CN111868032B - Kynurenine pathway inhibitors - Google Patents

Kynurenine pathway inhibitors Download PDF

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CN111868032B
CN111868032B CN201980012783.6A CN201980012783A CN111868032B CN 111868032 B CN111868032 B CN 111868032B CN 201980012783 A CN201980012783 A CN 201980012783A CN 111868032 B CN111868032 B CN 111868032B
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CN111868032A (en
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周明
陆剑宇
胡国平
胡利红
丁照中
黎健
陈曙辉
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CStone Pharmaceuticals Shanghai Co Ltd
CStone Pharmaceuticals Suzhou Co Ltd
CStone Pharmaceuticals
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CStone Pharmaceuticals Suzhou Co Ltd
CStone Pharmaceuticals
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines

Abstract

The invention discloses a novel compound serving as a kynurenine pathway inhibitor, and particularly discloses a compound shown as a formula (I) and a pharmaceutically acceptable salt thereof.

Description

Kynurenine pathway inhibitors
The following priority is claimed in the present application:
CN201810143151.0, application date 2018, 2 month 11.
Technical Field
The invention relates to a novel compound serving as a kynurenine pathway inhibitor, and particularly discloses a compound shown as a formula (I) and a pharmaceutically acceptable salt thereof. The invention also relates to application of the compound shown in the formula (I) and pharmaceutically acceptable salts thereof in preparing medicaments for treating tumors.
Background
Malignant tumors are now one of the major diseases that jeopardize human life safety. In recent centuries, in order to combat malignant tumors, many diagnostic and therapeutic approaches including most common chemotherapy, surgery, radiotherapy and targeted therapy have been developed. These therapies delay the development of tumors to some extent, prolonging patient life. However, due to the unlimited growth, infiltration and metastasis characteristics of malignant tumors, the above therapies still fail to achieve the desired inhibitory effect. Meanwhile, the toxic and side effects of the above therapies are also key factors limiting the application thereof.
In recent years, immunotherapy has been developed as an emerging therapy for the treatment of malignant tumors, characterized by combating the growth of tumors by mobilizing the host's natural defense mechanisms. The main approach is to enhance the host collective immune response to tumor cells by activating the original immune system of the host, and to achieve accurate and effective tumor killing by using the immune system capability, thereby inhibiting the development of the tumor.
The production of kynurenic acid inside tumors is mainly regulated by Indoleamine 2, 3-dioxygenase (IDO) and Tryptophan-2, 3-dioxygenase (Tryptophan2, 3-dioxygenase, TDO), which function to catalyze the rate-determining step of Tryptophan metabolism to kynurenic acid. The above enzymes can rapidly consume tryptophan in a tumor microenvironment, so that T cells infiltrated into the tumor are stagnated in the middle stage of G1 due to the lack of tryptophan, thereby inhibiting the proliferation of the T cells and preventing the signal conduction of the T cells and losing the functions. At the same time, the concentration of kynurenine is increased, which leads to the formation of an immunosuppressive microenvironment by the tumor. Therefore, inhibition of kynurenine production in tumors helps activate the collective immune system, counteracting tumor growth.
The kynurenine pathway inhibitor has good application prospect in the pharmaceutical industry as a medicament, but no kynurenine pathway inhibitor is on the market at present. The clinical kynurenine pathway inhibitors are (D) -1-methyltryptophan developed by NewLink Genetics, NLG-0919, INCB-24360 from Incyte, and BMS-985205 from Bethes. However, the existing clinical kynurenine pathway inhibitor has the problems of CYP inhibition (NLG 0919), large administration dose, short half-life, more administration times (INCB-24360), poor solubility (BMS-986205) and the like. Therefore, kynurenine pathway inhibitors that do not have the above disadvantages remain unmet medical needs.
The specific structures of NLG-0919, INCB-24360 and BMS-986205 are as follows:
Figure GPA0000292424410000021
disclosure of Invention
The invention provides a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof,
Figure GPA0000292424410000031
wherein the content of the first and second substances,
ring A is selected from the group consisting of phenyl, pyridyl, cyclopentyl 1H-indazolyl, 2H-indazolyl, 1H-indolyl and cyclohexyl;
ring B is selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, 1H-indazolyl, and 2H-indazolyl;
l is selected fromSingle bond, -O-, -CH2-、-CH2CH2-and-CH2CH2CH2-；
X is selected from CH and N;
l' is selected from a single bond and-O-;
R1each independently selected from halogen and NH2、CN、C1-3Alkyl, CF3、CHF2、CH2F、C1-3A heteroalkyl group;
R2each independently selected from halogen, CN, C1-3Alkyl, CF3、CHF2、CH2F、C1-3Heteroalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyl-O-, 3-6 membered heterocycloalkyl-O-, 3-6 membered cycloalkyl-NH-, 3-6 membered heterocycloalkyl-NH-;
m and n are each independently selected from 0, 1, 2 and 3;
"hetero" means a heteroatom or a heteroatom group, said C1-3"hetero" of heteroalkyl, 3-6 membered heterocycloalkyl-O-, and 3-6 membered heterocycloalkyl-NH-is selected from the group consisting of N, -NH-, -O-, -S-, -C (═ O) -, -C (═ S) -, -C (═ O) O-, -S (═ O) -, and-S (═ O)2-；
In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1, 2 and 3, respectively.
In some embodiments of the invention, R is as defined above1Each independently selected from F, Cl, Br, I, NH2、CN、CH3、CF3、CH3CH2、CH3O and CH3CH2O。
In some embodiments of the invention, R is as defined above2Each independently selected from F, Cl, Br, I, CN, CH3、CF3、CHF2、CH2F、CH3CH2、CH3O-、CH3CH2O-、
Figure GPA0000292424410000032
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000033
Is selected from
Figure GPA0000292424410000034
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000035
Is selected from
Figure GPA0000292424410000036
Figure GPA0000292424410000041
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000042
Is selected from
Figure GPA0000292424410000043
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000044
Is selected from
Figure GPA0000292424410000045
Figure GPA0000292424410000046
Figure GPA0000292424410000051
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000052
Is selected from
Figure GPA0000292424410000053
Figure GPA0000292424410000054
In some embodiments of the invention, R is as defined above1Each independently selected from F, Cl, Br, I, NH2、CN、CH3、CF3、CH3CH2、CH3O and CH3CH2O, other variables are as defined above.
In some embodiments of the invention, R is as defined above2Each independently selected from F, Cl, Br, I, CN, CH3、CF3、CHF2、CH2F、CH3CH2、CH3O-、CH3CH2O-、
Figure GPA0000292424410000055
The other variables are as defined above.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000056
Is selected from
Figure GPA0000292424410000057
The other variables are as defined above.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000058
Is selected from
Figure GPA0000292424410000059
Figure GPA0000292424410000061
Figure GPA0000292424410000062
The other variables are as defined above.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000063
Is selected from
Figure GPA0000292424410000064
Figure GPA0000292424410000065
The other variables are as defined above.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000066
Is selected from
Figure GPA0000292424410000067
Figure GPA0000292424410000068
Figure GPA0000292424410000071
Figure GPA0000292424410000072
The other variables are as defined above.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000073
Is selected from
Figure GPA0000292424410000074
Figure GPA0000292424410000075
Figure GPA0000292424410000076
The other variables are as defined above.
In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from
Figure GPA0000292424410000081
Wherein, ring A, X, m, n, L', R1And R2As defined above.
In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from
Figure GPA0000292424410000082
Wherein, L, R1And R2As defined above.
In some embodiments of the invention, R is as defined above1Each independently selected from F, Cl, Br, I, NH2、CN、CH3、CF3、CH3CH2、CH3O and CH3CH2O, other variables are as defined herein.
In some embodiments of the invention, R is as defined above2Each independently selected from F, Cl, Br, I, CN, CH3、CF3、CHF2、CH2F、CH3CH2、CH3O-、CH3CH2O-、
Figure GPA0000292424410000083
The other variables are as defined above.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000091
Is selected from
Figure GPA0000292424410000092
Other variables are as defined herein.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000093
Is selected from
Figure GPA0000292424410000094
Figure GPA0000292424410000095
Figure GPA0000292424410000096
Other variables are as defined herein.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000097
Is selected from
Figure GPA0000292424410000098
Figure GPA0000292424410000099
Other variables are as defined herein.
In some embodiments of the invention, the structural unit
Figure GPA00002924244100000910
Is selected from
Figure GPA00002924244100000911
Figure GPA0000292424410000101
Figure GPA0000292424410000102
Other variables are as defined herein.
In some embodiments of the invention, the structural unit
Figure GPA0000292424410000103
Is selected from
Figure GPA0000292424410000104
Figure GPA0000292424410000105
Figure GPA0000292424410000106
Other variables are as defined herein.
In some embodiments of the invention, the compound, or a pharmaceutically acceptable salt thereof, is selected from
Figure GPA0000292424410000111
Wherein, ring A, m, n, X, L', R1And R2As defined herein.
10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, selected from
Figure GPA0000292424410000112
Wherein, L, R1And R2As defined herein.
The invention also provides a compound or a pharmaceutically acceptable salt thereof selected from
Figure GPA0000292424410000113
Figure GPA0000292424410000121
Figure GPA0000292424410000131
The invention provides a pharmaceutical composition which comprises a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing a medicament for treating cancer.
Still other embodiments of the present invention are derived from any combination of the above variables.
Technical effects
The invention provides a kynurenine pathway inhibitor with a novel structure, which has excellent in vitro cell activity; the in vivo metabolic stability of the series of compounds can be enhanced by the cyclic structure in the ortho position of the amide in the structure. At the same dose, the structure of the invention has a higher AUC than BMS-986205, and the half-life is longer. Meanwhile, compared with BMS-986205, the series of compounds have better solubility, higher oral bioavailability, better tissue distribution in mice and better comprehensive pharmacokinetic property. The novel structures provided by the present invention are likely to be selective IDO inhibitors.
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended 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 term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amines or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Unless otherwise indicated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.
Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" results from the inability of a double bond or a single bond to rotate freely within a ring-forming carbon atom.
Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecules have two or more chiral centers and a non-mirror image relationship between the molecules.
Unless otherwise indicated, "(D)" or "(+)" means dextrorotation, "(L)" or "(-) -means levorotation," (DL) "or" (±) "means racemization.
Using solid wedge keys, unless otherwise indicated
Figure GPA0000292424410000151
And wedge dotted bond
Figure GPA0000292424410000152
Showing the absolute configuration of a solid centre, by means of straight solid keys
Figure GPA0000292424410000153
And straight dotted line bond
Figure GPA0000292424410000154
Showing the relative configuration of the centres of solids, by wavesThread
Figure GPA0000292424410000155
Representing solid-line keys of wedge shape
Figure GPA0000292424410000156
Or wedge dotted bond
Figure GPA0000292424410000157
Or by wavy lines
Figure GPA0000292424410000158
Indicating straight solid-line keys
Figure GPA0000292424410000159
And straight dotted line bond
Figure GPA00002924244100001510
The compounds of the invention may be present specifically. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be rapidly interconverted. If tautomers are possible (e.g., in solution), then the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (prototropic tautomers), also known as proton transfer tautomers (prototropic tautomers), include interconversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetatomer) include interconversion by recombination of some of the bonding electrons. A specific example of where keto-enol tautomerism is the interconversion between two tautomers of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one.
Unless otherwise indicated, the terms "enriched in one isomer", "isomer enriched", "enantiomer enriched" or "enantiomeric enrichment" refer to a content of one isomer or enantiomer of less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
Unless otherwise indicated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80%.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines). The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C) and C)3H) Iodine-125 (125I) Or C-14(14C) In that respect For example, deuterium can be used to replace hydrogen to form a deuterated drug, the bond formed by deuterium and carbon is stronger than the bond formed by common hydrogen and carbon, and compared with an undeuterated drug, the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life period of the drug and the like. Conversion of all isotopic compositions of the compounds of the present inventionWhether radioactive or not, are included within the scope of the present invention. "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, and may include variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., ═ O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When the number of one linking group is 0, e.g. - (CRR)0-, represents that the linking group is a single bond.
When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, for example, where L represents a single bond in A-L-Z means that the structure is actually A-Z.
When a substituent is absent, it indicates that the substituent is absent, e.g., when X is absent in A-X, it indicates that the structure is actually A. When no atom through which a substituent is attached to a substituted group is indicated in the listed substituents, such substituents may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be attached to a substituted group through any one of carbon atoms on the pyridine ring.
When the listed linking groups do not indicate their direction of attachment, the direction of attachment is arbitrary, for example,
Figure GPA0000292424410000161
wherein the linking group L is-M-W-, in which case-M-W-can be formed by connecting the ring A and the ring B in the same direction as the reading sequence from left to right
Figure GPA0000292424410000162
The ring A and the ring B may be connected in the reverse direction of the reading sequence from left to right
Figure GPA0000292424410000163
Combinations of the linking groups, substituents, and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, the term "hetero" denotes a heteroatom or a heteroatom group (i.e., a heteroatom-containing radical) including atoms other than carbon (C) and hydrogen (H) and radicals containing such heteroatoms, including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)2-, and optionally substituted-C (═ O) n (h) -, -C (═ NH) -, -S (═ O)2N (h) -or-S (═ O) n (h) -.
Unless otherwise specified, "cyclic" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The ring includes monocyclic ring, and also includes bicyclic or polycyclic ring systems such as spiro ring, fused ring and bridged ring. The number of atoms in the ring is generally defined as the number of ring members, for example, "5 to 7 membered ring" means 5 to 7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, "5-to 7-membered ring" includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term "5 to 7 membered heterocycloalkyl" includes pyridyl and piperidyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.
Unless otherwise specified, the term "alkyl" is used to denote a straight or branched chain saturated hydrocarbon group, in some embodiments the alkyl group is C1-12An alkyl group; in other embodiments, the alkyl is C1-6An alkyl group; in other embodiments, the alkyl is C1-3An alkyl group. It may be monosubstituted (e.g. -CH)2F) Or polysubstituted (e.g. -CF)3) And may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.
Unless otherwise specified, "alkenyl" is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds, which may be located anywhere in the group. In some embodiments, the alkenyl is C2-8An alkenyl group; in other embodiments, the alkenyl group is C2-6An alkenyl group; in other embodiments, the alkenyl group is C2-4An alkenyl group. It may be mono-or poly-substituted, and may be mono-, di-or polyvalent. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.
Unless otherwise specified, "alkynyl" is used to denote a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds, which may be located anywhere in the group. In some embodiments, the alkynyl is C2-8An alkynyl group; in other embodiments, the alkynyl is C2-6An alkynyl group; in other embodiments, the alkynyl is C2-4Alkynyl. It may be mono-or poly-substituted, and may be mono-, di-or polyvalent. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
Unless otherwise specified, the term "heteroalkyl", by itself or withThe other term "association" means a stable linear or branched alkyl radical or combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from-C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N (h) -and-S (═ O) n (h) -. In some embodiments, the heteroalkyl is C1-6A heteroalkyl group; in other embodiments, the heteroalkyl is C1-3A heteroalkyl group. The heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including the position of attachment of the alkyl group to the remainder of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used conventionally to refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to, -OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH2(CH3)2、-CH2-CH2-O-CH3、-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)(CH2CH3)、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH2(CH3)2、-CH2-S-CH2-CH3、-CH2-CH2、-S(＝O)-CH3、-CH2-CH2-S(＝O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3and-CH ═ CH-N (CH)3)-CH3. Up to two heteroatoms may be consecutive, e.g. -CH2-NH-OCH3。
Unless otherwise specified, terms"Heteroalkenyl" by itself or in combination with another term means a stable straight or branched chain alkenyl radical or combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from-C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N (h) -and-S (═ O) n (h) -. In some embodiments, the heteroalkenyl is C2-6A heteroalkenyl group; in other embodiments, the heteroalkyl is C2-4A heteroalkenyl group. The heteroatom or heteroatom group may be located at any internal position of the heteroalkenyl group, including the position of attachment of the alkenyl group to the rest of the molecule, but the terms "alkenyloxy", "alkenylamino" and "alkenylthio" are to be taken in their customary expression and refer to those alkenyl groups which are attached to the rest of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively. Examples of heteroalkenyl include, but are not limited to, -O-CH ═ CH2、-O-CH＝CHCH3、-O-CH＝C(CH3)2、-CH＝CH-O-CH3、-O-CH＝CHCH2CH3、-CH2-CH＝CH-OCH3、-NH-CH＝CH2、-N(CH＝CH2)-CH3、-CH＝CH-NH-CH3、-CH＝CH-N(CH3)2、-S-CH＝CH2、-S-CH＝CHCH3、-S-CH＝C(CH3)2、-CH2-S-CH＝CH2、-S(＝O)-CH＝CH2and-CH-S (O)2-CH3. Up to two heteroatoms may be consecutive, e.g. -CH-NH-OCH3。
Unless otherwise specified, the term "heteroalkynyl" by itself or in combination with another term refers to a stable straight or branched chain alkynyl radical, or combination thereof, composed of a number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from-C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N (h) -and-S (═ O) n (h) -. In some embodiments, the heteroalkynyl is C2-6A heteroalkynyl group; in other embodiments, the heteroalkyl is C2-4A heteroalkynyl group. The heteroatom or heteroatom group may be located at any internal position of the heteroalkynyl group including the position of attachment of the alkynyl group to the remainder of the molecule, but the terms "alkynyloxy", "alkynylamino" and "alkynylthio" are intended to be used with conventional expressions to refer to those alkynyl groups which are attached to the remainder of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively. Examples of heteroalkynyl groups include, but are not limited to
Figure GPA0000292424410000181
Figure GPA0000292424410000182
Figure GPA0000292424410000183
Up to two heteroatoms may be consecutive, e.g.
Figure GPA0000292424410000184
Unless otherwise specified, "cycloalkyl" includes any stable cyclic alkyl group including monocyclic, bicyclic, or tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, bicyclic, and bridged rings. In some embodiments, the cycloalkyl is C3-8A cycloalkyl group; in other embodiments, the cycloalkyl is C3-6A cycloalkyl group; in other embodiments, the cycloalkyl is C5-6A cycloalkyl group. It may be mono-or poly-substituted, and may be mono-, di-or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2 ] n]Bicyclo-octane, [4.4.0]Bicyclodecane and the like.
Unless otherwise specified, "cycloalkenyl" packetsIncluding any stable cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds at any position in the group, including monocyclic, bicyclic, or tricyclic ring systems, including spiro, fused, and bridged rings, but any ring of such systems is non-aromatic. In some embodiments, the cycloalkenyl group is C3-8A cycloalkenyl group; in other embodiments, the cycloalkenyl group is C3-6A cycloalkenyl group; in other embodiments, the cycloalkenyl group is C5-6A cycloalkenyl group. It may be mono-or poly-substituted, and may be mono-, di-or polyvalent. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
Unless otherwise specified, "cycloalkynyl" includes any stable cyclic alkynyl group containing one or more carbon-carbon triple bonds at any position in the group, including monocyclic, bicyclic, or tricyclic systems, including spirocyclic, bicyclic, and bridged rings. It may be mono-or poly-substituted, and may be mono-, di-or polyvalent.
Unless otherwise specified, the term "heterocycloalkyl" by itself or in combination with other terms denotes a cyclized "heteroalkyl," respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein bicyclic and tricyclic systems include spirocyclic, bicyclic, and bridged rings. Furthermore, with respect to the "heterocycloalkyl group," a heteroatom may occupy the position of the attachment of the heterocycloalkyl group to the rest of the molecule. In some embodiments, the heterocycloalkyl group is a 4-to 6-membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-to 6-membered heterocycloalkyl group. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or oxepanyl.
Unless otherwise specified, the term "heterocycloalkenyl" by itself or in combination with other terms denotes a cyclized "heteroalkenyl" group, respectively, which includes monocyclic, bicyclic, and tricyclic systems, including spiro, fused, and bridged rings, but any ring of such systems is non-aromatic. Further, with respect to the "heterocycloalkenyl," a heteroatom may occupy the position of the connection of the heterocycloalkenyl to the rest of the molecule. In some embodiments, the heterocycloalkenyl is a 4-6 membered heterocycloalkenyl; in other embodiments, the heterocycloalkenyl is a 5-6 membered heterocycloalkenyl. Examples of heterocycloalkenyl include, but are not limited to
Figure GPA0000292424410000191
Figure GPA0000292424410000192
Unless otherwise specified, the term "heterocycloalkynyl" by itself or in combination with other terms denotes a cyclized "heteroalkynyl" group, respectively, which includes monocyclic, bicyclic, and tricyclic systems, including spiro, fused, and bridged rings. Furthermore, with respect to the "heterocycloalkynyl," a heteroatom may occupy the position of the heterocycle alkynyl attachment to the rest of the molecule. In some embodiments, the heterocycloalkynyl is a 4-to 6-membered heterocycloalkynyl; in other embodiments, the heterocycloalkynyl is a 5-to 6-membered heterocycloalkynyl. Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)1-C4) Alkyl "is intended to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, and the like. Unless otherwise specified, examples of haloalkyl include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
"alkoxy" represents a group having a special group attached via an oxygen bridgeThe above alkyl radicals having a number of carbon atoms, unless otherwise specified, C1-6Alkoxy radicals comprising C1、C2、C3、C4、C5And C6Alkoxy group of (2). In some embodiments, the alkoxy is C1-3An alkoxy group. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy.
Unless otherwise specified, the terms "aromatic ring" and "aryl" are used interchangeably herein and the terms "aromatic ring" or "aryl" refer to a polyunsaturated carbocyclic ring system which may be a monocyclic, bicyclic or polycyclic ring system in which at least one ring is aromatic, each of the rings in the bicyclic and polycyclic ring systems being fused together. Which may be mono-or poly-substituted, and may be mono-, di-or polyvalent, and in some embodiments the aryl group is C6-12An aryl group; in other embodiments, the aryl is C6-10And (4) an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like). The substituents of any of the above aryl ring systems are selected from the group of acceptable substituents described herein.
Unless otherwise specified, the terms "heteroaryl ring" and "heteroaryl" are used interchangeably herein, the term "heteroaryl" refers to an aryl (or aromatic ring) containing 1, 2, 3 or 4 heteroatoms independently selected from B, N, O and S, which may be a monocyclic, bicyclic or tricyclic ring system, wherein the nitrogen atom may be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents already defined herein), and optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S (O))pAnd p is 1 or 2). The heteroaryl group may be attached to the rest of the molecule through a heteroatom. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a 5-6 membered heteroaryl. Examples of such heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and the like)And 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, 1H-1, 2, 4-triazolyl, and 4H-1, 2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furyl (including 2-furyl, and 3-furyl, etc.), thienyl (including 2-thienyl, and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), oxazolyl (including 2H-1, 2, 3, and 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, and 5-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, etc.), furyl, etc.) Pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), indolyl (including 5-indolyl, etc.), isoquinolinyl (including 1-isoquinolinyl, 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), quinolyl (including 3-quinolyl, 6-quinolyl, etc.), pyrazinyl, purinyl, phenylooxazolyl, indazolyl (including 1H-indazolyl, 2H-indazolyl). The substituents of any of the above heteroaryl ring systems are selected from the group of acceptable substituents described herein.
Unless otherwise specified, the term "aralkyl" is intended to include those groups in which the aryl group is attached to an alkyl group, in some embodiments the aralkyl group is C6-10aryl-C1-4An alkyl group; in other embodiments, the aralkyl is C6-10aryl-C1-2An alkyl group. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like. "aryloxy" and "arylthio" refer to those groups in which a carbon atom (e.g., methyl) in an aralkyl group has been replaced with an oxygen or sulfur atom, respectively, and in some embodiments, the aryloxy group is C6-10aryl-O-C1-2An alkyl group; in other embodiments, the aryloxy group is C6-10aryl-C1-2alkyl-O-. In some embodiments, the arylthio is C6-10aryl-S-C1-2An alkyl group; in other embodiments, the arylthio is C6-10aryl-C1-2alkyl-S-. Examples of aryloxy and arylthio groups include, but are not limited to, phenoxymethyl, 3- (1-naphthyloxy) propyl, phenylthiomethyl, and the like.
Unless otherwise specified, the term "heteroaralkyl" is intended to include those groups in which a heteroaryl group is attached to an alkyl group, in some embodiments the heteroaralkyl group is a 5-8 membered heteroaryl-C1-4An alkyl group; in other embodiments, the heteroaralkyl group is a 5-6 membered heteroaryl-C1-2An alkyl group. Examples of heteroaralkyl groups include, but are not limited to, pyrrolylmethyl, pyrazolylmethyl, pyridylmethyl, pyrimidinylmethyl and the like. "heteroaryloxy" and "heteroarylthio" refer to those groups in which a carbon atom (e.g., methyl) in a heteroarylalkyl group has been replaced by an oxygen or sulfur atom, respectively, and in some embodiments the heteroaryloxy group is a 5-8 membered heteroaryl-O-C1-2An alkyl group; in other embodiments, the heteroaryloxy group is a 5-6 membered heteroaryl-C1-2alkyl-O-. In some embodiments, the heteroarylthio is 5-8 membered heteroaryl-S-C1-2An alkyl group; in other embodiments, the heteroarylthio group is a 5-6 membered heteroaryl-C1-2alkyl-S-. Examples of heteroaryloxy and heteroarylthio include, but are not limited to, pyrrolooxymethyl, pyrazoloxymethyl, 2-pyridyloxymethyl, pyrrolothiomethyl, pyrazolthiomethyl, 2-pyridylthiomethyl and the like.
Unless otherwise specified, Cn-n+mOr Cn-Cn+mIncluding any one particular case of n to n + m carbons, e.g. C1-12Comprising C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11And C12Also included are any ranges of n to n + m, e.g. C1-12Comprising C1-3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12And C9-12Etc.; similarly, n to n + m means the number of atoms on the ring is n to n + m, for example, the 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring and 12-membered ring, and any range of n to n + m, for example, the 3-12 membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-8-membered ring, 6-10-membered ring and the like。
The term "leaving group" refers to a functional group or atom that can be substituted by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetyloxy, and the like.
The term "protecting group" includes, but is not limited to, "amino protecting group," hydroxyl protecting group, "or" thiol protecting group. The term "amino protecting group" refers to a protecting group suitable for use in preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl, for example alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups, such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
The invention employs the following abbreviations: DCM represents dichloromethane; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc and EA represent acetic acidEthyl ester; MeOH represents methanol; BOC represents tert-butoxycarbonyl as an amine protecting group; THF represents tetrahydrofuran; boc2O represents di-tert-butyl dicarbonate; na (Na)2SO4Represents sodium sulfate; TEA for triethylamine; pd (dppf) Cl2Represents [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride; NaOH represents sodium hydroxide; NaHMDS stands for sodium bis (trimethylsilyl) amide; HATU represents 2- (7-azobenzotriazol) -N, N, N, N-tetramethyluronium hexafluorophosphate; DIEA stands for diisopropylethylamine; HCl represents hydrogen chloride; CDI represents N, N' -carbonyldiimidazole; MTBE represents methyl tert-butyl ether; pd2(dba)3Represents tris (dibenzylideneacetone) dipalladium; xanphos represents 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene; PGE represents polyethylene glycol.
The compound is made by hand or
Figure GPA0000292424410000212
The software names, and the commercial compounds are under the supplier catalog name.
Drawings
FIG. 1 shows the results of the drug effect of CT26 mouse syngeneic transplanted tumor model.
FIG. 2 shows the body weight change of mice in the CT26 mouse syngeneic transplantation tumor model.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the invention without departing from the spirit and scope of the invention.
Example 1
Figure GPA0000292424410000211
Figure GPA0000292424410000221
Synthesis of Compound 1-b:
iodomethane (185.33g) was added to an acetone solution (1500mL) of Compound 1-a (98.5g) at 0 ℃ to react at 25 ℃ for 1 hour, followed by filtration and spin-drying of the filter cake to give Compound 1-b.
Synthesis of Compounds 1-d:
thionyl chloride (96.92g, 814.69mmol) was slowly added dropwise to an anhydrous ethanol solution (1000mL) at 0 ℃ followed by addition of compound 1-c (95g, hydrochloride salt), reaction at 80 ℃ for 12 hours, and concentration under reduced pressure gave compound 1-d.
Synthesis of Compounds 1-e:
to a solution of compound 1-d (98g, hydrochloride) and N, N-diisopropylethylamine (141.01g, 1.09mol) in dioxane (1400mL) and water (350mL) was added compound 1-b (208.74g, 818.28mmol) in portions at 90 ℃, after 12 hours of reaction at 9008, the solvent dioxane was removed by concentration under reduced pressure, 1000mL of ethyl acetate was added, the solution was washed with saturated sodium chloride solution 3 times, 1000mL each time, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1-e.
Synthesis of Compounds 1-f:
to a solution of compound 1-e (76g) and N, N-bis (trifluoromethanesulfonyl) aniline (126.55g) in tetrahydrofuran (1500mL) was added NaHMDS (1M, 371.09mL) dropwise at a temperature not higher than-60 ℃, reacted at 25 ℃ for 12 hours after completion of the dropwise addition, 1500mL of hydrochloric acid (0.2M) solution was added to quench the reaction, the solvent tetrahydrofuran was removed by concentration under reduced pressure, 1500mL of methyl t-butyl ether was added, the solution was washed with hydrochloric acid (0.2M) solution 2 times, 1500mL each time, 3 times with 5% NaOH solution, 1500mL each time, 1 time with saturated sodium chloride solution, 1500mL each time, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 1-f as a brown gum.
Synthesis of Compounds 1-h:
to a solution of compound 1-f (93.5g, 261.65mmol) and pinacol boronate (73.09g, 287.82mmol) in dioxane (1000mL) was added sodium bromide (10.77g, 104.66mmol, 3.37mL), potassium acetate (77.04g) and Pd (dppf) Cl2(9.57g), after 12 hours of reaction at 80 ℃ under nitrogen, 2000 ml of ethyl acetate are added, filtration is carried out, the filtrate is washed 2 times with saturated sodium chloride solution, 1500ml each time, then 1000ml of hydrochloric acid solution (0.2M) is added, the aqueous phase is separated to obtain the organic phase, the organic phase is extracted twice with hydrochloric acid solution (0.2M), 1000ml each time, the combined aqueous phase is washed 2 times with ethyl acetate, 2000 ml each time, then the pH is adjusted to 9 with saturated sodium carbonate solution, the organic phase is extracted twice with ethyl acetate, 1500ml each time, the combined organic phase of the two extractions is washed 2 times with saturated sodium chloride solution, 2000 ml each time, the organic phase is dried with anhydrous sodium sulfate, filtration is carried out, and concentration is carried out to obtain the compound 1-h.
Synthesis of Compounds 1-j:
to a solution of compound 1-h (29.85g) and 4-chloro-6-fluoroquinoline (14.7g) in dioxane (240mL) and water (60mL) was added triethylamine (24.57g) and Pd (dppf) Cl2(2.96g), after 12 hours of reaction at 100 ℃ under nitrogen, 1000mL of ethyl acetate was added, filtration was carried out, the filtrate was washed 2 times with saturated sodium chloride solution, 500mL each time, then the pH was adjusted to 1 with hydrochloric acid solution (1M), the aqueous phase was separated, the organic phase was extracted twice with hydrochloric acid solution (0.2M), 500mL each time, the combined aqueous phase was washed 2 times with ethyl acetate, 1000mL each time, then the pH was adjusted to 9 with saturated sodium carbonate solution, extracted twice with ethyl acetate, 750 mL each time, the combined organic phase was extracted twice with saturated sodium chloride solution, 2 times 1000mL each time, the organic phase was dried over anhydrous sodium sulfate, filtering, concentrating to obtain 30g of crude product, adding the crude product into 150 ml of acetonitrile, stirring for 1 hour at 25 ℃, filtering, and spin-drying a filter cake to obtain the compound 1-j.
Synthesis of Compounds 1-k:
to an isopropanol solution (400mL) of compound 1-j (21g) and pyridine (7.03g) was added palladium on carbon (4g, 10% purity), reacted at 50 ℃ under a hydrogen atmosphere (15psi) for 1 hour, and then filtered through celite, and concentrated to give compound 1-k.
Synthesis of Compounds 1-l:
after adding sodium hydroxide (6.73g) to a solution of compound 1-k (20g) in methanol (100mL), tetrahydrofuran (100mL) and water (50mL) and reacting at 70 ℃ for 12 hours, the solvents methanol and tetrahydrofuran were removed by concentration under reduced pressure, the pH was adjusted to 6-7 with hydrochloric acid (1M), a large amount of solid was precipitated, filtered, and the filter cake was dried under reduced pressure to give compound 1-l.
Synthesis of Compound 1:
adding N, N-diisopropylethylamine (5.90g) and HATU (8.11g) into a DMF solution (100mL) of compound 1-l (5g) and p-chlorophenylammonia (2.33g), reacting at 25 ℃ for 12 hours under the protection of nitrogen, adding 400mL of ethyl acetate for dilution, washing the solution with saturated sodium chloride solution for 3 times (500 mL each time), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to obtain 9g of crude product, adding the crude product into 45mL of acetonitrile, stirring for 12 hours at 25 acetonitrile, filtering, and spin-drying the filter cake to obtain the purified crude product, wherein the crude product is purified by preparative high-performance liquid chromatography (formic acid system) to obtain compound 1.
1H NMR(400MHz，DMSO-d6)δ＝9.58(s，1H)，8.82(d，J＝4.5Hz，1H)，8.08(dd，J＝6.0，9.2Hz，1H)，8.02(dd，J＝2.8，11.2Hz，1H)，，7.82-7.75(m，2H)，7.65(dt，J＝2.8，8.7Hz，1H)，7.48(d，J＝4.6Hz，1H)，7.41-7.34(m，2H)，3.39-3.34(m，1H)，2.99(d，J＝11.2Hz，2H)，2.45-2.23(m，6H)，1.91-1.68(m，6H).
Example 2
Figure GPA0000292424410000241
Synthesis of Compound 2
Compound 1-l (50mg) was dissolved in DMF (5mL) and DIEA (98.39mg) and HATU (86.84mg) were added to the solution at 25 ℃ and the resulting mixture was stirred at 25 ℃ for 30 minutes, then 2-a (23.59mg) was added to the reaction solution and the resulting mixture was stirred at 25 ℃ for 12 hours, the reaction was quenched by adding water (10mL) to the reaction solution and quenchedExtract with ethyl acetate (30 mL. times.3.) the combined organic phases were extracted with Na2SO4Drying, filtering, and concentrating under reduced pressure to obtain crude product, and purifying the crude product by preparative chromatography to obtain the compound 2.
1H NMR(400MHz，CCl3D)δppm 1.69-1.91(m，3H)2.00-2.10(m，3H)2.33-2.56(m，6H)3.00(br d，J＝11.74Hz，2H)3.18(br t，J＝11.80Hz，1H)6.77-6.88(m，2H)7.31(d，J＝4.65Hz，1H)7.39-7.48(m，1H)7.61(dd，J＝10.33，2.63Hz，1H)8.03-8.15(m，1H)8.28(td，J＝9.23，5.99Hz，1H)8.80(d，J＝4.65Hz，1H)9.42(br s，1H).
Example 3
Figure GPA0000292424410000242
Synthesis of Compound 3
Compound 1-l (50mg) was dissolved in DMF (3mL) and DIEA (98.39mg) and HATU (86.84mg) were added to the solution at 25 ℃ and the resulting mixture was stirred at 25 ℃ for 30 minutes, then 3-a (23.31mg) was added to the reaction mixture and the resulting mixture was stirred at 25 ℃ for 12 hours, the reaction was quenched by adding water (10mL) to the reaction mixture and extracted with ethyl acetate (20 mL. sup.3), the combined organic phases were extracted with Na2SO4Drying, filtering, and concentrating under reduced pressure to obtain crude product, and purifying the crude product by preparative chromatography to obtain the compound 3.
1H NMR(400MHz，CCl3D)δppm 1.68-1.92(m，3H)1.96-2.10(m，3H)2.25-2.58(m，6H)3.02(br d，J＝11.25Hz，2H)3.18(br t，J＝12.10Hz，1H)7.01(dd，J＝8.01，1.04Hz，1H)7.17(s，1H)7.21(s，1H)7.37-7.48(m，2H)7.60(dd，J＝10.33，2.63Hz，1H)7.66(s，1H)8.07-8.14(m，1H)8.80(d，J＝4.65Hz，1H)9.11(br s，1H).
Example 4
Figure GPA0000292424410000251
Synthesis of Compound 4
Compound 1-l (100 m)g) Dissolved in DMF (3mL), followed by addition of DIEA (118.07mg) and HATU (231.58 mg), and addition of 4-a (58.26mg) to the mixture, the reaction was performed at 25 ℃ N2The reaction solution is brown solution after 12 hours of reaction under protection. The reaction mixture was poured into 50mL of water, followed by extraction with 120mL (40 mL. times.3) of EA, and the combined organic phases were washed with 60mL (30 mL. times.2) of saturated brine, Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain 4.
1H NMR(400MHz，DMSO-d6)δppm 1.73-1.94(m，6H)2.24-2.45(m，7H)3.02(br d，J＝11.2Hz，2H)4.14(s，3H)7.42(dd，J＝9.2，1.6Hz，1H)7.49-7.57(m，2H)7.66(td，J＝8.8，2.6Hz，1H)7.99-8.12(m，2H)8.26(s，1H)8.83(d，J＝4.4Hz，1H)9.40(s，1H)
Example 5
Figure GPA0000292424410000252
Synthesis of Compound 5
Compound 1-l (100mg) was dissolved in DMF (5mL), DIEA (196.79mg), HATU (173.68mg), 5-a (43.25mg) was added and nitrogen was substituted three times, the resulting mixture was stirred at 25 ℃ for 12 hours, the reaction was extracted with EtOAc (10mL 3), the combined organic phases were washed with saturated brine (10mL 3), Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 5.
1H NMR(400MHz，DMSO-d6)δ＝9.67(s，1H)，8.83(d，J＝4.4Hz，1H)，8.20(s，1H)，8.11-8.01(m，2H)，7.96(br dd，J＝2.4，7.6Hz，1H)，7.92(br dd，J＝2.4，7.5Hz，1H)，7.66(dt，J＝2.8，8.7Hz，1H)，7.58-7.48(m，1H)，7.44-7.36(m，1H)，3.56-3.28(m，1H)，3.17(br s，2H)，3.00(s，2H)，2.97(br s，4H)，2.54-2.53(m，4H)，2.47-2.22(m，2H).
Example 6
Figure GPA0000292424410000261
Synthesis of Compound 6
Compound 1-l (100mg) was dissolved in DMF (5mL), followed by the addition of DIEA (196.79mg), HATU (173.68mg), 6-a (33.22 mg). The reaction mixture was extracted with EtOAc (10 mL. times.3), the combined organic phases were washed with saturated brine (10 mL. times.3), and Na was added2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 6.
1H NMR(400MHz，DMSO-d6)δ＝8.82(br d，J＝3.8Hz，1H)，8.19(s，1H)，8.14-8.04(m，1H)，8.01(s，1H)，7.99(br s，1H)，7.66(br t，J＝7.6Hz，1H)，7.47(br d，J＝3.8Hz，1H)，3.64(br s，1H)，3.35-3.25(m，1H)，2.90(br d，J＝10.4Hz，2H)，2.43-2.27(m，2H)，2.16(br dd，J＝8.8，19.4Hz，4H)，1.92-1.80(m，2H)，1.79-1.63(m，8H)，1.58(br d，J＝12.6Hz，1H)，1.36-1.18(m，4H)，1.14(br s，1H).
Example 7
Figure GPA0000292424410000262
Synthesis of Compound 7
Compound 1-l (50mg) was dissolved in DMF (5mL), DIEA (98.39mg), HATU (86.84mg), 7-a (28.81mg) was added and nitrogen was substituted three times, the resulting mixture was stirred at 25 ℃ for 12 hours, the reaction was extracted with EtOAc (10mL 3), and the combined organic phases were washed with saturated brine (10mL 3), Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain a compound 7.
1H NMR(400MHz，DMSO-d6)δ＝9.59(s，1H)，8.83(d，J＝4.4Hz，1H)，8.31(br s，1H)，8.12-8.07(m，2H)，8.04(d，J＝10.4Hz，2H)，7.76-7.64(m，1H)，7.54-7.47(m，3H)，3.63(br s，1H)，3.35(br t，J＝11.2Hz，2H)，2.99(br d，J＝11.0Hz，2H)，2.47-2.24(m，4H)，1.92-1.68(m，6H).
Example 8
Figure GPA0000292424410000271
Synthesis of Compound 8
Compound 1-l (50mg) was dissolved in DMF (5mL), DIEA (98.39mg), HATU (86.84mg), 8-a (18.61mg) was added and nitrogen was substituted three times, the resulting mixture was stirred at 25 ℃ for 12 hours, the reaction was extracted with EtOAc (10mL 3), and the combined organic phases were washed with saturated brine (10mL 3), Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 8.
1H NMR(400MHz，DMSO-d6)δ＝9.52(s，1H)，8.83(d，J＝4.6Hz，1H)，8.25(s，1H)，8.12-8.01(m，2H)，7.79-7.73(m，2H)，7.67(dt，J＝2.8，8.7Hz，1H)，7.50(d，J＝4.4Hz，1H)，7.17(t，J＝8.2Hz，2H)，3.36(br t，J＝12Hz，1H)，3.26(br s，2H)，3.00(br d，J＝10Hz，2H)，2.46-2.22(m，4H)，1.93-1.68(m，6H).
Example 9
Figure GPA0000292424410000272
Synthesis of Compound 9
Compound 1-l (50mg) was dissolved in DMF (5mL), followed by addition of DIEA (98.39mg), HATU (86.84mg), 9-a (18.11 mg). The reaction mixture was extracted with EtOAc (10 mL. times.3), the combined organic phases were washed with saturated brine (10 mL. times.3), and Na was added2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 9.
1H NMR(400MHz，DMSO-d6)δ＝9.56(s，1H)，8.83(d，J＝4.4Hz，1H)，8.76(d，J＝2.2Hz，1H)，8.22(s，1H)，8.13-7.97(m，3H)，7.66(dt，J＝2.8，8.7Hz，1H)，7.50(d，J＝4.4Hz，1H)，7.22(d，J＝8.4Hz，1H)，3.63(br s，1H)，3.35(br t，J＝11.2Hz，2H)，3.10(br d，J＝11.2Hz，4H)，3.00(br d，J＝11.2Hz，4H)，2.46-2.24(m，2H)，1.93-1.68(m，4H)，1.65-1.42(m，2H)。
Example 10
Figure GPA0000292424410000281
Synthesis of Compound 10
Compound 1-l (62.68mg) was dissolved in DMF (2mL), followed by the addition of HATU (108.86mg) and DIEA (74.00mg) under a nitrogen atmosphere and the mixture was stirred at 25 ℃ for 30 minutes. 10-a (32.43mg) was then added. The mixture was stirred at 25 ℃ for 11.5 hours. The mixture remained pale yellow. The reaction mixture was diluted with water (30mL) and extracted with EA (50 mL. multidot.2). the combined organic phases were washed with saturated brine (30 mL. multidot.4) and Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product was purified using preparative chromatography to afford compound 10.
1H NMR(400MHz，DMSO-d6)δ＝10.13(br s，1H)，8.92(d，J＝4.4Hz，1H)，8.23(dd，J＝2.8，10.8Hz，1H)，8.15(dd，J＝5.6，9.2Hz，1H)，7.75(dt，J＝2.8，8.8Hz，1H)，7.50-7.41(m，3H)，7.39-7.33(m，1H)，3.86-3.31(m，4H)，2.79-2.65(m，4H)，2.44-2.31(m，1H)，2.28(s，3H)，2.18-2.08(m，4H)，2.04-1.84(m，2H)。
Example 11
Figure GPA0000292424410000282
Synthesis of Compound 11
Compound 1-l (54mg) was dissolved in DMF (1mL), followed by the addition of HATU (93.79mg) and DIEA (63.76 mg) under a nitrogen atmosphere. The mixture was stirred at 25 ℃ for 30 minutes. Thereafter, 11-a (28.72mg) was added. The mixture was stirred at 25 ℃ for 11.5 hours. The reaction was diluted with water (30mL) and extracted with EA (50mL × 2), the combined organic phases were washed with saturated brine(30mL of Tu 4) with Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product was purified using preparative chromatography to afford compound 11.
1H NMR(400MHz，DMSO-d6)δ＝10.41(br s，1H)，8.94(d，J＝4.4Hz，1H)，8.24-8.12(m，2H)，8.07(dd，J＝2.4，6.8Hz，1H)，7.79-7.70(m，2H)，7.54-7.46(m，2H)，3.81(br s，1H)，3.62(br d，J＝11.2Hz，2H)，3.28(br s，2H)，2.84-2.61(m，4H)，2.18-2.03(m，4H)，2.00-1.77(m，2H)。
Example 12
Figure GPA0000292424410000291
Synthesis of Compound 12
Compound 1-l (62.68mg) was dissolved in DMF (1mL), followed by addition of HATU (108.86mg) and DIEA (74.00mg) under a nitrogen atmosphere. The mixture was stirred at 25 ℃ for 30 minutes. Thereafter, Compound 12-a (24.77mg) was added to the reaction solution. The mixture was stirred at 25 ℃ for 11.5 hours. The mixture was diluted with water (30mL) and extracted with EA (50mL × 2). The combined organic phases were washed with brine (30mL × 4), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product obtained is purified by preparative chromatography to afford compound 12.
1H NMR(400MHz，DMSO-d6)δ＝9.69(s，1H)，8.83(d，J＝4.8Hz，1H)，8.30(d，J＝5.6Hz，1H)，8.08(dd，J＝6.0，9.2Hz，1H)，8.03(dd，J＝2.8，11.2Hz，1H)，7.69-7.61(m，2H)，7.59(dd，J＝1.6，5.6Hz，1H)，7.48(d，J＝4.4Hz，1H)，3.43-3.21(m，1H)，2.98(br d，J＝11.2Hz，2H)，2.42(s，3H)，2.41-2.35(m，2H)，2.32(br d，J＝8.4Hz，4H)，1.91-1.68(m，6H)。
Example 13
Figure GPA0000292424410000292
Synthesis of Compound 13-b:
the reactants were added to dioxane (8mL) and water (2mL) in the order of 1-h (784.29mg, 2.34mmol), reactant 13-a (500mg, 2.13mmol), palladium catalyst (77.81mg, 106.34 μmol), triethylamine (645.62mg, 6.38mmol, 888.07uL), the reaction was heated to 90 ℃ under nitrogen and stirred for 12 hours, the reaction was filtered, the filtrate was diluted with water, extracted three times with ethyl acetate (50mL x 3), the organic phases were combined and washed three times with saturated brine (50mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to give a crude product, and purified by column chromatography to give compound 13-b.
Synthesis of Compound 13-c:
to ethyl acetate (10mL) was added reactant 13-b (750mg, 2.06mmol), wet palladium on carbon (70mg, 10% purity) in that order, and the resulting mixture was replaced three times with hydrogen. Heating to 50 deg.C under hydrogen atmosphere and normal pressure, stirring for 2 hr, filtering the reaction solution, and concentrating the filtrate to obtain compound 13-c.
Synthesis of Compound 13-d:
to ethanol (8mL) and water (2mL) were added successively reactant 13-c (700mg, 1.92mmol), sodium hydroxide (229.81mg, 5.75mmol), heated to 70 ℃ and stirred for 2 hours, the reaction was concentrated, diluted with water, extracted three times with ethyl acetate (30mL x 3), the aqueous phase was added diluted hydrochloric acid (1M) to adjust pH to 3, extracted three times with ethyl acetate (30mL x 3), the resulting organic phases were combined and washed three times with saturated brine (50mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 13-d.
Synthesis of compound 13:
to DMF (10mL) was added reactant 13-d (500mg, 1.48mmol), reactant 1-N (226.84mg, 1.78mmol), condensing agent HATU (845.12mg, 2.22mmol), N-diisopropylethylamine (574.51mg, 4.45mmol, 774.28uL) in this order, the reaction mixture was stirred at room temperature for 12 hours, the reaction mixture was diluted with ethyl acetate (30mL), washed three times with saturated ammonium chloride solution (30mL × 3), washed three times with saturated brine (30mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to give crude product, and purified by reverse phase chromatography to give compound 13.
1H NMR(400MHz，MeOD-d4)δppm 1.85-2.02(m，6H)2.40-2.55(m，6H)2.73-2.82(m，1H)3.12(s，3H)3.16(br d，J＝11.49Hz，2H)7.36(d，J＝7.78Hz，2H)7.57(d，J＝8.31Hz，2H)7.65(d，J＝8.46Hz，2H)7.91(d，J＝8.44Hz，2H)8.13(s，1H)。
Example 14
Figure GPA0000292424410000301
Synthesis of Compound 14-a
To a solution of compound 1-l (1g) in DCM (30mL) was added CDI (740.68mg), reacted at 25 ℃ for 12 hours, diluted with 100mL dcc and washed with saturated brine (100mL × 3), Na2SO4Drying, filtering and concentrating to obtain the compound 14-a.
Synthesis of Compound 14
Compound 14-b (20.47mg) was dissolved in THF (5mL), then NaHMDS (1M, 158.54uL) was added dropwise at 0 deg.C, nitrogen replaced three times, and then allowed to react at 0 deg.C for half an hour. Compound 14-a (50mg) was then added at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1h, the reaction was extracted with EtOAc (10 mL. times.3), the combined organic phases were washed with saturated brine (10 mL. times.3), Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 14.
1H NMR(400MHz，DMSO-d6)δ＝9.80(s，1H)，8.83(d，J＝4.4Hz，1H)，8.45(s，1H)，8.09(t，J＝7.0Hz，2H)，8.04(d，J＝10.4Hz，4H)，7.69-7.55(m，1H)，2.98(br d，J＝11.0Hz，2H)，2.81-2.60(m，1H)，2.57-2.53(m，6H)，2.44-2.37(m，4H)，2.37-2.22(m，2H)。
Example 15
Figure GPA0000292424410000311
Synthesis of Compound 15
Reacting compound 15-a (30.84mg) was dissolved in THF (2mL) after which NaHMDS (1M, 190.25uL) was added dropwise at-75 ℃ under a nitrogen atmosphere over 10 mins. The mixture was stirred at-75 ℃ for 20 min. 14-a (60mg, 158.54. mu. mol) was then added. The mixture was stirred at 25 ℃ for 9.5 hours. The reaction was diluted with water (30mL) and extracted with EA (50mL × 2). The combined organic phases were washed with saturated brine (30 mL. multidot.4) and Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product was purified using preparative chromatography to afford compound 15.
1H NMR(400MHz，DMSO-d6)δ＝10.05(s，1H)，9.10(d，J＝2.4Hz，1H)，8.82(d，J＝4.4Hz，1H)，8.48(dd，J＝2.0，8.4Hz，1H)，8.08(dd，J＝6.0，9.2Hz，1H)，8.02(dd，J＝2.8，11.2Hz，1H)，7.89(d，J＝8.8Hz，1H)，7.65(dt，J＝2.8，8.8Hz，1H)，7.48(d，J＝4.4Hz，1H)，3.01(br d，J＝11.2Hz，2H)，2.67(s，1H)，2.47-2.29(m，6H)，1.92-1.67(m，6H)。
Example 16
Figure GPA0000292424410000312
Synthesis of Compound 16
Compound 16-a (30.82mg) was dissolved in THF (2mL) after which NaHMDS (1M, 190.25uL) was added dropwise at 0 ℃ over 10 minutes under a nitrogen atmosphere. The mixture was stirred at 25 ℃ for 20 minutes. 14-a (60mg) was then added. The mixture was stirred at 25 ℃ for 2 hours. The reaction was diluted with water (30mL) and extracted with EA (50mL × 2). The combined organic phases were washed with saturated brine (30mL 4), Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product was purified using preparative chromatography to afford compound 16.
1H NMR(400MHz，DMSO-d6)δ＝9.72(s，1H)，8.83(d，J＝4.4Hz，1H)，8.31(s，1H)，8.15(d，J＝2.4Hz，1H)，8.08(dd，J＝5.6，9.2Hz，1H)，8.03(dd，J＝2.8，11.2Hz，1H)，7.76(dd，J＝2.4，8.8Hz，1H)，7.65(dt，J＝2.8，8.8Hz，1H)，7.58(d，J＝8.8Hz，1H)，7.48(d，J＝4.8Hz，1H)，2.98(br d，J＝11.2Hz，2H)，2.67(br d，J＝1.6Hz，1H)，2.41(br t，J＝10.4Hz，2H)，2.35-2.25(m，4H)，1.93-1.79(m，4H)，1.79-1.67(m，2H)。
Example 17
Figure GPA0000292424410000321
Synthesis of Compound 17
Compound 17-a (20.23mg) was dissolved in THF (5mL), then NaHMDS (1M, 158.54uL) was added dropwise at 0 ℃ three times with nitrogen substitution, then allowed to react at 0 ℃ for half an hour, then compound 14-a (50mg) was added at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1h, the reaction was extracted with EtOAc (10 mL. times.3), the combined organic phases were washed with saturated brine (10 mL. times.3), Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 17.
1H NMR(400MHz，DMSO-d6)δ＝9.94(s，1H)，8.85(d，J＝4.4Hz，1H)，8.26(dd，J＝1.4，8.2Hz，1H)，8.11(t，J＝7.0Hz，2H)，8.05(d，J＝10.4Hz，1H)，7.68(dt，J＝2.8，8.7Hz，1H)，7.53(d，J＝7.6Hz，1H)，7.47(d，J＝4.8Hz，1H)，7.37(t，J＝7.8Hz，1H)，2.96(br d，J＝11.4Hz，2H)，2.69-2.53(m，1H)，2.48-2.39(m，4H)，2.39-2.31(m，2H)，2.30-2.18(m，2H)，2.01-1.72(m，4H)。
Example 18
Figure GPA0000292424410000322
Synthesis of Compound 18
Compound 18-a (25.55mg) was dissolved in THF (5mL), then NaHMDS (1M, 158.54. mu.L) was added dropwise at-78 deg.C, nitrogen replaced three times, and then allowed to react at-78 deg.C for half an hour. Compound 14-a (50mg) was then added at-78 ℃. The resulting mixture was stirred at 25 ℃ for 11.5 h, the reaction was extracted with EtOAc (10 mL. multidot.3) and combined withThe organic phase was washed with saturated brine (10 mL. times.3), Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 18.
1H NMR(400MHz，DMSO-d6)δ＝9.81(s，1H)，8.83(d，J＝4.5Hz，1H)，8.12-7.93(m，4H)，7.72-7.63(m，3H)，7.49(d，J＝4.5Hz，1H)，3.62(br s，1H)，3.35(br t，J＝11.2Hz，2H)，3.01(br d，J＝11.1Hz，2H)，2.47-2.25(m，4H)，1.93-1.70(m，4H)，1.68-1.47(m，2H)。
Example 19
Figure GPA0000292424410000331
Synthesis of Compound 19
Compound 19-a (18.73mg) was dissolved in THF (5mL) and NaHMDS (1M, 158.54. mu.L) was added dropwise at-78 ℃. The nitrogen was purged three times and then allowed to react at-78 ℃ for half an hour. Compound 14-a (50mg) was then added at-78 ℃. The resulting mixture was stirred at 25 ℃ for 11.5 h, the reaction was extracted with EtOAc (10 mL. times.3), and the combined organic phases were washed with saturated brine (10 mL. times.3), Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 19.
1H NMR(400MHz，DMSO-d6)δ＝9.79(s，1H)，8.84(d，J＝4.4Hz，1H)，8.28(s，2H)，8.25(br s，3H)，8.12-8.01(m，1H)，7.66(dt，J＝2.8，8.7Hz，3H)，3.48-3.21(m，1H)，3.00(br d，J＝11.4Hz，2H)，2.83-2.62(m，2H)，2.57-2.53(m，4H)，2.47-2.23(m，4H)，1.93-1.69(m，2H).
Example 20
Figure GPA0000292424410000332
Synthesis of Compound 20
Compound 20-a (20.29mg) was dissolved in THF (2mL) and NaHMDS (1M, 158.54. mu.L) was added at 0The mixture was stirred dropwise at 0 ℃ for 1 hour, and 14-a (50mg) dissolved in THF (1mL) was added to the mixture, which was then reacted at 0 ℃ for 1 hour under protection of N2. Water (15mL) was added to the reaction, followed by extraction with EA 45mL (15 mL. times.3), and the combined organic phases were washed with saturated brine (40mL, 20 mL. times.2), Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product was purified by preparative chromatography to give product 20.
1H NMR(400MHz，DMSO-d6)δppm 1.72-1.91(m，6H)2.29-2.35(m，4H)2.43(br d，J＝11.00Hz，2H)2.99(br d，J＝10.88Hz，2H)3.35(br t，J＝11.25Hz，1H)7.48(d，J＝4.52Hz，1H)7.65(td，J＝8.71，2.63Hz，1H)7.79(d，J＝8.68Hz，2H)7.96-8.11(m，4H)8.82(d，J＝4.52Hz，1H)9.87(s，1H)
Example 21
Figure GPA0000292424410000341
Synthesis of Compound 21-b
Mixture 21-a (500mg) and 1-h (1.02g) were dissolved in dioxane (12mL) and water (3mL), followed by the addition of TEA (836.08mg) followed by Pd (dppf) Cl2(201.52mg) in N2Adding into the mixture under protection, and mixing the mixture with N2The reaction was stirred at 85 ℃ for 12 hours to give a black solution, the reaction was filtered, 50mL of water was added, followed by extraction with EA (50 mL. times.3), and the combined organic phases were washed with 50mL (25 mL. times.2) of saturated brine, Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product is purified by column chromatography to obtain the compound 21-b.
Synthesis of Compound 21-c
Compound 21-b (590mg) was dissolved in EtOAc (10mL) and Pd/C (60mg, 10% pure) was added under protection of N2 and the resulting mixture was passed through H2And exchanging for several times, reacting at 25 deg.C and H2Stirring (15psi) for 12 hours to give a black suspension. Filtering and concentrating the reaction solution to obtain 21-c.
Synthesis of Compound 21-d
Compound 21-c (510mg) was dissolved in MeOH (8mL) and a solution of NaOH (228.95mg) in water (2mL) was added and the mixture was stirred at 75 deg.C for 12 h to give a yellow solution. The reaction was concentrated, then 6mL of water was added, the pH of the solution was adjusted to about 7 with 3M HCl, the solution was stirred at 0 ℃ for 30min, a large amount of white precipitate formed, filtered, and the filter cake was concentrated to 21-d.
Synthesis of Compound 21
Compound 21-d (160mg) was dissolved in DMF (4mL), followed by addition of DIEA (188.95mg) and HATU (240.88mg), the mixture was stirred at 25 ℃ for 1 hour, and 1-N (80.82mg) was added to the mixture, and the reaction was allowed to react at 50 ℃ for 11 hours under protection of N2 to give a yellow solution. Then 40mL of water was added to the reaction solution, followed by extraction with EA 60mL (20 mL. times.3), and the combined organic phases were washed with saturated brine 40mL (20 mL. times.2), Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product was purified by preparative chromatography to afford compound 21.
1H NMR(400MHz，DMSO-d6)δppm 1.83-2.01(m，1H)1.83-2.01(m，2H)2.16(br s，4H)2.77(br s，4H)2.99-3.25(m，3H)3.61(br s，2H)7.53(br d，J＝7.6Hz，2H)7.65(br s，1H)7.77-7.86(m，3H)8.79(br d，J＝3.6Hz，1H)10.36(br s，1H)
Example 22
Figure GPA0000292424410000351
Synthesis of Compound 22-b
The mixture 22-a (500mg) and 1-h (980.66mg) were dissolved in dioxane (12mL) and water (3mL), followed by the addition of TEA (807.27mg) followed by Pd (dppf) Cl2(194.58mg) in N2Adding into the mixture under protection, and mixing the mixture with N2The reaction was stirred at 85 ℃ for 12 hours to obtain a brown solution, the reaction solution was filtered, 50mL of water was added, followed by extraction with EA 150(50 mL. times.3), and the combined organic phases were washed with 50mL (25 mL. times.2) of saturated brine, Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product is purified by column chromatography to obtain the compound 22-b.
Synthesis of Compound 22-c
Compound 22-b (500mg) was dissolved in EtOAc (10mL) and Pd/C (50mg, 10% purity) was added under protection of N2, the resulting mixture was passed through H2 and permuted several times at 50 ℃ H2Stirring (15psi) for 3 hours to give a black suspension. The reaction solution is filtered and concentrated to obtain 22-c.
Synthesis of Compound 22-d
Compound 22-c (520mg) (crude) was dissolved in MeOH (10mL) and a solution of NaOH (228.62mg) in water (2mL) was added and the resulting mixture was stirred at 70 deg.C for 12 h to give a yellow solution. The reaction was concentrated, then 15mL of water was added, the pH of the solution was adjusted to about 6 with 2M HCl, and the mixture was concentrated to give the crude product. 15mL of MeOH was added to the crude product, stirred for 30min, filtered, and the filtrate was concentrated to 22-d.
Synthesis of Compound 22
Compound 22-d (200mg) was dissolved in DMF (5mL), followed by addition of DIEA (267.07mg) and HATU (340.48mg), and addition of 1-N (114.23mg) to the mixture, which was reacted at 25 ℃ with N2The reaction solution is yellow solution after 12 hours of reaction under protection. 40mL of water was added to the reaction, followed by extraction with EA 60(20 mL. times.3), and the combined organic phases were washed with 40mL (20 mL. times.2) of saturated brine, Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product was purified by preparative chromatography to give compound 22.
1H NMR(400MHz，DMSO-d6)δppm 1.67-1.83(m，6H)2.13-2.35(m，7H)2.94(br d，J＝11.2Hz，2H)3.82(s，3H)6.67(s，1H)6.90(d，J＝5.2Hz，1H)7.37(d，J＝8.80Hz，2H)7.73-7.78(m，2H)8.06(d，J＝5.26Hz，1H)9.54(s，1H)。
Example 23
Figure GPA0000292424410000361
Synthesis of Compound 23-b
Compound 23-a (3.2g) was dissolved in EA (30mL), followed by addition of Me3OBF4(4.52g) under a nitrogen atmosphere. The mixture was stirred at 25 ℃ for 6 hours. The resulting suspension was filtered and the filter cake was dried in vacuo to give crude 23-b.
Synthesis of Compound 23-c
Compound 23-b (1.63g, 10.86mmol) was dissolved in DCM (17mL), after which pyridine (1.29g) and iodobenzene bis (trifluoroacetic acid) (5.60g) were added under a nitrogen atmosphere. The resulting mixture was stirred at 30 ℃ for 30 minutes, after which I was added2(3.31 g). The resulting mixture was stirred at 30 ℃ for 15.5 hours. The resulting suspension was filtered and the filter cake was dried in vacuo to give crude 23-c.
Synthesis of Compound 23-d
Compounds 1-h (2.40g, 7.17mmol, 1eq) and 23-c (1.98g, 7.17mmol, 1eq) were dissolved in dioxane (20mL) and water (5mL), after which Pd (dppf) Cl was added2(262.41mg, 358.63. mu. mol, 0.05eq) and Et3N (2.18g, 21.52mmol, 3.00mL, 3eq) was placed under nitrogen. The mixture was replaced with nitrogen three times. The mixture was stirred at 100 ℃ for 8 hours. The mixture was filtered and the cake was washed with EA (80mL), followed by addition of water (40mL) and liquid separation. The aqueous phase was extracted with EA (70mL × 2). The combined organic phases were washed with saturated brine (50 mL. multidot.2), Na2SO4Drying, filtering and concentrating to obtain a crude product. The resulting crude product was purified using column chromatography to give compound 23-d.
Synthesis of Compound 23-e
Compound 23-d (800mg, 2.24mmol) was dissolved in MeOH (10mL) before addition of Pd/C (80mg, 10% purity) in H2Atmosphere (35 psi). Replacing gas with mixed solution for three times by using H2. Adding the mixed solution in H2(15psi) the atmosphere was stirred at 50 ℃ for 20 hours. The mixture was filtered and the resulting solution was concentrated to give compound 23-e.
Synthesis of Compound 23-f
Compound 23-e (803mg, 2.23mmol) was dissolved in MeOH (10mL) and water (5mL), after which NaOH (268.09mg, 6.70mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred at 70 ℃ for 12 hours. The solution was adjusted to pH 8 using 3M HCl, at which time a solid precipitated, filtered and the filter cake was washed with water (10mL) and dried in vacuo to give crude 23-f.
Synthesis of Compound 23
After compound 23-f (100mg, 301.76. mu. mol) was dissolved in DMF (2mL), DIEA (117.00mg, 905.29. mu. mol, 157.68uL) and HATU (172.11mg, 452.65. mu. mol) were added under a nitrogen atmosphere. The resulting mixture was stirred at 25 ℃ for 30 min. Then 1-n (46.20mg, 362.12. mu. mol) was added. The mixture was stirred at 25 ℃ for 11.5 hours. The reaction was diluted with water (30mL) and extracted with EA (50mL × 2). The combined organic phases were washed with saturated brine (30mL 4) and Na2SO4Drying, filtering and concentrating to obtain a crude product. The crude product was purified by preparative chromatography to afford compound 23.
1H NMR(400MHz，DMSO-d6)δ＝9.66(s，1H)，7.79(d，J＝8.8Hz，2H)，7.65-7.53(m，2H)，7.38(d，J＝8.8Hz，2H)，7.09(dt，J＝2.4，9.2Hz，1H)，4.09(s，3H)，2.99(br d，J＝11.2Hz，2H)，2.67(s，1H)，2.37-2.22(m，6H)，2.19-2.04(m，2H)，1.92-1.83(m，2H)，1.79-1.69(m，2H).
Example 24
Figure GPA0000292424410000371
Synthesis of Compound 24
Compound 14-a (23.32mg) was dissolved in THF (3mL) and NaHMDS (1M, 158.54. mu.L) was added dropwise to the solution at-78 deg.C, the resulting mixture was stirred at-78 deg.C for 30 minutes, then 24-a (50mg, 132.12. mu. mol) dissolved in THF (3mL) was added dropwise to the reaction at that temperature, and the resulting mixture was stirred at 25 deg.C for 12 hours. The reaction was quenched by addition of water (10mL) and extracted with ethyl acetate (20mL x 3). the combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by preparative chromatography to give compound 24.
1H NMR(400MHz，DMSO-d6)δppm 1.67-1.97(m，6H)2.24-2.37(m，5H)2.42(br t，J＝10.45Hz，2H)2.97(br d，J＝11.37Hz，2H)7.49(d，J＝4.52Hz，1H)7.67(td，J＝8.71，2.63Hz，1H)7.78(dd，J＝10.58，6.54Hz，2H)7.98-8.14(m，2H)8.84(d，J＝4.52Hz，1H)9.80(s，1H).
Example 25
Figure GPA0000292424410000381
Synthesis of Compound 25
Compound 25-a (22.38mg) was dissolved in THF (3mL) and NaHMDS (1M, 158.54 μ L) was added dropwise to the solution at-78 deg.C, the resulting mixture was stirred at-78 deg.C for 30 minutes, then 14-a (50mg) dissolved in THF (3mL) was added dropwise to the reaction at that temperature, the resulting mixture was stirred at 20 deg.C for 12 hours, water (10mL) was added to the reaction and the reaction was quenched and extracted with ethyl acetate (20mL x 3), the combined organic phases were Na2SO4Drying, filtering and concentrating under reduced pressure to obtain crude product, and purifying the phase product by preparative chromatography to obtain the compound 25.
1H NMR(400MHz，DMSO-d6)δppm 1.74-2.03(m，6H)2.21(br t，J＝8.86Hz，2H)2.31-2.36(m，1H)2.34(br s，1H)2.33-2.46(m，1H)2.38-2.46(m，1H)2.38-2.44(m，1H)2.93(br d，J＝11.00Hz，2H)3.92(s，3H)6.78(td，J＝8.74，2.69Hz，1H)7.01(dd，J＝10.76，2.69Hz，1H)7.50(d，J＝4.52Hz，1H)7.63-7.74(m，1H)8.00-8.22(m，3H)8.88(d，J＝4.52Hz，1H)9.71(s，1H)。
Example 26
Figure GPA0000292424410000382
Synthesis of Compound 26-a
To an ethanol solution (30mL) of compound 1-e (2g) was added sodium borohydride (503.80mg), and after 12 hours at 25 ℃, 100mL of ethyl acetate was added for dilution, the solution was washed three times with 100mL of saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 26-a.
Synthesis of Compound 26-b
To a solution of compound 26-a (50mg) and 4-chloro-6-fluoroquinoline (39.95mg) in DMF (5mL) was added potassium tert-butoxide (74.05mg), reacted at 90 ℃ for 12 hours, diluted with 30mL of ethyl acetate, the solution washed 3 times with 30mL of saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 26-b (300mg) as a yellow gum which was used directly in the next reaction.
Synthesis of Compound 26-c
To a solution of compound 26-b (300mg) in methanol (5mL) and water (5mL) was added sodium hydroxide (161.09mg), and after 12 hours at 65 ℃, the pH was adjusted to 6-7 with hydrochloric acid (1M), and the mixture was concentrated under reduced pressure to give a crude product, which was purified by a reverse phase flash column system to give compound 26-c.
Synthesis of Compound 26
To a solution of compound 26-c (40mg) and 1-N (16.30mg) in DMF (5mL) was added N, N-diisopropylethylamine ((75.06mg) and HATU (66.25mg), and after 12 hours of reaction under nitrogen at 25 ℃, 30mL of ethyl acetate was added for dilution, the solution was washed 3 times with saturated sodium chloride solution, 30mL each, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was purified by preparative chromatography (formic acid system) to give 26.
1H NMR(400MHz，DMSO-d6)δ＝9.56(s，1H)，8.67(d，J＝5.1Hz，1H)，8.00(dd，J＝5.4，9.2Hz，1H)，7.77-7.60(m，4H)，7.36(d，J＝8.9Hz，2H)，7.14(d，J＝5.1Hz，1H)，4.81(br s，1H)，2.80-2.70(m，2H)，2.50-2.40(m，2H)，2.32-2.17(m，4H)，2.15-2.05(m，2H)，1.95-1.80(m，2H)，1.80-1.57(m，2H).
Example 27
Figure GPA0000292424410000391
Synthesis of Compound 27-b
Compound 26-a (50mg), 27-a (39.93mg) was dissolved in DMF (5mL), followed by addition of t-BuOK (74.05mg) and nitrogen substitution three times, and the resulting mixture was stirred at 90 ℃ for 12 hours under nitrogen. The reaction was extracted with EtOAc (15 mL. about.3.) the combined organic phases were washed with saturated brineWash (15mL x 3), Na2SO4Drying, filtering and concentrating to obtain 27-b.
Synthesis of Compound 27-c
Compound 27-b (460mg) was dissolved in MeOH (5mL) and water (5mL), NaOH (148.22mg, 3.71mmol) was added, the resulting mixture was stirred at 60 deg.C under nitrogen for 12 h, after the methanol was pulled dry, the pH was adjusted to 7 with 1M HCl at 0 deg.C, and the aqueous phase was spun dry directly. The crude product was purified by preparative chromatography to give compound 27-c.
Synthesis of Compound 27
Compound 27-c (50mg) was dissolved in DMF (5mL), DIEA (93.84mg, 726.05. mu. mol, 126.47uL), HATU (82.82mg), p-chloroaniline (20.38mg) was added three times, nitrogen was substituted, the resulting mixture was stirred at 25 ℃ for 12 hours, the reaction was extracted with EtOAc (10 mL. about.3), the combined organic phases were washed with saturated brine (10 mL. about.3), Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by preparative chromatography to obtain the compound 27.
1H NMR(400MHz，DMSO-d6)δ＝9.55(s，1H)，8.53(d，J＝5.6Hz，1H)，7.75(d，J＝8.0Hz，2H)，7.44-7.34(m，1H)，7.31-7.25(m，2H)，7.29(dd，J＝2.4，5.7Hz，1H)，4.72(td，J＝4.4，8.3Hz，1H)，3.43(br s，2H)，2.81-2.71(m，4H)，2.44-2.17(m，2H)，2.12-1.94(m，2H)，1.78-1.63(m，4H)。
Example 28
Figure GPA0000292424410000401
Synthesis of Compound 28-b
Compound 28-a (1g, 6.04mmol, HCl) was dissolved in dioxane (8mL) and water (2mL) before DIEA (1.56g) was added. Then 1-b (2.31g, 9.06mmol) was added to the mixture at 90 ℃. The resulting mixture was stirred at 90 ℃ for 12 hours. The mixture was extracted with EtOAc (10mL × 3), the combined organic phases were washed with saturated brine (10mL × 3), dried and Na was used2SO4Filtering, filtering and concentrating to obtain 28-b.
Synthesis of Compound 28-c
Compound 28-b (670mg, 3.17mmol) was dissolved in THF (10mL), followed by addition of N, N-bis (trifluoromethanesulfonyl) aniline (1.25g, 3.49 mmol). The mixture was replaced with nitrogen three times. NaHMDS (1M, 4.12mL) was then added dropwise to the mixture at-78 ℃. The resulting mixture was stirred at-78 ℃ for 1 hour. The mixture was then stirred at 25 ℃ for 11 hours. The mixture was quenched by addition of 0.2M HCl (10mL), followed by extraction with MTBE (10mL _ 3), the combined organic phases were washed with 0.2M HCl (10mL _ 3), 0.5% NaOH (10mL _ 3) and saturated brine (10mL _ 3), dried over Na2SO4, filtered, and concentrated to give compound 28-c.
Synthesis of Compound 28-d
Compound 28-c (200mg, 582.55. mu. mol), bis-pinacolato borate (192.31mg, 757.31. mu. mol), KOAc (171.51mg, 1.75mmol), NaBr (23.98mg, 233.02. mu. mol, 7.49. mu.L) were dissolved in dioxane (2mL), after which Pd (dppf) Cl was added under a nitrogen atmosphere2(21.31mg, 29.13. mu. mol). The mixture was replaced with nitrogen three times. The mixture was stirred at 100 ℃ for 12 hours. The reaction was filtered and washed with EA (80mL), after which water (40mL) was added. The organic phase obtained was washed with saturated brine (30mL _ 2). 1M HCl was used to adjust the pH of the solution to 3. The resulting aqueous phase was washed with EA (30mL × 2). The pH of the aqueous phase was adjusted to pH 10 using saturated sodium carbonate solution and extracted with EA (40mL × 2). The obtained organic phase was washed with saturated brine (20mL × 2), dried and used Na2SO4Filtered and concentrated to give crude 28-d.
Synthesis of Compound 28-e
Compound 28-d (210mg, 653.76. mu. mol) and 1-i (98.93mg, 544.80. mu. mol) were dissolved in dioxane (4mL) and water (1mL), followed by addition of Et3N (165.39mg, 1.63mmol, 227.49. mu.L) and Pd (dppf) Cl2(19.93mg, 27.24. mu. mol) under nitrogen. The mixture was replaced with nitrogen three times. The mixture was stirred at 110 ℃ for 8 hours. The reaction mixture was filtered using EA (40mL), followed by washing with water (20 mL). The organic phase was washed with saturated brine (15mL × 2). 1M HCl was used to adjust the pH of the solution to 3. After that cleaningEA (15mL × 2) was used for the aqueous phase. Saturated sodium carbonate solution was used to adjust the pH of the solution to pH 10 and EA (20mL × 2) was used for extraction. The obtained organic phase was washed with saturated brine (20mL × 2), dried and used Na2SO4Filtered and concentrated to 28-e.
Synthesis of Compound 28-f
Compound 28-e (156mg, 458.30. mu. mol) and pyridine (54.38mg, 687.44. mu. mol, 55.49uL) were dissolved in IPA (2mL), after which Pd/C (32mg, 10% purity) in H was added2(15psi) atmosphere. The mixture was replaced three times with hydrogen. Adding the mixed solution in H2(15psi) the atmosphere was stirred at 50 ℃ for 8 hours. The mixture was filtered and the filtrate was concentrated to give compound 28-f.
Synthesis of Compound 28-g
Compound 28-f (152mg, 443.92. mu. mol) was dissolved in MeOH (2mL) and water (1mL), after which NaOH (71.03mg, 1.78mmol) was added under a nitrogen atmosphere. The mixture was stirred at 70 ℃ for 12 hours. Concentrating the mixture to obtain crude product, and purifying by preparative chromatography to obtain 28-g.
Synthesis of Compound 28
Compound 28-g (26mg, 82.71. mu. mol) was dissolved in DMF (1mL) before HATU (47.17mg, 124.06. mu. mol) and DIEA (32.07mg, 248.13. mu. mol, 43.22. mu.L) were added under nitrogen. The mixture was stirred at 25 ℃ for 30 min. Then 1-n (12.66mg, 99.25. mu. mol) was added. The mixture was stirred at 25 ℃ for 11.5 hours. The mixture was diluted with water (30mL) and extracted with EA (50mL × 2). The combined organic phases were washed with saturated brine (30mL 4) and Na was used2SO4 was dried, filtered and concentrated in vacuo to give the crude product. The crude product was purified by preparative chromatography to afford compound 28.
1H NMR(400MHz，DMSO-d6)δ＝10.11(s，1H)，8.86(d，J＝4.4Hz，1H)，8.18-8.05(m，2H)，7.98(dd，J＝2.8，10.8Hz，1H)，7.77(d，J＝8.8Hz，2H)，7.68(dt，J＝2.8，8.8Hz，1H)，7.58(d，J＝4.4Hz，1H)，7.39(d，J＝8.8Hz，2H)，3.29-3.25(m，1H)，2.88(br d，J＝11.1Hz，2H)，2.54(br s，2H)，2.09-2.01(m，2H)，1.86(br d，J＝12.0Hz，2H)，1.15(br d，J＝15.6Hz，4H).
Example 29
Figure GPA0000292424410000411
Synthesis of Compound 29
To DMF (5mL) was added successively reactant 1-l (50mg), reactant 29-a (34.72mg), HATU (86.84mg), diisopropylethylamine (59.04mg), and the reaction mixture was stirred at room temperature for 12 hours, ethyl acetate (30mL) was added to the reaction system, followed by washing three times with saturated ammonium chloride solution (30mL 3), washing three times with saturated brine (30mL 3), drying with anhydrous sodium sulfate, filtration, concentration of the filtrate to give a crude product, and purification of the crude product with a conventional reverse phase chromatography column to give compound 29.
1H NMR(400MHz，MeOD-d4)δppm 1.83-1.93(m，2H)1.94-2.01(m，2H)2.04(br s，2H)2.36-2.44(m，2H)2.45-2.52(m，2H)2.54-2.61(m，2H)3.10-3.15(m，2H)3.36-3.39(m，1H)7.21(t，J＝8.68Hz，1H)7.58(d，J＝4.65Hz，1H)7.61(d，J＝2.69Hz，1H)7.63(d，J＝2.81Hz，1H)7.94(dd，J＝10.70，2.63Hz，1H)8.07-8.08(m，1H)8.08-8.12(m，1H)8.79(d，J＝4.65Hz，1H)。
Example 30
Figure GPA0000292424410000421
Synthesis of Compound 30
To DMF (5mL) was added successively reactant 1-l (50mg), reactant 30-a (28.80mg), HATU (86.84mg), diisopropylethylamine (59.04mg), and the reaction mixture was stirred at room temperature for 12 hours, ethyl acetate (30mL) was added to the reaction system, followed by washing three times with saturated ammonium chloride solution (30mL × 3), washing three times with saturated brine (30mL × 3), drying with anhydrous sodium sulfate, filtration, concentration of the filtrate to give a crude product, and purification of the crude product with a conventional reverse phase chromatography column to give compound 30.
1H NMR(400MHz，METHANOL-d4)δppm 1.92-2.00(m，2H)2.01-2.09(m，2H)2.09-2.16(m，2H)2.48-2.63(m，4H)2.71-2.83(m，2H)3.23-3.29(m，2H)3.48-3.53(m，1H)3.93(s，3H)7.21(dd，J＝8.56，2.20Hz，1H)7.33(d，J＝8.56Hz，1H)7.57(d，J＝4.65Hz，1H)7.61(d，J＝2.08Hz，1H)7.64(dd，J＝8.74，2.14Hz，1H)7.96(dd，J＝10.51，2.69Hz，1H)8.12(d，J＝3.55Hz，1H)8.81(d，J＝4.65Hz，1H)。
Example 31
Figure GPA0000292424410000422
Synthesis of Compound 31
The reaction product 14-a (23.08mg) was added to tetrahydrofuran (5mL), sodium hexamethyldisilazide (1M, 264.24uL) was slowly added dropwise at-78 ℃, the reaction solution was stirred at that temperature for half an hour, then the reaction product 31-a (50mg) was added, the reaction solution was stirred at room temperature for 1 hour, ethyl acetate (30mL) was added to the reaction system, followed by washing three times with saturated ammonium chloride solution (30mL 3), then three times with saturated saline solution (30mL 3), drying with anhydrous sodium sulfate, filtration, concentration of the filtrate to give a crude product, and the crude product was purified by a conventional reverse phase chromatography column to give compound 31.
1H NMR(400MHz，MeOD-d4)δppm 1.84-1.95(m，2H)1.98(br d，J＝12.72Hz，2H)2.04(br d，J＝5.50Hz，2H)2.35-2.43(m，2H)2.46-2.60(m，4H)3.11(br d，J＝10.88Hz，2H)3.37-3.47(m，1H)7.43(br s，2H)7.56-7.65(m，2H)7.81(br d，J＝11.86Hz，1H)7.93(br d，J＝10.76Hz，1H)8.08-8.13(m，1H)8.77-8.81(m，1H)。
Example 32
Figure GPA0000292424410000431
Synthesis of Compound 32
To DMF (5mL) was added successively reactant 1-l (50mg), reactant 32-a (25.87mg), HATU (86.84mg), diisopropylethylamine (59.04mg), and the reaction mixture was stirred at room temperature for 12 hours, ethyl acetate (30mL) was added to the reaction system, followed by washing three times with saturated ammonium chloride solution (30mL × 3), washing three times with saturated brine (30mL × 3), drying with anhydrous sodium sulfate, filtration, concentration of the filtrate to give a crude product, and purification of the crude product with a conventional reverse phase chromatography column to give compound 32.
1H NMR(400MHz，DMSO-d6)δppm 1.81-1.99(m，2H)2.06-2.14(m，3H)2.28-2.42(m，5H)2.57-2.84(m，5H)2.86-2.93(m，2H)3.19-3.41(m，1H)7.42-7.50(m，2H)7.63(dd，J＝8.50，2.26Hz，1H)7.69-7.77(m，2H)8.11-8.20(m，2H)8.91(d，J＝4.52Hz，1H)10.15-10.28(m，1H)。
Example 33
Figure GPA0000292424410000432
Synthesis of Compound 33-b
After compound 33-a (2g, 27.75mmol) was dissolved in MTBE (30mL), zinc iodide (88.59mg, 277.54. mu. mol) and TMSCN (2.75g, 27.75mmol, 3.47mL) were added and the resulting mixture was stirred at 25 ℃ for 12 hours and the reaction was concentrated to give crude compound 33-b.
Synthesis of Compound 33-c
After dissolving compound 33-b (3g, 17.52mmol, 1eq) and compound 33-h (3.26g, 17.52mmol, 1eq) in MTBE (50mL), the mixture was stirred at 25 ℃ for 12 hours and the reaction mixture was concentrated to give crude compound 33-c.
Synthesis of Compound 33-d
33-c (2g, 7.48mmol) was dissolved in MeOH (20mL) and water (4mL) and NaOH (897.72mg, 22.44mmol) was added, the resulting mixture was stirred at 60 ℃ for 4h, the reaction was concentrated and extracted with diluted EA (60 mL. times.2) with water (50mL), the aqueous phase was adjusted to pH 5 with HCl (1M, 20mL), EA (100 mL. times.2) was extracted, the resulting organic phase was washed with saturated brine (100 mL. times.2), Na2SO4Drying, filtering and concentrating to obtain the compound 33-d.
Synthesis of Compound 33-f
Coupling 33-d (780mg, 2.73mmol), 33-e (782.20mg, 3.28mmol), Pd2(dba)3(250.32mg, 273.36. mu. mol), Xantphos (316.34mg, 546.72. mu. mol) and cesium carbonate (1.78g, 5.47mmol) were dissolved in 1, 4 dioxane (20 mL). N for the resulting mixture2After three times of substitution, the reaction mixture was stirred at 80 ℃ for 12 hours, the reaction mixture was filtered, the filtrate was diluted with water (50mL), EA (80 mL. times.3) was extracted, the resulting mixed organic phase was washed with saturated brine (80 mL. times.2), and Na2SO4Drying, filtering and concentrating to obtain a crude product, and purifying the crude product by a silica gel plate to obtain the compound 33-f.
Synthesis of Compound 33-g
Compound 33-f (640mg, 1.62mmol) was dissolved in MeOH (10mL) and HCl dioxane solution (4M, 4.04mL) was added and the resulting mixture was stirred at 25 deg.C for 2h and the reaction was concentrated to give compound 33-g.
Synthesis of Compound 33
Compounds 33-g (200mg, 676.22. mu. mol), 1-i (61.40mg, 338.11. mu. mol), Pd2(dba)3(61.92mg, 67.62. mu. mol), Xantphos (78.25mg, 135.24. mu. mol) and cesium carbonate (440.65mg, 1.35mmol) were dissolved in 1, 4 dioxane (10mL) and N was added2The substitution was carried out three times. The resulting mixture was stirred at 80 ℃ for 12 hours, the reaction was filtered, diluted with water (20mL), extracted with ethyl acetate (30 mL. times.3), and the resulting organic phase was washed with saturated brine (30 mL. times.2), washed with Na2SO4Drying, filtration and concentration followed by purification by preparative chromatography gave compound 33.
1H NMR(400MHz，MeOD-d4)δppm 2.95-3.04(m，4H)3.88-4.08(m，4H)4.86(br s，4H)7.29(d，J＝6.85Hz，1H)7.34-7.38(m，2H)7.64-7.70(m，2H)7.79-7.97(m，2H)8.05(dd，J＝9.29，4.89Hz，1H)8.58(d，J＝6.85Hz，1H).
Example 34
Figure GPA0000292424410000451
Synthesis of Compound 34-a
Compound 23-f (100mg, 301.76umol) was dissolved in DCM (5mL), CDI (73.40mg, 452.65umol) was added to the solution, and the resulting mixture was stirred at 25 deg.CReaction for 12 hours, quench the reaction by adding water (20mL) to the reaction and extract with ethyl acetate (20 mL. times.3), combine the organic phases, wash with saturated sodium chloride solution (20 mL. times.3), Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 34-a.
Synthesis of Compound 34
Compound 20-a (29.73mg, 251.67umol) was dissolved in THF (5mL) and NaHMDS (1M, 251.67uL) was added dropwise to the solution at-78 deg.C, the resulting mixture was stirred at-78 deg.C for 30 minutes, then 34-a (80mg, 209.73umol) dissolved in THF (2mL) was added dropwise to the reaction solution at that temperature, the resulting mixture was stirred at 20 deg.C for 12 hours, water (10mL) was added to the reaction solution to quench the reaction and extract with ethyl acetate (20mL x 3), the combined organic phases were Na2SO4Drying, filtering and concentrating under reduced pressure to obtain crude product, and purifying the crude product by preparative chromatography to obtain the compound 34.
1H NMR(400MHz，DMSO-d6)δppm 1.70-1.94(m，4H)2.03-2.21(m，2H)2.22-2.39(m，6H)2.99(brd，J＝11.13Hz，2H)3.14(ddd，J＝12.10，8.68，3.67Hz，1H)4.09(s，3H)7.09(td，J＝9.26，2.38Hz，1H)7.52-7.65(m，2H)7.79(d，J＝8.68Hz，2H)8.00(d，J＝8.68Hz，2H)9.94(s，1H).
Experimental example 1: evaluation of Compounds on inhibition of the kynurenine pathway Activity of Hela cells
Purpose of the experiment:
the inhibitory effect of the compounds of the present invention on the kynurenine pathway activity of Hela cells was examined.
The experimental method comprises the following steps:
the compound was dissolved in dimethyl sulfoxide to 3mM, and 15. mu.l of the compound was added to a 96-well plate. Compounds (10. mu.l + 20. mu.l) were diluted 3-fold serially. 192. mu.l of detection medium was added to one 96-well plate, 78. mu.l of DMEM medium (Dulbecco's modified Eagle's medium) was added to the compound plate and mixed well, and 8. mu.l of the compound diluted with DMEM medium was transferred to the 96-well plate to which the detection medium had been added. The cell culture plate was removed and the medium was discarded, 100. mu.l of the compound was transferred to the cell culture plate, and the cell culture plate was transferred to an incubator for another 48 hours.
The cell culture plate was removed and 50. mu.l of the supernatant was transferred to a new 96-well plate, 200. mu.l of acetonitrile was added to the plate and mixed well, and 40. mu.l of the supernatant was transferred to another 96-well plate by 4-degree centrifugation. Add 360 u l containing 2u g/ml internal reference deionized water, fully mixing to detect the sample.
The experimental results are as follows: see table 1.
TABLE 1 in vitro screening test results
Test compounds EC50(nM)
1 11
5 82
7 17
8 36
13 65
20 16
21 11
22 14
23 3
26 22
27 24
30 30
31 26
And (4) conclusion: the compound of the invention has obvious inhibition effect on the production of kynurenine in Hela cells.
Experimental example 2: evaluation of Compound pharmacokinetics
Test animal
Healthy adult female Balb/c mice used in this study were purchased from Shanghai Ling Biotech, Inc.
Preparation of drugs
Preparation of intravenous injection group administration solution
Accurately weighing a proper amount of compound, adding a certain amount of PEG400, performing ultrasonic treatment for 2 minutes to obtain a clear solution, and then adding a proper amount of pure water. A clear solution was obtained at a final concentration of 1mg/mL, with the dosing vehicle being 60% PEG400+ 40% pure water. The intravenous solution was filtered through a 2um filter before administration.
Preparation of oral administration solution
Accurately weighing a proper amount of compound, adding a certain amount of PEG400, performing ultrasonic treatment for 2 minutes to obtain a clear solution, and then adding a proper amount of pure water. A suspension solution with a final concentration of 10mg/mL was obtained, and the administration vehicle was 60% PEG400+ 40% pure water.
Administration of drugs
24 female Balb/c mice were divided into 4 groups of 6 mice each. Group one, 2mg/kg of BMS-986205 administered intravenously; second group, intragastric administration of 50mg/kg BMS-986205; third, compound 1 was administered at 2mg/kg intravenously; in the fourth group, 50mg/kg of Compound 1 was gavaged.
Sample collection
Blood was collected from three animals at each time point by a cross-bleed method. 40uL of whole blood was collected before and 0.0833 (intravenous group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, respectively. Whole blood was placed in an anticoagulation tube, centrifuged at 3000g for 15 minutes at 4 ℃ to prepare plasma and stored at-80 ℃. Drug concentrations in plasma were determined using LC/MS-MS.
TABLE 2 pharmacokinetic parameters
Figure GPA0000292424410000471
"-" indicates that no data has been obtained yet
And (4) conclusion: compared with the clinical molecule BMS-986205, the invention in example 1 has better tissue distribution, higher AUC under the same dosage, longer half-life, higher oral bioavailability and better comprehensive pharmacokinetic property.
Experimental example 3: evaluation of drug efficacy of compound and drug combination with PD-1 monoclonal antibody in CT26 mouse syngeneic transplantation tumor model
Test animals:
BALB/c mice, female, 18-22 g, Shanghai Slek.
The test drugs are:
example 1 and the control compound BMS-986205, PD-1 mab.
Cell and inoculation:
1. cell line: CT26 cell (mouse colon cancer cell)
2. Inoculation amount: 3X 105/0.1mL
3. The inoculation route is as follows: subcutaneous injection
Grouping and dosing regimens:
Figure GPA0000292424410000472
Figure GPA0000292424410000481
the experimental results are as follows: see fig. 1, fig. 2, and table 3.
TABLE 3 mouse tumor volume data in CT26 mouse syngeneic transplantation tumor model
Figure GPA0000292424410000482
a. The relative tumor proliferation rate T/C (%) ═ TRTV/CRTV × 100% (TRTV: mean RTV in the treatment group; CRTV: mean RTV in the negative control group).
b. Tumor growth inhibition rate TGI (%) -1- (average tumor volume on day of treatment group measurement-average tumor volume on day of treatment group measurement)/(average tumor volume on day of vehicle group measurement-average tumor volume on day of vehicle group measurement) × 100%
c.P value: day 18 tumor volume refers to comparison to vehicle control
And (4) conclusion: the compound shows excellent in-vivo anti-tumor activity and can play a synergistic role in PD-1 monoclonal antibody. Compared with the clinical molecule BMS-986205, the single drug and the combined drug effect are better under the same dosage.

Claims (12)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure FDA0003163265340000011
wherein the content of the first and second substances,
ring A is selected from phenyl;
ring B is selected from phenyl, pyridyl, quinolinyl, and 2H-indazolyl;
l is selected from-CH2-；
X is selected from CH;
l' is selected from a single bond and-O-;
R1each independently selected from halogen, CN, C1-3A heteroalkyl group;
R2each independently selected from halogen, C1-3Alkyl, CF3、C1-3A heteroalkyl group;
m and n are each independently selected from 0, 1, 2 and 3;
"hetero" means a heteroatom or a heteroatom group, said C1-3The "hetero" of heteroalkyl is selected from the group consisting of-O-and-S (═ O)2The heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including the position of attachment of the alkyl group to the rest of the molecule;
in any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1, 2 and 3, respectively.
2. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1Each independently selected from F, Cl, Br, I, CN, CH3O and CH3CH2O。
3. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R2Each independently selected from F, Cl, Br, I, CH3、CF3、CH3CH2、CH3O-、CH3CH2O-、
Figure FDA0003163265340000021
Figure FDA0003163265340000022
4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the building block
Figure FDA0003163265340000023
Is selected from
Figure FDA0003163265340000024
5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the building block
Figure FDA0003163265340000025
Is selected from
Figure FDA0003163265340000026
Figure FDA0003163265340000027
6. A compound according to claim 2 or 5, or a pharmaceutically acceptable salt thereof, wherein the building block
Figure FDA0003163265340000028
Is selected from
Figure FDA0003163265340000029
7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the building block
Figure FDA0003163265340000031
Is selected from
Figure FDA0003163265340000032
Figure FDA0003163265340000033
8. According to claim 3 or7 or a pharmaceutically acceptable salt thereof, wherein the structural unit
Figure FDA0003163265340000034
Is selected from
Figure FDA0003163265340000035
Figure FDA0003163265340000036
9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from
Figure FDA0003163265340000041
Wherein, ring A, m, n, X, L', R1And R2As defined in claim 1.
10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from
Figure FDA0003163265340000042
Wherein, L, R1And R2As defined in claim 1.
11. A compound or a pharmaceutically acceptable salt thereof selected from
Figure FDA0003163265340000051
Figure FDA0003163265340000061
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106999450A (en) * 2014-11-05 2017-08-01 弗莱塞斯生物科学公司 immunomodulator
CN107205970A (en) * 2014-11-05 2017-09-26 弗莱塞斯生物科学公司 Immunomodulator
WO2017192813A1 (en) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN107427499A (en) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 Immunomodulator

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106999450A (en) * 2014-11-05 2017-08-01 弗莱塞斯生物科学公司 immunomodulator
CN107205970A (en) * 2014-11-05 2017-09-26 弗莱塞斯生物科学公司 Immunomodulator
CN107427499A (en) * 2014-11-05 2017-12-01 弗莱塞斯生物科学公司 Immunomodulator
WO2017192813A1 (en) * 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
442896-85-7;Registry;《Registry》;20020807;442896-85-7 *

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