Tyrosine kinase inhibitor and pharmaceutical composition containing the same

Abstract

The present invention relates to a tyrosine kinase inhibitor and a pharmaceutical composition comprising the tyrosine kinase inhibitor. The tyrosine kinase inhibitor of the present invention has a structure represented by the following formula (II): The above-mentioned compound of the present invention has excellent inhibitory activity against VEGFR2, FGFR1 and PDGFRB.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Chinese Patent Application No. 201510161674.4, filed on April 7, 2015, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] The present invention belongs to the field of medical technology, and specifically relates to a class of tyrosine kinase inhibitors or pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the tyrosine kinase inhibitor. Background Art

[0004] Protein tyrosine kinases are a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues located on protein substrates, which play a role in normal cell growth. Many growth factor receptor proteins act through tyrosine kinases and affect signals through this process, thereby regulating cell growth. For example, FGFR (Fibroblast growth factor receptor), VEGFR (Vascular endothelial growth factor receptor) and PDGFR (Platelet-derived growth factor receptor). However, under certain conditions, these receptors either mutate or are overexpressed, become abnormal, cause uncontrolled cell proliferation, lead to tumor growth, and ultimately cause the well-known disease - cancer. Growth factor receptor protein tyrosine kinase inhibitors play a role in treating cancer and other diseases characterized by uncontrolled or abnormal cell growth by inhibiting the above-mentioned phosphorylation process.

[0005] Uncontrolled angiogenesis is a hallmark of cancer. In 1971, Dr. Judah Folkman proposed that tumor growth depends on angiogenesis, (see Folkman, New England Journal of Medicine, 285: 1182-86 (1971). According to Dr. Judah Folkman, tumors can only grow to a certain size without growing additional blood vessels to nourish the tumor. In its simplest form, it is pointed out that once tumor "survival" has occurred, each increase in the tumor cell population must be accompanied by the increase of new capillaries converging on the tumor. The "survival" of a tumor as currently understood refers to the prevascular phase of tumor growth, in which a tumor cell population occupying a volume of several cubic millimeters and not exceeding a few million cells can survive on the existing host microvasculature.

[0006] It has been shown that tumors can be treated by inhibiting angiogenesis rather than inhibiting the proliferation of tumor cells themselves. Angiogenesis has been associated with a large number of different types of cancer, including solid tumors and blood-borne tumors. Solid tumors associated with angiogenesis include, but are not limited to, rhabdomyosarcoma, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma. Angiogenesis is associated with breast cancer, prostate cancer, lung cancer, and colon cancer. Angiogenesis is also associated with blood-borne tumors, such as leukemia, lymphoma, multiple myeloma, and any of a variety of acute or chronic myeloid neoplastic diseases, in which unrestricted proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood coagulation, and enlargement of lymph nodes, liver, and spleen. It is also believed that angiogenesis plays a role in bone marrow abnormalities that cause leukemia, lymphoma, and multiple myeloma.

[0007] Angiogenesis plays a major role in the metastasis of cancer, and if angiogenic activity can be inhibited or eliminated, then tumors will not grow despite their presence. In disease states, preventing angiogenesis can reduce the damage caused by the invasion of new microvasculature. Therapies directed at the control of angiogenic processes may lead to the elimination or alleviation of these diseases.

[0008] Among them, the research on inhibiting angiogenesis by FGFR (Fibroblast growth factor receptor), VEGFR (Vascular endothelial growth factor receptor) and PDGFR (Platelet-derived growth factor receptor) inhibitors is becoming more and more mature. Summary of the invention

[0009] The present invention provides a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the tyrosine kinase inhibitor.

[0010] The technical solution of the present invention is as follows:

[0011] The present invention provides a compound represented by the following formula (II) or a pharmaceutically acceptable salt thereof.

[0012]

[0013] R1 is selected from optionally substituted C 1-6 Alkoxy, C 1-6 heteroalkyl-O- or imidazolyl;

[0014] More preferably, R1 is selected from C 1-6Alkoxy, O(CH2) n R 1d1 or Where n is an integer from 1 to 6, R 1d1 C 1-6 Alkoxy or NR 1d5 R 1d6 , where R 1d5 and R 1d6 Each independently is H or C 1-6 Alkyl (including chain alkyl and cycloalkyl), R 1d2 , R 1d3 and R 1d4 Each independently is H, C 1-6 An alkyl group (including a chain alkyl group and a cycloalkyl group) or an aryl group (such as a phenyl group);

[0015] Most preferably, R1 is

[0016] R2 is selected from H, OH, NH2, halogen, CN, -C(=O)N(R 2d1 )(R 2d2 )、-N(R 2d1 )C(=O)R 2d2 、-C(=O)OR 2d3 , optionally substituted C 1-7 Alkyl (including chain alkyl and cycloalkyl);

[0017] R2 is selected from H, CN, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, -C(=O)N(R 2d1 )(R 2d2 ), -N(R 2d1 )C(=O)R 2d2 , -C(=O)OR 2d3 ;

[0018] More preferably, R2 is selected from H, CN, CF3,

[0019] Among them, R 2d1 , R 2d2 , R 2d3 are each independently selected from H, OH, NH2, CN or an optionally substituted C 1-7 Alkyl, C 1-7 heteroalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, or, R 2d1 and R 2d2 Together they form a 4- to 7-membered ring;

[0020] More preferably, R2d1 , R 2d2 , R 2d3 Each independently selected from H, OH, methyl,

[0021] In some embodiments of the present invention, the structural unit -N(R 2d1 R 2d2 ) is selected from optionally substituted More specifically, the structural unit -N(R 2d1 R 2d2 )

[0022] Alternatively, in the above formula (II), R1 and R2 together with the two carbon atoms on the benzene ring form a 4-7 membered ring; preferably, R1, R2 together with the two carbon atoms on the benzene ring form an optionally substituted 5-6 membered ring.

[0023] R 10 Selected from H, OH, NH2, CN or halogen.

[0024] A is selected from optionally substituted phenyl; preferably, A is selected from optionally substituted More preferably, A is selected from

[0025] R 11 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl, 5-6 membered heteroaryl,

[0026] (wherein, Y is S, and the above R7, R8, and R9 are each independently selected from H or optionally substituted: C 1-4 Alkyl, C 1-2 Alkyl-SC 1-3 Alkyl-, C 1-2 Alkyl-NC 1-3 Alkyl-, C 1-2 Alkyl-OC 1-3 Alkyl-, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C 1-2 Alkyl, pyrrolidinone, 5-6-membered ring lactone, pyrrolidinyl, piperidinyl, tetrahydropyranyl, morpholinyl, thiazolyl, pyrazolyl, phenyl, pyridinyl, morpholinyl-C 1-2 Alkyl-, phenyl-C 1-2 Alkyl-, pyridyl-C 1-2 Alkyl-, C 0-2 Alkyl-alkynyl-C 1-2 alkyl-,

[0027] Further preferably, the above R7, R8, and R9 are each independently selected from H or optionally substituted: Me,

[0028] The above R8 and R9 together form an optionally substituted 4- to 6-membered ring.

[0029] The above R7 and R8 together form an optionally substituted 4- to 6-membered ring.

[0030] Preferably, formula (II) has the general structure of the following formula (III):

[0031]

[0032] The above formula (II) can be a compound of the following general structure:

[0033]

[0034] Wherein, in the above formula (V), Y is S;

[0035] T is selected from N;

[0036] Preferably, the above R3, R4, and R5 are each independently selected from H, F, Cl, Br, I, OH, CN, NH2,

[0037] The above formula (II) can be a compound of the following general structure:

[0038]

[0039] Wherein, in the above formula (IX), Y is S;

[0040] T is selected from N;

[0041] Preferably, the above R3, R4, and R5 are each independently selected from H, F, Cl, Br, I, OH, CN, NH2,

[0042] Specifically, the compounds of the present invention are selected from:

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055] Definition and Description

[0056] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0057] C 1-7 Selected from C1, C2, C3, C4, C5, C6 or C7; 3-6 members are selected from 3, 4, 5 or 6 members.

[0058] The term "pharmaceutically acceptable" as used herein refers 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 humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0059] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the 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 base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the 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 a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into either base or acid addition salts.

[0060] Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0061] As used herein, "pharmaceutically acceptable salts" are derivatives of the compounds of the invention, wherein the parent compound is modified by salification with an acid or alkali. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.

[0062] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0063] In addition to the form of salts, compounds provided by the present invention also exist in prodrug forms. Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0064] Some compounds of the present invention may exist in non-solvated form or solvated form, including hydrate form. Generally speaking, solvated form is suitable with non-solvated form, all included in the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous form.

[0065] Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0066] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise indicated. Likewise, all tautomeric forms are intended to be within the scope of the present invention.

[0067] 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, and racemic mixtures 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. All of these isomers and their mixtures are included within the scope of the present invention.

[0068] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present 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 (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamates are generated from amines).

[0069] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0070] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical drugs. For additional information about the carrier, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0071] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0072] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0073] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0074] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemical achievable.

[0075] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0076] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0077] When a substituent's bond can cross-link to two atoms on a ring, the substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom through which it is bonded to the compound included in the chemical formula but not specifically mentioned, the substituent can be bonded through any atom. Combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. For example, the structural unit It means that it can be substituted at any position on the cyclohexyl group or the cyclodiene.

[0078] Substituents of alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents" and may be selected from, but are not limited to, one or more of the following groups: -R', -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -SiR'R"R"', OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O)2R', -NR""'-C(NR'R"R'")=NR"", NR""C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", NR"S02R', -CN, -NO2, -N- 3. -CH(Ph)2 and fluoro(C1-C4)alkyl, the number of substituents is 0 to (2m'+1), where m' is the total number of carbon atoms in such radicals. R', R", R"', R"" and R""' are each independently preferably hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkoxy or aralkyl. When the compounds of the present invention include more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R', R", R"', R"" and R""' groups are present. When R' and R" are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'R" is intended to include but is not limited to 1-pyrrolidinyl and 4-morpholinyl. Based on the above discussion on substituents, those skilled in the art will understand that the term "alkyl" is intended to include groups consisting of carbon atoms bonded to non-hydrogen groups, such as haloalkyl (e.g., -CF3, -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0079] Similar to the substituents described for alkyl radicals, aryl and heteroaryl substituents are generally referred to as "aryl substituents" and are selected from, for example, -R', -OR', -NR'R", -SR', -halogen, -SiR'R"R"', OC(O)R', -C(O)R', -C02R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O)2R', -NR""', -C(NR'R"R'")=NR"", NR""C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", NR ”SO2R', -CN, -NO2, -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, etc., the number of substituents is between 0 and the total number of open valences on the aromatic ring; wherein R', R", R"', R"" and R""' are independently preferably selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compounds of the present invention include more than one R group, for example, each R group is independently selected, as are each of these groups when there are more than one R', R", R"', R"" and R""' groups.

[0080] Two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with a substituent of the general formula -TC(O)-(CRR')qU-, wherein T and U are independently selected from -NR-, -O-, CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with a substituent of the general formula -A(CH2)rB-, wherein A and B are independently selected from -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 4. Optionally, a single bond on the new ring thus formed may be replaced with a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the general formula -A(CH2)rB-, wherein s and d are independently selected from integers of 0 to 3, and X is -O-, -NR', -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. The substituents R, R', R" and R'" are independently selected from hydrogen and substituted or unsubstituted (C1-C6)alkyl.

[0081] Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom. In addition, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C1-C4) alkyl" is intended to include but is not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl, etc.

[0082] Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with a specified number of carbon atoms attached through an oxygen bridge. 1-6 Alkoxy includes C1, C2, C3, C4, C5 and C6 alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy. "Cycloalkyl" includes saturated cyclic groups, such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C3, C4, C5, C6 and C7 cycloalkyl. "Alkenyl" includes hydrocarbon chains of straight or branched configuration, wherein one or more carbon-carbon double bonds are present at any stable site on the chain, such as vinyl and propenyl.

[0083] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0084] Unless otherwise specified, the term "hetero" means a heteroatom or heteroatom group (i.e., an atom group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and atom groups containing these heteroatoms, for example, including oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-.

[0085] Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The so-called ring includes a monocyclic, linked ring, spirocyclic, cyclic or bridged ring. The number of atoms on the ring is usually defined as the number of members of the ring, for example, "5-7 membered ring" means 5 to 7 atoms arranged around. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Therefore, "5-7 membered ring" includes, for example, phenyl, pyridine and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl ring" includes pyridinyl and piperidinyl, but does not include phenyl. The term "ring" also includes a ring system containing at least one ring, each of which "rings" independently meets the above definition.

[0086] Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a heteroatom or heteroatom group, which may be saturated, partially unsaturated or unsaturated (aromatic), and which contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)p). Nitrogen atoms may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined herein). The heterocycle may be attached to any heteroatom or carbon atom side group to form a stable structure. The heterocycles described herein may be substituted at the carbon or nitrogen position if the resulting compound is stable. Nitrogen atoms in the heterocycle are optionally quaternized. A preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means an aromatic ring of a stable 5-, 6-, 7-membered monocyclic or bicyclic or 7-, 8-, 9- or 10-membered bicyclic heterocyclic group, which contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents defined herein). The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocyclic ring does not exceed 1. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (i.e., C, O, N or S) connect two non-adjacent carbon atoms or nitrogen atoms. Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and a carbon-nitrogen group. It is worth noting that a bridge always converts a monocyclic ring into a tricyclic ring. In a bridged ring, substituents on the ring may also appear on the bridge.

[0087] Examples of heterocyclic compounds include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2,3-b]tetrahydrofuranyl, furanyl, furazanyl yl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolene, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, pyran, isoindolyl, isoindolyl, isoindolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidine oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxaline The invention also includes 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthienyl, thienyl, thienoxazolyl, thienothiazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Condensed ring and spirocyclic compounds are also included.

[0088] Unless otherwise specified, the term "hydrocarbyl" or its subordinate concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means a straight-chain, branched or cyclic hydrocarbon radical or a combination thereof, which may be fully saturated, mono- or poly-unsaturated, mono-, di- or poly-substituted, monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine), and may include divalent or polyvalent radicals, having a specified number of carbon atoms (such as C1-C 10Represents 1 to 10 carbons). "Hydrocarbon" includes but is not limited to aliphatic and aromatic hydrocarbons, the aliphatic hydrocarbons include chain and ring, specifically including but not limited to alkyl, alkenyl, alkynyl, the aromatic hydrocarbons include but are not limited to 6-12 yuan of aromatic hydrocarbons, such as benzene, naphthalene, etc. In some embodiments, the term "hydrocarbon" means a linear or branched atomic group or a combination thereof, which may be completely saturated, mono- or poly-unsaturated, and may include divalent and polyvalent atomic groups. Examples of saturated hydrocarbon atomic groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologues or isomers of atomic groups such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups have one or more double or triple bonds, examples of which include, but are not limited to, ethenyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers.

[0089] Unless otherwise specified, the term "heteroalkyl" or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term refers to a stable straight chain, branched or cyclic hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. In a typical embodiment, 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. The heteroatom or heteroatom group can be located at any interior position of the heteroalkyl group (including the position at which the hydrocarbon group is attached to the rest of the molecule). Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3.

[0090] The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are customary expressions referring to those alkyl groups which are attached to the remainder of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively.

[0091] Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl" or their subordinate concepts (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.) by themselves or in combination with other terms refer to a cyclized "alkyl", "heteroalkyl", respectively. In addition, in the case of heteroalkyl or heterocycloalkyl (such as heteroalkyl, heterocycloalkyl), a heteroatom can occupy the position at which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuranindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

[0092] Unless otherwise specified, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent, which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, may be monocyclic or polycyclic (e.g., 1 to 3 rings; at least one of which is aromatic), which are fused together or covalently linked. The term "heteroaryl" refers to an aryl group (or ring) containing one to four heteroatoms. In an exemplary embodiment, the heteroatoms are selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the rest of the molecule via a heteroatom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for any of the above aryl and heteroaryl ring systems are selected from the acceptable substituents described below.

[0093] For simplicity, aryl when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced, for example, by an oxygen atom, e.g., phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl, etc.

[0094] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0095] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl 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 (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0096] The compounds of the present invention can 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 combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0097] The solvent used in the present invention can be obtained commercially. The present invention uses the following abbreviations: aq represents water; HATU represents O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amine protection group; BOC stands for tert-butylcarbonyl, which is an amine protecting group; HOAc stands for acetic acid; NaCNBH3 stands for sodium cyanoborohydride; rt stands for room temperature; O / N stands for overnight; THF stands for tetrahydrofuran; Boc2O stands for di-tert-butyldicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl2 stands for thionyl chloride; CS2 stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu4NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for lithium diisopropylamide.

[0098] Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names. DETAILED DESCRIPTION

[0099] The present invention is further described in detail below in conjunction with specific embodiments. The given examples are only for illustrating the present invention, rather than for limiting the scope of the present invention.

[0100] Process A

[0101]

[0102] Compound 1A

[0103]

[0104] 2-Methoxy-4-amino-benzoic acid methyl ester (500.00 g, 2.76 mol), 2,2-dimethyl-1,3-dioxane-4,6-dione (397.73 g, 2.76 mol) and trimethyl orthoformate (292.84 g, 2.76 mol) were added to isopropanol (5.00 liters). The reaction solution was heated to 90 degrees and refluxed for 1 hour. TLC detected that the reaction was complete. The reaction solution was cooled to 20 degrees in an ice bath and then filtered. The solid was washed with MTBE (300 ml * 2) and concentrated to dryness in a water bath. A total of compound 1A (873.00 g, 2.47 mol, yield 89.62%, purity 95%) was obtained, and the properties were light red powder. NMR (DMSO) proved that the product was correct.

[0105] 1 H NMR(400MHz,DMSO-d6)ppm 1.67(s,6H)3.76(s,3H)3.86(s,3H)7.19(dd,J=8.41,1.63Hz,1H)7.43(d,J=1. 25Hz,1H)7.71(d,J=8.28Hz,1H)8.69(d,J=10.04Hz,1H)11.25(d,J=9.03Hz,1H)

[0106] Compound 1B

[0107]

[0108] Compound 1A (270.00 g, 805.23 mmol) was added to diphenyl ether (2.70 L). The system was heated to 220 degrees and refluxed for half an hour. TLC detected that the reaction was complete. The reaction solution was naturally cooled to 140 ° C and then methyl tert-butyl ether (1 L) was slowly added dropwise. The reaction solution was then allowed to stand for 12 hours and cooled to 30 degrees. The reaction solution was filtered, and the solid was washed with methyl tert-butyl ether (300 ml * 3) and then pulled dry by oil pump. A total of compound 1B (160.00 g, 583.14 mmol, yield 72.42%, purity 85%) was obtained, and the properties were gray solid. NMR (DMSO) judged that the product was correct.

[0109] 1 H NMR(400MHz, DMSO-d6)ppm 3.81(s,3H)3.90(s,3H)5.99(d,J=7.28Hz,1H)7.02(s,1H)7.84-7.92(m,1H)8.43(s,1H)11.72(d,J=3.76Hz,1H)

[0110] Compound 1C

[0111]

[0112] Sodium hydroxide (233.60 g, 5.84 mol) was dissolved in tap water (1.50 L) and added to a solution of compound 1B (680.00 g, 2.92 mol) in methanol (1.50 L). The reaction solution was stirred at an external temperature of 30 degrees for two hours. TLC detected that the reaction was complete. The reaction solution was pulled dry with a water pump. After adding water (1 L) to the residue, hydrochloric acid (3 equivalents, 1.5 L) was added to pH = 3. After the solution was filtered, the solid was washed with water (300 ml * 2) and methyl tert-butyl ether (300 ml * 2). The solid was then pulled dry with toluene (300 ml * 3) with water. A total of compound 1C (650.00 g, crude product) was obtained in the form of a yellow solid. NMR (DMSO) determined that it was the correct product.

[0113] 1 H NMR(400MHz, DMSO-d6)ppm 3.89(s,3H)6.22(d,J=7.28Hz,1H)7.14(s,1H)8.04(d,J=7.28Hz,1H)8.42(s,1H)

[0114] Compound 1D

[0115]

[0116] Compound 1C (140.00 g, 638.72 mmol) and N,N-dimethylformamide (9.34 g, 127.74 mmol) were added to 1,2-dichloroethane (500.00 ml). Then thionyl chloride (379.94 g, 3.19 mol) was added to the above reaction system. The reaction liquid was protected by nitrogen and then heated to 110 degrees for reflux reaction for two hours. The system gradually changed from a gray turbid system to a black uniform state. TLC detected that the reaction was complete. The reaction liquid was directly used in the next reaction after being dried by a water pump. A total of compound 1D (140.00 g, crude product) was obtained, which was a gray solid. LCMS (ESI) m / z: 252 (M+1) + .

[0117] Compound 1E

[0118]

[0119] Compound 1D (300.00 g, 1.17 mol) was dissolved in dichloromethane (750.00 ml) and added to ammonia water (1.03 kg, 5.85 mol), and the temperature was controlled at 0-5 degrees in an ice bath. The reaction solution was stirred at 25 degrees for half an hour. TLC detected that the reaction was complete. Then the turbid liquid was filtered. The solid was washed with water (50 ml) and then pulled dry. The filtrate was extracted with a mixture of dichloromethane and isopropanol (3:1, 100 ml * 3). The organic phase was washed with brine (50 ml), dried with sodium sulfate and then pumped dry. The residue was slurried with a mixture of dichloromethane and ethyl acetate (1:1, 20 ml) for 15 hours and then filtered and dried. A total of compound 1E (176.00 g, 669.34 mmol, yield 57.21%, purity 90%) was obtained, and the properties were gray solid.

[0120] 1 H NMR(400MHz, DMSO-d6)ppm 4.02(s,3H)7.58(s,1H)7.64(d,J=4.77Hz,1H)7.77-7.93(m,2H)8.48(s,1H)8.81(d,J=5.02Hz,1H)

[0121] Compound 1F

[0122]

[0123] 3-Chloro-4-nitro-phenol (4.5 g, 0.026 mol) was added to a solution of 4-chloro-6-amide-7-methoxy-quinoline (5 g, 0.021 mol) in toluene (100 ml). After stirring at 140° C. for 12 hours, thin layer preparative chromatography showed that 4-chloro-6-amide-7-methoxy-quinoline had reacted completely. The reaction solution was cooled to 22° C. and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (first with ethyl acetate and then with dichloromethane / methanol = 20 / 1) to obtain compound 1F (light yellow solid, 5 g, 70% yield).

[0124] 1H NMR(400MHz,METHANOL-d4)9.02-9.11(m,1H),8.89-8.98(m,1H),7.64-7.78(m,2H), 7.54-7.61(m,1H),7.45(dd,J=2.64,8.66Hz,1H),7.10(d,J=6.78Hz,1H),4.23(s,3H)

[0125] Compound 1G

[0126]

[0127] Iron powder (3.8 g, 66.9 mmol) and acetic acid (10 ml) were added to a solution of compound 1F (5 g, 13.4 mmol) in ethanol (50 ml). After stirring at 80°C for 16 hours, the reaction was completed by TLC detection. The reaction solution was cooled to 22°C and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (dichloromethane / methanol=40-20 / 1) to obtain compound 1G (yellow solid, 2.1 g, 46% yield).

[0128] 1H NMR(400MHz, METHANOL-d4)8.97(s,1H),8.62(d,J=5.27Hz,1H),7.51(s,1H), 7.20(d,J=2.01Hz,1H),6.94-7.03(m,2H),6.56(d,J=5.52Hz,1H),4.14(s,3H)

[0129] Compound 1H

[0130]

[0131] 1,1'-Thiocarbonyldi-2(1H)pyridone (760 mg, 3.3 mmol) was added to a solution of compound 1G (1.03 g, 3 mmol) in 1,4-dioxane (2.5 ml). The reaction solution was stirred at 15°C for 1 hour and then heated to reflux for 12 hours. The solvent was evaporated under reduced pressure, and the residue was separated by column chromatography (ethyl acetate, Rf = 0.24) to obtain compound 1H (light yellow solid, 810 mg, yield 70%). LCMS (ESI) m / z: 385.9 (M+1) + .

[0132] 1 H NMR(400MHz,CHLOROFORM-d)9.22(s,1H),8.74(d,J=5.02Hz,1H),7.83(br.s.,1H),7.58 (s,1H),7.28(s,1H),7.11(dd,J=2.51,8.78Hz,1H),6.55(d,J=5.02Hz,1H),4.16(s,3H)

[0133] Example 1

[0134]

[0135] To a solution of 1H (500 mg, 1.3 mmol) in 20 ml of tetrahydrofuran was added cyclopropylamine (222.65 mg, 3.9 mmol) at room temperature under nitrogen protection, and then stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure at 35 degrees, and the residue was purified by preparative HPLC to give Example 1 (yellow solid, 90 mg, yield: 15.63%). LCMS (ESI) m / z: 443.0 (M+1) + .

[0136] 1 H NMR(400MHz, METHANOL-d4)9.03(s,1H),8.93(d,J=6.78Hz,1H),7.91(br.s.,1H),7.57-7.68(m ,2H),7.39(d,J=8.78Hz,1H),7.21(br.s.,1H),4.22(s,3H),2.73(br.s.,1H),0.53-1.09(m,4H)

[0137] The following compounds were also prepared using a method similar to that of Example 1 above:

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158] Process B

[0159]

[0160] Compound 72A

[0161]

[0162] To a solution of trimethoxyphenol (100 mg, 805.54 μmol) in acetic acid (2 mL) was added concentrated nitric acid (55.83 mg, 886.09 μmol), and the mixture was stirred at 0°C for 3 hours. The aqueous phase was extracted with ethyl acetate (20 mL*2), and the combined organic layers were washed with brine (20 mL*2), dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give compound 72A (48 mg, 35.23%).

[0163] 1 H NMR(400MHz, METHANOL-d4)=10.914(s,1H),7.901–7.887(d,1H),6.614-6.609(d,1H),6.50-6.48(m,1H),3.875(s,3H)

[0164] Compound 72B

[0165]

[0166] Compound 1E (600 mg, 2.54 mmol) was added to a solution of compound 72A (428.81 mg, 2.54 mmol) in chlorobenzene (10 mL), and the mixture was stirred at 130°C for 16 hours. After vacuum drying, the residue was washed with ethyl acetate (30 mL) to give compound 72B (820 mg). LCMS (ESI) m / z: 370 (M+1).

[0167] Compound 72C

[0168]

[0169] To a solution of compound 72C (900 mg, 2.44 mmol) in ethanol / water = 8.5 / 1.5 (20 mL) was added reduced iron powder (1.36 g, 24.40 mmol) and ammonium chloride (1.30 g, 24.37 mmol). The mixture was reacted at 100°C for 1 hour. Water (20 mL) was added, and the mixture was extracted with a solution of ethanol / dichloromethane = 3 / 1 (50 mL*3). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give compound 72C (700 mg) which was used directly in the next step without further purification. LCMS (ESI) m / z: 340 (M+1).

[0170] Embodiment 72

[0171]

[0172] 1,1'-thiocarbonyldi-2(1H)pyridone (116.85 mg, 503.09 μmol) was added to a solution of compound 72C (450 mg, 1.33 mmol) in dioxane (10 mL), and the mixture was reacted at 120°C under nitrogen protection for 2 hours. After cooling to 28°C, cyclopropylamine (1.14 g, 19.95 mmol) was added to the reaction solution, and the mixture was stirred at 28°C for 2 hours. The solution was removed in vacuo, and the residue was purified by preparative HPLC to give Example 72 (120 mg, 20.58% yield). LCMS (ESI) m / z: 439 (M+1).

[0173] 1 H NMR(400MHz, METHANOL-d4)=9.43(s,1H),8.88-8.70(m,1H),7.91(br.s.,1H),7.68-7.50(m,2H), 7.38(d,J=6.5Hz,1H),7.24-7.06(m,1H),4.31-4.15(m,3H),3.95–3.75(s,3H),1.02-0.62(m,4H)

[0174] Process C

[0175]

[0176] Compound 24A

[0177]

[0178] Sodium cyanoborohydride (4.72 g, 75.1 mmol) was added in batches to a solution of 5-hydroxy-1-hydrogen-indole (4 g, 30 mmol) in acetic acid (120 ml). The reaction mixture was stirred at 25°C for 12 hours. The solvent was then removed by rotary evaporation, dissolved in ethyl acetate (200 ml), and washed with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate 3x150 ml. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.3) to give compound 24A (off-white solid, 1.3 g, 32%).

[0179] 1 H NMR (400MHz, CHLOROFORM-d) = 6.69 (s, 1H), 6.59-6.49 (m, 2H), 3.55 (t, J = 8.3Hz, 2H), 3.01 (t, J = 8.3Hz, 2H), 2.20 (s, 1H)

[0180] Compound 24B

[0181]

[0182] Example 1E (100 mg, 423 μmol), compound 24A (63 mg, 465 μmol) and cesium carbonate (303 mg, 930 μmol) were added to NMP (1 ml). The reaction solution was heated to 120°C and stirred for 2 hours. Water was then added to quench the reaction, and 3×10 ml of ethyl acetate were extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel plate chromatography (dichloromethane / methanol=10 / 1, Rf=0.2) to obtain compound 24B (yellow solid, 80 mg, 57%).

[0183] LCMS (ESI) m / z: 336.1 (M+1) +

[0184] Embodiment 24

[0185]

[0186] Compound 24B (25 mg, 75 μmol) and cyclopropyl isothiocyanate (15 mg, 150 μmol) were added to tetrahydrofuran (2 ml). The reaction solution was stirred at 25°C for 15 hours. The solvent was evaporated under reduced pressure and the residue was separated by preparative HPLC to obtain Example 24 (yellow solid, 18 mg, 49%). LCMS (ESI) m / z: 435.1 (M+1) + .

[0187] 1H NMR (400MHz, METHANOL-d4)9.06(s,1H),8.88(d,J=7.0Hz,1H),8.75(d,J=8.5Hz,1H),7.59(s,1H),7.27(s,1H),7.16(dd,J=2.5,9. 0Hz,1H),7.01(d,J=7.0Hz,1H),4.27-4.21(m,5H),3.21(t,J=8.3Hz,2H),3.08(br.s.,1H),0.88(d,J=5.5Hz,2H),0.76-0.70(m,2H)

[0188] Process D

[0189]

[0190] Compound 26A

[0191]

[0192] 6-Methoxyquinoline (3.0 g, 18.85 mmol) and PtO2 (0.2 g, 0.8 mmol) were dissolved in methanol (20 ml), heated to 45° C. and stirred for 24 hours. The reaction process was monitored by TLC. After the reaction was cooled to room temperature, the solvent was dried in vacuo and separated by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to obtain compound 26A (light yellow oil, 1.2 g, yield 39%).

[0193] 1 H NMR(400MHz, CHLOROFORM-d)d 6.51-6.66(m,2H),6.45(d,J=8.5Hz,1H),3.73(s,3H),3.20-3.30(m,2H),2.76(t,J=6.5Hz,2H),1.86-1.98(m,2H).

[0194] Compound 26B

[0195]

[0196] Compound 26A (3.00 g, 18.38 mmol) was dissolved in 50 ml of dichloromethane, BBr3 (13.81 g, 55.14 mmol) was added at 0°C, and then stirred at 15°C for 2 hours. The reaction solution was concentrated, 5 ml of methanol was used to quench the reaction, saturated sodium bicarbonate solution (20 ml) was added, stirred for 30 min, and then extracted three times with 20 ml of ethyl acetate. The organic phases were combined, washed with anhydrous sodium sulfate, dried and concentrated to give a crude product, and purified by silica gel column (petroleum ether / ethyl acetate from 3 / 1 to 1 / 1) to give compound 26B (1.95 g, yield 71.11%).

[0197] 1 H NMR (400MHz, DMSO-d6) 8.24 (s, 1H), 6.22-6.35 (m, 3H), 4.93 (br.s., 1H), 3.02-3.10 (m, 2H), 2.57 (t, J = 6.4Hz, 2H), 1.67-1.80 (m, 2H).

[0198] Compound 26C

[0199]

[0200] Compound 26C was prepared in a similar manner as described for compound 24B, except that the starting material used in the synthesis of this compound was 5-hydroxytetrahydroquinoline.

[0201] Embodiment 26

[0202]

[0203] Compound 26C (90 mg, 257.6 μmol) was dissolved in tetrahydrofuran (5 ml), and cyclopropyl thiocyanate (51.1 mg, 515.2 μmol) was added at room temperature. The mixture was stirred at room temperature for 12 hours under nitrogen protection. The reaction solution was dried under vacuum, separated by HPLC (hydrochloric acid), and freeze-dried to obtain Example 26 (yellow solid, 65 mg, yield 56.2%).

[0204] 1 H NMR(400MHz,DMSO-d6)d 9.05(d,J=6.5Hz,1H),8.72(s,1H),8.29(br.s.,1H),8.01(br.s.,1H),7.93(br.s.,1H), 7.81(s,1H),7.37(d,J=8.8Hz,1H),7.28(d,J=2.5Hz,1H),7.18(dd,J=2.5,8.8Hz,1H),7. 00(d,J=6.5Hz,1H),4.09(s,3H),3.98-3.98(m,1H),4.01(t,J=6.2Hz,2H),3.06(br.s.,1 H), 2.76 (t, J = 6.6 Hz, 2H), 1.91 (quin, J = 6.4 Hz, 2H), 0.66-0.77 (m, 2H), 0.56-0.66 (m, 2H).

[0205] Embodiment 34

[0206]

[0207] This example was prepared in a similar manner as described in Example 26.

[0208] 1 H NMR(400MHz,DMSO-d6)d 8.89(d,J=5.8Hz,1H),8.70(s,1H),8.33(s,1H),7.93(br.s.,1H),7.84(br.s.,1H ),7.58(s,1H),7.44(d,J=8.8Hz,1H),7.28(d,J=2.3Hz,1H),7.20(dd,J=2.5,8.8H z,1H),6.83(d,J=6.0Hz,1H),6.37-6.42(m,1H),6.26(s,1H),6.10-6.14(m,1H),4 .05-4.13(m,5H),3.93-4.01(m,2H),2.76(t,J=6.6Hz,2H),1.93(t,J=6.6Hz,2H).

[0209] Process E

[0210]

[0211] Compound 25A

[0212]

[0213] A 120 ml tetrahydrofuran solution of ethyl isocyanate (9.06 g, 80.13 mmol) and DBU (12.20 g, 80.13 mmol) was heated to 50 degrees. Then a 40 ml tetrahydrofuran solution of acetaldehyde (4.42 g, 100.43 mmol) was added dropwise to the solution over 30 minutes. The resulting mixed solution was stirred at 50 degrees for one hour. Cooled to room temperature, neutralized with acetic acid and then rotary evaporated. The resulting residue was dissolved with 300 ml ethyl acetate and then washed with 1 molar hydrochloric acid, saturated sodium bicarbonate solution and saturated brine in sequence. The organic layer was dried over anhydrous sodium sulfate, filtered and rotary evaporated, and the residue was purified by column chromatography to obtain a light yellow solid of compound 25A (3.7 g, yield: 20.5%)

[0214] 1 H NMR(400MHz, CHLOROFORM-d)=9.38(br.s.,1H),7.50(d,J=3.3Hz,1H),4.36(q,J=7.0 Hz,2H),4.30(q,J=7.3Hz,2H),2.62(s,3H),1.40(t,J=6.3Hz,3H),1.38-1.32(m,3H)

[0215] Compound 25B

[0216]

[0217] 60% sodium hydride (550 mg, 13.75 mmol) was suspended in 150 ml of dry tetrahydrofuran and cooled to 0 degrees. Compound 25A (2.2 g, 9.77 mmol) and O-(diphenylphosphine)hydroxylamine (3.3 g, 14.15 mmol) were then added to the suspension. The mixture was then stirred at 0 degrees for 2 hours. The mixture was poured into 200 ml of saturated aqueous ammonium chloride solution, then extracted with 100 ml of ethyl acetate, the organic layer was washed with 100 ml of saturated brine, then dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain compound 25B (yellow, 3.38 g crude product), which was used directly in the next step.

[0218] 1 H NMR(400MHz,CHLOROFORM-d)=7.50(s,1H),5.65(br.s.,2H),4.37(q,J=7.2Hz,2H ),4.28(q,J=7.0Hz,2H),2.59(s,3H),1.41(t,J=7.2Hz,3H),1.35(t,J=7.2Hz,3H)

[0219] Compound 25C

[0220]

[0221] Compound 25B (1.55 g, 6.45 mmol) was dissolved in formamide (16.98 g, 377 mmol) and placed in a microwave tube, and then reacted in a microwave reactor at 180 degrees for 30 minutes. After cooling to 80 degrees, the mixture was poured into 100 ml of water, filtered, and the filter cake was washed with 200 ml of water and then dried to obtain a gray compound 25C (solid, 1.38 g, yield 96.72%).

[0222] 1 H NMR (400MHz, DMSO-d6) = 11.63 (br.s., 1H), 7.91 (s, 1H), 7.83 (s, 1H), 4.22 (q, J = 7.0Hz, 2H), 2.60 (s, 3H), 1.27 (t, J = 7.0Hz, 3H).

[0223] Compound 25D

[0224]

[0225] In a dry ice bath, under nitrogen protection, 27 ml of 3 mol methylmagnesium bromide was added dropwise to a 50 ml tetrahydrofuran solution of compound 25C (3.5 g, 15.82 mmol) over 10 minutes. The mixture was then heated to 18 to 20 degrees and stirred at this temperature for 6 hours. The reaction was slowly quenched with a saturated ammonium chloride solution, then extracted with ethyl acetate 50 ml*3, the combined extracts were washed with saturated brine 20 ml*2, then dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain 3.2 g of a yellow solid crude compound 25D, which was used directly in the next step.

[0226] 1 H NMR (400MHz, DMSO-d6)=11.28(br.s.,1H),7.71-7.57(m,1H),7.28(s,1H),4.85(s,1H),2.53(s,3H),1.45(s,6H)

[0227] Compound 25E

[0228]

[0229] Compound 25D (7.2 g, 34.74 mmol) was dissolved in 50 ml of tetrahydrofuran, cooled to -15 degrees, and then 30% hydrogen peroxide solution (39.38 g, 347.4 mmol) was added. Ice-cold methanesulfonic acid (33.39 g, 347.4 mmol) was diluted with 10 ml of water and added dropwise to the previous solution at -20 to -15 degrees, and then the mixed solution was stirred at -15 to -10 degrees for 4 hours. Then cold saturated sodium sulfite was added dropwise at 0 degrees to quench the reaction, and then alkalized with 28% ammonia water. 100 mL*3 of ethyl acetate was extracted, and the combined organic layer solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain 800 mg of yellow semi-liquid and semi-solid crude compound 25E, which was directly used in the next step. LCMS (ESI) m / z: 165.8 (M+1) + .

[0230] Compound 25F

[0231]

[0232] Compound 25E (2.5 g, 15.15 mmol) and 4-dimethylaminopyridine (55.49 mg, 0.454 mmol) were suspended in 50 ml of tetrahydrofuran, then cooled to 0 degrees, and then pivaloyl chloride was added over about 3 minutes. The mixture was then stirred at 18 degrees for 18 hours. 100 ml of saturated sodium bicarbonate solution was added, and then extracted with 100 ml of ethyl acetate * 3. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain a yellow solid crude product of compound 25F (3.2 g), which was directly used in the next step.

[0233] 1 H NMR(400MHz,CHLOROFORM-d)=10.59(br.s.,1H),7.52(s,2H),2.41(s,3H),1.39(s,9H)

[0234] Compound 25G

[0235]

[0236] Compound 25F (3.5 g, 14.04 mmol) was suspended in 80 ml of toluene. Then phosphorus oxychloride (17 g, 110.87 mmol) and diisopropylethylamine (2.18 g, 16.85 mmol) were added. The mixture was heated to 110 degrees and stirred for 17 hours, cooled to 19 degrees, and rotary evaporated. The residue was washed with disodium hydrogen phosphate solution and then extracted with 50 ml of ethyl acetate*3. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated, and the residue was purified by column chromatography to obtain a yellow solid compound 25G (3.1 g, yield 82.48%)

[0237] LCMS (ESI) m / z: 267.9 [M+1] +

[0238] Compound 25H

[0239]

[0240] Compound 25G (118 mg, 0.44 mmol), 2-chloro-4-hydroxyphenol cyclopropylthiourea (117 mg, 0.729 mmol) and triethylenediamine (140 mg, 1.25 mmol) were dissolved in 8 ml of acetonitrile and then stirred at 18 degrees for 1 hour under nitrogen protection. The mixture was dispersed in 10 ml of water and 30 ml of ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated, and the residue was purified by thin layer chromatography to obtain oily light yellow compound 25H (160 mg, yield: 76.58%).

[0241] 1H NMR(400MHz,CHLOROFORM-d)=8.54(br.s.,1H),8.30(br.s.,1H),7.93(s,1H),7.88(s,1H),7.42(d,J=2.5Hz,1H),7.28(s,1H ),7.25(dd,J=2.5,9.0Hz,1H),2.76(br.s.,1H),2.49-2.40(m,3H),1.49-1.37(m,9H),1.01(d,J=5.5Hz,2H),0.89(br.s.,2H)

[0242] Compound 25I

[0243]

[0244] Compound 25H (160 mg, 0.337 mmol) was dissolved in 2 ml methanol and 2 ml tetrahydrofuran solution, and then 0.17 ml of 4M sodium hydroxide solution was added at 17 degrees. Stirring was continued for 1.5 hours, and the reaction solution was treated with 1M hydrochloric acid to pH 3, and then extracted with ethyl acetate, 10 ml * 3, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain a solid yellow compound 25I crude product (150 mg), which was directly used in the next step. LCMS (ESI) m / z: 389.9 [M+1] + .

[0245] Embodiment 25

[0246]

[0247] Example 25I (80 mg, 0.205 mmol), 1-bromoisopropanol (324 mg, 2.33 mmol) and cesium carbonate (200 mg, 0.613 mmol) were dissolved in 5 ml of ethanol, then heated to 50 degrees and stirred for 2 hours, 1-bromoisopropanol (324 mg, 2.33 mmol) and cesium carbonate (200 mg, 0.613 mmol) were added, then stirred at room temperature overnight, 1-bromoisopropanol (324 mg, 2.33 mmol) and cesium carbonate (200 mg, 0.613 mmol) were added, and then heated to 50 degrees and stirred for 2 hours. 50 ml of dichloromethane and 10 ml of water were added to the mixture, and the organic layer was separated and rotary evaporated. The residue was purified by preparative HPLC to obtain Example 25 (20.8 mg, yield 26.16%)

[0248] LCMS (ESI) m / z: 448.1 [M+1] +

[0249] 1H NMR(400MHz, METHANOL-d4)=7.86-7.78(m,1H),7.71-7.64(m,2H),7.60-7.41(m,2H),4.36-4.08(m,1H),3.64 -3.43(m,1H),3.31-3.15(m,1H),2.90(dd,J=3.5,7.0Hz,1H),2.45(s,3H),1.43-1.24(m,3H)1.08-0.83(m,4H)

[0250] The following compound was also prepared using a method similar to that used to prepare Example 25 above:

[0251]

[0252] Process F

[0253]

[0254] Compound 31A

[0255]

[0256] At -65°C, boron tribromide (15.6 g, 62.27 mmol) was added dropwise to a 20 ml solution of Example 1F (2 g, 5.35 mmol) over 10 minutes, and the temperature was raised to 20°C for 30 minutes, and then stirred at this temperature for 16 hours. The reaction was quenched with 20 ml methanol, and 100 ml saturated sodium bicarbonate was added, and then extracted with a mixed solvent of dichloromethane / methanol (5 / 1). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1.69 g of a yellow solid crude product of Compound 31A, which was used directly in the next step.

[0257] 1 H NMR(400MHz, DMSO-d6)=13.02(br.s.,1H),8.91(s,1H),8.77(d,J=5.0Hz,2H),8.27(d,J=9.0Hz,1H),8.1 8(br.s.,1H),7.86(d,J=2.5Hz,1H),7.52(dd,J=2.5,9.0Hz,1H),7.45-7.39(m,1H),6.86(d,J=5.5Hz,1H)

[0258] Compound 31B

[0259]

[0260] Potassium carbonate (115.26 mg, 0.834 mmol) was added to 4 ml of DMF containing compound 31A (100 mg, 0.278 mmol) and 2-bromo-N,N-diethylethylamine hydrobromide (87.07 mg, 0.333 mmol). The mixture was heated to 80 degrees and stirred for 16 hours under nitrogen protection, poured into 40 ml of water, stirred for 20 minutes, and the aqueous layer was extracted with 30 ml of a mixed solvent of dichloromethane / methanol (10 / 1)*3. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 127.57 mg of crude oily compound 31B, which was used directly in the next step. LCMS (ESI) m / z: 459.0 [M+1] + .

[0261] Compound 31C

[0262]

[0263] Zinc powder (181.78 mg, 2.78 mmol) was added to a 5 ml ethanol solution of compound 31B (127.57 mg, 0.278 mmol) and acetic acid (166.94 mg, 2.78 mmol), and then heated to 80 degrees under nitrogen and stirred for 16 hours. After cooling, the mixture was alkalized with 10 ml saturated sodium bicarbonate, diluted with 20 ml ethanol, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give a yellow solid compound 31C (33.3 mg, yield: 28%).

[0264] 1 H NMR(400MHz, CHLOROFORM-d)=9.29-9.21(m,1H),8.82(br.s.,1H),8.65(d,J=5.3Hz,1H),7.50(s,1H),7.14(d,J=2.5Hz,1H),6.95 -6.83(m,2H),6.46(d,J=5.3Hz,1H),5.89-5.76(m,1H),4.41-4.30(m,2H),3.01-2.91(m,2H),2.71-2.57(m,4H),1.13-1.00(m,6H)

[0265] Compound 31D

[0266]

[0267] 1,1'-thiocarbonyldi-2(1H)pyridone (29.53 mg, 0.128 mmol) was added to a solution of compound 31C (50 mg, 0.1166 mmol) in 1.5 ml of dioxane, and then heated to 80-100 degrees and stirred for 16 hours under nitrogen protection. The mixture was rotary evaporated and the residue obtained was purified by preparative thin layer chromatography to give an oily yellow compound 31D (40 mg, yield: 72.86%). LCMS (ESI) m / z: 471.0 [M+1] + .

[0268] Embodiment 31

[0269]

[0270] Cyclopropylamine (164 mg, 2.87 mmol) was added to 2 ml of tetrahydrofuran of compound 31D (40 mg, 0.08493 mmol), and then stirred at 20 degrees for 16 hours. Finally, the mixture was purified by preparative HPLC to obtain oily white Example 31 (15 mg, yield 29.39%). LCMS (ESI) m / z: 528.0 [M+1] + .

[0271] 1 H NMR(400MHz, METHANOL-d4)=8.99(d,J=6.8Hz,1H),8.79(s,1H),7.94(br.s.,1H),7.77(s,1H),7.65(br.s.,1H),7.41(d,J=7.0Hz,1H),7.27(d,J =6.0Hz,1H),4.86-4.75(m,2H),3.83(br.s.,2H),3.49-3.39(m,4H),2.1 4-2.03(m,1H),1.45(t,J=7.3Hz,6H),0.94(br.s.,2H),0.78(br.s.,2H)

[0272] The following compound was also prepared using a method similar to that used to prepare Example 31 above:

[0273]

[0274]

[0275] Process G

[0276]

[0277] Compound 37A

[0278]

[0279] Compound 1B (3.00 g, 12.86 mmol) was added to thionyl chloride (30.00 ml). N,N-dimethylformamide (93.99 mg, 1.29 mmol) was then added to the reaction system. The reaction liquid was protected by nitrogen and then heated to 90 degrees for reflux reaction for 1 hour. TLC detected that the reaction was complete. The organic phases were combined and concentrated to dryness. The residue was dissolved in ice water (50 ml) and extracted with ethyl acetate (20 ml * 2). The aqueous phase was extracted with dichloromethane (30 ml * 5). The dichloromethane phase was washed with brine (20 ml * 2), dried with sodium sulfate and then pumped dry. A total of compound 37A (2.60 g, 9.81 mmol, yield 76.32%, purity 95%) was obtained, and the properties were gray solid.

[0280] 1 H NMR(400MHz, DMSO-d6)ppm 3.87(s,3H)3.98(s,3H)7.60(s,1H)7.66(d,J=4.77Hz,1H)8.41(s,1H)8.83(d,J=4.77Hz,1H)

[0281] Compound 37B

[0282]

[0283] Compound 37A (5.00 g, 19.87 mmol) and 3-chloro-4-nitro-phenol (3.45 g, 19.87 mmol) were added to chlorobenzene (50 ml). The reaction liquid was refluxed at 140 degrees for 15 hours under nitrogen protection. TLC detected that the reaction was complete. The reaction liquid was vacuum-dried by oil pump. The residue was purified by running a silica gel column (the mobile phase was ethyl acetate: methanol = 10:1). A total of compound 37B (4.90 g, yield 63.43%) was obtained.

[0284] Compound 37C

[0285]

[0286] Compound 37B (1.60 g, 4.12 mmol), iron powder (230.08 mg, 4.12 mmol) and ammonium chloride (220.38 mg, 4.12 mmol) were added to a mixed solution of ethanol (20 ml) and water (6 ml). The reaction solution was heated to 90 degrees and refluxed for 2 hours. TLC detected that the reaction was complete. The reaction solution was filtered through diatomaceous earth and the filtrate was directly dried. Flash chromatography was performed on a silica gel column (the mobile phase was ethyl acetate: methanol = 10:1). A total of 37C (1.20 g, 3.34 mmol, yield 81.18%) was obtained.

[0287] 1H NMR(400MHz, METHANOL-d4)8.75(s,1H),8.63(d,J=5.52Hz,1H),7.47(s,1H),7.21(d ,J=2.26Hz,1H),6.94-7.03(m,2H),6.55(d,J=5.52Hz,1H),4.05(s,3H),3.96(s,3H)

[0288] Compound 37D

[0289]

[0290] Compound 37C (1.20 g, 3.34 mmol) and 1,1'-thiocarbonyldi-2(1H)-pyridone (1.16 g, 5.01 mmol) were added to dioxane (15 ml) and stirred at 25 degrees for half an hour under nitrogen protection. The reaction solution was refluxed at 120 degrees for 12 hours. TLC detected that the reaction was complete. The reaction solution was dried by vacuum water pump. The residue was purified by silica gel column (mobile phase was ethyl acetate: methanol = 10:1). A total of compound 37D (610.00 mg, 1.52 mmol, yield 45.56%) was obtained.

[0291] 1 H NMR(400MHz, METHANOL-d4)7.13-7.20(m,2H),5.95-6.05(m,3H),5.77(dd,J=2.51,8.53Hz,1H), 5.15(d,J=5.02Hz,1H),5.03(d,J=9.03Hz,1H),4.89(t,J=6.78Hz,1H),2.52(s,3H),2.42(s,3H)

[0292] Compound 37E

[0293]

[0294] Compound 37D (280.00 mg, 698.53 μmol) and cyclopropylamine (39.88 mg, 698.53 μmol) were added to tetrahydrofuran (5 ml) and stirred at 25°C for 2 hours. TLC detected that the reaction was complete. The reaction solution was vacuum dried. The residue was purified by HPLC. Compound 37E (230.00 mg, 502.26 μmol, yield 71.90%) was obtained.

[0295] 1H NMR (400MHz, METHANOL-d4)8.76(s,1H),8.69(d,J=5.52Hz,1H),7.83(d,J=8.78Hz,1H),7.46-7.54(m,2H),7.28(dd,J=2 .38,8.66Hz,1H),6.77(d,J=5.27Hz,1H),4.06(s,3H),3.97(s,3H),2.79(br.s.,1H),0.92(br.s.,3H),0.77(br.s.,3H)

[0296] Compound 37F

[0297]

[0298] Compound 37E (230.00 mg, 502.26 μmol) and lithium hydroxide (120.29 mg, 5.02 mmol) were added to a mixture of tetrahydrofuran (3 ml), methanol (2 ml) and water (1 ml). The reaction solution was stirred at 25 degrees for 2 hours. TLC detected that the reaction was complete. The reaction solution was adjusted to pH = 5 with saturated citric acid (5 ml). The system was extracted with a mixture of dichloromethane and isopropanol (16 ml, 3:1 ratio). The organic phase was spin-dried. A total of compound 37F (195.00 mg, 439.29 μmol, yield 87.46%) was obtained.

[0299] 1 H NMR(400MHz, METHANOL-d4)9.04(s,1H),8.98(d,J=6.53Hz,1H),8.18(br.s.,1H),8.01(d,J=8.03Hz,1H),7.64(s,1H), 7.58(d,J=9.03Hz,1H),7.17(d,J=6.53Hz,1H),4.24(s,3H),2.86(br.s.,1H),0.93(d,J=5.02Hz,2H),0.74(br.s.,2H)

[0300] Embodiment 37

[0301]

[0302] Compound 37F (20.00 mg, 45.06 μmol), 2,2-difluoroethylamine (6.00 mg, 74.02 μmol), tetramethyluronium hexafluorophosphate (17.13 mg, 45.06 μmol) and diisopropylethylamine (5.82 mg, 45.06 μmol) were added to a small sealed tube of N,N-dimethylformamide (1 ml). The reaction solution was stirred at 25 degrees for 15 hours. LCMS detected that the reaction was complete. The reaction solution was added to water (4 ml) and extracted with dichloromethane (10 ml). The organic phase was spin-dried. The residue was dissolved in N,N-dimethylformamide (3 ml) and sent to HPLC (hydrochloric acid system). Example 37 (4.80 mg, 9.47 μmol, yield 21.01%) was obtained in total.

[0303] 1 H NMR(400MHz, METHANOL-d4)7.34-7.45(m,2H),6.37(br.s.,1H),6.02-6.13(m,2H),5.84(d,J=9.03Hz,1H),5.66(br.s.,1H),4.69(t,J=3.76Hz,1H), 4.55(t,J=4.02Hz,1H),4.41(t,J=3.76Hz,1H),2.67(s,3H),2.32(dt,J=3 .51,15.06Hz,2H),1.17(br.s.,1H),-0.61(br.s.,2H),-0.76(br.s.,2H).

[0304] The following compound was also prepared using a method similar to that used for Example 37 above:

[0305]

[0306]

[0307]

[0308]

[0309] Process H

[0310]

[0311] Compound 45A

[0312]

[0313] At -65°C, boron tribromide (15.6 g, 62.27 mmol) was added dropwise to a 20 ml solution of compound 1F (2 g, 5.35 mmol) over 10 minutes, and the temperature was raised to 20°C for 30 minutes, and then stirred at this temperature for 16 hours. The reaction was quenched with 20 ml methanol, and 100 ml saturated sodium bicarbonate was added, and then extracted with a mixed solvent of dichloromethane / methanol (5 / 1). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1.69 g of a yellow solid crude product of compound 45A, which was used directly in the next step.

[0314] 1 H NMR(400MHz, DMSO-d6)=13.02(br.s.,1H),8.91(s,1H),8.77(d,J=5.0Hz,2H),8.27(d,J=9.0Hz,1H),8.1 8(br.s.,1H),7.86(d,J=2.5Hz,1H),7.52(dd,J=2.5,9.0Hz,1H),7.45-7.39(m,1H),6.86(d,J=5.5Hz,1H)

[0315] Compound 45B

[0316]

[0317] To a 100 ml chloroform solution of compound 45A (500 mg, 1.39 mmol) and trioxymethylene (313.03 mg, 3.47 mmol), 20 drops of concentrated sulfuric acid were added dropwise, and then heated to 65-70 degrees and stirred for 2.5 hours. The mixture was cooled to 25 degrees, alkalized with 50 ml saturated sodium bicarbonate, and then 25 ml ethanol was added. The organic layer was separated and concentrated, and the residue was purified by preparative HPLC to give a yellow solid compound 45B (120 mg, yield: 23.22%).

[0318] 1 H NMR(400MHz, METHANOL-d4)=8.94(s,1H),8.80(d,J=5.0Hz,1H),8.18(d,J=9.0Hz,1H),7.70( d,J=2.5Hz,1H),7.61(s,1H),7.46(dd,J=2.5,9.0Hz,1H),6.88(d,J=5.5Hz,1H),5.36(s,2H)

[0319] Compound 45C

[0320]

[0321] To a 20 ml methanol solution of compound 45B (35 mg, 0.094 mmol) was added Raney nickel (5 mg), then stirred at 25-28 degrees under 15 psi hydrogen for half an hour, filtered, and the filtrate was concentrated to obtain a crude yellow oil compound 45C (30 mg), which was used directly in the next step. LCMS (ESI) m / z: 341.9 [M+1] + .

[0322] Embodiment 45

[0323]

[0324] To a solution of compound 45C (30 mg, 0.8779 mmol) in 3 ml of dioxane was added 1,1'-thiocarbonyldi-2(1H)pyridone (30 mg, 129.04 μmol), heated to 60-70 degrees and stirred for 1 hour, cooled to 25 degrees, added cyclopropylamine (82 mg, 1.44 mmol), and stirred at 25-28 degrees for 1 hour. The reaction solution was concentrated, and the residue was purified by preparative HPLC to give a yellow solid of Example 45 (12 mg, yield: 26.83%). LCMS (ESI) m / z: 440.9 [M+1] + .

[0325] 1 H NMR(400MHz, METHANOL-d4)=9.21(s,1H),9.04-8.95(m,1H),7.96(br.s.,1H),7.68(s,2H),7.42(d ,J=8.8Hz,1H),7.27(br.s.,1H),5.49(s,2H),2.75(br.s.,1H),0.94(br.s.,2H),0.79(br.s.,2H)

[0326] Embodiment 46

[0327]

[0328] This example has the same structure as compound 37E.

[0329] Embodiment 178

[0330]

[0331] This example was prepared as described for compound 37E.

[0332] 1H NMR(400MHz,METHANOL-d4)8.88-8.98(m,1H),7.75(d,J=8.53Hz,1H),7.66(br.s.,1H),7.59(s,1H) ,7.41(d,J=7.03Hz,1H),7.17(d,J=7.03Hz,1H),4.62(t,J=11.80Hz,4H),4.16(s,3H),4.00(s,3H).

[0333] Process I

[0334]

[0335] Compound 76A

[0336]

[0337] 1-(Trifluoromethyl)cyclopropylcarboxylic acid (300.00 mg, 1.95 mmol) and triethylamine (197.32 mg, 1.95 mmol) and di-tert-butyl dicarbonate tert-butyl carbonate (851.18 mg, 3.90 mmol) were added to tert-butyl alcohol (5 ml) at 25 degrees. [Azido(phenoxy)phosphoryl]oxybenzene (590.30 mg, 2.15 mmol) was slowly added to the reaction system. The reaction liquid was refluxed at 100 degrees for 18 hours under nitrogen protection. TLC detected that the reaction was complete. The reaction liquid was dried by rotation. The residue was dissolved in methyl tert-butyl ether (8 ml) and washed with water (3 ml). The aqueous phase was extracted with ethyl acetate (5 ml * 3). The combined organic phases were washed with citric acid (1N, 3 ml), saturated sodium carbonate (3 ml) and saturated sodium chloride (3 ml). The organic phase was dried by rotation. Compound 76A (350.00 mg, 1.55 mmol, yield 79.70%) was obtained in the form of a white solid.

[0338] 1 H NMR(400MHz,CHLOROFORM-d)1.45(br.s.,9H),1.27(br.s.,2H),1.12(br.s.,2H)

[0339] Compound 76B

[0340]

[0341] Compound 76A (100.00 mg, 444.03 μmol) and hydrochloric acid (5.10 g, 139.88 mmol) were added to water (5 ml) and then protected with nitrogen. The reaction solution was refluxed at 120 degrees for 2 hours and then stirred at 25 degrees for 12 hours. TLC determined that the reaction was complete. The reaction solution was spin-dried. Acetone (2 ml*2) was added to the residue and spin-dried again. Compound 76B (50.00 mg, crude product) was obtained as a white solid.

[0342] 1 H NMR(400MHz,METHANOL-d4)2.17(br.s.,2H),2.14(br.s.,2H),1.95-2.01(m,1H),1.83(br.s.,1H)

[0343] Compound 76C

[0344]

[0345] Example 37D (100.00 mg, 249.48 μmol) and 1-(trifluoromethyl)cyclopropylamine (50 mg, crude), triethylamine (75.73 mg, 748.44 μmol) were added to a sealed tube of tetrahydrofuran (2 ml) and stirred at 25 degrees for 2 hours. LCMS judged that there was a reaction but it was impure. The reaction solution was concentrated to dryness. The residue was dissolved in N, N-dimethylformamide (0.2 ml) and acetonitrile (3 ml) and purified by preparative HLPC (TFA). A total of compound 76C (70.00 mg, crude) was obtained, which was a white solid. LCMS (ESI) m / z: 526.2 [M+1] + .

[0346] Compound 76D

[0347]

[0348] Compound 76C (52.60 mg, 100.01 μmol) was added to a mixture of tetrahydrofuran (1.5 ml), methanol (1 ml) and water (0.5 ml). Lithium hydroxide (23.95 mg, 1.00 mmol) was added to the reaction system at 25 degrees and stirred at this temperature for 2 hours. LCMS detected that the reaction was complete. The reaction solution was acidified with citric acid (1N, 5 ml) and extracted with a mixture of dichloromethane and isopropanol (3:1 ratio, 10 ml*5). The combined organic phase was washed with saturated brine (5 ml), dried with sodium sulfate, filtered and dried. The residue was washed with a mixture of petroleum ether and ethyl acetate (5:1, 5 ml). A total of compound 76D (100.00 mg, crude product) was obtained, which was a yellow solid. LCMS (ESI) m / z: 511.9 [M+1] + .

[0349] Embodiment 76

[0350]

[0351] Compound 76D (50.00 mg, 97.68 μmol), triethylamine (29.65 mg, 293.04 μmol) and HATU (44.57 mg, 117.22 μmol) were added to a sealed tube of dichloromethane (3 ml). Ammonium chloride (7.84 mg, 146.52 μmol) was then added to the reaction system. The reaction solution was stirred at 25 degrees for 12 hours. LCMS detected that there was a reaction but it was not complete. The reaction solution was spin-dried. The residue was dissolved in N, N-dimethylformamide (0.2 ml) and acetonitrile (3 ml) and purified by HPLC (hydrochloric acid). Example 76 (5.90 mg, yield 11.82%) was obtained in total, and the properties were white solid.

[0352] 1 H NMR(400MHz, METHANOL-d4)9.06(s,1H),8.95(d,J=7.03Hz,1H),7.81(br.s.,1H),7.66(d,J=2.51Hz,1H),7.61 (s,1H),7.41(dd,J=2.26,8.78Hz,1H),7.23(d,J=6.53Hz,1H),4.23(s,3H),1.53(br.s.,2H),1.44(br.s.,2H)

[0353] Process J

[0354]

[0355] Compound 80A

[0356]

[0357] To a solution of compound 37B (500.00 mg, 1.29 mmol) dissolved in tetrahydrofuran (6 ml), lithium hydroxide (308.96 mg, 12.90 mmol) was added, and the mixture was stirred at 20°C for 4 hours. The reaction solution became a yellow clear liquid. LCMS showed that the reaction was complete. The reaction solution was adjusted to pH 5-6 by adding citric acid (1 mol / L), and then washed with a mixture of dichloromethane and isopropanol (3:1, 25 ml). The organic phase was washed with saturated brine (10 mL*1), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 80A (light yellow solid, 390 mg, crude product). LCMS (ESI) m / z: 375.0 [M+1] + .

[0358] Compound 80B

[0359]

[0360] To a solution of compound 80A (350 mg, 934.01 μmol) dissolved in dichloromethane (6 ml), DIEA (21.84 mg, 168.96 μmol), HATU (426.16 mg, 1.12 mmol) and ammonium chloride (74.94 mg, 1.40 mmol) were added, and the reaction solution was stirred at 20°C for 12 hours. LCMS showed that the reaction was almost complete. The reaction solution was quenched with water (5 ml), then extracted with ethyl acetate (15 ml * 3), the organic phase was washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (containing 0.1% HCl) to obtain compound 80B (yellow solid, 12 mg, 42.53% yield). LCMS (ESI) m / z: 374.0 [M+1] + .

[0361] Compound 80C

[0362]

[0363] Compound 80B (100.00 mg, 267.56 μmol) was dissolved in a solution of thionyl chloride (2 ml), stirred at 25°C for 10 minutes, and then heated to 80°C and stirred for 3 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a residue, which was separated and purified by thin layer chromatography to obtain compound 80C (yellow solid, 85 mg, 71.44% yield). LCMS (ESI) m / z: 355.9 [M+1] + .

[0364] Compound 80D

[0365]

[0366] Iron powder (36.11 mg, 646.55 μmol) and ammonium chloride (85.71 mg, 1.60 mmol) were added to a mixed solution of compound 80C (100 mg, 281.11 μmol) dissolved in ethanol and water (6 ml), and the reaction solution was stirred at 90°C for 2 hours. LCMS showed that the reaction was almost complete. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 80D (yellow solid, 72.00 mg, crude product). LCMS (ESI) m / z: 325.9 [M+1] + .

[0367] Compound 80E

[0368]

[0369] 1,1'-thiocarbonyldi-2(1H)pyridone (102.67 mg, 442.06 mmol) was added to a solution of compound 80D (72.00 mg, 221.03 μmol) dissolved in dioxane (3 ml), and the reaction solution was stirred at 10°C for 10 minutes, then the reaction temperature was heated to 110°C, and the reaction was stirred at 110°C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was quenched with water (10 ml), then extracted with ethyl acetate (30 ml*3), the organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 80E (light yellow solid, 72 mg, crude product). LCMS (ESI) m / z: 367.8 [M+1] + .

[0370] Embodiment 80

[0371]

[0372] Cyclopropylamine (15.52 mg, 271.88 μmol) was added to a solution of compound 80E (50.00 mg, 135.94 μmol) dissolved in dioxane (3 ml), and the mixture was stirred at 20°C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (containing 0.5% HCl, v / v) to obtain Example 80 (yellow solid, 8 mg, 13.85% yield). LCMS (ESI) m / z: 425.1 [M+1] + .

[0373] 1 H NMR(400MHz,METHANOL-d4)ppm 0.61-1.10(m,3H)4.25(s,3H)7.16-7.23(m,1H)7.28-7.35(m,1H)7.40(dd,J=8.03,2.51Hz ,1H)7.61(s,1H)7.66(m,1H)9.00(d,J=7.03Hz,1H)9.01(s,1H)LCMS(ESI)m / z:431.9(M+1).

[0374] Embodiment 81

[0375]

[0376] Compound 1H (60 mg, 155 μmol) was added to 1,2-dichloroethane (2 ml), and 2-methylaminoacetic acid (27.71 mg, 311.02 μmol) and triethylamine (47 mg, 466 μmol) were added, and the mixture was reacted under microwave conditions at 120 degrees for 20 minutes. The reaction solution was concentrated to a solid crude product, and Example 81 (15 mg, yield 19.16%) was obtained as a yellow powder by preparative HPLC (containing 0.5% HCl, v / v). LCMS (ESI) m / z: 457.1 [M+1] + .

[0377] 1 H NMR (400MHz, DMSO-d6)8.98(d,J=6.2Hz,1H),8.72(s,1H),7.94-8.03(m,1H),7.87(d,J=2.5Hz,2H),7. 62-7.73(m,2H),7.54-7.61(m,1H),6.91(d,J=6.2Hz,1H),4.48-4.67(m,2H),4.08(s,3H),3.32(s,3H).

[0378] Embodiment 82

[0379]

[0380] Compound 1H (100 mg, 249 μmol), ethylene glycol (5 ml), potassium carbonate (86 mg, 624 μmol) and chloroacetyl chloride (112.71 mg, 997.95 μmol) were stirred at 80 degrees for 1 hour. Filtered, the mother liquor was concentrated to obtain a crude product. Then, it was purified by preparative HPLC (containing 0.5% HCl, v / v) to obtain Example 82 (12.00 mg, yield 9.75%) as a yellow powder. LCMS (ESI) m / z: 478.9 [M+1] + .

[0381] 1 H NMR (400MHz, DMSO-d6)8.90-8.98(m,1H),8.72(s,1H),7.92-8.03(m,1H),7.83-7.92(m,1H),7.71(s,1H) ,7.65(s,1H),7.37-7.46(m,1H),7.26(s,1H),6.85-6.93(m,1H),4.13(s,2H),4.08(s,3H),3.22(s,3H).

[0382] Process K

[0383]

[0384] Compound 83A

[0385]

[0386] 3,5-Difluoro-p-nitrophenol (1.00 g, 7.69 mmol) was dissolved in dichloromethane (10 ml), and stirred at 0 degrees for ten minutes under nitrogen protection. Concentrated nitric acid (538.39 mg, 7.69 mmol) was slowly added to the reaction system and stirred at 0 degrees for 2 hours. TLC determined that the reaction was complete. Ice water (10 ml) was added to the reaction solution and then extracted with dichloromethane (5 ml * 5). The combined organic phases were washed with saturated brine (5 ml), dried over sodium sulfate, filtered and dried. The residue was purified by flash chromatography on a silica gel column (the mobile phase was petroleum ether: ethyl acetate = 10:1). A total of compound 83A (580.00 mg, 3.31 mmol, yield 43.08%) was obtained, which was a red oil.

[0387] 1 H NMR(400MHz,METHANOL-d4)6.61(s,1H),6.58(s,1H)

[0388] Compound 83B

[0389]

[0390] Compound 83A (580.00 mg, 3.31 mmol) was dissolved in a mixture of ethanol (5 ml) and water (1.5 ml). Iron powder (425.19 mg, 7.61 mmol) and ammonium chloride (1.01 g, 18.87 mmol) were added to the reaction system at 25 degrees. The reaction solution was heated to 90 degrees and refluxed for 2 hours. TLC determined that the reaction was complete. The reaction solution was filtered through diatomaceous earth. The filtrate was dried by rotary evaporation. Flash chromatography was performed on a silica gel column (the mobile phase was petroleum ether: ethyl acetate = 5:1). A total of compound 83B (413.00 mg, 2.70 mmol, yield 81.69%, purity 95%) was obtained, and the properties were gray solid.

[0391] 1 H NMR(400MHz,DMSO-d6)9.22(s,1H),6.28-6.39(m,2H),4.37(s,2H)

[0392] Compound 83C

[0393]

[0394] Compound 83B (534.00 mg, 3.68 mmol) and Example 1E (1.05 g, 4.42 mmol) were added to a sealed tube of N-methylpyrrolidone (3 ml). The reaction solution was stirred for five minutes and cesium carbonate (2.40 g, 7.36 mmol) was added. The reaction solution was heated to 140 degrees and microwaved for 2 hours. LCMS detected that the reaction was complete. After adding water (15 ml), the reaction solution was extracted with a mixture of dichloromethane and isopropanol (3:1 ratio, 10 ml*3). The system was difficult to stratify. The reaction solution was completely separated after filtration through diatomaceous earth. The organic phase was washed with saturated brine (5 ml), dried with sodium sulfate, filtered and dried. A gray oil compound 83C was obtained and used directly in the next step. LCMS (ESI) m / z: 345.9 [M+1] + .

[0395] Compound 83D

[0396]

[0397] Compound 83C (150.00 mg, 434.40 μmol) and sodium carbonate (101.29 mg, 955.68 μmol) were added to tetrahydrofuran (3 ml). Stir at 0 degrees for ten minutes. Thiophosgene (54.94 mg, 477.84 μmol) was slowly added to the reaction system at 0 degrees. The reaction solution was then stirred at 25 degrees for 2 hours. LCMS determined that the reaction was complete. The reaction system was added with water (10 ml) and then extracted with ethyl acetate (5 ml * 3). The organic phase was washed with saturated brine (3 ml), dried with sodium sulfate, filtered and dried. A total of compound 83D (150.00 mg, crude product) was obtained, which was a black oil. LCMS determined that the product was correct. LCMS (ESI) m / z: 388.1 [M+1] + .

[0398] Embodiment 83

[0399]

[0400] Example 83D (150.00 mg, 387.24 μmol) was added to tetrahydrofuran (3 ml). Cyclopropylamine (66.32 mg, 1.16 mmol) was then added to the reaction system. The reaction solution was stirred at 20 degrees for 1 hour under nitrogen protection. LCMS determined that the reaction was complete. The reaction solution was added with water (10 ml) and extracted with ethyl acetate (8 ml * 3). The combined organic phases were washed with saturated brine, dried with sodium sulfate, filtered and dried. The residue was dissolved in N, N-dimethylformamide (0.2 ml) and acetonitrile (3 ml) and sent to HPLC (hydrochloric acid) for purification to obtain Example 83 (19.50 mg, 43.64 μmol, yield 11.27%, purity 99.472%), which was a gray solid.

[0401] 1 H NMR(400MHz,METHANOL-d4)8.95-9.10(m,2H),7.67(br.s.,1H),7.29(d,J=7.0 3Hz,3H),4.24(br.s.,3H),2.73(br.s.,1H),0.94(br.s.,2H),0.76(br.s.,2H)

[0402] The following compound was also prepared using a method similar to that used to prepare Example 83 above:

[0403]

[0404] Process L

[0405]

[0406] Compound 84A

[0407]

[0408] To a solution of Example 1B (1 g, 4.29 mmol) in 15 ml of acetic acid was added N-chlorosuccinimide (916.08 mg, 6.86 mmol), followed by stirring at 25 degrees for 12 hours, filtering, and washing the filter cake with 20 ml of a mixed solvent of methanol and dichloromethane (3:1), and then washing with 20 ml of petroleum ether and drying to give an off-white solid of Compound 84A (800 mg, yield 62.70%).

[0409] 1 H NMR(400MHz, DMSO-d6)=12.22(br,1H),8.47(s,1H),8.38(d,J=6.0Hz,1H),7.07(s,1H),3.90(s,3H),3.82(s,3H)

[0410] Compound 84B

[0411]

[0412] Compound 84A (800 mg, 2.99 mmol) was dissolved in 10 ml of thionyl chloride, and then DMF (65.56 mg, 897.00 μmol) was added, heated to 120 degrees and stirred for 2.5 hours. Concentration and column chromatography purification gave an orange solid compound 84B (500 mg, yield 58.45%)

[0413] 1H NMR(400MHz, DMSO-d6)=9.02(s,1H),8.42(s,1H),7.64(s,1H),4.01(s,3H),3.90(s,3H)

[0414] Compound 84C

[0415]

[0416] 3-Chloro-4-nitrophenol (273.34 mg, 1.58 mmol) was added in one portion to a 20 ml chlorobenzene solution of compound 84B (300.42 mg, 1.05 mmol). The mixture was then heated to 130-140 degrees and stirred for 96 hours under nitrogen protection. The residue was then purified by preparative HPLC to give a yellow solid compound 84C (200 mg, yield: 45.01%).

[0417] 1 H NMR(400MHz, DMSO-d6)=9.09(s,1H),8.19(s,1H),8.13(d,J=9.0Hz,1H),7.71(s, 1H),7.59(d,J=2.5Hz,1H),7.15(dd,J=2.8,9.3Hz,1H),4.01(s,3H),3.83(s,3H)

[0418] Compound 84D

[0419]

[0420] Add ammonium chloride (252.79 mg, 4.73 mmol) and iron powder (395.91 mg, 7.09 mmol) to a 40 ml ethanol solution of compound 84C (200 mg, 0.472 mmol), heat to 70 degrees under nitrogen protection and stir for 16 hours, filter, and rotary evaporate the filtrate to obtain 400 mg of a grey solid crude compound 84D, which is used directly in the next step. LCMS (ESI) m / z: 393.1 [M+1] + .

[0421] Compound 84E

[0422]

[0423] Compound 84D (360 mg, 457.76 mmol) was added to a 7.86% ammonia methanol solution (94.22 g, 434.87 mmol) at once, and then stirred at 20 to 29 degrees for 16 hours, rotary evaporated, and then 15 ml (5:1) of a mixed solution of dichloromethane and methanol was added to the residue. Then washed with 4 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated to obtain an off-white solid of compound 84E (100 mg, yield: 57.76%), which was used directly in the next step. LCMS (ESI) m / z: 377.9 [M+1] + .

[0424] Embodiment 84

[0425]

[0426] To a solution of compound 84E (38 mg, 0.1 mmol) in 3.8 ml of dioxane was added 1,1'-thiocarbonyldi-2(1H)pyridone (70.01 mg, 0.301 mmol), then heated to 60-70 degrees and stirred for 2 hours. After cooling to 20 degrees, cyclopropylamine (41 mg, 0.718 mmol) was added, and then stirred at 25-28 degrees for 16 hours. Cooling and rotary evaporation were performed, and the residue was purified by preparative HPLC to give a yellow solid of Example 84 (20 mg, yield 35.95%). LCMS (ESI) m / z: 477.0 [M+1] + .

[0427] 1 H NMR(400MHz, METHANOL-d4)=9.24-9.08(m,1H),8.87-8.57(m,1H),7.70-7.49(m,2H),7.3 3-7.14(m,1H),6.98-6.86(m,1H),4.22-4.06(m,3H),2.89-2.66(m,1H),0.98-0.59(m,4H)

[0428] The following compound was also prepared using a method similar to that used to prepare Example 84 above:

[0429]

[0430] Process M

[0431]

[0432] Compound 95A

[0433]

[0434] 2,3-Difluoro-6-nitro-aniline (4.80 g, 27.57 mmol) was added to dioxane (75.00 ml). Potassium hydroxide (6.19 g, 110.28 mmol) was dissolved in water (20.00 ml) and added to the reaction system. The reaction solution was heated to 100 degrees and stirred for 15 hours. TLC determined that the reaction was complete. The reaction solution was added with water (20 ml) and then extracted with ethyl acetate (20 ml * 3). The organic phase was washed with water (10 ml), washed with brine (10 ml), dried with sodium sulfate, filtered and dried. The residue was recrystallized from a mixture of ethyl acetate and petroleum ether (5:1 ratio, 20 ml). A total of compound 95A (3.50 g, 20.34 mmol, yield 73.76%) was obtained, which was a yellow solid.

[0435] 1 H NMR(400MHz,CHLOROFORM-d)7.94(dd,J=1.88,9.66Hz,1H),6.34-6.47(m,1H),6.16(br.s.,3H)

[0436] Compound 95B

[0437]

[0438] Compound 95A (1.00 g, 5.81 mmol) was added to acetonitrile (6.00 ml). Cuprous chloride (898.69 mg, 8.71 mmol) was then added to the reaction system. The system was protected by nitrogen and then ice-bathed to 0 degrees. Then tert-butyl nitrite (898.69 mg, 8.71 mmol) was slowly added to the reaction system at 0-10°C. The reaction solution was stirred at 0 degrees for 1 hour and then stirred at 25 degrees for 5 hours. TLC judged that the reaction was basically completed. Water (5 ml) was added to the reaction and then extracted with ethyl acetate (10 ml * 3). The combined organic phases were washed with water (5 ml), dried with sodium sulfate, filtered and dried. Flash chromatography was performed on a silica gel column (the mobile phase was petroleum ether: ethyl acetate = 10: 1). A total of compound 95B (390.00 mg, 1.73 mmol, yield 29.79%, purity 85%) was obtained, and the properties were yellow solid.

[0439] 1 H NMR (400MHz, METHANOL-d4) 7.86 (dd, J=1.51, 9.03Hz, 1H), 7.01 (t, J=8.78Hz, 1H)

[0440] Compound 95C

[0441]

[0442] Compound 95B (350.00 mg, 1.83 mmol) and 4-chloro-7-methoxy-quinoline-6-carboxamide (476.38 mg, 2.01 mmol) were added to chlorobenzene (5.00 ml). The reaction liquid was protected by nitrogen and reacted at 140 degrees for 15 hours. LCMS detected that there was a reaction but it was not completely reacted. The reaction liquid was directly spin-dried. Flash chromatography silica gel column purification (mobile phase is dichloromethane: methanol = 5:1) was used. A total of compound 95C (200.00 mg, 362.49 micromol, yield 19.81%, purity 71%) was obtained, and the properties were yellow solid.

[0443] 1 H NMR (400MHz, METHANOL-d4)8.95(s,1H),8.75-8.80(m,1H),8.07(d,J=8.28Hz,1H),7.56-7.66(m,2H),6.85(d,J=5.02Hz,1H),4.15-4.21(m,3H)

[0444] Compound 95D

[0445]

[0446] Compound 95C (350.00 mg, 893.45 μmol), iron powder (114.77 mg, 2.05 mmol) and ammonium chloride (272.41 mg, 5.09 mmol) were added to a mixture of ethanol (5.00 ml) and water (1.50 ml) at 30 degrees. The reaction solution was heated to 90 degrees and refluxed for 5 hours. LCMS determined that the reaction was complete. The reaction solution was filtered through diatomaceous earth. The filtrate was directly spin-dried. Flash chromatography silica gel column purification (mobile phase was ethyl acetate: petroleum ether = 1:1). A total of compound 95D (199.00 mg, 390.57 μmol, yield 43.72%, purity 71%) was obtained, which was a brown solid.

[0447] 1 H NMR(400MHz, METHANOL-d4)8.99(s,1H),8.65(d,J=5.27Hz,1H),7.54(s,1H),7. 11(t,J=8.66Hz,1H),6.76(d,J=9.03Hz,1H),6.56(d,J=5.27Hz,1H),4.15(s,3H)

[0448] Compound 95E

[0449]

[0450] Compound 95D (200.00 mg, 552.87 μmol) and 1,1'-thiocarbonyldi-2(1H)-pyridone (154.09 mg, 663.44 μmol) were added to dioxane (3.00 ml). The reaction solution was stirred at 28 degrees for hours. The reaction solution was stirred at 100 degrees for 1 hour. LCMS detection showed that there was a reaction but it was not completely reacted. After adding 1,1'-thiocarbonyldi-2(1H)-pyridone (154.09 mg, 663.44 μmol), it was stirred for another half an hour. LCMS detection showed that only a small amount of raw material was left. After adding 1,1'-thiocarbonyldi-2(1H)-pyridone (154.09 mg, 663.44 μmol), it was reacted for another half an hour. LCMS judged that the reaction was basically complete. The reaction solution was spin-dried to obtain compound 95E residue, which was directly used in the next step reaction. LCMS (ESI) m / z: 403.8 [M+1] + .

[0451] Embodiment 95

[0452]

[0453] Compound 95E (100.00 mg, 247.64 μmol), 3,3-difluorocyclobutane hydrochloride (64.16 mg, 495.28 μmol) and triethylamine (50.12 mg, 495.28 μmol) were added to tetrahydrofuran (2.00 ml). The reaction solution was stirred at 28 degrees for 1 hour. LCMS determined that the reaction was complete. The reaction solution was spin-dried. The residue was dissolved in N,N-dimethylformamide (0.5 ml) and acetonitrile (3 ml) and then sent to HPLC (hydrochloric acid) for purification. Example 95 (14.00 mg, 28.18 μmol, yield 11.38%, purity 100%) was obtained in total, and the properties were white solid.

[0454] 1 H NMR(400MHz, METHANOL-d4)9.05(s,1H),8.95(d,J=6.53Hz,1H),7.63(s,1H),7 .51-7.60(m,2H),7.19(d,J=6.53Hz,1H),4.63(t,J=11.80Hz,4H),4.23(s,3H)

[0455] The following compound was also prepared using a method similar to that used to prepare Example 95 above:

[0456]

[0457]

[0458]

[0459]

[0460] Process N

[0461]

[0462] Compound 113A

[0463]

[0464] Under nitrogen protection at 28°C, compound 95D (600 mg, 1.66 mmol) and pyridine (131.20 mg, 1.66 mmol) were added to N,N-dimethylformamide (2 ml), and then phenyl chloroformate (389.53 mg, 2.49 mmol) was added, and the mixture was stirred at 28°C for 2 hours under nitrogen protection. Compound 113A (799 mg) was obtained by evaporation, and the product was used directly in the next step without purification. LCMS (ESI) m / z: 482.1 [M+1] + .

[0465] Embodiment 113

[0466]

[0467] At 28°C under nitrogen protection, N,N-diisopropylethylamine (100 mg, 276.43 μmol) and (3R)-3-fluoropyrrole hydrochloride (21.87 mg, 276.44 μmol) were added to N,N-dimethylformamide (0.3 ml), and then the mixture of compound 113A (95.44 mg, 552.86 μmol) dissolved in N,N-dimethylformamide (2 ml) was added, and stirred at 28°C under nitrogen protection for 1 hour. The solution was filtered and purified by liquid chromatography to obtain Example 113 (yellow solid, 30 mg, 22.53% yield). LCMS (ESI) m / z: 477.2 [M+1] + .

[0468] 1 H NMR (400MHz, METHANOL-d4) = 9.00 (s, 1H), 8.68 (d, J = 5.3Hz, 1H), 7.66 (dd, J = 1.8, 9.0Hz, 1H), 7.56 (s, 1H), 7.40 (t, J = 8.7Hz, 1H), 6.65(d,J=5.3Hz,1H),5.46-5.29(m,1H),4.15(s,3H),3.89-3.58(m,4H),2.43-2.14(m,2H),1.31(s,5H),0.91(d,J=9.5Hz,3H).

[0469] The following compound was also prepared using a method similar to that used to prepare Example 113 above:

[0470]

[0471]

[0472]

[0473]

[0474] Process O

[0475]

[0476] Compound 130A

[0477]

[0478] To a solution of compound 1G (1.5 g, 4.36 mmol) and 3,4-diethoxycyclobut-3-ene-1,2-dione (2.3 g, 13.06 mmol) in ethanol (20 ml) was added zinc trifluoromethanesulfonate (1.59 g, 4.36 mmol). After stirring at 23°C for 3 days, a yellow solid precipitated. The mixture was filtered and the filter cake was washed with ethanol (20 ml) to give compound 130A (yellow solid, 1.02 g, 50% yield).

[0479] 1 H NMR(400MHz,METHANOL-d4)ppm 1.20(t,J=7.15Hz,3H)1.51(t,J=7.03Hz,2H)3.63(q,J=7.03Hz,2H)4.18-4.28(m,3H)7.10(d,J=6.78 Hz,1H)7.45(dd,J=8.66,2.64Hz,1H)7.57-7.61(m,1H)7.66-7.73(m,2H)8.92-8.97(m,1H)9.06(s,1H)

[0480] Embodiment 130

[0481]

[0482] Cyclopropylamine (5 mg, 0.085 mmol) was added to a solution of compound 130A (40 mg, 0.085 mmol) in isopropanol (5 ml) at 21°C, and the reaction solution was microwaved at 130°C for 4 minutes. The reaction was purified by preparative HPLC (0.5% HCl) to give Example 130 (yellow solid, 5.6 mg, 8% yield). LCMS (ESI) m / z: 479.0 (M+1) + .

[0483] 1 H NMR(Methanol-d4,Bruker Avance 400MHz): δ9.05(s,1H),8.93(d,J=6.8Hz,1H),8.07-8.01(m,1H),7.67-7.59(m,2H),7.42(dd,J=8.9,2 .6Hz,1H),7.12(d,J=6.8Hz,1H),4.23(s,3H),3.27-3.19(m,1H),0.99-0.91(m,2H),0.86-0.73(m,2H).

[0484] The following compound was also prepared using a method similar to that used to prepare Example 130 above:

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493] Process P

[0494]

[0495] Compound 131A

[0496]

[0497] At 25 degrees, 6-methoxybenzothiazole-2-amine (30 grams, 0.17 mole) was slowly added in batches to a mixed solution of tert-butyl nitrite (27.8 grams, 0.27 mole) and cuprous chloride (19.8g, 0.20mol) in acetonitrile (300mL). After the addition was complete, the reaction solution was stirred for 2 hours at 25 degrees. The reaction solution was poured into a hydrochloric acid (6 mol per liter, 600 milliliters) solution and stirred for 10 minutes. Filter, extract the filtrate with ethyl acetate (50 milliliters x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. Purification by column chromatography (petroleum ether / ethyl acetate = 40 / 1-10 / 1) gave yellow solid compound 131A (13.8 g, 41.4% yield).

[0498] 1 H NMR(CDCl3,400MHz)7.82(d,J=9.00Hz,1H),7.23(d,J=2.35Hz,1H),7.07(dd,J=2.35,9.00Hz,1H),3.87(s,4H)

[0499] Compound 131B

[0500]

[0501] Compound 131A (13.8 g, 0.069 mol), cyclopropylamine (7.9 g, 0.138 mol), and triethylamine (28.8 ml, 0.21 mol) were added to NMP (160 ml), heated to 100 degrees and stirred for 18 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and water (100 ml) was added to the system, and ethyl acetate was extracted (120 ml x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. It was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1-2 / 1) to obtain a yellow solid compound 131B (10.8 g, 71% yield).

[0502] 1 H NMR(CDCl3,400MHz)7.43(d,J=8.61Hz,1H),7.17(d,J=2.35Hz,1H),6.83-7.01(m,2 H),3.82(s,4H),2.70(tt,J=3.42,6.55Hz,1H),0.81-0.89(m,2H),0.68-0.77(m,2H)

[0503] Compound 131C

[0504]

[0505] Compound 131B (9 g, 41 mmol) was dissolved in anhydrous dichloromethane (100 ml), and boron tribromide (14 mL, 82 mmol) was added dropwise at 0 degrees. After the addition was completed, the reaction solution was stirred at 10-15 degrees overnight. After the reaction was completed, the reaction solution was quenched with ice water, the pH was adjusted to neutral with 15% sodium hydroxide solution, and extracted with ethyl acetate (100 ml x 4), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain yellow solid compound 131C (5.3 g, 63%).

[0506] 1 H NMR(DMSO-d6,Bruker Avance 400MHz): δ9.13(s,1H),7.98(s,1H),7.21(d,J=8.5Hz,1H),7.08(d,J=2.5Hz,1H),6 .68(dd,J=2.5,8.5Hz,1H),2.68-2.58(m,1H),0.76-0.68(m,2H),0.56-0.49(m,2H)

[0507] Embodiment 131

[0508]

[0509] Compound 131C (1.5 g, 7.28 mmol), Example 1E (2.1 g, 8.74 mmol), and cesium carbonate (4.7 g, 14.56 mmol) were added to 25 ml of NMP. The mixture was heated to 100 degrees and stirred overnight under nitrogen protection. Water (15 ml) was added to the system, and ethyl acetate was extracted (30 ml x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The white solid Example 131 (340 mg, 11.5%) was obtained by column chromatography.

[0510] Process Q

[0511]

[0512] Compound 132A

[0513]

[0514] To a solution of 2-chloro-4-hydroxy-benzoic acid (5 g, 0.03 mmol) in methanol (10 ml) was added SOCl2 (1.5 ml), and the mixture was slowly heated from room temperature to reflux. The reaction solution was refluxed for 12 hours and concentrated under reduced pressure to give compound 132A (red solid, 5.4 g, 100% yield).

[0515] 1H NMR (400MHz, DMSO-d6) δ: 10.71 (s, 1H), 7.84-7.71 (m, 1H), 6.91 (d, J = 2.4Hz, 1H), 6.82 (dd, J = 2.4, 8.7Hz, 1H), 3.79 (s, 3H).

[0516] Compound 132B

[0517]

[0518] Compound 132A (500 mg, 2.68 mmol) was slowly added to a solution of lithium aluminum tetrahydride (255 mg, 6.70 mmol) in 10 ml of tetrahydrofuran at 0°C. The reaction solution was stirred overnight at room temperature. The reaction solution was quenched by adding water (0.26 ml) and 10% sodium hydroxide (0.26), and then water (0.78 ml) was added. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 132B (400 mg, yield: 94%).

[0519] 1H NMR (400MHz, DMSO-d6) δ: 9.93-9.55 (m, 1H), 7.30 (d, J = 8.3Hz, 1H), 6.85-6.65 (m, 2H), 5.14 (t, J = 5.6Hz, 1H), 4.44 (d, J = 5.4Hz, 2H).

[0520] Compound 132C

[0521]

[0522] Compound 132B (100 mg, 0.63 mmol), triethoxyphosphine (300 mg, 1.9 mmol), zinc iodide (302 mg, 0.95 mmol) were dissolved in dioxane (10 mL), and the mixture was stirred at 80° C. for 14 hours. Water and ethyl acetate were added to dilute the mixture, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by preparative thin layer chromatography to obtain compound 132C (110 mg, 72%).

[0523] 1 H NMR (400MHz, DMSO-d6) δ: 9.82 (s, 1H), 7.21 (dd, J = 2.6, 8.5Hz, 1H), 6.88-6.78 (m, 1H), 6.72 (dd, J = 2.3, 8.3Hz, 1H), 4.05 (m, 2H), 3.94 (m, 4H), 1.17 (t, J = 7.1Hz, 6H).

[0524] Compound 132D

[0525]

[0526] To a solution of compound 132C (100 mg, 0.36 mmol) in dithionyl chloride (3 ml) was added 1 drop of DMF, the reaction solution was heated under reflux for 12 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude compound 132D.

[0527] Compound 132E

[0528]

[0529] Compound 132D (100 mg, crude product), triethylamine (202 mg, 2 mmol) and cyclopropylamine (100 mg, 1.8 mmol) were dissolved in dichloromethane (3 ml) solution, and the mixture was stirred at room temperature for 2 hours. Water and dichloromethane were added to dilute, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue, which was purified by preparative thin layer chromatography to obtain compound 132E (50 mg, 49% yield). LCMS (ESI) m / z: 290 [M+1] + .

[0530] Embodiment 132

[0531]

[0532] Compound 132E (100 mg, 0.34 mmol), Example 1E (81 mg, 0.34 mmol), cesium carbonate (318 mg, 0.98 mmol) were dissolved in DMF (4 mL), and the mixture was stirred at 80°C for 12 hours. The mixture was dissolved in methanol and purified by preparative HPLC to give Example 132 (20 mg, yield 12%). LCMS (ESI) m / z: 490 [M+1] + .

[0533] 1H NMR(400MHz,DMSO-d6)δ:8.71(d,J=5.3Hz,1H),8.65(s,1H),7.87(s,1H),7.76(s,1H ),7.62(dd,J=2.4,8.6Hz,1H),7.54(s,1H),7.51(d,J=2.0Hz,1H),7.30(dd,J=2.4,8. 5Hz,1H),6.55(d,J=5.3Hz,1H),5.18(d,J=11.5Hz,1H),4.04(s,3H),3.95-3.81(m,2H ),3.32(s,2H),2.27(s,1H),1.27-1.14(m,3H),0.57-0.45(m,2H),0.43-0.31(m,2H).

[0534] Embodiment 133

[0535]

[0536] Lithium hydroxide (100 mg, 2.38 mmol) was added to a mixed solution of tetrahydrofuran (5 ml) and water (1 ml) in Example 132 (150 mg, 0.31 mmol), heated to 50 degrees Celsius and stirred for 12 hours. After the reaction was completed, the reaction solution was diluted with water and ethyl acetate, and after stratification, the Example 133 (30 mg, yield 21%) was obtained by preparative high performance liquid separation. LCMS (ESI) m / z: 462 [M+1] + .

[0537] 1H NMR (400MHz, METHANOL-d4) δ: 9.06-8.89 (m, 1H), 8.65 (d, J = 5.4Hz, 1H), 7.76 (dd, J = 2.3, 8.5Hz, 1H), 7.53 (s, 1H), 7.33 (d, J = 2.0Hz, 1H),7.15(dd,J=2.3,8.5Hz,1H),6.67(d,J=5.5Hz,1H),4.14(s,3H),3.28(d,J=19.4Hz,2H),2.45-2.33(m,1H),0.50-0.38(m,4H).

[0538] Process R

[0539]

[0540] Compound 134A

[0541]

[0542] At 26°C, 3-chloro-4-nitrophenol (5.0 g, 28.8 mmol) was added to ethanol (50 ml), followed by iron powder (9.6 g, 172.9 mmol) and acetic acid (10 ml), and the solution was stirred at 80°C for 16 hours. The solution was then cooled to 15°C, concentrated, and purified by column chromatography to obtain compound 134A (light red solid, 3.6 g, 88% yield).

[0543] Compound 134B

[0544]

[0545] Compound 134A (1.5 g, 10.4 mmol) was added to an ethanol (15 ml) solution at 15°C, and then (2-nitro-1,1-position)-trans-carbazyl (3.4 g, 20.8 mmol) was added, and stirred at 80°C for 16 hours. Then the solution was cooled to 12°C, concentrated, and purified by column chromatography to obtain compound 134B (yellow solid, 1.1 mg, 41% yield).

[0546] 1 H NMR(DMSO-d6,Bruker Avance 400MHz): δ11.25(s,1H),10.26(s,1H),7.28(d,J=8.5Hz,1H),6.96(d,J=2.3Hz,1H),6.80(dd,J=8.7,2.4Hz,1H),6.74(s,1H),2.43(s,3H).

[0547] Compound 134C

[0548]

[0549] Compound 134B (1.1 g, 4.22 mmol) was added to an ethanol (15 ml) solution at 12°C, followed by cyclopropylamine (481 mg, 8.44 mmol), and stirred at 80°C for 16 hours. The mixture was then cooled to 15°C, concentrated, and purified by column chromatography to give compound 134C (light yellow solid, 845 mg, 74% yield).

[0550] 1 H NMR(DMSO-d6,Bruker Avance 400MHz): δ10.57-9.68(m,2H),7.25(d,J=8.8Hz,1H),6.98(d,J=2.3Hz,1H),6.82(dd,J=8.5,2.3Hz,1H),2.74-2.55(m,1H),1.00-0.61(m,4H).

[0551] Compound 134

[0552]

[0553] Compound 134C (845 mg, 3.13 mmol) was added to a dimethyl sulfoxide (5 ml) solution at 15°C, and then Example 1E (247 mg, 1.04 mmol) and cesium carbonate (678 mg, 2.08 mmol) were added, and stirred at 80°C for 16 hours under nitrogen protection. The solution was purified by HPLC to obtain compound 134 (yellow solid, 112 mg, 21% yield). LCMS (ESI) m / z: 470 (M+1).

[0554] 1 H NMR(Methanol-d4,Bruker Avance 400MHz): δ9.12(d,J=6.3Hz,1H),8.74(s,1H),8.05-7.87(m,4H),7.74-7.53(m,2H),7.22-7.06(m,1H),2.82-2.60(m,1H),1.07-0.67(m,4H).

[0555] Process S

[0556]

[0557] Compound 135A

[0558]

[0559] To a solution of Example 1G (343 mg, 1.00 mmol) and triethylamine (500 mg, 5.0 mmol) in N,N-dimethylformamide / dichloromethane (10 ml / 10 ml) were added 1,3-di-tert-butoxycarbonyl-2-methylisothiourea sulfate (580 mg, 2.0 mmol) and silver nitrate (850 mg, 5.0 mmol). The mixture was stirred at 12°C for 12 hours, filtered, and ethyl acetate (50 ml) and water (50 ml) were added to the filtrate. The mixture was extracted and separated. The organic layer was washed with water (30 ml x 3), dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (dichloromethane / methanol: 500 / 1-20 / 1) to give compound 135A (white solid, 300 mg, 51% yield). H NMR(DMSO-d6):(s,1H),(s,1H),(d,J=5.2Hz,1H),(s,1H),(d,J=9.2Hz,1H),(s, 1H),(s,1H),(s,1H),(s,1H),(m,1H),(d,J=5.2Hz,3H),(s,3H),(s,9H),(s,9H).

[0560] Compound 135B

[0561]

[0562] Triethylamine (2 ml) was added to a dichloromethane solution (2 ml) of compound 135A (300 mg, 0.5 mmol) at 0°C, and the mixture was reacted at 14°C for 2 hours. The solvent was evaporated under reduced pressure to give compound 135B (320 mg, black oil) which was used directly in the next step without further purification. LCMS (ESI) m / z: 386.10 (M+1).

[0563] Embodiment 135

[0564]

[0565] Compound 5 (130 mg, 1 mmol) was added to a mixture of compound 135B (200 mg), potassium carbonate (280 mg, 2 mmol) in DMF (5 mL). The mixture was stirred at 140°C for 2 hours, filtered, ethyl acetate (20 mL) and water (20 mL) were added to the filtrate, the organic layer was washed with water (20 mL x 3), the organic layer was dried over sodium sulfate, filtered and evaporated, and the residue was purified by preparative HPLC (5‰ HCl as additive) to give Example 135 (white solid, 1.2 mg) LCMS (ESI) m / z: 452.0 (M+1).

[0566] H NMR (DMSO-d6): (s,1H), (d,J=6.8Hz,1H), (d,J=8.8Hz,1H), (s,1H), (s,1H), (m,1H), (d,J=6.8Hz,1H), (s,1H), (s,3H), (s,3H).

[0567] Process T

[0568]

[0569] Compound 161A

[0570]

[0571] Add hydrobromic acid (208.60 g, 1.3 mol) to a 250 ml round-bottom flask with mechanical stirring over 15 minutes, and then add 2-amino-5-methoxybenzothiazole (17 g, 94.32 mmol). Heat and reflux with stirring for 4 hours, cool to 0-5 degrees, and solid precipitates. 0-5 degrees, stir for half an hour, filter under reduced pressure, transfer the solid to a 1 liter round-bottom flask, and then slowly add saturated sodium carbonate solution under mechanical stirring, adjust the pH to 6.5 to 7, stir at room temperature for 0.5 hours, filter, wash the filter cake with 300 ml of water, and then vacuum dry at 50 degrees to obtain a gray solid of compound 161A (11.7 g, yield 74.64%).

[0572] 1 H NMR (400MHz, DMSO-d6) = 9.11 (s, 1H), 7.15 (s, 1H), 7.12 (s, 2H), 7.03 (d, J = 2.3Hz, 1H), 6.65 (dd, J = 2.3, 8.5Hz, 1H)

[0573] Compound 161B

[0574]

[0575] Compound 161A (105.34 mg, 0.634 mmol), Example 1E (100 mg, 0.422 mmol) and cesium carbonate (275.36 mg, 0.845 mmol) were mixed with 2.5 ml of DMF, then placed in a microwave reactor and stirred at 100 degrees for 30 minutes, cooled to room temperature, poured into 20 ml of water, filtered, and the filter cake was washed with water and finally dried to obtain a yellow solid crude product of Compound 161B (70 mg), which was directly used in the next step.

[0576] 1 H NMR(400MHz, DMSO-d6)=8.92(d,J=6.3Hz,1H),8.78-8.72(m,1H),8.50-8.13(m,2H),7.98(br.s.,1H),7.96(s,1H),7.91(br.s. ,1H),7.82(d,J=2.3Hz,1H),7.65(s,1H),7.52(d,J=8.5Hz,1H),7.27(dd,J=2.1,8.7Hz,1H),6.84(d,J=6.3Hz,1H),4.09(s,3H)

[0577] Embodiment 161

[0578]

[0579] Compound 161B (35 mg, 0.0955 mmol) was dissolved in 2 ml of dry DMF and m-trifluoromethylbenzaldehyde (24.95 mg, 143.29 μmol) was added and stirred at room temperature for 10 minutes. Sodium triacetyl borohydride (60.74 mg, 286.59 μmol) was added and stirred at room temperature overnight. Then, the mixture was heated to 100-110 degrees and stirred for three hours. Then, m-trifluoromethylbenzaldehyde (24.95 mg, 143.29 μmol) and sodium triacetyl borohydride (60.74 mg, 286.59 μmol) were added to the mixture and then heated to 90-110 degrees and stirred overnight. Finally, the mixture was directly purified by preparative HPLC to give a yellow solid of Example 161 (5 mg, yield 8.2%).

[0580] 1 H NMR(400MHz, METHANOL-d4)=9.08(s,1H),8.84(d,J=6.8Hz,1H),7.78-7.68(m,3H),7.65-7.55 (m,4H),7.29(d,J=8.8Hz,1H),6.97(d,J=6.8Hz,1H),4.79(s,2H),4.22(s,3H)LCMS:525[M+1].

[0581] The following example was prepared as described in Example 161:

[0582]

[0583]

[0584]

[0585] Process U

[0586]

[0587] Compound 162A

[0588]

[0589] To a solution of 5-methyl-3-nitrile-1-hydrogen-indole (220 mg, 1.28 mmol) in dichloromethane (3 ml) was added dropwise a dichloromethane solution of boron tribromide (2 mol / L, 1.92 ml) at 0°C. The reaction solution was stirred at 0°C for 2 hours and then quenched by adding methanol. The solution was extracted with methyl tert-butyl ether 3X30 ml. The layers were washed with saturated brine and dried over anhydrous sodium sulfate, filtered and the solvent was dried by spin drying. The residue was separated by column chromatography (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.3) to give compound 162A (gray solid, 544 mg, 43%).

[0590] 1 H NMR(400MHz, METHANOL-d4)7.84(s,1H),7.34(d,J=8.78Hz,1H),7.00(d,J=2.26Hz,1H),6.84(dd,J=2.26,8.78Hz,1H)

[0591] Embodiment 162

[0592]

[0593] Compound 162A (62 mg, 392 mmol), compound 1E (111 mg, 470 μmol) and cesium carbonate (383 mg, 1.81 mmol) were added to NMP (2 ml) solution. The reaction solution was heated to 110° C. by microwave for 30 minutes, filtered and separated by preparative HPLC to obtain Example 162 (yellow solid, 18 mg, 13%).

[0594] LCMS (ESI) m / z: 359.0 (M+1)

[0595] 1 H NMR(400MHz, METHANOL-d4)9.12(s,1H),8.84(d,J=6.53Hz,1H),8.18(s,1H),7.78(d,J=8.78Hz,1H),7 .73(d,J=2.01Hz,1H),7.59(s,1H),7.33(dd,J=2.26,8.78Hz,1H),6.93(d,J=6.78Hz,1H),4.23(s,3H)

[0596] Embodiment 163

[0597]

[0598] Under nitrogen protection at -10°C, methylsulfonyl chloride (45 μg, 0.35 μmol) was added dropwise to a solution of compound 1G (30 mg, 87.27 μmol) and pyridine (490.00 mg, 6.19 mmol) in 2 ml of nitrogen methyl pyrrolidone, while maintaining the temperature below -5°C. After the addition was completed, the reaction solution was heated to 20°C and then stirred at this temperature for 18 hours. Finally, the mixture was directly purified by preparative HPLC under alkaline conditions to obtain Example 163 (5 mg, yield 13.11%). LCMS (ESI) m / z: 437.0 (M+1).

[0599] 1H NMR(400MHz, METHANOL-d4)=8.97(s,1H),8.68(d,J=5.5Hz,1H),7.78(d,J=9.0Hz,1H),7.59-7.52(m,1 H),7.46(d,J=2.8Hz,1H),7.26(dd,J=2.8,9.0Hz,1H),6.64(d,J=5.5Hz,1H),4.15(s,3H),2.71(s,3H)

[0600] Process V

[0601]

[0602] Compound 164A

[0603]

[0604] 5-Methoxy-2-nitro-benzaldehyde (500.00 mg, 2.76 mmol) and 2,2-difluoroethylamine (223.74 mg, 2.76 mmol) were dissolved in dichloromethane (7 mL), and the reaction solution was stirred at 20°C for 2 hours. Then, sodium borohydride (114.85 mg, 3.04 mmol) was added, and the reaction solution was stirred at 18°C ​​for 16 hours. The solvent was evaporated under reduced pressure, and the obtained residue was separated by rapid silica gel column (eluent was petroleum ether: ethyl acetate, ethyl acetate content 0-15%) to obtain compound 164A (slightly yellow oil, 150.00 mg, yield: 22.07%).

[0605] 1 H NMR (400MHz, CDCl3)7.50-7.45(m,2H),7.15-7.12(m,1H),5.99-5.71(m,1H),4.04(s,2H),3.87(s,3H),3.02-2.93(m,2H).

[0606] Compound 164B

[0607]

[0608] Compound 164A (150.00 mg, 609.24 μmol) was dissolved in methanol (5 mL), and Raney nickel (35.76 mg) was added. The reactants were stirred at 20°C and 15 psi of hydrogen for 1 hour, filtered, and the filtrate was distilled under reduced pressure to obtain compound 164B (yellow oil, 120.00 mg, yield: 91.09%).

[0609] 1H NMR (400MHz, CDCl3)6.92(dd,J=6.0,3.2Hz,1H),6.26-6.23(m,2H),6.26-5.68(m,1H),4.57(s,2H),3.82(s,2H),3.76(s,3H),3.01-2.91(m,2H).

[0610] Compound 164C

[0611]

[0612] Compound 164B (100.00 mg, 462.47 μmol) and carbonyldiimidazole (112.48 mg, 693.71 μmol) were dissolved in DMF (6 mL), and the reaction solution was stirred at 70°C for 16 hours. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude compound 164C (yellow oil, 120.00 mg), which was directly used in the next step.

[0613] Compound 164D

[0614]

[0615] Compound 164C (100.00 mg, 412.85 μmol) was dissolved in DCM (5 mL), cooled to -78°C, and boron tribromide (517.14 mg, 2.06 mmol) was slowly added dropwise. After the addition was completed, the reaction solution was reacted at -78°C for half an hour, and then heated to 20°C for 5 hours. Water was added dropwise to the reaction solution under dry ice-acetone bath cooling, and the organic layer was separated, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and distilled under pressure to obtain a crude compound 164D (light yellow oil, 100.00 mg), which was directly used in the next step.

[0616] Embodiment 164

[0617]

[0618] Compound 164D (40.00 mg, 175.28 μmol) and Example 1E (41.48 mg, 175.28 μmol) were dissolved in nitrogen-methylpyrrolidone (3 mL), and cesium carbonate (85.66 mg, 262.92 μmol) was added. The reactants were subjected to microwave reaction at 100°C for 1.5 hours, filtered, and directly separated by preparative chromatography (DIKMA Diamonsil C18 200*25*5um, trifluoroacetic acid) to obtain Example 164 (9.00 mg, yield 11.99%). LCMS (ESI) m / z: 429.0 (M+1).

[0619] 1 H NMR(400MHz, CD3OD)9.04(s,1H),8.86(d,J=6.8Hz,1H),7.59(s,1H),7.36(d,J=6.8Hz,1H),6.98-6 .96(m,2H),6.82(d,J=2.0Hz,1H),6.26-5.98(m,1H),4.72(s,2H),4.21(s,3H),3.86-3.78(m,2H).

[0620] Process W

[0621]

[0622] Compound 16A

[0623]

[0624] Example 84D (200.00 mg, 557.44 μmol) was dissolved in acetonitrile (10 mL), and cuprous bromide (159.93 mg, 1.11 mmol) was added, followed by tert-butyl nitrosoate (114.97 mg, 1.11 mmol), stirred at 20 degrees for 2 hours, and then kept at 70 degrees for 1 hour. Methanol (10 mL) and dichloromethane (20 mL) were added to the mixture, filtered, and the filtrate was concentrated and purified by preparative separation plate (petroleum ether / ethyl acetate ratio: 2 / 1) to give compound 16A (110.00 mg, crude) as a yellow powder. LCMS (ESI) m / z: 423.7 (M+2).

[0625] Compound 16B

[0626]

[0627] A solution of compound 16A (50.00 mg, 118.30 μmol) in dioxane (5 ml) was added with imidazolinone (20.37 mg, 236.60 μmol), Pd2(dba)3 (21.67 mg, 23.66 μmol), BINAP (44.20 mg, 70.98 μmol) and cesium carbonate (77.09 mg, 236.60 μmol), and the mixture was stirred at 120 degrees for 12 hours. The reaction solution was cooled, ethyl acetate (20 ml) and water (20 ml) were added, the layers were separated, dried, and concentrated to obtain a crude product, which was purified by a preparative separation plate (PE / EA = 1 / 1 for the first time, DCM / MeOH = 10 / 1 for the second time) to obtain compound 16B (40.00 mg) as a yellow powder. LCMS (ESI) m / z: 428.0 (M+1).

[0628] Embodiment 165

[0629]

[0630] Compound 16B (40.00 mg, 93.49 μmol) was added to 10 ml of methanol with a saturated methanolic ammonia solution (5 ml), and the mixture was stirred at 20 degrees for 24 hours. The mixture was concentrated and the crude product was purified by preparative HPLC (HCl system) to give Example 165 (8 mg, yield 19.05%) as a white powder. LCMS (ESI) m / z: 413.2 (M+2).

[0631] 1 H NMR (400MHz, DMSO-d6): 8.96(d,J=6.02Hz,1H),8.73(s,1H),7.99(br.s.,1H),7.92(br.s.,1H),7.74(d,J=2.51Hz,1H),7.71(s,1H ), 7.65 (d, J = 8.53Hz, 1H), 7.47 (dd, J = 2.51, 9.03Hz, 1H), 6.93 (d, J = 6.53Hz, 2H), 4.09 (s, 3H), 3.81-3.86 (m, 2H), 3.50 (br.s., 2H).

[0632] Embodiment 166

[0633]

[0634] Example 1G (60.00 mg, 155.51 μmol) was added to 2-aminoacetic acid (23.35 mg, 311.02 μmol) and triethylamine (47.21 mg, 466.53 μmol) in DCE (2 ml), and the mixture was reacted at 120 degrees for 15 minutes under microwave conditions, and the reaction solution was diluted with 10 ml of methanol and 10 ml of dichloromethane, and concentrated to obtain a crude product, which was purified by a preparative separation plate (DCM / MeOH=10 / 1) to obtain a secondary crude product, and then purified by prep-HPLC (HCl system) to obtain pure Example 166 (5.00 mg, yield 6.71%) as a white powder. LCMS (ESI) m / z: 443.1 (M+1).

[0635] 1 H NMR (400MHz, DMSO-d6)10.56-10.64(m,1H),8.88-8.96(m,1H),8.66-8.73(m,1H),7.90-7.98(m,1H),7.79- 7.89(m,2H),7.59-7.67(m,2H),7.48-7.56(m,1H),6.81-6.88(m,1H),4.34-4.51(m,2H),4.03-4.11(m,3H).

[0636] Embodiment 167

[0637]

[0638] The title compound was obtained as a white solid by a method similar to Example 166, yield: 6.5%. LCMS (ESI) m / z: 443.0 (M+1).

[0639] 1 H NMR (400MHz, DMSO-d6)8.69-8.74(m,1H),8.65-8.69(m,1H),7.85-7.91(m,1H),7.73-7.78(m,1H),7.55-7 .59(m,1H),7.52-7.55(m,1H),7.25-7.33(m,1H),7.14-7.24(m,1H),6.56-6.62(m,1H),3.98-4.09(m,5H).

[0640] Process X

[0641]

[0642] Compound 168A

[0643]

[0644] Under nitrogen protection at 25°C, 1,1-cyclopropyl dicarbonate (1.0 g, 5.37 mmol) was added to tetrahydrofuran (3 ml), and then a mixed solution of sodium hydroxide / methanol (1 mol / L, 5.37 ml) was added, and stirred at 25°C for 16 hours under nitrogen protection. The solution was concentrated under reduced pressure at 30°C and added to water (20 ml), and the aqueous phase was washed with ethyl acetate (20 ml* twice). The aqueous phase was adjusted to pH 2 with hydrochloric acid (2 mol / L), and extracted with ethyl acetate (20 ml* twice), and the organic phase was dried, filtered, and concentrated with anhydrous sodium sulfate to obtain compound 168A (off-white solid, 500 mg, 64.6% yield).

[0645] 1 H NMR(400MHz,CHLOROFORM-d)3.79(s,3H),1.80-1.88(m,2H),1.72-1.79(m,2H)

[0646] Compound 168B

[0647]

[0648] Compound 1G (400.68 mg, 2.78 mmol) was added to N,N-dimethylformamide (20 ml) solution under nitrogen protection at 25°C, HATU (2.11 g, 5.56 mmol), DIPEA (1.44 g, 11.12 mmol) was added, and then compound 168A (955.65 mg, 2.78 mmol) was added. The solution was stirred at 25°C for 16 hours, and the reaction solution was added to water (200 ml). The aqueous phase was extracted with ethyl acetate (100 ml * 3 times), and the organic phase was washed with saturated brine (100 ml * 2 times), and then washed with hydrochloric acid (2 mol / L, 50 ml * 2 times), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 168B (yellow solid, 710 mg, 54.35% yield). LCMS S (ESI) m / z: 470 (M + 1).

[0649] Compound 168C

[0650]

[0651] Compound 168B (710 mg, 1.51 mmol) was added to a tetrahydrofuran (5 ml) solution at 25°C, and then sodium hydroxide solution (2 mol / L, 3.78 ml) was added, and the solution was stirred at 25°C for 3 hours. The solution was acidified to a pH value of 2. The aqueous phase was filtered, and the filter cake was washed with water (20 ml*2 times), dried and concentrated to obtain compound 168C (white solid, 650 mg, 94.43% yield).

[0652] 1H NMR (400MHz, DMSO-d6)11.70(s,1H),8.96(d,J=6.02Hz,1H),8.74(s,1H),8.47(d,J=9.03Hz,1H),7.86-8.06(m,2H) ,7.77(br.s.,1H),7.60(s,1H),7.44(d,J=8.03Hz,1H),6.95(d,J=6.02Hz,1H),4.10(s,3H),1.65(d,J=10.29Hz,4H)

[0653] Embodiment 168

[0654]

[0655] Compound 168C (100 mg, 219.37 μmol) and cyclopropylamine (37.57 mg, 658.11 μmol) were added to a solution of N,N-dimethylformamide (3 ml) under nitrogen protection at 25°C, and then HATU (166.82 mg, 438.74 μmol) was added, and the mixture was stirred at 25°C for 3 hours under nitrogen protection. The solution was concentrated under reduced pressure at 30°C and purified by HPLC to give Example 168 (white solid, 1.2 mg, 1.03% yield).

[0656] 1 H NMR(400MHz, DMSO-d6)9.05(s,1H),8.91-8.90(d,J=6.8Hz,1H),8.49-8.46(d,1H),7.65-7.64(d,J=2.8Hz,1H),7.60(s,1H),7.39-7.36( dd,J=2.8Hz,J=9.2,1H),7.05-7.03(s,1H),2.73-2.70(s,1H),1.70-1.67(m,2H),1.52-1.49(m,2H),0.79-0.76(m,2H),0.59-0.55(m,2H)

[0657] Process Y

[0658]

[0659] Compound 169A

[0660]

[0661] Compound 1F (400 mg, 1.07 mmol) and 1,2-vinylidene carbonate diester (150 mg, 1.74 mmol) were stirred in polyphosphoric acid (4.6 g, 1.07 mmol), heated to 180-190 degrees and stirred for 30 minutes under nitrogen protection. Cooled to 60 degrees, poured into 100 ml of water, alkalized with saturated sodium bicarbonate, and then extracted with a mixed solvent of dichloromethane / methanol (6 / 1) 30 ml * 3, the combined organic layer was washed with 10 ml of saturated brine, dried over anhydrous sodium sulfate, filtered and rotary evaporated, and the residue was purified by preparative thin layer chromatography to obtain a purple solid compound 169A (20 mg, yield 4.7%) LCMS (ESI) m / z: 398.0 (M+1) + .

[0662] 1 H NMR(400MHz, METHANOL-d4)=8.85(s,1H),8.77(d,J=5.5Hz,1H),8.18(d,J=9.0Hz,1H),8.12(s,1H),7.69( d,J=2.5Hz,1H),7.63(s,1H),7.45(dd,J=2.5,9.0Hz,2H),7.43(s,1H),6.88(d,J=5.0Hz,2H),4.14(s,3H)

[0663] Compound 169B

[0664]

[0665] Iron powder (60 mg, 1.07 mmol) and ammonium chloride (26.89 mg, 502.80 mmol) were added to a mixed solution of compound 169A (20 mg, 50.28 μmol) in 8.5 ml of ethanol and 1.5 ml of water, and then heated to 75-80 degrees under nitrogen protection and stirred for one hour, filtered, and 100 ml of dichloromethane and 10 ml of water were added to the filtrate, separated to obtain an organic layer, dried over anhydrous sodium sulfate, and concentrated to obtain 18.49 mg of a purple solid crude product of compound 169B, which was used directly in the next step. LCMS (ESI) m / z: 368.0 (M+1) + .

[0666] Embodiment 169

[0667]

[0668] Example 169 Compound 169B was prepared by a similar method to Example 45 to obtain a yellow solid, yield: 19.55%. LCMS (ESI) m / z: 467.0 (M+1) + .

[0669] 1 H NMR(400MHz, METHANOL-d4)=9.15(s,1H),8.95(d,J=6.8Hz,1H),8.20(s,1H),8.00-7.82(m,1H),7.72-7.64(m,2H) ,7.50(s,1H),7.43(d,J=6.8Hz,1H),7.24(d,J=6.5Hz,1H),4.33-4.17(m,4H),2.88-2.65(m,1H),1.08-0.64(m,4H)

[0670] Process Z

[0671]

[0672] Compound 171A

[0673]

[0674] Under nitrogen protection at 24°C, 4-chloro-7-methoxyquinoline (508 mg, 2.62 mmol) and 3-chloro-4-nitrophenol (682.98 mg, 3.94 mmol) were added to a chlorobenzene (20 ml) solution. After stirring at 130°C for 18 hours under nitrogen protection, the mixture was cooled to 25°C and filtered. The filter cake was washed with toluene (10 ml) and then washed once with petroleum ether (10 ml). The filter cake was evaporated to dryness at 45°C to obtain compound 171A (yellow solid, 570 mg, crude product). The product was used directly in the next step without purification. LCMS (ESI) m / z: 331 (M+1).

[0675] Compound 171B

[0676]

[0677] Compound 171A (570 mg, 1.72 mmol), ammonium chloride (921.91 mg, 17.24 mmol), and iron powder (962.58 mg, 17.24 mmol) were added to a mixed solution of ethanol and water, and stirred at 100°C for 1 hour under nitrogen protection. The solution was cooled to 25°C and filtered, and the filtrate was evaporated to dryness to obtain compound 171B (yellow solid, 300 mg, crude product), which was used directly in the next step without purification. LCMS (ESI) m / z: 301 (M+1).

[0678] Compound 171C

[0679]

[0680] Compound 171B (100 mg, 332.51 μmol) was added to dioxane (5 ml), and then 1,1'-thiocarbonyldi-2(1H)pyridone (115.84 mg, 498.77 mg) was added, and stirred at 80°C-100°C for 18 hours. The mixture was concentrated until no liquid dropped out to obtain compound 171C (yellow solid, 100 mg, crude product), which was used directly in the next step without purification. LCMS (ESI) m / z: 343 (M+1) + .

[0681] Embodiment 171

[0682]

[0683] 2-Fluorocyclobutane (15.07 mg, 161.9 μmol) and triethylamine (22.44 μl) were added to dioxane (5 ml), and the mixture was stirred at 25°C for 50 minutes under nitrogen protection. Then compound 171C (37 mg, 107.93 μmol) was added, and the mixture was stirred at 25°C for 30 minutes under nitrogen protection. The mixture was concentrated and the solid was separated by HPLC (acidic) to obtain Example 171 (yellow solid, 20 mg, 41% yield). LCMS (ESI) m / z: 436.0 (M+1) + .

[0684] 1 H NMR(400MHz, METHANOL-d4)=8.89-8.83(m,1H),8.58(d,J=9.3Hz,1H),7.74(d,J=8.8Hz,1H),7.67-7.59(m,2H) ,7.50(d,J=2.3Hz,1H),7.40(dd,J=2.6,8.7Hz,1H),7.14(d,J=6.8Hz,1H),4.62(t,J=11.9Hz,4H),4.12(s,3H).

[0685] Embodiment 170

[0686]

[0687] Compound 171C (15.07 mg, 161.9 μmol) and cyclopropylamine (22.44 μL) were added to dioxane (5 mL), stirred at 26°C for 30 minutes under nitrogen protection, the mixture was concentrated, and the solid was separated by HPLC (acidic) to obtain Example 170 (yellow solid, 20 mg, 33% yield). LCMS (ESI) m / z: 400 (M+1) + .

[0688] Process AA

[0689]

[0690] Compound 172A

[0691]

[0692] Compound 31A (100 mg, 277.99 μmol) and 2,2-dimethoxypropane (5 g, 48.01 mmol) were added with p-toluenesulfonic acid (47.87 mg, 277.99 μmol) in 20 ml toluene solvent, and then heated under reflux for 14 hours. Cool, rotary evaporate, add 10 ml saturated sodium bicarbonate to the residue, and extract with 10 ml*3 of a 5:1 dichloromethane-methanol mixed solution. Combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate to obtain a yellow solid crude product of compound 172A (110.1 mg), which is directly used in the next step. LCMS (ESI) m / z: 400 (M+1) + .

[0693] Compound 172B

[0694]

[0695] Compound 172B was prepared from Example 172A by a similar method to that of compound 171B to obtain a crude yellow solid, which was used directly in the next step. LCMS (ESI) m / z: 370.0 (M+1) + .

[0696] Compound 172C

[0697]

[0698] Compound 172C was prepared from Example 172B by a similar method to Example 171 to obtain a yellow solid, yield: 15.17%. LCMS (ESI) m / z: 469.0 (M+1) + .

[0699] 1 H NMR(400MHz, METHANOL-d4)=9.17(s,1H),8.95(d,J=6.8Hz,1H),7.94(br.s.,1H),7.66(d,J=2.0Hz,1H),7. 61(s,1H),7.45-7.36(m,1H),7.21(d,J=6.0Hz,1H),2.98-2.68(m,1H),1.87-1.69(m,6H),1.02-0.69(m,4H)

[0700] Embodiment 173

[0701]

[0702] Example 173 was prepared by a similar method to Example 172 to give a yellow solid, yield: 12.18%. LCMS (ESI) m / z: 490.9 (M+23).

[0703] 1 H NMR(400MHz, METHANOL-d4)=9.19(s,1H),8.99(d,J=6.5Hz,1H),7.95(br.s.,1H),7.66(s,2H),7.42(d,J=7.0Hz,1H), 7.24(br.s.,1H),5.59(t,J=5.1Hz,1H),2.76(br.s.,1H),2.11-1.99(m,2H),1.20(t,J=7.4Hz,3H),1.00-0.65(m,4H)

[0704] Embodiment 175

[0705]

[0706] Under nitrogen protection, Example 46 (130 mg, 55.7 mmol) was added to a tetrahydrofuran (10 ml) solution, cooled to -20°C under nitrogen protection, and then methylmagnesium bromide (3M, 1.89 ml) was slowly added. Stir at 26°C for 18 hours under nitrogen protection. The mixed solution was slowly introduced into ice-cold saturated ammonium chloride (50 ml) and stirred for ten minutes. The aqueous phase was extracted with ethyl acetate (50 ml*3), and the organic phase was washed once with saturated brine (50 ml), dried over anhydrous sodium sulfate, concentrated, and separated by high performance liquid chromatography to obtain Example 175 (yellow solid, 14 mg, 9.9% yield). LCMS (ESI) m / z: 495 (M+1).

[0707] 1 H NMR(400MHz, METHANOL-d4)=8.82(s,1H),8.78(d,J=6.5Hz,1H),7.90(br.s.,1H),7.59(d,J=2.3Hz,1H),7.50(s,1H),7.35(d d,J=2.4,8.4Hz,1H),7.08(br.s.,1H),4.15(s,2H),2.75(s,1H),2.68(s,1H),1.71(s,6H),0.94(br.s.,2H),0.78(br.s.,1H)

[0708] Process AB

[0709]

[0710] Compound 176A

[0711]

[0712] Under nitrogen protection, 1E (500 mg, 2.11 mmol) and methyl p-hydroxyphenylacetate (525 mg, 3.17 mmol) were added to a chlorobenzene (15 ml) solution and stirred at 130°C for 18 hours under nitrogen protection. The reaction solution was cooled to 25°C and separated by column to obtain compound 176A (yellow solid, 450 mg). LCMS (ESI) m / z: 367 (M+1).

[0713] Compound 176B

[0714]

[0715] Compound 176A (220 mg, 600.49 μmol) was added to a methanol (15 ml) solution, and then a 2 mol sodium hydroxide (750.61 μl) solution was added and stirred at 26°C for 18 hours. The mixture was reacted at 100°C for 16 hours. The reaction solution was evaporated at 40°C until no liquid was dripped out, water (50 ml) was added, the aqueous phase was washed twice with ethyl acetate (50 ml), the aqueous phase was adjusted to pH 6 with a 1 mol hydrochloric acid solution, the aqueous phase was washed three times with dichloromethane (100 ml), the combined organic phases were washed once with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to obtain compound 176B (110 mg), which can be used directly in the next step without further purification. LCMS (ESI) m / z: 353 (M+1).

[0716] Embodiment 176

[0717]

[0718] Under nitrogen protection at 25°C, compound 176B (50 mg, 141.91 μmol) and pyrrole (12.11 mg, 170.29 μmol) were added to a THF (10 mL) solution, followed by the addition of triethylamine (17.23 mg, 170.29 μmol) and HATU (64.75 mg, 170.29 μmol), and the mixture was stirred at 26°C for 3 hours under nitrogen protection. The reaction solution was evaporated and separated by high performance liquid chromatography to give Example 176 (yellow solid, 14 mg, 19.6% yield). LCMS (ESI) m / z: 406 (M+1).

[0719] 1H NMR(400MHz, METHANOL-d4)=9.05(s,1H),8.89(d,J=6.5Hz,1H),7.65(s,1H),7.53(d,J=8.0Hz,2H),7.36(d,J=8.3Hz,2H),7.04 (d,J=6.5Hz,1H),4.23(s,3H),3.85(s,2H),3.64(t,J=6.7Hz,2H),3.49(t,J=6.8Hz,2H),2.09-2.00(m,2H),1.99-1.89(m,2H).

[0720] Embodiment 177

[0721]

[0722] This example was prepared as described in Example 176. LCMS (ESI) m / z: 428 (M+1).

[0723] 1 H NMR(400MHz, METHANOL-d4)=9.05(s,1H),8.89(d,J=6.5Hz,1H),7.65(s,1H),7.55(d,J=8.3Hz,2H),7.37(d, J=8.3Hz,2H),7.02(d,J=6.5Hz,1H),4.73(t,J=11.9Hz,2H),4.39(t,J=12.3Hz,2H),4.23(s,3H),3.75(s,2H)

[0724] Process AC

[0725]

[0726] Compound 179A

[0727]

[0728] 2-Chloro-4-hydroxy-phenylboronic acid (150 mg, 870.22 μmol), 2-isopropyl-5-bromoimidazole (82.26 mg, 435.11 μmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride (31.84 mg, 435.11 μmol) and sodium carbonate (92.23 mg, 870.22 μmol) were stirred in 5 ml of tetrahydrofuran and 0.5 ml of water. Then heated to 70 degrees and stirred for 16 hours under nitrogen protection. After cooling, it was diluted with 10 ml of water, and then extracted with 20 ml of ethyl acetate * 3, the organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain 150 mg of a dark yellow-green solid crude product of compound 179A, which was used directly in the next step. LCMS (ESI) m / z: 236.9 [M+1] + .

[0729] Embodiment 179

[0730]

[0731] To a solution of compound 179A (150 mg, 633.71 μmol) in 2 ml of chlorobenzene was added Example 1E (149.97 mg, 633.71 μmol), and then heated to 130 degrees under nitrogen and stirred for 16 hours. After cooling, the mixture was directly purified by preparative HPLC to give a light yellow solid of Example 179 (4 mg, yield: 1.12%). LCMS (ESI) m / z: 436.9 [M+1] + .

[0732] 1 H NMR(400MHz, METHANOL-d4)=9.19-9.07(m,1H),8.28-8.16(m,1H),7.97-7.90(m,1H),7.84-7.74(m,2H),7.66-7.62(m,1H), 7.04(d,J=2.5Hz,1H),6.93(dd,J=2.5,8.5Hz,1H),4.19(s,3H),3.07-2.99(m,1H),1.41(d,J=6.8Hz,3H),1.34-1.26(m,3H).

[0733] Process AD

[0734]

[0735] Compound 180A

[0736]

[0737] To a solution of compound 37A (8 g, 31.79 mmol) in tetrahydrofuran / methanol / water = 3 / 2 / 1 (80 mL) was added lithium hydroxide (3.81 g, 158.95 mmol) and stirred at 28°C for 3 hours. The pH was adjusted to 3-4 with dilute hydrochloric acid, the aqueous phase was extracted with isopropanol / dichloromethane = 3 / 1 (200 mL*2), the combined organic layer was washed with brine (50 mL*2), dried over sodium sulfate, filtered and evaporated to give compound 180A (8 g, crude product) which was directly used in the next step without further purification. LCMS (ESI) m / z: 238 (M+1).

[0738] Compound 180B

[0739]

[0740] DPPA (3.47 g, 12.62 mmol) was added to DMF (10 mL) of compound 180A (2.00 g, 8.42 mmol), triethylamine (1.28 g, 12.62 mmol). Stir for 3 hours at 28°C under nitrogen protection. Add 20 ml of water and heat to 100°C for 1 hour. The aqueous phase was extracted with ethyl acetate (50 mL*3) and the combined organic layer was washed with brine (50 mL*2), dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to obtain compound 180B (260 mg, yield: 14.80). LCMS (ESI) m / z: 209 (M+1).

[0741] Compound 180C

[0742]

[0743] To compound 180B (220 mg, 1.05 mmol), triethylamine (320.10 mg, 3.16 mmol) in dichloromethane (3 mL) was added acetic anhydride (214.39 mg, 2.1 mmol). Stir at 40°C for 16 hours. Add 15 mL of water and extract with dichloromethane (20 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give compound 180C (267 mg), which was used directly in the next step without further purification. LCMS (ESI) m / z: 251 (M+1).

[0744] Compound 180D

[0745]

[0746] 3-Chloro-4-nitrophenol (277.27 mg, 1.60 mmol) was added to a chlorobenzene solution of compound 180C (267 mg, 1.07 mmol), stirred at 130°C under nitrogen protection for 16 hours, and dried by rotation at 60°C. The residue was washed with ethyl acetate (10 mL) to give compound 180D (300 mg) which was directly used in the next step without further purification. LCMS (ESI) m / z: 388 (M+1).

[0747] Compound 180E

[0748]

[0749] To a solution of compound 180D (300 mg, 773.65 mmol) in ethanol / water = 8.5 / 1.5 (30 mL) was added reduced iron powder (432.08 mg, 7.74 mmol) and ammonium chloride (413.83 mg, 7.74 mmol). The mixture was reacted at 100°C for 1 hour. Water (20 mL) was added, and the mixture was extracted with a solution of ethanol / dichloromethane = 3 / 1 (50 mL*3). The combined organic layer was dried over sodium sulfate, filtered and evaporated to give compound E (267 mg), which was used directly in the next step without further purification. LCMS (ESI) m / z: 358 (M+1).

[0750] Compound 180F

[0751]

[0752] 1,1'-thiocarbonylbis-2(1H)pyridone (116.85 mg, 503.09 μmol) was added to a solution of compound 180E (150 mg, 419 μmol) in dioxane (8 mL), and the mixture was reacted at 120° C. for 2 hours under nitrogen protection. Compound 180E remained, and 1,1'-thiocarbonylbis-2(1H)pyridone (116.85 mg, 503.09 μmol) was added, and the mixture was reacted at 120° C. for 12 hours to obtain compound 180F. The reaction solution was directly used in the next step without further purification. LCMS (ESI) m / z: 400 (M+1).

[0753] Embodiment 180

[0754]

[0755] To a solution of compound 180F (50 mg, 125.05 μmol) in dioxane (3 mL) were added 3,3-difluorocyclobutaneamine (161.99 mg, 1.25 mmol) and triethylamine (151.85 mg, 1.50 mmol), stirred at 28°C for 16 hours, the solution was removed in vacuo, and the residue was purified by preparative HPLC to give Example 180 (11.70 mg, 17.50%). 1 H NMR(400MHz, METHANOL-d4)=9.43(s,1H),8.82-8.72(m,1H),7.74(d,J=8.5Hz,1H),7.66-7.61(m,1H),7.56(s,1H),7.39 (dd, J = 2.4, 8.7 Hz, 1H), 7.15 (d, J = 6.8 Hz, 1H), 4.62 (t, J = 11.9 Hz, 4H), 4.23 (s, 3H), 2.32 (s, 3H) LCMS (ESI) m / z: 493 (M+1).

[0756] The following compound was also prepared using a method similar to that used to prepare Example 180 above:

[0757]

[0758]

[0759] Process AE

[0760]

[0761] Compound 184A

[0762]

[0763] 3-Methoxy, 4-trifluoromethylaniline (1.00 g, 5.23 mmol, 1.00 eq) was dissolved in diethyl ethoxymethylenemalonate (3.39 g, 15.69 mmol, 3.00 eq). The reaction was refluxed at 110 °C for 12 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated at 60 °C to obtain the crude product of compound 184A (1.80 g, yellow solid), which was directly used in the next step without purification. LCMS-ESI: m / z 362.1 (M+1) + .

[0764] Compound 184B

[0765]

[0766] Compound 184A (1.80 g, 4.98 mmol, 1.00 eq) was dissolved in diphenyl ether (10 mL) and heated to 240-250°C and refluxed for 1.5 hours. LCMS detection was complete. The reactant was cooled to 30°C and then poured into n-hexane (50 mL) and stirred for 10 minutes. A large amount of solid precipitated and filtered to obtain a crude product of compound 184B (1.50 g, black solid). The crude product was directly used for the next step without purification. LCMS-ESI: m / z 244.0 (M+H) + .

[0767] Compound 184C

[0768]

[0769] Compound 184B (1.50 g, 6.17 mmol, 1.00 eq) was dissolved in phosphorus oxychloride (10 mL), and the reaction was refluxed at 106°C for 5 hours. The reaction was completed by LCMS. The reaction solution was concentrated to remove phosphorus oxychloride, and the crude product was purified by flash chromatography (eluted with 0-10% methanol / dichloromethane) to obtain compound 184C (250.00 mg, 590.53 umol, 9.57% yield, 61.8% purity). LCMS-ESI: m / z 262.0 (M+H) + .

[0770] Compound 184D

[0771]

[0772] Compound 184C (250.00 mg, 955.55 umol, 1.00 eq) was dissolved in chlorobenzene (5.00 mL), and 3-chloro-4-nitrophenol (199.00 mg, 1.15 mmol, 1.20 eq) was added. The mixture was refluxed at 131° C. for 12 hours under nitrogen protection. LCMS detected that the reaction was complete, the reaction was concentrated, and the crude product was purified by flash chromatography (eluent 0-10% methanol / dichloromethane) to obtain compound 184D (10.00 mg, 17.81 umol, 1.86% yield, 71% purity). LCMS-ESI: m / z 399.0 (M+H) + .

[0773] Compound 184E

[0774]

[0775] Compound 184D (30.00 mg, 75.24 umol, 1.00 eq) was dissolved in methanol (3.00 mL) and radium nickel (10%, 0.005 g) was added under nitrogen protection. The reaction solution was replaced with hydrogen several times and the reaction was carried out at 25°C and 15 psi hydrogen pressure for 0.5 hours. LCMS detection was complete. The reaction was filtered and concentrated to obtain a crude product of compound 184E (25.00 mg, gray solid). LCMS-ESI: m / z 369.1 (M+H) + .

[0776] Embodiment 184

[0777]

[0778] Compound 184E (25.00 mg, 67.80 umol, 1.00 eq) was dissolved in dioxane (2.00 mL) and 1,1'-thiocarbonyldi-2(1H)pyridone (23.62 mg, 101.70 umol, 1.50 eq) was added. The reaction was refluxed at 101°C for 2 hours. LCMS detected that the reaction was not completed. 20 mg of 1,1'-thiocarbonyldi-2(1H)pyridone was added and refluxed for 1 hour. LCMS detected that 41% of compound 7 did not react and 10% of thioisocyanate was formed. The reaction was stopped and the reaction solution was cooled to 25°C. Under nitrogen protection, 3,3-difluorocyclobutylamine (6.31 mg, 67.80 umol, 1.00 eq) and DIEA (8.76 mg, 67.80 umol, 1.00 eq) were added. The reaction was stirred at 25°C for 12 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the crude product was separated and purified by preparative HPLC (Gemini 150*25mm 10u, HCl) to obtain Example 184 (1.00 mg, 1.98 umol, 2.93% yield). LCMS-ESI: m / z 504.1 (M+H) + .

[0779] 1 H NMR(400MHz, METHANOL-d4)7.42(d,J=6.5Hz,1H),7.31(s,1H),6.20(d,J=8.5Hz,1H),6.1 5-6.04(m,2H),5.94-5.81(m,1H),5.70-5.53(m,1H),3.07(t,J=12.0Hz,4H),2.66(s,3H)

[0780] Process AF

[0781]

[0782] Compound 185A

[0783]

[0784] Under nitrogen protection at 28°C, 2,4-dihydroxybenzaldehyde (10 g, 72.4 mmol) was added to dichloromethane (100 ml), and then boron trifluoride etherate (1.17 g, 7.24 mmol) was added, and ethyl diazoacetate (33.04 g, 289.6 mmol) diluted with dichloromethane (50 ml) was slowly added dropwise, and the temperature was controlled below 36°C until no gas was released, and stirred at 28°C for 30 minutes. The solution was concentrated to a residual volume of 20 ml, and concentrated sulfuric acid (7.1 g, 72.4 mmol) was slowly added dropwise. Stirring was continued at 28°C for 2 hours. The deep red reaction solution was treated with dichloromethane (100 ml), and the excess sulfuric acid was neutralized with solid sodium bicarbonate, and filtered through a column to obtain compound 185A (yellow solid, 4.3 g, 23.04% yield).

[0785] Compound 185B

[0786]

[0787] Compound 185A (4.3 g, 20.85 mmol) was added to tetrahydrofuran (20 ml) under nitrogen protection at 22°C, and then sodium hydroxide (4 mol / L, 15.64 ml) was added, and stirred at 22°C for 16 hours under nitrogen protection. The reaction solution was diluted with water (100 ml) and washed once with ethyl acetate (30 ml). The aqueous phase was adjusted to pH 5 with hydrochloric acid (2 mol / L), extracted with ethyl acetate (60 ml*3), and the organic phase was washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate to obtain compound 185B (1.5 mg). The product was used directly in the next step without purification.

[0788] Compound 185C

[0789]

[0790] Under nitrogen protection at 22°C, compound 185B (120 mg, 673.63 μmol) and cyclopropylamine hydrochloride (38.46 mg, 673.63 μmol) were added to N,N-dimethylformamide (3 ml), and then HATU (256.13 mg, 673.63 mmol) and N,N-diisopropylethylamine (435.3 mg, 3.37 mmol) were added. The mixture was stirred at 22°C for 1.5 hours under nitrogen protection. The reaction solution was added to water (20 ml) and extracted with ethyl acetate (50 ml*3). The organic phase was washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate to obtain compound 185C (146 mg). LCMS (ESI) m / z: 218 (M+1).

[0791] Embodiment 185

[0792]

[0793] Under nitrogen protection at 22°C, compound 1E (105.46 mg, 445.63 μmol), Example 185C (121 mg, 557.04 μmol), sodium tert-butoxide (22.48 mg, 233.96 mmol) were added to dimethyl sulfoxide (2 ml), and reacted at 100°C for 16 hours under nitrogen protection. The solution was cooled to room temperature, added to water (20 ml), and washed once with ethyl acetate (80 ml*3 times), and the organic phase was washed once with saturated brine (100 ml), concentrated, filtered, and purified by liquid chromatography to obtain Example 185 (yellow solid, 30 mg, 13.77% yield). LCMS (ESI) m / z: 418 (M+1).

[0794] 1 H NMR(400MHz, METHANOL-d4)=9.03(s,1H),8.65(d,J=5.5Hz,1H),8.38(s,1H),8.22(d,J=8.8Hz,1H),7.59-7.54(m,2H ),7.31(dd,J=2.1,8.4Hz,1H),6.59(d,J=5.5Hz,1H),4.16(s,3H),2.89(m,1H),0.89-0.83(m,2H),0.71-0.66(m,2H)

[0795] The following examples were prepared using a similar procedure as described in Preparative Example 185:

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804] Process AG

[0805]

[0806] Compound 193A

[0807]

[0808] 2-Fluoro-4-hydroxybenzeneacetonitrile (3 g, 22 mmol) was dissolved in methylhydrazine (30 g, 260 mmol). The reaction solution was heated to 90°C and reacted for 16 hours. The solvent was evaporated under reduced pressure and the residue was separated by column chromatography (dichloromethane / methanol=10 / 1, Rf=0.2) to obtain compound 193A (yellow solid, 1.1 g, 31%).

[0809] 1 H NMR(400MHz,CHLOROFORM-d)7.35(d,J=8.53Hz,1H),6.58-6.62(m,1H),6.56(s,1H),3.74(s,3H)

[0810] Example 193B

[0811]

[0812] Compound 193A (300 mg, 1.84 mmol), Example 1E (218 mg, 0.92 mmol) and cesium carbonate (899 mg, 2.76 mmol) were added to a dimethyl sulfoxide (4 ml) solution. The reaction solution was heated to 100°C for 14 hours. The reaction solution was diluted with water and extracted with a mixed solution of dichloromethane / isopropanol (3 / 1) for 3X10 ml. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was subjected to column chromatography (dichloromethane / methanol=10 / 1, Rf=0.3) to obtain compound 193B (yellow-brown oily liquid, 190 mg, 34%). LCMS (ESI) m / z: 364.1 (M+1).

[0813] Embodiment 193

[0814]

[0815] Pyridine (46 mg, 575 μmol) was added to a DMF (2 ml) solution of Example 193B (317 mg, 523 μmol) and phenylthiochloroformate (135 mg, 784 μmol). The reaction solution was stirred at 30°C for 2 hours. Cyclopropylamine (60 mg, 1.05 mmol) and N', N'diisopropylethylamine (135 mg, 1.05 mmol) were then added to the reaction solution and stirred for 30 minutes. The reaction solution was diluted with water and extracted with a mixed solution of dichloromethane / isopropanol (3 / 1) for 3X5 ml. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was separated by preparative HPLC to give Example 193 (reddish brown solid, 6 mg, 2%). LCMS (ESI) m / z: 463.1 (M+1).

[0816] 1 H NMR(400MHz, METHANOL-d4)9.11(s,1H),8.90(d,J=7.03Hz,1H),8.19-8.26(m,1H),7.62-7.65(m,1H ),7.16(d,J=8.78Hz,1H),7.02(d,J=6.78Hz,1H),4.24-4.25(m,1H),4.00(s,1H),0.73-1.02(m,3H)

[0817] Process AH

[0818]

[0819] Compound 212A

[0820]

[0821] Under nitrogen protection at 28°C, 4-chloro-7-hydroxyquinoline (500 mg, 2.78 mmol) and pyridine (484.47 mg, 6.12 mmol) were added to dichloromethane (50 ml), and then trifluoromethanesulfonic anhydride (1.18 g, 4.17 mmol) was slowly added dropwise at 0°C. The mixture was stirred at 28°C for 2 hours. The solution was quenched with saturated ammonium chloride solution and extracted with dichloromethane (100 ml*2). The organic phase was washed with saturated brine (100 ml), dried and filtered to obtain compound 212A (300 mg). The product was used directly in the next step without further purification. LCMS (ESI) m / z: 312 (M+1).

[0822] Compound 212B

[0823]

[0824] Under nitrogen protection at 28°C, compound 212A (200 mg, 641.72 μmol), bis-pyridinol borate (195.55 mg, 770.07 μmol), ferrocenepalladium dichloride (140.87 mg, 192.52 μmol), potassium acetate (188.94 mg, 1.93 mmol) were added to 1,4-dioxane (2 ml), and the solution was heated to 80°C and stirred for 16 hours under nitrogen protection. The solution was cooled to room temperature, diluted with ethyl acetate (50 ml), filtered, and water (50 ml) was added. The aqueous phase was extracted with ethyl acetate (50 ml*2), and the organic phases were combined, washed once with saturated brine (100 ml), dried and evaporated to obtain compound 212B (50 mg). The product was used directly in the next step without further purification. LCMS (ESI) m / z: 208 (M+1).

[0825] Compound 212C

[0826]

[0827] Under nitrogen protection at 28°C, compound 212B (120 mg, 578.54 μmol) and 4-iodo-1-methylimidazole (144.4 mg, 694.24 μmol) were added to 1,4-dioxane (1.5 ml), and then cesium carbonate (565.5 mg, 1.74 mmol) and ferrocene palladium dichloride (84.66 mg, 115.71 μmol) were added. The mixture was stirred at 100°C for 16 hours under nitrogen protection. The reaction solution was filtered and evaporated to dryness to obtain compound 212C (120 mg). The product was used directly in the next step without further purification. LCMS (ESI) m / z: 244 (M+1).

[0828] Compound 212D

[0829]

[0830] Under nitrogen protection at 22°C, compound 212C (222.52 mg, 940.3 μmol) and 3-chloro-4-nitro-phenol (215 mg, 940.3 μmol) were added to chlorobenzene (5 ml), and reacted at 140°C for 16 hours under nitrogen protection. The solution was cooled to room temperature 60°C, evaporated to dryness, diluted with water (30 ml), extracted with dichloromethane (50 ml*3), and the organic phase was washed once with saturated brine (100 ml), dried and evaporated to dryness to obtain compound 212D (152 mg). LCMS (ESI) m / z: 381 (M+1).

[0831] Compound 212E

[0832]

[0833] Compound 212D (222.52 mg, 940.3 μmol) was added to a mixture of ethanol (8 ml) and water (1 ml) at 22°C under nitrogen protection, followed by ammonium chloride (323.09, 6.04 mmol) and iron (337.35 mg, 6.04 mmol) and reacted at 80°C for 2 hours under nitrogen protection. The solution was cooled to room temperature, filtered, evaporated to dryness at 45°C, and separated with water (100 ml) and dichloromethane (100 ml). The aqueous phase was extracted with dichloromethane (100 ml*2), and the organic phase was washed once with saturated brine (60 ml), dried, and evaporated to dryness to obtain compound 212E (180 mg). LCMS (ESI) m / z: 351 (M+1).

[0834] Embodiment 212

[0835]

[0836] Under nitrogen protection at 22°C, compound 212E (50 mg, 142.53 μmol) and pyridine (56.37 mg, 712.65 mmol) were added to N,N-dimethylformamide (2 ml), and then ES891-99 (98.42 mg, 570.12 μmol) was added, and the mixture was reacted at 24°C for 2 hours under nitrogen protection. Cyclopropylamine (32.55 mg, 570.12 μmol) was then added, and the mixture was reacted at 24°C for 0.5 hours under nitrogen protection. The reaction solution was separated by liquid chromatography to obtain Example 212 (yellow solid, 3 mg, 4.2% yield). LCMS S (ESI) m / z: 450 (M+1).

[0837] 1 H NMR(400MHz, METHANOL-d4)=9.22(s,1H),9.14(d,J=6.8Hz,1H),8.87(d,J=8.8Hz,1H),8.49(s,1H),8.23(d,J=8.8Hz,1H),8.11 (s,1H),7.96(br.s.,1H),7.69(s,1H),7.44(d,J=7.3Hz,2H),4.10(s,3H),2.92-2.67(m,1H),0.95(br.s.,2H),0.78(br.s.,2H)

[0838] Embodiment 213

[0839]

[0840] This example was prepared as described in Example 212. LCMS (ESI) m / z: 450 (M+1).

[0841] 1 H NMR(400MHz, METHANOL-d4)=8.96(d,J=6.3Hz,1H),8.70(d,J=9.0Hz,1H),8.65(s,1H),8.46(s,1H),8.26(d,J=9. 0Hz,1H),8.20(s,1H),7.64(s,1H),7.39(d,J=9.0Hz,1H),7.25(s,1H),4.00(s,3H),0.94(br.s.,2H),0.77(s,1H)

[0842] Process AI

[0843]

[0844] Compound 214A

[0845]

[0846] Phosphorus oxychloride (106.76 g, 696.28 mmol) was added in batches to a solution of 4-chloro-7-bromo-quinoline (60 g, 267.8 mmol) in dioxane (660 ml) at 30°C. After stirring at 100°C for 40 minutes, the thin layer preparative chromatography plate showed that 4-chloro-7-bromo-quinoline had reacted completely. The reaction solution was quenched with water (200 ml), then extracted with ethyl acetate (200 ml*2), the organic phase was washed with saturated brine (100 ml*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 214A (light yellow solid, 59 g, 81.77% yield). LCMS (ESI) m / z: 243.8 (M+1).

[0847] Compound 214B

[0848]

[0849] A mixture of compound 214A (25 g, 103.09 mmol), 2-fluoro-3-chloro-4-nitro-phenol (39.49 g, 206.19 mmol) and chlorobenzene (250 ml) was reacted at 130°C for 12 hours. Thin layer preparative chromatography showed that compound 216A had reacted completely. The reaction solution was cooled to room temperature, and a yellow solid was produced. Compound 214B was obtained by filtration and was directly used in the next step without further purification. LCMS (ESI) m / z: 396.8 (M+1).

[0850] Compound 214C

[0851]

[0852] At 20°C, ammonium chloride (9.69 g, 181.10 mmol) and reduced iron powder (7.59 g, 135.82 mmol) were added to a mixed solution of compound 214B (18 g, 45.27 mmol) in ethanol (18 ml) and water (2 ml). After stirring at 90°C for 2 hours, thin layer preparative chromatography showed that compound 214B had reacted completely. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a residue. Water (10 ml) was added to the residue and then extracted with dichloromethane (150 ml*2). The organic phase was washed with sodium hydroxide (0.5 mol / L, 50 ml*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 214C (brown-red solid, 6.20 g, 29.81% yield). LCMS (ESI) m / z: 368.8 (M+1).

[0853] Compound 214D

[0854]

[0855] Under nitrogen protection, potassium acetate (4.81 g, 48.97 mmol) and Pd(dppf)Cl2 (1.19 g, 1.63 mmol) were added to a solution of compound 214C (6 g, 16.32 mmol) in dioxane (60 ml), and nitrogen was replaced three times. After the reaction solution was stirred at 70°C for 4 hours, the thin layer preparation chromatography plate showed that compound 216B had reacted completely. The reaction solution was quenched with water (20 ml), then extracted with ethyl acetate (50 ml*2), the organic phase was washed with saturated brine (20 ml*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 214D (light yellow solid, 6.50 g, 81.64% yield). LCMS (ESI) m / z: 243.8 (M+1).

[0856] Compound 214E

[0857]

[0858] Under nitrogen protection, 4-iodo-1-methyl-imidazole (651.66 mg, 3.13 mmol) and potassium carbonate (1 g, 7.23 mmol) were added to a mixed solution of compound 214D (1 g, 2.41 mmol) in N,N'-dimethylformamide (6 ml) and water (2 ml), and nitrogen was replaced three times. The reaction solution was microwaved at 110°C for 30 minutes. Thin layer preparation chromatography plate detection showed that compound 214D had reacted completely. The reaction solution was quenched with water (10 ml), then extracted with ethyl acetate (20 ml * 3), the organic phase was washed with saturated brine (10 ml * 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to obtain compound 214E (light yellow solid, 300 mg, 29.03% yield). LCMS (ESI) m / z: 369.0 (M+1).

[0859] 1 H NMR(400MHz,DMSO-d6)ppm 3.75(s,3H)5.83(s,2H)6.47-6.56(m,1H)6.73(d,J=9.03Hz,1H)7.11-7.25(m,1H)7.75(s,1H) 7.91 (s, 1H) 8.08 (d, J = 8.03Hz, 1H) 8.29 (d, J = 8.53Hz, 1H) 8.32-8.38 (m, 1H) 8.60-8.67 (m, 1H).

[0860] Compound 214F

[0861]

[0862] Under ice bath, triphosgene (160.93 mg, 542.31 μmol) was added to a tetrahydrofuran (20.00 ml) solution of compound 214E (200.00 mg, 542.31 μmol) and N,N-diisopropylethylamine (350.44 mg, 2.71 μmol) stirred under ice bath for 10 minutes, and stirred for 3 hours. Cyclopropylamine (619.21 mg, 10.85 mmol) was then added to the reaction solution and stirred for 1 hour. After the reaction was completed by LC-MS detection, the reaction solution was quenched with water (15.00 ml), and a white solid appeared at this time, which was filtered to obtain compound 214F (210.00 mg, 464.73 μmol, yield 85.69%). LCMS (ESI) m / z: 452.1 (M+1).

[0863] 1H NMR(400MHz,METHANOL-d4)d ppm 0.58(br.s.,2H)0.81(d,J=5.77Hz,2H)2.66(m,1H)3.85(s,3H)6.63(d,J=4.77Hz,1H)7.36(t,J=8.78Hz ,1H)7.77(d,J=3.51Hz,2H)8.09(d,J=7.78Hz,2H)8.33-8.39(m,1H)8.39-8.45(m,1H)8.58-8.73(m,1H)

[0864] Embodiment 214

[0865]

[0866] Compound 214F (643 mg, 1.42 mmol) was added to methanol (33 ml), and the reaction solution was heated to reflux. Dilute hydrochloric acid (1 mol / L, 30 drops) was added dropwise under reflux until the solution was clear. The reaction solution was cooled to room temperature, and the solution was evaporated to 10 ml by rotary evaporation, and then ethyl acetate (100 ml) was added. A large amount of white solid precipitated, filtered, and the solid was washed with ethyl acetate and dried in vacuo to obtain Example 214 (white solid, 560 mg, yield 74.7%). LCMS (ESI) m / z: 452.1 (M+1).

[0867] 1 H NMR(400MHz, METHANOL-d4)=9.24(s,1H),9.11(d,J=6.5Hz,1H),8.85(d,J=9.0Hz,1H),8.64(s,1H),8.47(s,1H),8.37(d,J=8.8Hz,1H) ,8.23(d,J=9.0Hz,1H),7.51(t,J=8.8Hz,1H),7.30(d,J=6.5Hz,1H),4.11(s,3H),2.67(m,1H),0.81(d,J=5.5Hz,2H),0.59(br.s.,2H).

[0868] The following examples were prepared using a similar method as described in Preparation Example 214:

[0869]

[0870]

[0871]

[0872]

[0873]

[0874] Process AJ

[0875]

[0876] Compound 215A

[0877]

[0878] Phosphorus oxychloride (35.6 g, 232 mmol) was added dropwise to 7-bromo-4-hydroxyquinoline (20 g, 89.3 mmol) in toluene (220 ml) at 30°C over 10 minutes. The reaction solution was heated to 100°C and reacted for 40 minutes. The excess phosphorus oxychloride was evaporated by rotary evaporation, and the residue was added to dichloromethane (200 ml), washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was separated by column chromatography (dichloromethane, Rf = 0.5) to obtain compound 215A (off-white solid, 12 g, 55%). LCMS (ESI) m / z: 243.8 (M+1).

[0879] 1 H NMR(400MHz, CHLOROFORM-d)7.53(d,J=4.77Hz,1H)7.76(dd,J=9.03,1.76Hz,1H)8.13(d,J=9.03Hz,1H)8.34(d,J=1.76Hz,1H)8.80(d,J=4.77Hz,1H)

[0880] Compound 215B

[0881]

[0882] Compound 215A (12 g, 49.5 mmol), 1,1-bis(triphenylphosphino)ferrocenepalladium dichloride (3.62 g, 4.95 mmol), cynamol borate (18.85 g, 74.2 mmol) and potassium acetate (14.6 g, 148.4 mmol) were added to a 1,4-dioxane (120 ml) solution. Nitrogen was added to the reaction solution for degassing for 3 minutes, and then heated to 70°C under nitrogen protection for 3 hours. 50 ml of water was added to quench the reaction, and the reaction solution was extracted with ethyl acetate 2X200 ml. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was separated by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1, Rf = 0.5) to obtain compound 215B (white solid, 11 g, 69%). LCMS (ESI) m / z: 290.1 ​​(M+1).

[0883] 1H NMR(400MHz,CHLOROFORM-d)8.89-8.77(m,1H),8.67-8.57(m,1H),8.29-8.15(m,1H),8.07-7.94(m,1H),7.59-7.47(m,1H),1.42(s,10H)

[0884] Compound 215C

[0885]

[0886] Compound 215B (710 mg, 2.45 mmol), 5-iodo-1-methyl-imidazole (561 mg, 2.7 mmol), 1,1-bis(triphenylphosphino)ferrocenepalladium dichloride (359 mg, 490 μmol) and cesium carbonate (2.4 g, 7.36 mmol) were added to a mixed solution of 1,4-dioxane (6 ml) and water (6 ml). The reaction solution was heated to 100°C under nitrogen protection for 16 hours. The reaction solution was diluted with water (5 ml) and extracted with ethyl acetate 3X5 ml. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was separated by column chromatography (dichloromethane / methanol=20 / 1, Rf=0.4) to obtain compound 215C (yellow solid, 350 mg, 59%).

[0887] LCMS (ESI) m / z: 243.9 (M+1).

[0888] 1 H NMR(400MHz,CHLOROFORM-d)=8.84(d,J=4.5Hz,1H),8.32(d,J=8.8Hz,1H),8.17(s,1H), 7.80-7.73(m,1H),7.66(br.s.,1H),7.54(d,J=4.8Hz,1H),7.41(br.s.,1H),3.86(s,3H)

[0889] Compound 215D

[0890]

[0891] Compound 215C (350 mg, 1.44 mmol) and compound 95B (414 mg, 2.16 mmol) were added to chlorobenzene (8 ml). The reaction solution was heated to 140°C for 14 hours. The solvent was evaporated to dryness, and the residue was separated by column chromatography (dichloromethane / methanol=20 / 1, Rf=0.4) to obtain compound 215D (yellow solid, 150 mg, 26%). LCMS (ESI) m / z: 399.1 (M+1).

[0892] Compound 215E

[0893]

[0894] Iron powder (63 mg, 1.13 mmol) and ammonium chloride (81 mg, 1.5 mmol) were added to a mixed solution of compound 215D (150 mg, 376 μmol) in ethanol (2 ml) and water (0.2 ml). The reaction solution was heated to 80°C for 15 minutes and filtered. The solvent was evaporated to dryness to obtain compound 215E (brown jelly, 50 mg, 36%), which was used directly in the next step. LCMS (ESI) m / z: 369.0 (M+1).

[0895] Compound 215F

[0896]

[0897] Compound 215E (50 mg, 136 μmol), phenyl chloroformate (21 mg, 136 μmol) and pyridine (11 mg, 136 μmol) were added to anhydrous DMF (1 ml). The reaction solution was reacted at 25°C for 2 hours. After the reaction was completed, the reaction solution was directly used for the next step. LCMS (ESI) m / z: 489.1 (M+1).

[0898] Embodiment 215

[0899]

[0900] Cyclopropylamine (7 mg, 123 μmol) and N,N-diisopropylethylamine (16 mg, 123 μmol) were added to a DMF solution of compound 215F (the crude product was used directly in this step). The reaction solution was reacted at 25°C for 1 hour. Water (3 ml) was added to quench the reaction, and 3×5 ml of ethyl acetate were extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was separated by preparative HPLC to obtain Example 215 (yellow solid, 11 mg, 18%). LCMS (ESI) m / z: 452.0 (M+1).

[0901] 1H NMR (400MHz, METHANOL-d4)8.72(d,J=5.3Hz,1H),8.52(d,J=8.8Hz,1H),8.15(s,1H),8.11(d,J=9.3Hz,1H),7.90-7.83(m, 2H),7.40-7.36(m,1H),7.34(br.s.,1H),6.73(d,J=5.0Hz,1H),3.91(s,3H),2.67(td,J=3.5,6.8Hz,1H),0.84-0.49(m,4H)

[0902] The following examples were prepared using a similar method as described in Preparation Example 215:

[0903]

[0904]

[0905] Process AK

[0906]

[0907] Compound 222A

[0908]

[0909] Under nitrogen protection at 28°C, 4-chloro-7-hydroxyquinoline (500 mg, 2.78 mmol) and pyridine (484.47 mg, 6.12 mmol) were added to dichloromethane (50 ml), and then trifluoromethanesulfonic anhydride (1.18 g, 4.17 mmol) was slowly added dropwise at 0°C. The mixture was stirred at 28°C for 2 hours. The solution was quenched with saturated ammonium chloride solution and extracted with dichloromethane (100 ml*2). The organic phase was washed with saturated brine (100 ml), dried and filtered to obtain compound 222A (300 mg). The product was used directly in the next step without further purification. LCMS (ESI) m / z: 312 (M+1).

[0910] Compound 222B

[0911]

[0912] Under nitrogen protection at 28°C, compound 222A (200 mg, 641.72 μmol), bis-pyridinol borate (195.55 mg, 770.07 μmol), ferrocenepalladium dichloride (140.87 mg, 192.52 μmol), potassium acetate (188.94 mg, 1.93 mmol) were added to 1,4-dioxane (2 ml), and the solution was heated to 80°C and stirred for 16 hours under nitrogen protection. The solution was cooled to room temperature, diluted with ethyl acetate (50 ml), filtered, and water (50 ml) was added. The aqueous phase was extracted with ethyl acetate (50 ml*2), and the organic phases were combined, washed once with saturated brine (100 ml), dried and evaporated to obtain compound 222B (50 mg). The product was used directly in the next step without further purification. LCMS (ESI) m / z: 208 (M+1).

[0913] Compound 222C

[0914]

[0915] Under nitrogen protection at 28°C, compound 222B (120 mg, 578.54 μmol) and 4-iodo-1-methylimidazole (144.4 mg, 694.24 μmol) were added to 1,4-dioxane (1.5 ml), and then cesium carbonate (565.5 mg, 1.74 mmol) and ferrocene palladium dichloride (84.66 mg, 115.71 μmol) were added. The mixture was stirred at 100°C for 16 hours under nitrogen protection. The reaction solution was filtered and evaporated to dryness to obtain compound 222C (120 mg). The product was used directly in the next step without further purification. LCMS (ESI) m / z: 244 (M+1).

[0916] Compound 222D

[0917]

[0918] Under nitrogen protection at 22°C, compound 185B (100 mg, 561.36 μmol) and ethylamine hydrochloride (45.77 mg, 561.36 μmol) were added to N,N-dimethylformamide (2 ml), and then HATU (213.45 mg, 561.36 mmol) and N,N-diisopropylethylamine (362.75 mg, 2.81 mmol) were added. The mixture was stirred at 22°C for 2 hours under nitrogen protection. The reaction solution was added to water (100 ml) and extracted with ethyl acetate (50 ml*3). The organic phase was washed with saturated brine (115 ml) and dried over anhydrous sodium sulfate to obtain compound 222D (200 mg). LCMS (ESI) m / z: 206 (M+1).

[0919] Embodiment 222

[0920]

[0921] Under nitrogen protection at 22°C, compound 222C (163.88 mg, 672.48 μmol), compound 222D (138 mg, 672.48 μmol), cesium carbonate (438.21 mg, 1.88 mmol) were added to N,N-dimethylformamide (2 ml), and reacted at 120°C for 1 hour under microwave conditions. The solution was filtered and purified by liquid chromatography to obtain Example 222 (yellow solid, 46 mg, 15.92% yield). LCMS (ESI) m / z: 413 (M+1).

[0922] 1 H NMR(400MHz, METHANOL-d4)=8.61-8.54(m,1H),8.40-8.30(m,3H),8.16(d,J=8.3Hz,1H),8.01(d,J=8.5Hz,1H),7.78-7.65(m,2H),7.47(d,J =1.5Hz,1H),7.23(dd,J=1.6,8.4Hz,1H),6.56(d,J=5.3Hz,1H),3.82(s,3H),3.45(q,J=7.1Hz,2H),1.30-1.28(m,1H),1.27(t,J=7.2Hz,3H)

[0923] The following compound was prepared using a method similar to that of Example 223 above

[0924]

[0925]

[0926] Experimental Example 1: In vitro enzyme activity test of the compounds of the present invention

[0927] Purpose

[0928] By Z′-LYTE TM Detection Kinase Assay detects enzyme activity and uses the IC 50 The value is used as an indicator to evaluate the inhibitory effect of the compound on three kinases: VEGFR2, FGFR1, and PDGFRB.

[0929] Experimental Materials

[0930] Recombinant human VEGFR2 and FGFR1 proteases were purchased from Life technology, and PDGFRB protease was purchased from Millipore.

[0931] Z-LYTE TM Kit Tyr1 and Tyr4 were purchased from Life technology. The plate was read using a multi-link microplate reader Envision (PerkinElmer).

[0932] Experimental methods

[0933] The test compound was diluted 3-fold in a gradient, with a final concentration ranging from 10 μM to 0.17 nM in 11 concentrations, with two replicate wells for each concentration; the content of DMSO in the detection reaction was 1%.

[0934] VEGFR2 enzyme reaction:

[0935] 3nM VEGFR2 protein kinase, 2μM Tyr1 peptide, 100μM ATP, 50mM HEPES (pH7.5), 10mM MgCl2, 1mM EGTA, 0.01% BRIJ-35. The detection plate is Black Proxiplate 384-Plus plate (PerkinElmer), the reaction is carried out at room temperature for 60 minutes, and the reaction system is 10μl.

[0936] FGFR1 enzyme reaction:

[0937] 1nM FGFR1 protein kinase, 2uM Tyr4 peptide, 25μM ATP, 50mM HEPES (pH 7.5), 10mM MgCl2, 1mM EGTA, 0.01% BRIJ-35, 2mM MnCl2, 1mM DTT. The detection plate is Black Proxiplate 384-Plus plate (PerkinElmer), the reaction is carried out at room temperature for 60 minutes, and the reaction system is 10μl.

[0938] PDGFRB enzyme reaction:

[0939] 40nM PDGFRB protein kinase, 2μM Tyr4 peptide, 100μM ATP, 50mM HEPES (pH7.5), 10mM MgCl2, 1mM EGTA, 0.01% BRIJ-35, 2mM MnCl2, 1mM DTT. The detection plate is Black Proxiplate 384-Plus plate (PerkinElmer), the reaction is carried out at room temperature for 60 minutes, and the reaction system is 10μl.

[0940] Reaction detection:

[0941] The reaction was terminated by adding 5ul DV reagent B (1:128) to the kinase reaction solution and incubated at 23°C for 60 minutes. The plate was read using the Envision instrument.

[0942] Data analysis

[0943] The data were converted into phosphorylation rate and inhibition rate, and the compound IC was obtained by parameter curve fitting (Model 205 in XLFIT5, iDBS). 50 The experimental results are shown in Table 1.

[0944] Table 1 Z′-LYTE TM Detection IC 50 Test Results

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954] Note: VEGFR2: 200nM≤A<1uM, 50nM≤AA<200nM, AAA<50nM, N / A, means not measured.

[0955] FGFR1: 200nM≤A<1uM, 50nM≤AA<200nM, AAA<50nM, N / A, means not measured.

[0956] PDGFRB: 200nM≤A<1uM, 50nM≤AA<200nM, AAA<50nM, N / A, means not measured.

[0957] Conclusion: The compounds of the present invention have excellent in vitro inhibitory activity against VEGFR2, FGFR1, and PDGFRB, among which:

[0958] 1. By comparing Example 122 with Example 123, Example 113 with Example 108, Example 115 with Example 111, Example 117 with Example 103, Example 118 with Example 106, Example 119 with Example 95, Example 120 with Example 98, it was found that the thiourea structure can greatly improve its inhibitory activity against VEGFR2 and FGFR1 kinases compared with the urea structure;

[0959] 2. By comparing: Example 1 with Example 78, Example 28 with Example 112, Example 32 with Example 98, Example 56 with Example 124, Example 74 with Example 106, Example 87 with Example 123, it was found that adding fluorine to the position adjacent to chlorine on the benzene ring can greatly improve its FGFR1 kinase inhibitory activity;

[0960] 3. By comparing Example 77 with Example 78, fluorine and chlorine on the same side can greatly improve their FGFR1 kinase inhibitory activity compared with the opposite side.

[0961] Experimental Example 2: In vitro cytostatic activity of the compounds of the present invention

[0962] Purpose

[0963] By CellTiter- Luminescent Cell Viability Assay detects changes in intracellular ATP and uses the IC 50 The value was used as an indicator to evaluate the inhibitory effect of the compound on HUVEC cells in vitro.

[0964] Experimental Materials

[0965] HUVEC cell line (ATCC), EGM-2 Bullet Kit (Lonza), hVEGF-165 (Cell Signaling), trypsin (Invitrogen), DPBS (Hyclone), 384 cell plate (Greiner), 384 compound plate (Greiner), CO2 incubator (Thermo), centrifuge (Eppendorf), Vi-cell cell counter (Beckman Coulter), Bravo automatic liquid workstation (Agilent), Envision (Perkin Elmer)

[0966] Experimental methods

[0967] A cells recover and grow.

[0968] B cell plating: resuspend HUVEC cells in starvation medium (containing only 2% FBS and 0.1% GA-1000) to a concentration of 20,000 / mL, add the diluted cells to a 384 plate (Greiner), 50 μl / well. Place the cell plate in a 37°C, 5% CO2 incubator overnight.

[0969] C drug addition: The test compound was diluted 4-fold to obtain 10 doses from 10uM to 0.038nM, with two replicates. 47.6uL starvation medium was added to each well of the middle plate, and 2.4μl of compound was transferred from the gradient dilution compound plate to the middle plate and mixed thoroughly. Then 5μl of liquid was transferred from the middle plate to the cell plate, and incubated in a 37°C, 5% CO2 incubator for 1 hour, and then 5μl of starvation medium containing a final concentration of 20ng / ml hVEGF-165 and a final concentration of 1ng / mL Heparin was added, and cultured in a 37°C, 5% CO2 incubator for 72 hours.

[0970] D After 72 hours, add 30 μl of detection reagent, incubate at room temperature for 10-30 minutes, and read the plate using Envision.

[0971] Data processing

[0972] The readings were converted into inhibition rate (%) by the following formula: (Max-Sample) / (Max-Min)*100%. IC was determined by parametric curve fitting (Model 205 in XLFIT5, iDBS) 50 The experimental results are shown in Table 2.

[0973] Table 2 CellTiter- Detection IC 50 Test Results

[0974]

[0975]

[0976]

[0977] Note: AA<100nM, 100nM≤A<1μM.

[0978] Conclusion: The compounds of the present invention have excellent inhibitory activity against HUVEC.

[0979] Experimental Example 3: Tumor growth inhibition (TGI) analysis

[0980] The evolution and growth potential of tumors was evaluated by the relationship between tumor volume and time. The long axis (L) and short axis (W) of subcutaneous tumors were measured twice a week by calipers, and the tumor volume (TV) was calculated by the formula ((LxW 2 ) / 2). TGI was calculated by the difference between the median tumor volume of mice in the solvent group and the median tumor volume of mice in the drug group, expressed as a percentage of the median tumor volume of the solvent control group, using the following formula:

[0981] %TGI=((median tumor volume (control) - median tumor volume (drug group)) / median tumor volume (control group))×100%

[0982] The original statistical analysis was done by repeated variance analysis. Then multiple comparisons were performed by Scheffe psot hoc experimental method. The single solvent (0.5% methylcellulose + 0.2% Tween aqueous solution) was used as negative control. The experimental results are shown in Table 3.

[0983] Table 3 Results of in vivo antitumor activity test in mice

[0984] Calu 6 transplant model TGI% (last dose) Example 1 50 mg / kg, QD 57 Embodiment 200 100 mg / kg, QD 59 Embodiment 216 10 mg / kg, QD 83

[0985] The compound of the present invention has excellent in vitro VEGFR2, FGFR1, PDGFRB trikinase inhibitory activity and HUVEC cell inhibitory activity, can be used as a small molecule tyrosine kinase inhibitor, has the effect of inhibiting cell proliferation and angiogenesis, has excellent anti-tumor activity, and has excellent effects on the treatment of tumor diseases in various mammals (including humans).

Claims

1. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof; wherein: The structural formula of formula (II) is as follows: R1 is selected from C 1-6 Alkoxy and O(CH2) n R 1d1 , where n is an integer from 1 to 6, R 1d1 C 1-6 Alkoxy or NR 1d5 R 1d6 , where R 1d5 and R 1d6 Each independently is H or C 1-6 The alkyl group, R 1d2 , R 1d3 and R 1d4 Each independently is H, C 1-6 The alkyl group; R2 is selected from -C(=O)N(R 2d1 )(R 2d2 ); Among them, R 2d1 , R 2d2 , R 2d3 Each independently selected from H, OH, NH2, CN or C 1-7 Alkyl, C 1-7 heteroalkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, Or, R 2d1 and R 2d2 Together they form a 4-7 membered ring, or the structural unit -N(R 2d1 R 2d2 ) R 10 is selected from H, OH, NH2, CN or halogen; A is selected from phenyl, R 11 for Among them, Y is S, R7 is selected from H or C 1-4 Alkyl; R8 and R9 together form a 4- to 6-membered ring.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: A is selected from 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: A is selected from R1 is 4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: R 2d1 , R 2d2 , R 2d3 Each independently selected from H, OH, methyl, Structural unit -N(R 2d1 R 2d2 ) 5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: The structural unit -N(R 2d1 R 2d2 ) 6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: R2 is selected from 7. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the structure is shown in formula (III):

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for regulating protein kinase activity.

10. The use according to claim 9, characterized in that: The protein kinase is a tyrosine kinase selected from VEGFR2, FGFR1 and PDGFRB.

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