, acne vulgaris, seborrhea, hirsutism, androgenic alopecia, premature or andrological disorder, more preferably said cancer is selected from prostate cancer, breast cancer, ovarian cancer, bladder cancer, uterine cancer, pancreatic cancer or hepatocellular carcinoma.
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