TW201808953A - Fused-ring or tricyclic aryl pyridine compuond used as kinase inhibitor - Google Patents

Abstract

The present invention discloses a fused-ring or tricyclic aryl pyridine compound used as a mutation selective EGFR inhibitor. And more specifically, the present invention discloses a compound used as an EGFR inhibitor or pharmaceutically acceptable salt thereof. The structure of the compound is shown in Formula (I).

Description

Fused or tricyclic arylpyrimidine compounds as kinase inhibitors

The present invention relates to a fused or tricyclic arylpyrimidine compound as a mutant selective EGFR inhibitor. In particular, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an EGFR inhibitor.

Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group on a protein substrate from ATP or GTP to a tyrosine residue. Receptor tyrosine kinases initiate secondary signaling pathways by causing phosphorylation by transmitting signals from outside the cell to the cell. A variety of cellular processes are regulated by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival. In addition, many diseases or conditions are associated with abnormalities, abnormalities or disorders of one or more kinases.

The epidermal growth factor receptor belongs to the transmembrane tyrosine kinase receptor ErbB family, which includes EGFR (also known as ErbB or HER1), ErbB2 (HER2 or neu gene), ErbB3 (HER3) and ErbB4 (HER4) . In addition to HER3, it has tyrosine kinase activity. The EGFR/ErbB family tyrosine kinase receptor has an indispensable role in cell proliferation, differentiation and apoptosis, and thus becomes an effective target for preventing tumor growth and metastasis. The first generation of epidermal growth factor receptor tyrosine kinase inhibitors (in EGFR-TKI), including gefitinib (J Med 2004; 350: 2129-39) and erlotinib (Lancet Oncol 2011; 12: 735-42), they have been shown to be effective in patients with advanced NSCLC with somatic activating mutations. These mutations are in the kinase domain encoding the epidermal growth factor receptor, such as the in-frame deletion of exon 19 of the polynucleotide and the substitution of leucine at position 858 on exon 21 to the point mutation of arginine (L858R) (Nat Rev Cancer 2007; 7: 169-81). However, patients who eventually receive the first generation of EGFR-TKIs will eventually develop secondary growth due to drug resistance. The second mutation of the threonine substitution at position 790 to methionine (T790M) is the most commonly recognized mechanism of resistance. This mutation is detected in tumor cells of patients with 50% to 60% of disease progression (N Engl J Med 2005; 353: 207-8). Second-generation EGFR-TKIs, such as afatinib (Lancet Oncol 2014; 15: 213-22) and dacomitinib (Cancer 2014; 120: 1145-54) were developed to overcome the resistance of first-generation TKIs. They can irreversibly bind covalently to the cysteine at position 797 on EGFR. The covalent mechanism is thought to overcome the increased affinity of ATP for double mutants. However, cysteine-797 is present in all forms of EGFR. Therefore, these second-generation compounds are not only active against active and secondary mutant EGFR, but also active against wild-type EGFR. Inhibition of wild-type EGFR is not thought to contribute to its clinical efficacy, but rather to side effects of rash and diarrhea (Curr. Med. Chem. 2006, 13, 3483−3492).

Therefore, the third generation of EGFR-TKIs, including AZD9291 (Cancer Discov 2014; 4: 1046-61), CO-1686 (Cancer Res. 2013; 19: 2240-2247) and HM61713 (US 2013011213), are irreversible oral. EGFR-TKIs with mutation selectivity can inhibit T790M mutations and traditional EGFR mutations, but have no effect on wild-type EGFR. They are highly effective in T790M-positive tumors, but they still have some toxicity, such as diarrhea, rash, nausea and even high blood sugar (J Clin Oncol 2014;32:abstr 8009; J Clin Oncol 2014;32 :abstr 8010) It is clear that a compound with higher activity and lower toxicity will bring greater benefits.

The present invention relates to a novel series of fused or tricyclic arylpyrimidine compounds which exhibit excellent activity against sensitive and double mutant EGFR (sensitive and T790M resistance) and have a high selectivity for wild type EGFR. Sex. They are likely to provide a more effective treatment for diseases caused by abnormalities of the enzyme of the epidermal growth factor receptor.

It is an object of the present invention to provide a compound of the formula (I) or a pharmaceutically acceptable salt thereof, Where W is selected from: , , ; n = 0, 1 or 2; m = 1, 2 or 3Y ₁ , Y ₂ , Y ₃ , and Y ₄ are each independently selected from -O-, -S-, -C(R) ₂ -, -N (R)-, -S(=O) ₂ -, -S(=O)-, -C(=O)-, -C(=S)-; X _{1 is} selected from CR _X1 , N; X _{2 is} selected From CR _X2 , N; X _{3 is} selected from CR _X3 , N; R _X1 , R _X2 , R _X3 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , or R _X1 , R _X2 , R _X3 are each independently selected from C _{1 1-6} alkyl, C _1-6 heteroalkyl optionally substituted by 1, 2, 3 or 4 R; R _{1 is} selected from H, F, Cl , Me, CN, CF ₃ ; R _{2 is} selected from R ₀₂ , OR ₀₂ , SR ₀₂ ; R _{02 is} independently selected from, optionally substituted by 1, 2, 3 or 4 R: C _1-4 alkyl, C _1-4 heteroalkyl, C _3-5 cycloalkyl-(CH ₂ ) _0-3 -; R _{3 is} selected from C _{1 1-6} alkyl optionally substituted by 1, 2, 3 or 4 R, C _1-6 heteroalkyl, C _{2 -4} alkynyl, 3-7-membered cycloalkyl, 3-7-membered cycloalkyl-L-, 3-7-membered heterocycloalkyl, 3-7-membered heterocycloalkane The group -L-;L is selected from -O-, -S-, -C(=O)-, -S(=O) ₂ -, -S(=O)-, or L is selected from the group consisting of 3 or 4 substituents R a: NH, C _1-4 alkyl, C _1-4 heteroalkyl; "heteroaryl" represents a heteroatom or a heteroatom group selected from: -C (= O) NH- -NH-, -O-, -S-, N, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O -, -S(=O) ₂ -; the number of heteroatoms or heteroatoms is independently selected from 0, 1, 2, 3; R is selected from H, F, Cl, Br, I, OH, CN, or R is selected from the group consisting of 1, 2, 3 or 4 R's substituted: NH ₂ , C _1-4 alkyl, C _1-4 heteroalkyl, 3 to 7 membered cycloalkyl, or 3 to 7 Heterocycloalkyl; R' is selected from the group consisting of F, Cl, Br, I, CN, OH, NH ₂ , CF ₃ , NHCH ₃ , CH ₂ OCH ₃ , N(CH ₃ ) ₂ .

In one embodiment of the invention, the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, Me, Et, CF ₃ , N(CH ₃ ) ₂ , N(CD ₃ ) ₂ , NHCH ₃ , , .

In one aspect of the invention, the above Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently selected from: -O-, -S-, -CH ₂ -, -CF ₂ -, -CHF-, -C ( Me) ₂ -, -CH(Me)-, -CH(OH)-, -C(=O)-, -S(=O) ₂ -, -S(=O)-.

In one aspect of the invention, the above Y1 and Y3 are selected from the group consisting of: -CH2-, -C(Me)2-, -CH(Me)-, -C(=O)-, -CF2-, -CHF-, - CH(OH)-.

In one embodiment of the present invention, the above Y ₂ and Y ₄ are each independently selected from the group consisting of: a single bond, —O—, —S—, —S(=O) ₂ —, —CH ₂ —, —C(Me) ₂ — , -C(=O)-, -CF ₂ -, -CH(OH)-, -CH(Me)-, -CHF-.

In one aspect of the invention, the structural unit From: , , , , , , , , , , , , , , , , , , .

In one aspect of the invention, the structural unit From: , , , .

In one aspect of the invention, the structural unit From: , , , .

In one aspect of the invention, the L is selected from the group consisting of -O-, -S-, -C(=O)-, -S(=O) _2- , -S(=O)-, or L is selected from the group consisting of Substituted by 1, 2 or 3 R: NH, C _1-3 alkyl, -OC _1-3 alkyl, -S-alkyl, -NH-C _1-3 alkyl.

In one aspect of the invention, the L is selected from the group consisting of: -O-, -S-, -C(=O)-, -S(=O) _2- , -S(=O)-, or L is selected from any Selected by 1, 2 or 3 R: -NH-, -CH ₂ -, , , , , .

In one aspect of the present invention, the above-mentioned L is selected from: -O -, - S -, - C (= O) -, - NH -, - N (CH 3) -, - CH 2 -, , , , , .

In one embodiment of the invention, the above R _{3 is} selected from the group consisting of: ₁ , 2, 3 or 4 R substituted: -C _1-4 alkyl, -NH-C _1-4 alkyl, -NH-C ( =O)-C _1-4 alkyl, -OC _1-4 alkyl, -S-alkyl, -S(=O)-C _1-4 alkyl, -S(=O) ₂ -C _{1- 4} alkyl, C _{2 -3} alkynyl, 3-6-membered cycloalkyl, 3-6-membered cycloalkyl-L-, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkyl-L- The "hetero" represents a hetero atom or a hetero atom selected from: -C(=O)NH-, -NH-, -O-, -S-, N, =O, =S, -C(= O) O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) ₂ -, the number of heteroatoms or heteroatoms is independently selected from 0, 1, 2, 3.

In one aspect of the invention, the above R _{3 is} selected from the group consisting of: 1, 2, 3 or 4 R: , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In one aspect of the invention, the above R _{3 is} selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In one aspect of the invention, the above R _{02 is} selected from the group consisting of Me, CHF ₂ , CH ₂ CH ₃ , and CH(CH ₃ ) ₂ .

In one embodiment of the invention, the above compound is selected from the group consisting of .

Definition and description.

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.

C _{1-6 is} selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ ; 3 to 7 elements are selected from 3 yuan, 4 yuan, 5 yuan, 6 yuan and 7 yuan.

The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and 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 invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the fourth ammonium salts of the parent compounds, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-ethyloxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid. , benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid , hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, nitric acid, oxalic acid , pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin , tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.

Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.

Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.

Graphical representations of racemates, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E , Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the ( R )- and ( S )-enantiomers, diastereomeric a conformation, a ( D )-isomer, a ( L )-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

The optically active ( R )- and ( S )-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary groups cleaved to provide a pure Enantiomers are required. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art. The diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, vegetables. And minerals, cream bases, lotion bases, ointment bases, and the like. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.

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

The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in 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 will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease or condition.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. . When the substituent is a keto group (ie, =0), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

When any variable (e.g., R) occurs more than once in the composition or structure of the compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When one of the variables is selected from a single bond, it means that the two groups to which they are attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.

When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, structural unit or It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.

The substituents of the alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents" and may be selected from 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', -CO ₂ R'-CONR'R",-OC(O)NR'R",-NR"C(O)R',NR'C(O)NR"R"',-NR"C(O) ₂ R', -NR""'-C(NR'R"R'")=NR"", NR""C(NR'R")=NR'",-S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", NR"SO ₂ R', -CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ and fluoro(C ₁ -C ₄ )alkyl , the number of substituents is 0 to (2m'+1), where m' is the total number of carbon atoms in such a group. R', R", R"', R'''' and R''''' Each independently preferably hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (eg substituted by 1 to 3 halogen aryl), substituted or unsubstituted alkyl, alkane An oxy group, a thioalkoxy group or an aralkyl group. When the compound of the present invention includes more than one R group, for example, each R group is independently selected as if Each of these groups when more than one R', R", R"', R'''', and R'''' group. When R' and R" are attached to the same nitrogen atom, They can combine 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. In light of the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include carbon. a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF ₃ , -CH ₂ CF ₃ ) and a mercapto group (e.g., -C(O)CH ₃ , -C(O)CF ₃ , -C(O)CH ₂ OCH _{3 ,} etc.).

Similar to the substituents of the alkyl group, the aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected, for example, from -R', -OR', -NR'R", -SR', - Halogen, -SiR'R"R"', OC(O)R', -C(O)R', -CO2R', -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) ₂ R', -S(O) ₂ NR'R", NR"SO ₂ R',- CN, -NO ₂ , -N ₃ , -CH(Ph) ₂ , fluorine (C ₁ -C ₄ ) alkoxy, and fluorine (C ₁ -C ₄ ) alkyl, etc., the number of substituents is 0 to an aromatic ring Between the total number of open valencies; wherein R', R", R"', R"" and R""' are independently preferred from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted a heteroalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. When the compound of the present invention includes more than one R group, for example, each R group is independently added. Each of these groups is selected as when more than one R', R", R"', R"" and R"" group are present.

Unless otherwise specified, two substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, where 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 the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH ₂ )r B- wherein A and B are independent Selected from -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) ₂ -, -S(O) ₂ NR'- or a single bond, r is 1~ An integer of 4. Optionally, a single bond on the new ring thus formed can 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 formula -A(CH ₂ )r B-, wherein s and d are independently An integer selected from 0 to 3, and X is -O-, -NR', -S-, -S(O)-, -S(O) ₂ - or -S(O) ₂ NR'-. The substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C ₁ -C ₆ )alkyl.

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.

Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge. The C _1-6 alkoxy group includes a C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, bis-butoxy, tert-butoxy, n-pentyloxy, and S -pentyloxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. The 3-7 cycloalkyl group includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl groups. "Alkenyl" includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.

The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

Unless otherwise specified, the term "hetero" denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O). ), nitrogen (N), sulfur (S), antimony (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C (= O) O-, -C(=O) -, -C(=S)-, -S(=O), -S(=O) ₂ -, and -C(=O) optionally substituted N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- or -S(=O)N(H)-.

Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring" means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenyl, pyridine, and acridinyl; on the other hand, the term "5- to 7-membered heterocycloalkyl ring" includes pyridyl and acridinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom 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 phenyl ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein). The heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites. The nitrogen atom in the heterocycle is 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 one. The term "aromatic heterocyclic group" or "heteroaryl" as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It 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 as already 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 heterocycle does not exceed one. Bridged rings are also included in the definition of heterocycles. A bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon 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 one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4a H -carbazolyl , porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2 H , 6 H -1, 5,2-dithiazinyl, dihydrofuran [2,3 - b ] tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H -carbazolyl, nonenyl, indanyl, mesoindolyl, fluorenyl , 3 H -mercapto, isatino, isobenzofuranyl, pyran, isodecyl, isoindoline, isodecyl, fluorenyl, isoquinolyl, isothiazolyl, Isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, isomer , hydroxyindenyl, pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine, benzoxanthyl, phenoloxazinyl, pyridazinyl, pyridazinyl, acridinyl, anthracene Acridine, 4-acridone, piperonyl, pteridinyl, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinium Azole, pyridoimidazole, pyridothiazole, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2 H -pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolyl, 4 H -quina Azinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6 H -1,2,5-thiadiazinyl, 1,2 , 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazide, thiazolyl, isothiazole Thienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic The hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C ₁ -C ₁₀ represents 1 to 10 carbons). "Hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "hydrocarbyl" means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, t-butyl, isobutyl, cyclohexyl, (ring Hexyl) methyl, cyclopropylmethyl, and homologs or isomers of radicals such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , - CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

Unless otherwise specified, the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are customary and are meant to be attached to the molecule through an oxygen, amino or sulfur atom, respectively. The rest of those alkyl groups.

Unless otherwise specified, the term "cycloalkyl", "heterocycloalkyl" or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl) A heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized "hydrocarbyl group" or "heterohydrocarbyl group", respectively. Further, in the case of a heterohydrocarbyl group or a heterocycloalkyl group (such as a heteroalkyl group or a heterocycloalkyl group), a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule. Examples of cycloalkyl groups 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-tetrahydropyridyl), 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-pyridazinyl and 2-pyridazinyl.

Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 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 (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through 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-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. Unless otherwise specified, aryl groups, when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen. Those alkyl groups substituted by an atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.

The term "leaving group" refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Ester and the like; an oxime group such as an ethoxy group, a trifluoroacetoxy group or the like.

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, formazan; anthracenyl, such as alkanealkyl (e.g., ethyl, trichloroethyl or trifluoroethyl); alkoxycarbonyl, such as third Butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr , 1,1-di-(4'-methoxyphenyl)methyl; formylalkyl, such as trimethylmethanyl (TMS) and tert-butyldimethylformamidin (TBS), etc. Wait. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing hydroxy side reactions. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; fluorenyl groups such as alkane fluorenyl groups (e.g., ethenyl); arylmethyl groups such as benzyl (Bn) , p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); formyl, such as trimethylmethanyl (TMS) And tert-butyldimethylformamidinyl (TBS) and the like.

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, combinations thereof with other chemical synthesis methods, and equivalents well known to those skilled in the art. Alternatively, preferred embodiments include, but are not limited to, embodiments of the invention.

The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: aq for water; DCM for methylene chloride; PE for petroleum ether; DMF for N,N-dimethylformamide; DMA for N,N-dimethylacetamide; MeCN stands for acetonitrile; NMP stands for N-methyl-2-pyrrolidone; DME stands for 1,2-dimethoxyethane; TsOH stands for p-toluenesulfonic acid; DMSO stands for dimethyl hydrazine; EtOH stands for ethanol; MeOH stands for methanol; HOAc stands for acetic acid; NaCNBH3 stands for sodium cyanoborohydride; THF stands for tetrahydrofuran; Boc2O stands for di-tert-butyldicarbonate; TFA stands for trifluoroacetic acid; DIEA stands for diisopropylethylamine; Pd(dppf)Cl2 stands for [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride; NaH represents sodium hydride; LAH represents lithium aluminum hydride; Pd(OAc) ₂ represents palladium (II) acetate; Pd ₂ (dba) ₃ represents tris(dibenzylideneacetone)dipalladium; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethyl; MeSO ₃ H represents methanesulfonic acid; -BuOK stands for potassium butoxide; MsCl stands for methanesulfonyl chloride; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; Cs ₂ CO ₃ Representative carbonate ; K ₂ CO ₃ potassium carbonate Representative; NaHCO ₃ sodium bicarbonate Representative; Na ₂ SO ₄ sodium Representative; KOAc potassium acetate Representative; t-BuOH tert-butanol Representative; representatives of TFAA trifluoroacetic anhydride; the FA on behalf acid; of DBU Represents 1,8-diazabicyclo[5.4.0]undec-7-ene; m-CPBA represents 3-chloroperoxybenzoic acid; DAST represents diethylaminosulfur trifluoride.

Compound by hand or ChemDraw ^® software name, commercially available compounds using vendor directory name.

In some embodiments, a compound of formula (I) can be prepared according to the synthetic methods described in Scheme A. Where W is selected from the following structures:

Option A:

In the above scheme A, the dichloropyrimidine derivative (A) undergoes a Fuch-like reaction with a triphenyl or bicyclic compound (B) in the presence of a Lewis acid such as FeCl ₃ or AlCl ₃ , or with boric acid The ester (C) is reacted via a Suzuki coupling reaction to give the compound (D). Compound (D) and arylamine (E) are substituted by SNAr in the presence of TsOH or TfOH acid, or by palladium catalysis, in a base such as anhydrous potassium phosphate, in the presence of a ligand such as XPhos to give (F), The yield is moderate to excellent. (F) with a different nucleophile such as N1, N1 dimethylethane-1,2-diamine, in the presence of a base such as DIEA to give compound (G) which can be used in reducing agents such as Pd/C, NH4Cl/ Reduction under Fe conditions gives the amine (H). The amine (H) can be directly deuterated with acrylonitrile (I) in the presence of a base such as DIEA at a low temperature such as ((-40~0 °C) to obtain a compound (K) or an amine (H). The 3-chloropropionyl chloride (J) is first deuterated and then eliminated in the presence of a base such as NaOH to give the compound (K) of the formula 1.

Scheme B is synthesis A general method wherein n is equal to 0, Y ₁ , Y ₂ and Y ₃ are CH ₂ .

Option B:

The aldehyde (L) and the phosphate are reacted via wittig to obtain (M), which is reduced with a reducing agent such as LAH (M), followed by esterification with MsCl to obtain (N), which can be cyclized in the presence of a base such as NaH (O). ), which can be reacted with the dichloropyrimidine derivative (A) according to Scheme A to give (D).

Scheme C is synthesis A general method wherein n is equal to 1, Y ₁ and Y ₃ are CH ₂ and Y ₂ is O.

Substituting 2-hydroxymethyl hydrazine (P) with diphenylvinyl sulfonium salt (Q) in the presence of a base such as potassium hydroxide, a solvent such as dichloromethane, by addition and intramolecular ring closure reaction (R) It can be reacted with the dichloropyrimidine derivative (A) according to Scheme A to obtain (D).

Scheme D is a synthesis A general method wherein Y ₁ , Y ₂ and Y ₃ are CH ₂ .

Process C:

The substituted 7-hydroxyindole and the halohydrin (T) are reacted via Mitsunobu to obtain an anthracene derivative (U), and the compound (U) is ring-closed in the presence of a base such as sodium hydrogen to obtain a compound (V) which can be combined with The chloropyrimidine derivative (A) is reacted according to Scheme A to give (D).

The following illustrative examples have been prepared, isolated and characterized using the methods of the methods disclosed herein. In order to explain the present invention in more detail, the following examples are given, but the scope of the invention is not limited thereto.

Process 1

General preparation methods for intermediates A and B:

Example A1.

4-fluoro-2-methoxyaniline.

2-Methoxy-4-fluoronitrobenzene (100.00 g, 584.35 mmol) was dissolved in methanol (400 mL), and then Pd/C (10%, 10 g) was added after nitrogen. The mixture was heated to 40 ° C in H ₂ (pressure 50 Psi) and stirred for 12 hours. TLC showed the reaction was completed. EtOAc m. LCMS (ESI) (10-80CD): m/z: 1421.

Example A2.

4-fluoro-2-methoxy-5-nitroaniline.

Example A1 (83.00 g, 558.67 mmol) was slowly added dropwise to concentrated H ₂ SO ₄ (415 mL) at 0 ° C, then KNO ₃ (56.48 g, 558.67 mmol) was added portionwise. The mixture was stirred at 0-10 ° C for 3 hours. TLC showed the reaction was completed, and NH ₃ ·H ₂ O was added to the reaction mixture to pH 8. The temperature was controlled at 10 ° C. The obtained mixture was filtered, and the filtered cake was washed with water (500 mL), EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The title compound (yellow solid, 60.00 g, yield 54.81%) was obtained. ¹ H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 7.2 Hz, 1 H), 6.64 (d, J = 12.4 Hz, 1 H), 3.86 - 3.97 (m, 5 H).

Example A3.

(E)-Ethyl ethyl 3-(1H-indol-2-yl)acrylate.

Diethyl 2-phosphonate-ethyl acetate (18.53 g, 82.67 mmol) was dissolved in THF (100 mL), and NaH (4.13 g, 60% w, 103.33 Mohr), stirring for 1 hour. A solution of 1 -hydro-2-(formaldehyde) oxime (10 g, 69.89 mmol) in THF (80 mL) was then added dropwise, warmed to 20 ° C and stirred for 10 hours. TLC showed the reaction was complete, the addition of saturated NH ₄ Cl (100mL) was added to the reaction mixture, after removal of THF, extraction with EA (100mL x 3) and concentrated, and washed with saturated brine (100mL x 2) washed, dried over anhydrous sodium sulfate, Concentration gave the title compound (yellow solid, 12.20 g, yield 74.05%). ¹ H NMR (400MHz, CDCl3): δ, 8.60 (br. s., 1H), 7.71 (d, J = 16.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4Hz, 1H), 7.30-7.26 (m, 1H), 7.15-7.14 (m, 1H), 6.84 (s, 1H), 6.28 (d, J = 16.0Hz, 1H), 4.33-4.28 (m, 2H), 1.39-1.35 (m, 3H).

Example A4.

3-(1H-indol-2-yl)propan-1-ol.

LiAlH ₄ (4.58 g, 120.79 mmol) was suspended in THF (100 mL) at 0 ° C, and a solution of Example A3 (13.00 g, 60.69 mmol) in THF (50 mL) 8 hours. TLC showed the reaction was completed, and water (4.5 mL), 15% NaOH (4.5 mL) and water (13.5 mL) were sequentially added to the reaction mixture, and the mixture was stirred for 30 minutes and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ¹ H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.34-7.27 (m, 1H), 7.18-7.08 (m, 2H), 6.27 ( s, 1H), 3.83-3.71 (m, 2H), 2.94-2.81 (m, 2H), 2.04-1.91 (m, 2H).

Example A5.

3-(1H-indol-2-yl)propyl methanesulfonate.

Example A4 (9.23 g, 42.12 mmol) and TEA (8.52 g, 84.24 mmol) were dissolved in DCM (100 mL) at 0 ° C, and methanesulfonium chloride (7.24 g, 63.18 millimoles), stirred for 10 hours. TLC showed the reaction was completed, water (30 mL) was added to the mixture, and the mixture was evaporated to ethyl acetate (30 mL). Purification gave the title compound (br. ¹ H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.34-7.27 (m, 1H), 7.18-7.08 (m, 2H), 6.28 ( s, 1H), 4.32-4.29 (m, 2H), 3.02 (s, 3H), 2.94-2.90 (m, 2H), 2.20-2.13 (m, 2H).

Example A6.

2,3-Dihydro-1H-pyrrolo[1,2-α]indole.

Example A5 (4.50 g, 17.76 mmol) was dissolved in THF (150 mL) at 25 ° C. NaH (852.48 mg, 60% w, 35.52 mmol) was added to the mixture and stirred for 12 hours. TLC showed the reaction was completed. To a mixture was added saturated aqueous NH ₄ Cl to neutral. After concentrated to remove THF, it was extracted with EA (30 mL×3), and the organic layer was dried over anhydrous sodium sulfate. The title compound (yellow solid, 2.80 g, yield 95.27%). ¹ H NMR (400MHz, CDCl3): δ 7.57 (d, J = 8.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.14-7.11 (m, 1H), 7.10-7.04 (m, 1H), 6.19 (br. s., 1H), 4.12-4.06 (m, 2H), 3.09-3.00 (m, 2H), 2.69-2.59 (m, 2H).

Example A.

9 - (2-Chloropyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-α]indole.

Example A6 (3.50 g, 22.26 mmol) and 2,4 - dichloro pyrimidine (6.63 g, 44.53 mmol) was dissolved in DME (40mL), this mixture was added FeCl ₃ (3.61 g, 22.26 mmol Mohr) and heated to 70 ° C for 12 hours. The TLC showed 60% of the title compound and 40% of the titled compound from EtOAc, EtOAc, EtOAc (EtOAc) After purification by column chromatography (EtOAc: EtOAc = EtOAc: EtOAc: ¹ H NMR (400MHz, CDCl3): δ 8.41 (d, J = 5.2Hz, 1H), 8.36-8.31 (m, 1H), 7.38 (d, J = 5.6Hz, 1H), 7.33-7.27 (m, 3H ), 4.20-4.15 (m, 2H), 3.44-3.37 (m, 2H), 2.79-2.73 (m, 2H). LCMS (ESI) (5-95): m/z:

Example B.

4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidine 2-amine.

Example A (2.40 g, 8.90 mmol) and 2 -methoxy-4- 4 -fluoro-5-nitroaniline (1.66 g, 8.90 mmol) were dissolved in 1,4-dioxane (40 mL) To the mixture was added TsOH (1.53 g, 8.90 mmol), and the mixture was warmed to 120 ° C and stirred for 10 hours. LCMS showed the reaction was complete, saturated NaHCO ₃ solution (30mL) added to the mixture, concentrated to remove 1,4 - dioxane, was added water (50 mL), and extracted with DCM (50mL x3), the organic layer was dried over anhydrous sodium sulfate After concentration, a crude product is obtained. The title compound (yellow solid, 3.30 g, yield: 83.99%). ¹ H NMR (400MHz, CDCl3): δ 9.46 (d, J = 8.0Hz, 1H), 8.41 (d, J = 5.2Hz, 1H), 8.33-8.23 (m, 1H), 7.58 (s, 1H), 7.35-7.30 (m, 1H), 7.28-7.24 (m, 2H), 7.15 (d, J = 5.2Hz, 1H), 6.78 (d, J = 12.4Hz, 1H), 4.22-4.16 (m, 2H) , 4.06 (s, 3H), 3.47 (t, J = 7.2 Hz, 2H), 2.78-2.73 (m, 2H). LCMS (ESI) (5-95.

Process 2.

General preparation method of Example 1:

Example 1.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2((2-( Dimethylamino)ethyl)amino)-4-methoxyphenyl) acrylamide.

Example 1A.

N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N4-(2-(dimethylamino)ethyl ))-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

Example B (2.80 g, 6.68 mmol) and N,N',N'-trimethyl-1,2-diethylenediamine (1.02 g, 10.01 mmol) were dissolved in DMA (50 mL). DIEA (1.29 g, 10.01 mmol) was added to the mixture and the mixture was warmed to 90 ° C and stirred for 2 hours. LCMS showed the reaction was completed. EtOAc was evaporated. The title compound (red solid, 3.20 g, yield 90.73%) was obtained after eluting with EtOAc (EtOAc) ¹ H NMR (400MHz, CDCl3): δ 9.03 (s, 1H), 8.35-8.24 (m, 2H), 7.36 (d, J = 7.2Hz, 1H), 7.24-7.12 (m, 3H), 7.09 (s , 1H), 4.21-4.14 (m, 2H), 4.10 (s, 3H), 3.53-3.48 (m, 2H), 3.43-3.37 (m, 4H), 2.99 (s, 6H), 2.88 (s, 3H) ), 2.76-2.69 (m, 2H). LCMS (ESI) (0-60): m.

Example 1B.

N4-(4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N 1 -(2-(dimethylamino) Ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

Example 1A (3.20 g, 6.38 mmol) was dissolved in MeOH (100 mL) at 25 ° C. The mixture was in H ₂ (pressure 15 Psi) and stirred for 2 hours. </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI></RTI><RTIgt; ¹ H NMR (400MHz, CDCl3): δ 8.53-8.48 (m, 1H), 8.33 (d, J = 5.2Hz, 1H), 8.16 (s, 1H), 7.56 (s, 1H), 7.33-7.29 (m , 1H), 7.28-7.23 (m, 2H), 6.95 (d, J = 5.2Hz, 1H), 6.70 (s, 1H), 4.17 (t, J = 7.2Hz, 2H), 3.87 (s, 3H) , 3.39 (t, J = 7.6Hz, 2H), 3.22 (t, J = 6.4Hz, 2H), 2.83 (t, J = 6.0Hz, 2H), 2.78-2.71(m, 5H), 2.63 (s, 6H). LCMS (ESI) (0-60.).

Example 1C.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2((2-( Dimethylamino)ethyl)amino)-4-methoxyphenyl) acrylamide.

Example 1B (2.40 g, 5.09 mmol) and DIEA (789.40 mg, 6.11 mmol) were dissolved in DCM (150 mL) at -40 ° C, and ethyl acetate (460.00 mg, 5.09 millimoles), stirred for 1 hour. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0> Hydrochloride, 859.00 mg, yield 29.87%). ¹ H NMR (400MHz, CD3OD): δ 8.30 (br. s., 1H), 8.01 (d, J = 7.2Hz, 1H), 7.88 (br. s., 1H), 7.43-7.39 (m, 1H) , 7.31-7.17 (m, 3H), 7.10 (s, 1H), 6.75-6.70 (m, 1H), 6.47 (dd, J1 = 1.6Hz, J2 = 16.8Hz, 1H), 5.89-5.84 (m, 1H) ), 4.22 (t, J = 7.2Hz, 2H), 3.98 (s, 3H), 3.65-3.54 (m, 2H), 3.41-3.39 (m, 4H), 2.93 (s, 6H), 2.83 (s, 3H), 2.75 (t, J = 7.2 Hz, 2H). LCMS (ESI) (0-60): m/z:

Example 2.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)azetidin-1-yl)-4-methoxyphenyl)propenylamine.

Example 2A.

4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(3-(dimethylamino)azetidin-1 -yl)-2-methoxy-5-nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 1A, replacing N,N',N'-trimethyl-1,2-diethylenediamine with 3-N,N-dimethylaminecyclobutylamine hydrochloride. The title compound (red solid, 180.00 mg, yield 90.67%) was obtained. ¹ H NMR (400MHz, CDCl3): δ 9.01 (br. s., 1H), 8.30-8.12 (m, 2H), 7.28-7.24 (m, 1H), 7.19 (d, J = 2.4Hz, 2H), 7.04 (d, J = 5.6Hz, 1H), 6.09 (s, 1H), 4.19-4.09 (m, 4H), 3.98-3.96 (m, 5H), 3.60 (br. s., 1H), 3.19-3.12 (m, 2H), 2.69-2.67 (m, 2H), 2.51 (br. s., 6H). LCMS (ESI) (0-60.).

Example 2B.

N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)nitrogen Heterocyclobutane-1-yl)-6-methylbenzene-1,3-diamine.

This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 2A. The title compound (brown solid, 170.00 mg, yield 94.50%) was obtained. LCMS (ESI) (5-95): m.

Example 2C.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)azetidin-1-yl)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 2B. The title compound (TFA salt, 40.00 mg, yield 26.1%) was obtained. ^{1 H NMR (400MHz, DMSO-} d6): δ 8.97 (br s, 1H..), 8.29-8.23 (m, 2H), 7.90 (s, 1H), 7.53 (s, 1H), 7.39-7.34 (m , 1H), 7.18-7.12 (m, 2H), 6.97 (d, J = 5.6Hz, 1H), 6.53-6.39 (m, 1H), 6.26 (s, 1H), 6.19 (dd, J1 = 2.0Hz, J2 = 17.2Hz, 1H), 5.65 (d, J = 10.4Hz, 1H), 4.15 (t, J = 7.2Hz, 2H), 3.97-3.94 (m, 2H), 3.87 (s, 3H), 3.64- 3.62 (m, 2H), 3.31 (t, J = 7.6Hz, 2H), 2.66-2.62 (m, 3H), 2.14 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 3.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(2-( Dimethylamino)ethoxy)-4-methoxyphenyl) acrylamide.

Example 3A.

4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(2-(dimethylamino)ethoxy)-2- Methoxy-5-nitrophenyl)pyrimidine-2-amine.

2 - N,N-dimethylaminoethanol (47.82 mg, 536.47 micromoles) was dissolved in DMA (3 mL) at 0-10 ° C. To this mixture was added Example B (2.80 g, 6.68 m) Mohr) and N,N',N'-trimethyl- 1,2-ethanediamine, NaH (28.61 mg, 715.29 micromolar) was added to the mixture, and the temperature was raised to 20-30 ° C and stirred 30 minute. The temperature was lowered to 0-10 ° C, and a solution of EtOAc (8 mL) of Example B (150.00 mg, 357.65 micromoles) was added and the mixture was warmed to 40 ° C and stirred for 12 hours. TLC showed that the reaction was completed, the mixture was cooled to 0-10 ° C, and a saturated solution of NH ₄ Cl (8 mL) was added and extracted with DCM (8 mL×3). The title compound (yellow solid, 140.00 mg, yield 72.11%). LCMS (ESI) (10-80): m/z:

Example 3B.

N1-(4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(2-(dimethylamino) A Oxy)-6-methylbenzene-1,3-diamine.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 3A. The title compound (yellow solid, 70.00 mg, yield: 34.80%) was obtained. LCMS (ESI) (10-80): m/z:

Example 3C.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2 - (2-( Dimethylamino)ethoxy)-4-methoxyphenyl) acrylamide.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 3B. The title compound (FA salt, 20.00 mg, yield 24.79%) was obtained. ¹ H NMR (400 MHz, MeOH-d4): δ 8.59-8.63 (m, 1H), 8.45-8.52 (m, 1H), 8.25-8.31 (m, 1H), 8.18-8.25 (m, 1H), 7.27 -7.34 (m, 1H), 7.07-7.18 (m, 2H), 7.00-7.05 (m, 1H), 6.87-6.92 (m, 1H), 6.50-6.60 (m, 1H), 6.35-6.44 (m, 1H), 5.79-5.86 (m, 1H), 4.42-4.50 (m, 2H), 4.11 (s, 2H), 3.99 (s, 3H), 3.38-3.42 (m, 2H), 3.37 (s, 2H) , 2.87 (s, 6H), 2.60-2.70 (m, 2H). LCMS (ESI) (5-95): m/z:

Example 4.

2 – (2 – methoxy – 4 –(N –methyl)pyridazine-5 – acrylamidoanilino) – 4 -(3 - (1,2,3 - dihydropyrrolo[1,2 -a]吲哚)) Pyrimidine.

Example 4A.

4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(2-methoxy-4-(4-methylpyridazine-1- Base)-5-nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 1A, replacing N,N',N'-trimethyl-1,2-diethylenediamine with N-methylpyridazine. The title compound (yellow solid, 80.00 mg, yield 43.88%) was obtained. LCMS (ESI) (5-95): m/z: 500.1 [M+1].

Example 4B.

N1-(4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-6-methoxy-4-(4-A Pyridazin-1-yl)benzene-1,3-diamine.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 4A. The title compound (yellow solid, 80.00 mg, yield 43.88%) was obtained. LCMS (ESI) (5-95): m/z:

Example 4C.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(4-Methyloxazin-1-yl)phenyl)propenylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 4B. The title compound (FA salt, 17.60 mg, yield 19.33%) was obtained. ¹ H NMR (400 MHz, METHANOL-d6): δ 8.85 (s, 1 H), 8.34 (br. s., 2H), 8.18 - 8.28 (m, 2H), 7.25 - 7.30 (m, 1H), 7.09 - 7.18 (m, 2H), 7.03 (d, J = 4 Hz, 1H), 6.92 (s, 1H), 6.57 (dd, J = 16, 12 Hz, 1H), 6.31 (d, J = 20 Hz, 1H), 5.79 (d, J = 8 Hz, 1H), 4.07 (t, J = 8 Hz, 2H), 3.95 (s, 3H), 3.32 - 3.35 (m, 2H), 3.24 - 3.30 (m, 4H) ), 3.17 (m, 4H), 2.87 (s, 3H), 2.56 - 2.66 (m, 2H). LCMS (ESI) (0-60): m/z:

Example 5.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(Methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)propenylamine.

Example 5A.

Third butyl (2-(pyrrolidin-1-yl)ethyl)carbamate.

2 - pyrrole ethylamine (2.50 g, 21.89 mmol) was dissolved in THF (50 mL) at 0 ° C, and (Boc) ₂ O (4.78 g, 21.89 mmol) was added dropwise to the mixture. The mixture was heated to 15 ° C and stirred for 12 hours. The reaction was completed with EtOAc EtOAc EtOAc. ¹ H NMR (400 MHz, CDCl3): δ 5.09 (br. s., 1H), 3.22 (m, 2H), 2.54 (t, J = 6.0 Hz, 2H), 2.48 (br. s., 4H), 1.74 (m, 4H), 1.43 (s, 9H). LCMS (0-60CD): m/z:21.21.

Example 5B.

N-methyl-2-(pyrrolidin-1-yl)ethylamine.

Example 5A (2.00 g, 9.33 mmol) was dissolved in THF (100 mL) at EtOAc. Stir for 12 hours. TLC showed that the reaction was completed, and the mixture was warmed to 0° C., and then EtOAc (1N, 2 mL) and water (2 mL) was added to the reaction mixture, and the mixture was filtered. The filtrate was diluted with DCM (50 mL) The title compound (yellow oil, 1.00 g, yield 79.42%) was obtained. ¹ H NMR (400 MHz, CDCl3): δ 2.67 - 2.72 (m, 2H), 2.57 - 2.61 (m, 2H), 2.48 - 2.53 (m, 4H), 2.44 (s, 3H), 1.74 - 1.80 (m , 4H).

Example 5C.

N1-(4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-2-methoxy-N 4 -methyl- 5-Nitro-N-4-(2-(pyrrolidin-1-yl)ethyl)benzene-1,4-diamine.

This example was prepared according to the method of Example 1A, replacing N,N',N'-trimethyl-1,2-diethylenediamine with Example 5B. The title compound was obtained (yellow solid, 200.00 mg, yield 79.49%). LCMS (5-95AB):m/z: 528.2 [M+1].

Example 5D.

N4-(4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-5-methoxy-N 1 -methyl- N1-(2-(pyrrolidin-1-yl)ethyl)benzene-1,2,4-triamine.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 5C. The title compound (white solid, 160.00 mg, mp. LCMS (5-95AB):m/z: 498.2 [M+1].

Example 5E.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(Methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)propenylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 5D. The title compound (FA salt, 16.20 mg, yield 7.34%) was obtained. ¹ H NMR (400MHz, CD3OD): δ 8.47 (s, 1H), 8.43 (br. s., 1H), 8.25 - 8.29 (m, 1H), 8.23 (d, J = 4 Hz, 1H), 7.27 - 7.32 (m, 1H), 7.07 - 7.15 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.95 (s, 1H), 6.3 6 - 6.57 (m, 2H), 5.87 (dd, J = 10, 2.0 Hz, 1H), 4.06 - 4.12 (m, 2H), 4.00 (s, 3H), 3.44 - 3.53 (m, 2H), 3.32 - 3.38 (m, 4H), 3.23 - 3.31 (m, 4H ), 2.73 (s, 3H), 2.60 - 2.68 (m, 2H), 2.09 - 2.22 (m, 4H). LCMS (0-60AB): m/z: 55:21.

Example 6.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)propenylamine.

Example 6A.

N,N-Dimethylpyrrolidin-3-amine.

3 - (N,N-dimethylamino)pyrrolecarboxylic acid tert-butyl ester (300.00 mg, 1.40 mmol) was dissolved in DCM (20 mL) at 25 ° C, and TFA (1.60 g) was added to the mixture. , 14.00 millimoles), and stirred for 30 minutes. The reaction was completed with EtOAc (EtOAc m.

Example 6B.

4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(3-(dimethylamino)pyrrolidin-1-yl) 2-methoxy-5-nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 1A, replacing N,N',N'-trimethyl-1,2-diethylenediamine with Example 6A. The title compound (yellow solid, 250.00 mg, yield 75.95%) was obtained. LCMS (0-60AB): m/z: 514.2 [M+1].

Example 6C.

N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)pyrrole Alkyl-1-yl)-6-methylbenzene-1,3-diamine.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 6B. The title compound (white solid, 200.00 mg, yield 80.54%) was obtained. LCMS (5-95AB): m.

Example 6D.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 6C. The title compound (FA salt, 17.75 mg, yield 6.17%) was obtained. ¹ H NMR (400MHz, CD3OD): δ 8.46 (s, 1H), 8.26-8.15 (m, 2H), 7.28 (dd, J = 2.0, 8.0Hz, 1H), 7.17-7.10 (m, 2H), 7.00 (d, J = 6.0Hz, 1H), 6.71 (s, 1H), 6.59-6.49 (m, 1H), 6.31 (dd, J = 2.0, 16.0Hz, 1H), 5.76 (dd, J = 2.0, 12.0 Hz, 1H), 4.08 (t, J = 8.0Hz, 2H), 3.93 (s, 3H), 3.37-3.32 (m, 2H), 3.29-3.23 (m, 4H), 3.16-3.06 (m, 1H) , 2.67-2.56 (m, 2H), 2.45 (s, 6H), 2.31-2.20 (m, 1H), 2.00-1.90 (m, 1H). LCMS (0-60AB): m/z: 353.

Example 7.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-((3- (Dimethylamino)propyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 7A.

N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N4-(3-(dimethylamino)propane 2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 1A, replacing N,N',N'-trimethyl-1,2-diethylenediamine with N,N',N'-trimethyl-1,2-propane Diamine. The title compound was obtained (200.00 mg, crude). LCMS (ESI) (0-60): m/z:

Example 7B.

N4-(4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N 1 -(3-(dimethylamino) Propyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 7A. The title compound (white solid, 200.00 mg, crude) was obtained. LCMS (ESI) (0-60): m/z:

Example 7C.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-((3- (Dimethylamino)propyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 7B. The title compound (FA salt, 40.00 mg, yield 17.58%) was obtained. ¹ H NMR (400MHz, CD3OD): δ 8.78 (s, 1H), 8.45 (br. s., 1H), 8.19-8.33 (m, 2H), 7.30 (d, J=5.09 Hz, 1H), 6.99- 7.19 (m, 3H), 6.96 (s, 1H), 6.49-6.71 (m, 1H), 6.33 (d, J=16.95 Hz, 1H), 5.80 (d, J=10.55 Hz, 1H), 4.12 (t , J = 6.88 Hz, 2H), 3.96 (s, 3H), 2.99-3.20 (m, 4H), 2.54-2.93 (m, 11H), 1.76-2.00 (m, 2H). LCMS (ESI) (0-60): m/z:

Process 3.

Example 8.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl) acrylamide.

Example 8A.

4-bromo-2-methoxy-5-nitroaniline.

Add 2-methoxy-4-bromoaniline (5.00 g, 24.75 mmol) to concentrated H ₂ SO ₄ (50 mL) at 0~5 ° C, then add cerium nitrate (3.02 g) in portions. , 24.75 millimoles). The mixture was stirred at 0 to 5 ° C for 30 minutes. TLC showed the reaction was complete, the reaction mixture was slowly added dropwise aqueous NaHCO ₃ (100 g) (1L) solution, controlling the temperature at 15 ° C. The obtained mixture was filtered to give the title compound (yield:yield ^{1 H NMR (400MHz, CDCl3)} : δ, 7.39 (s, 1H), 7.01 (s, 1H), 4.09 (. Br s, 2H.), 3.96 (s, 3H).

Example 8B.

N-(4-Bromo-2-methoxy-5-nitrophenyl)-4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidine 2-amine.

Example 8A (1.51 g, 5.56 mmol) and Example A (1.50 g, 5.56 mmol) were added to 1,4-dioxane (20 mL), and TsOH·H ₂ was added to the mixture. O (1.27 g, 6.67 mmol) and warmed to 75-85 ° C for 12 hours. TLC showed the reaction was complete, the reaction mixture was concentrated, DCM (20mL) was dissolved, after phase was concentrated with saturated NaHCO ₃ (20mL), dried organic by column chromatography (DCM / MeOH = 100: 0 to 100: 1) separation and purification, The title compound was obtained (yellow solid, 2.40 g, yield: 85.38%). ¹ H NMR (400 MHz, DMSO-d6): δ, 9.08 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.35 (d, J = 8 Hz, 1H), 8.30 (s, 1H) ), 7.53 (s, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.12-7.21 (m, 3H), 4.18 (t, J = 7.2 Hz, 2H), 4.05 (s, 3H), 3.23 -3.33 (m, 2H), 2.64-2.67 (m, 2H).

Example 8C.

4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(3-(dimethylamino)prop-1-yne-1 -yl)-2-methoxy-5-nitrophenyl)pyrimidine-2-amine.

Example 8B (1.00 g, 2.08 mmol), CuI (39.65 mg, 208.00 micromoles) and Pd(PPh ₃ ) ₂ Cl ₂ (73.07 mg, 104.00 micromoles) at 10-20 °C Add to DMF (20 mL) and stir for 1 hour, then add 1 - dimethylamino-2 - propyne (345.82 mg, 4.16 mmol) and DIEA (537.64 mg, 4.16 mmol) to this mixture. ), and heated to 65 ~ 75 ° C for 23 hours. TLC showed the reaction was completed, EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LCMS (ESI) (0-60): m/z:

Example 8D.

N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)propane 1--1-yn-1-yl)-6-methylbenzene-1,3-diamine.

Example 8C (200.00 mg, 414.48 micromoles) and NH ₄ Cl (110.85 mg, 2.07 mmol) were added to acetone (9 mL) and water (1 mL), and zinc powder (110.85 mg, 2.07 millimolar), and heated to 60~70 ° C for 16 hours. TLC showed the reaction was completed, the reaction mixture was filtered and saturated Na ₂ CO _{3 was added} to pH 9. The title compound (yellow solid, 20.00 mg, yield: 10.12%). LCMS (ESI) (0-60): m/z:

Example 8E.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)prop-1-yn-1-yl)-4-methoxyphenyl) acrylamide.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 8D. The title compound (FA salt, 7.00 mg, yield 20.84%) was obtained. ¹ H NMR (400MHz, CD3OD): δ 8.88 (s, 1H), 8.43 (br. s., 1H), 8.27-8.29 (m, 2H), 7.30-7.32 (m, 1H), 7.08-7.18 (m , 4H), 6.50-6.54 (m, 1H), 6.34-6.39 (m, 1H), 5.81 (dd, J = 1.13, 10 Hz, 1H), 4.07-4.09 (m, 2H), 3.99 (s, 3H ), 3.90 (s, 2H), 3.29-3.30 (m, 2H), 2.55-2.72 (m, 8H). LCMS (ESI) (0-60): m/z: 507.2.

Example 9.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(morpholinomethyl)phenyl)propenylamine.

Example 9A.

3-methoxy-4-(2,2,2-trifluoroethyl)benzoic acid.

4-Amino-3-methoxybenzoic acid (10.00 g, 59.82 mmol) was added to TFA (60 mL) at 0 to 5 ° C, and TFAA (31.41 g, 59.82) was added dropwise to the mixture. Millions) and stir for 30 minutes. TLC showed the reaction was completed. EtOAc EtOAc m. ¹ H NMR (400MHz, CDCl3): δ 8.74 (br. s., 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.87 (dd, J = 1.2, 7.2 Hz, 1H), 7.68 (d, J = 1.2 Hz, 1H), 4.05 (s, 3H).

Example 9B.

5-methoxy-2-nitro-4-(2,2,2-trifluoroethyl)benzoic acid.

Example 9A (13.50 g, 51.30 mmol) was added portionwise to fuming nitric acid (100 mL) at 0 ° C, and TFAA (31.41 g, 59.82 mmol) was added dropwise to the mixture and stirred. 30 minutes. TLC showed the reaction was completed. EtOAc EtOAc m. ¹ H NMR (400 MHz, CDCl3): δ 9.01 (s, 1H), 8.65 (br. s., 1H), 7.36 (s, 1H), 4.13 (s, 3H).

Example 9C.

2,2,2-Trifluoro-N-(2-methoxy-4-(morpholin-4-carbonyl)-5-nitrophenyl)acetamidine.

Example 9B (5.00 g, 16.22 mmol) and morpholine (1.70 g, 19.46 mmol) were added to DMF (50 mL) at 10-20 ° C, and HATU (7.40 g) was added to this mixture. , 19.46 millimoles) and DIEA (3.14 grams, 24.33 millimoles) and stirred for 3 hours. TLC showed the reaction was completed. EtOAc EtOAc m. ¹ H NMR (400 MHz, CDCl3): δ 9.22 (s, 1H), 8.60 (br. s., 1H), 6.90 (s, 1H), 4.09 (s, 3H), 3.60-3.94 (m, 6H) , 3.22 (t, J=4.8 Hz, 2H).

Example 9D.

(4-Amino-5-methoxy-2-nitrophenyl)(morpholino)methanone.

The embodiment of Example 9C (4.00 g, 10.60 mmol) was added to MeOH / H ₂ O: In (1 1,40mL), was added to this mixture K ₂ CO ₃ (7.33 g, 53.00 mmol), and warmed Stir at 65 ° C for 5 hours. The reaction was completed with EtOAc EtOAc EtOAc.

Example 9E.

2-methoxy-4-(morpholino)-5-nitroaniline.

Example 9D (1.00 g, 3.56 mmol) was added to THF (10 mL) at 5~15 ° C, then BH ₃ -Me ₂ S (10M, 1.78 mL) Stir at 66 ° C for 2 hours. TLC showed the reaction was completed, MeOH (5 mL) was slowly added dropwise to the reaction mixture, and stirred at 66 ° C for one hour. The reaction mixture was concentrated to give the title compound (yield: 70% LCMS (ESI) (0-60): m/z:

Example 9F.

4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(2-methoxy-4-(morpholinomethyl)-5- Nitrophenyl)pyrimidine-2-amine.

Example 9E (435.13 mg, 1.63 mmol) and Example A (400.00 mg, 1.48 mmol) were added to t- BuOH (10 mL) and methanesulfonic acid (170.69 mg, 1.78 m) was added to this mixture. Mohr), and heated to 75 ~ 85 ° C for 48 hours. TLC showed the reaction was complete, the reaction mixture was concentrated, dissolved in DCM (10mL), was washed with NaHCO ₃ (5mL) and brine (5 mL), concentrated and purified by column chromatography (DCM / MeOH = 100: 1 : 0 to 100) separated Purification gave the title compound (m.j. LCMS (ESI) (0-60): m/z:

Example 9G.

N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-6-methoxy-4-(morpholino) Methyl) benzene-1,3-diamine.

This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 9F. The title compound (red oil, 300.00 mg, crude) was obtained. LCMS (ESI) (0-60): m/z: 4721.

Example 9H.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-4-methoxy- 2-(morpholinomethyl)phenyl)propenylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 9G. The title compound (FA salt, 37.00 mg, yield 11.02%) was obtained. ¹ H NMR (400MHz, CD3OD) : δ 8.84 (s, 1H), 8.18-8.37 (m, 4H), 7.34 (d, J = 7.6 Hz, 1H), 7.05-7.23 (m, 3H), 6.34-6.52 (m, 2H), 5.86 (dd, J = 2.38, 9.16 Hz, 1H), 4.13 (t, J = 7.1 Hz, 2H), 4.00 (s, 3H), 3.85 (d, J = 12.8 Hz, 6H) , 2.84 (br. s., 4H), 2.53-2.73 (m, 3H). LCMS (ESI) (0-60): m/z: 525.2 [M+1].

Example 10.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)propyl)-4-methylphenyl)acrylamide.

Example 10A.

3-methoxy-4-nitrobenzaldehyde.

3-methoxy-4-nitrobenzyl alcohol (4.70 g, 25.66 mmol) was added to DCM (50mL) was added to this mixture MnO ₂ (13.39 g, 153.96 mmol), and warmed to Stir at 40 ° C for 12 hours. TLC showed the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated to give the title compound (yellow solid, 3.90 g, yield ^{79.71%) 1 H NMR (300} MHz, CDCl3): δ 10.0 -10.20 (m, 1 H), 7.87 - 8.05 (m, 1 H), 7.47 - 7.72 (m, 2 H), 3.96 - 4.14 (m, 3 H).

Example 10B.

(Z) - Ethyl-3-(3-methoxy-4-nitrophenyl) acrylate.

Example 10A (3.90 g, 21.53 mmol) was added to THF (20 mL) at 5 ° C. NaH (60%, 1.29 g, 32.30 m. 30 minutes. Further, ethyl ethoxyphosphonium phthalate (7.24 g, 32.30 mmol) was added dropwise to the mixture, and the mixture was heated to 20 ° C and stirred for 2.5 hours. TLC showed the reaction was complete, a saturated aqueous solution of NH ₄ Cl (5mL) added to the reaction mixture was concentrated to remove THF. The obtained mixture was dissolved in DCM (20 mL), washed with H ₂ O (30 mL×3), dried over anhydrous sodium sulfate, and then concentrated and purified by column chromatography (PE/EA = 10:1-5:1) The title compound (yellow solid, 2.95 g, yield 53.89%) was obtained. LCMS (ESI) (5-95): m/z: 2521.

Example 10C. (3-(4-Amino-3-methoxyphenyl)propionate.

Example 10B (2.75 g, 10.95 mmol) was dissolved in MeOH (25 mL) at 16 &lt;0&gt;C. The mixture was stirred at H ₂ (pressure 15 Psi) for 5 hours. </RTI></RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> LCMS (ESI) (5-95): m/z: 224.2 [M+1].

Example 10D.

3-(4-Amino-3-methoxyphenyl)propan-1-ol.

Example 10C (1.90 g, 8.51 mmol) was added to THF (10 mL) at 20 <0> C, and then, to the mixture was added LAH (322.95 g, 8.51 mmol) and stirred for 5 hours. LCMS showed the reaction was completed and water (0.3 mL) and NaOH (1M, 1 mL) were sequentially applied to the mixture. The resulting mixture was filtered, EtOAcjjjjjjjj LCMS (ESI) (5-95): m/z:

Example 10E.

Third butyl (4-(3-hydroxypropyl)-2-methylphenyl)carbamate.

Example 10D (1.50 g, 8.28 mmol) was added to THF (10 mL). To this mixture was added Boc ₂ O (1.81 g, 8.28 mmol) and warmed to 60-70 ° C. 5 hours. The reaction was completed with EtOAc (EtOAc): LCMS (ESI) (5-95): m/z:

Example 10F.

Third butyl (2-methoxy-4-(3-oxopropyl)phenyl)carbamate.

To a mixture of DCM (1. TLC showed completion of the reaction, saturated aqueous Na ₂ CO ₃ (5mL) to the reaction mixture and extracted with DCM (10mL × 6), the organic phase water (20mL) wash, dried over anhydrous sodium sulfate, and concentrated to give the title compound ( Red oil, 1.23 g, crude). LCMS (ESI) (5-95:): m/z:

Example 10G.

Third butyl (4-(3-(dimethylamino)propyl)-2-methoxyphenyl)carbamate.

Example 10F (1.2 g, crude) was taken in MeOH (20 mL). dimethylamine hydrochloride (701.24 mg, 8.60 mM) and NaBH ₃ CN (810.64) Mg, 12.90 mmol, and stirred for 5 hours. LCMS showed the reaction was complete, saturated aq Na ₂ CO ₃ (5mL) added to the reaction mixture. The mixture was extracted with EtOAc EtOAc m. LCMS (ESI) (5-95): m/z: 309.2.

Example 10H.

4-(3-(Dimethylamino)propyl)-2-methoxy-5-nitroaniline.

Example 10G (720.00 mg, 2.33 mmol) was added to H ₂ SO ₄ (3 mL) at 0 ° C. To this mixture was added cerium nitrate (284.45 mg, 2.33 mmol) and stirred 2 After an hour, the temperature was further raised to 20 ° C and stirred for 1 hour. TLC showed completion of the reaction, saturated aqueous Na ₂ CO ₃ was added to the reaction mixture to pH 7-8, and extracted with DCM (10mL × 2), the organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (DCM / MeOH = 10:1) EtOAc (EtOAc: EtOAc) LCMS (ESI) (5-95): m/z:

Example 10I.

4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-N-(4-(3-(dimethylamino)propyl)-2-yl Oxy-5-nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 1A, replacing N,N',N'-trimethyl-1,2-diethylenediamine with Example 10H. The title compound (red solid, 300.00 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 10J.

N1-(4-(2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-4-(3-(dimethylamino)propane Base)-6-methylbenzene-1,3-diamine.

This example was prepared according to the method of Example 1B, and Example 1A was replaced with Example 10I. The title compound (yellow solid, 200.00 mg, yield 66.21%). LCMS (ESI) (5-95AB): m/z: 457.2 [M+1].

Example 10K.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-(3-( Dimethylamino)propyl)-4-methylphenyl)acrylamide.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 10J. The title compound (FA salt, 30.00 mg, yield 11.80%) was obtained. ¹ H NMR (400 MHz, CDCl3) ppm δ 9.22 (br. s., 1 H), 8.58 - 8.78 (m, 1 H), 8.50 (s, 1 H), 8.19 - 8.37 (m, 2 H), 7.65 - 7.79 (m, 1 H), 7.16 - 7.26 (m, 2 H), 7.00 (d, J = 5.40 Hz, 1 H), 6.63 - 6.72 (m, 1 H), 6.35 - 6.52 (m, 2 H), 5.63 - 5.78 (m, 1 H), 4.10 (t, J = 7.15 Hz, 2 H), 3.82 - 3.92 (m, 3 H), 3.28 - 3.43 (m, 2 H), 2.53 - 2.78 ( m, 12 H), 1.88 - 2.18 (m, 2 H). LCMS (ESI) (5-95): m/z:

Example 11.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-((1- (Dimethylamino)propan-2-yl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 11A.

2-((4-Amino-5-methoxy-2-nitrophenyl)(methyl)amino)-N,N-dimethylpropanamide.

N,N-Dimethyl-2-(methylamino)propanamide (4.80 g, 36.87 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (6.86 g, 36.87 m) Moer) was added to MeCN (10 mL), and Cs ₂ CO ₃ (48.05 g, 147.48 mmol) was added to the mixture, and the mixture was warmed to 100 ° C and stirred for 12 hours. TLC showed the reaction was completed. Water (25 mL) was then evaporated. The organic phase was washed with EtOAc EtOAc EtOAc. Yield 6.49%). ¹ H NMR (400MHz, CDCl3): δ 7.25 (s, 1H), 6.71 (s, 1H), 4.11-4.17 (m, 1H), 3.92 (s, 3H), 2.93 (d, J = 8.0 Hz, 6H ), 2.82 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). LCMS (ESI) (10-80_CD): m/z:

Example 11B.

N1-(1-(Dimethylamino)propan-2-yl)-5-methoxy N1methyl-2-nitrobenzene-1,4-diamine.

Example 11A (1.00 g, 3.37 mmol) was added to THF (40 mL). To this mixture was added BH ₃ /Me ₂ S (10 M, 1.69 mL), and the mixture was warmed to 80 ° C and stirred for 3 hours. After cooling to room temperature, MeOH (40 mL) was added and the mixture was stirred for 30 min and then warmed to <RTIgt; The reaction was completed with EtOAc (EtOAc)EtOAc. ¹ H NMR (400MHz, CDCl3): δ 7.20 (s, 1H), 6.59 (s, 1H), 3.84 (s, 3H), 3.55-3.72 (m, 2H), 3.38-3.42 (m, 1H), 2.61 (s, 3H), 2.45-2.48 (m, 1H), 2.23-2.32 (m, 1H), 2.15 (s, 6H), 1.14 (d, J = 6.4 Hz, 3H). LCMS (ESI) (10-80_CD): m/z:

Example 11C.

N1-(4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N4-(1-(dimethylamino)propane 2-yl)-2-methoxy-N-4-methyl-5-nitrobenzene-1,4-diamine.

Example 11B (165.00 mg, 584.40 micromoles) and Example A (173.39 mg, 642.84 micromoles) were added to dioxane (10 mL), and Pd(OAc) ₂ (13.12 mg) was added to the mixture. , 58.44 micromolar), Xantphos (33.81 mg, 58.44 micromolar) and K ₃ PO ₄ (248.10 mg, 1.17 mmol), after nitrogen substitution, the temperature was raised to 100 ° C and stirred for 12 hours. LCMS showed the reaction was complete, the reaction mixture was concentrated, saturated aqueous Na ₂ CO ₃ (10 mL), and extracted with DCM (30mL × 3). The organic phase was washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHH ). LCMS (ESI) (0-60_?): m/z:

Example 11D.

N4-(4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)-N 1 -(1-(dimethylamino) Prop-2-yl)-5-methoxy-N 1 -methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 11C. The title compound (brown oil, 200.00 mg, yield: 92.81%). LCMS (ESI) (0-60_?): m/z:

Example 11E.

N-(5-((4-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)pyrimidin-2-yl)amino)-2-((1- (Dimethylamino)propan-2-yl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 11D. The title compound (FA salt, 75.92 mg, yield 30.52%) was obtained. ¹ H NMR (400MHz, CD3OD) δ 8.51 (s, 1H), 8.26-8.31 (m, 2H), 7.32-7.35 (m, 1H), 6.87-7.17 (m, 3H), 6.88 (s, 1H), 6.47-6.51 (m, 2H), 5.85-5.88 (m, 1H), 4.16 (t, J = 7.2 Hz, 2H), 3.91-4.07 (m, 4H), 3.35-3.42 (m, 2H), 3.12- 3.15 (m, 1H), 2.83-2.97 (m, 7H), 2.67-2.74 (m, 5H), 1.40 (d, J = 6.4 Hz, 3H). LCMS (ESI) (0-60_?): m/z:

Process 4.

Example 12.

N-(2-(2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-oxo-2,3-dihydro-) 1H-pyrrolo[1,2-a]indol-9-ylpyrimidin-2-yl)amino)phenyl)propenylamine.

Example 12A.

Methyl-1-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-2-carboxylate.

Ethyl 2-carboxylate (4.00 g, 21.14 mmol) and methyl acrylate (3.28 g, 38.05 mmol) were added to toluene (200 mL) and NaH (60%, 974. Mg, 40.59 mmol, and warmed to 100 ° C for 16 hours. LCMS showed the reaction was complete, the addition of saturated NH (100mL) ₄ Cl solution to the reaction mixture. The mixture was extracted with EtOAc (EtOAc m. LCMS (ESI) (5-95): m/z:

Example 12B.

2,3-Dihydro-1H-pyrrolo[1,2-a]indol-1-one.

Example 12A (3.73 g, 16.27 mmol) was added to dioxane (150 mL). To this mixture was added hydrochloric acid (2 M, 40 mL) and warmed to 80 ° C and stirred for 16 hours. LCMS showed the reaction was completed and a sodium hydroxide solution (2 M, 100 mL) was added to the mixture. The resulting mixture was extracted with EtOAc (EtOAc EtOAc (EtOAc). %). ¹ H NMR (400 MHz, CDCl3): d, 7.80-7.78 (m, 1H), 7.47-7.39 (m, 2H), 7.39-7.22 (m, 1H), 7.04 (d, J = 0.8 Hz, 1 H ), 4.49-4.46 (m, 2 H), 3.27-3.24 (m, 2 H). LCMS (ESI) (5-95): m.

Example 12C.

9-Bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one.

Example 12B (6.00 g, 35.05 mmol) was added to DMF (100 mL) at 20 ° C, and NBS (6.24 g, 35.05 mmol) was added to this mixture and stirred for 2 hours. The reaction mixture was filtered, and then evaporated tolululululululululululululululululululu ¹ H NMR (400 MHz, CDCl3): d, 7.74 (d, J = 8.4 Hz, 1 H), 7.47-7.42 (m, 2 H), 7.31-7.27 (m, 1), 4.46-4.43 (m, 2 H), 3.26-3.29 (m, 2 H). LCMS (ESI) (5-95): m/z:

Example 12D.

9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]吲哚-1-ketone.

Example 12C (7.80 g, 31.19 mmol) and B ₂ Pin ₂ (11.98 g, 93.57 mmol) were added to toluene (150 mL), and Pd ₂ (dba) ₃ (571.23 mg, 623.80 micromoles), X-phos (1.19 g, 2.50 mmol) and TEA (9.47 g, 93.57 mmol), after nitrogen substitution, the temperature was raised to 80 ° C and stirred for 3 hours. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI> LCMS (ESI) (5-95): m.

Example 12E.

9-(2-Chloropyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one.

Example 12D (11.00 g, 37.02 mmol) and 2,4-dichloropyrimidine (11.03 g, 74.03 mmol) were added to dioxane/water (15:1, 160 mL) to this mixture Pd(dppf)Cl ₂ (812.56 mg, 1.11 mmol), K ₂ CO ₃ (10.23 g, 74.03 mmol) was added thereto, and after nitrogen substitution, the mixture was heated to 70 ° C and stirred for 10 hours. LCMS showed the reaction was completed, the title compound was purified (jjjjjjjjj The rate is 12.00%). ¹ H NMR (400MHz, CDCl3): δ 9.00 (d, J = 8.8Hz, 1H), 8.73-8.80 (m, 1H), 8.61 (d, J = 5.2Hz, 1H), 7.53-7.40 (m, 3H ), 4.55 (t, J = 6.4 Hz, 2H), 3.43-3.36 (m, 2H). LCMS (ESI) (5-95): m/z:

Example 12F.

9-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-2,3-dihydro-1H-pyrrolo[1,2-a ]吲哚-1-ketone.

This example was prepared according to the method of Example B, replacing Example A with Example 12E. The title compound (yellow solid, 280.00 mg, yield 8.31%) was obtained. LCMS (ESI) (5-95): m.

Example 12G.

9-(2-((4-(Dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl) -2,3-Dihydro-1H-pyrrolo[1,2-a]indol-1-one.

This example was prepared according to the method of Example 1A, and Example B was replaced with Example 12F. The title compound (brown solid, 140.00 mg, yield 54.04%). ¹ H NMR (400MHz, CDCl3): δ, 9.03 (s, 1H), 8.35-8.24 (m, 2H), 7.36 (d, J = 7.2Hz, 1H), 7.24-7.12 (m, 3H), 7.09 ( s, 1H), 4.21-4.14 (m, 2H), 4.10 (s, 3H), 3.53-3.48 (m, 2H), 3.43-3.37 (m, 4H), 2.99 (s, 6H), 2.88 (s, 3H), 2.76-2.69 (m, 2H). LCMS (ESI) (0-60): m.

Example 12H.

9-(2-((5-amino)ethyl)(methyl)amino)-2-methylphenyl)amino)pyrimidin-4-yl)-2 , 3-dihydro-1H-pyrrolo[1,2-a]indol-1-one.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 12G. The title compound (brown solid, 140.00 mg, crude) was obtained. 1H NMR (400MHz, CDCl3): δ 8.98 (d, J = 8.4 Hz, 1H), 8.51 (d, J = 5.2Hz, 1H), 8.20 (s, 1H), 8.06-8.01 (m, 1H), 7.68 (s, 1H), 7.50-7.48 (m., 2H), 7.02-6.99 (m, 1H), 6.74-6.69 (m, 1H), 4.55 (t, J = 6.0Hz, 2H), 3.89 (s, 3H), 3.38-3.37 (m, 2H), 3.28-3.26 (m, 2H), 3.11 (s, 3H), 2.95-2.94 (m., 2H), 2.75 (s, 6H). LCMS (ESI) (0-60.).

Example 12I.

N-(2-(2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-oxo-2,3-dihydro-) 1H-pyrrolo[1,2-a]indol-9-ylpyrimidin-2-yl)amino)phenyl)propenylamine.

This example was prepared according to the method of Example 1C, replacing Example 1B with Example 12H. The title compound (FA salt, 50.00 mg, yield 28.78%) was obtained. ¹ H NMR (400MHz, CD3OD): δ 8.75-8.64 (m, 2H), 8.21 (d, J = 6.4Hz, 1H), 7.82-7.68 (m, 2H), 7.52 (t, J = 8.0Hz, 1H ), 7.38-7.35 (m, 1H), 7.11 (s, 1H), 6.71-6.60 (m, 1H), 6.53-6.43 (m, 1H), 5.87 (dd, J1 = 1.6, J2 = 10.4Hz, 1H ), 4.6-4.63 (m, 2H), 3.97 (s, 3H), 3.64-3.56 (m, 2H), 3.46-3.36 (m, 4H), 2.94 (s, 6H), 2.84 (s, 3H). LCMS (ESI) (5-95): m/z:

Process 5.

Example 13.

N-[2-[2-(dimethylamino)ethyl-methyl-amino]-5-[[4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2- a] Ind-4-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enylamine.

Example 13A.

Ethyl-5-fluoro-1H-indole-2-carboxylate.

To the mixture was added SOCl ₂ (9.84 g, 82.71 mmol) by adding 5 - fluoro-2-carboxylate (5.00 g, 27.91 mmol) to ethanol (50 mL) at 0 °C. And stirred at reflux for 5 hours. TLC showed the reaction was completed, the reaction mixture was concentrated, and a saturated aqueous NaHCO ₃ (15 mL) was added. The mixture was extracted with EtOAc EtOAc EtOAc. ¹ H-NMR (400 MHz, CDCl3) δ 9.00 (br. s., 1 H), 7.31 - 7.39 (m, 2 H), 7.19 (d, J = 1.2 Hz, 1 H), 7.10 (td, J = 9.0, 2.4 Hz, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 1.43 (t, J = 7.1 Hz, 3 H).

Example 13B.

Methyl 6-fluoro-3-oxo-1,2-dihydropyrrolo[1,2-a]indole-2-carboxylate.

This example was prepared according to the method of Example 12A, replacing ethyl 2-carboxylate with Example 13A. The title compound (yellow oil, 8.20 g, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 13C.

6-Fluoro-1,2-dihydropyrrolo[1,2-a]indol-3-one.

This example was prepared according to the method of Example 12B, replacing Example 12A with Example 13B. The title compound (yellow solid, 3.08 g, yield 48.43%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.35 - 7.45 (m, 1 H), 7.10 - 7.20 (m, 1 H), 6.96 (s, 1 H), 4.44 (t, J = 6.1 Hz, 2 H), 3.23 (t, J = 6.0 Hz, 2 H).

Example 13D.

6-Fluoro-2,3-dihydro-1H-pyrrolo[1,2-α]indole.

The embodiment of Example 13C (3.04 g, 16.07 mmol) was added to diethylene glycol (50 mL), was added to this mixture K ₂ CO ₃ (15.00 g, 108.53 mmol) and N ₂ H _4. H ₂ O (5.96 g, 119.07 mmol), after nitrogen substitution, the mixture was heated to 160 ° C for 2.5 hours, and then heated to 180 ° C for 2.5 hours. TLC showed the reaction was completed and EA (100 mL) was added to the mixture. After washing with water (30 mL × 2), EtOAc (EtOAc m. ¹ H-NMR (400 MHz, CDCl3) δ 7.21 (dd, J = 10.0, 2.5 Hz, 1 H), 7.14 (dd, J = 8.7, 4.5 Hz, 1 H), 6.87 (td, J = 9.1, 2.5 Hz, 1 H), 6.15 (s, 1 H), 4.07 (t, J = 7.0 Hz, 2 H), 3.04 (t, J = 7.4 Hz, 2 H), 2.56 - 2.70 (m, 2 H).

Example 13E.

4-(2-Chloropyrimidin-4-yl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-α]indole.

This example was prepared according to the method of Example A, replacing Example A6 with Example 13D. The title compound was obtained (yellow solid, 716.00 mg, yield 38.35%). ¹ H-NMR (400 MHz, CDCl3) δ 8.41 (d, J = 5.5 Hz, 1 H), 8.08 (dd, J = 10.3, 2.4 Hz, 1 H), 7.28 (s, 1 H), 7.27 (s , 1 H), 7.20 (dd, J=8.7, 4.5 Hz, 1 H), 7.00 (td, J=8.9, 2.5 Hz, 1 H), 4.17 (t, J=7.2 Hz, 2 H), 3.40 ( t, J = 7.5 Hz, 2 H), 2.77 (quin, J = 7.3 Hz, 2 H).

Example 13F.

4-(6-Fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-4-yl)-N-(4-fluoro-2-methoxy-5-nitro Base-phenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example B, replacing Example A with Example 13E. The title compound (yellow solid, 378.00 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 13G.

N4-[2-(Dimethylamino)ethyl]-N 1 -[4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-4-yl Pyrimidine-2-yl]-2-methoxy-N-4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 1A, and Example B was replaced with Example 13F. The title compound (brown solid, 373.00 mg, yield 69.78%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.09 (s, 1 H), 8.36 (d, J = 4.0 Hz, 1 H), 7.99 (d, J = 8.91 Hz, 1 H), 7.44 (s, 1 H), 7.20 (dd, J=8.72, 4.58 Hz, 1 H), 6.92 - 7.01 (m, 2 H), 6.72 (s, 1 H), 4.15 (t, J=7.15 Hz, 2 H), 4.01 (s, 3 H), 3.42 (t, J=7.47 Hz, 2 H), 3.32 (t, J=7.03 Hz, 2 H), 2.90 (s, 3 H), 2.74 (quin, J=7.31 Hz , 2 H), 2.66 (d, J = 6.65 Hz, 2 H), 2.34 (s, 6 H).

Example 13H.

N1-[2-(Dimethylamino)ethyl]-N4-[4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-4-yl)pyrimidine 2-yl]-5-methoxy-N 1 -methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 12G. The title compound was obtained (yellow solid, 306.00 mg, yield 64.46%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.21 - 8.29 (m, 2 H), 8.05 (s, 1 H), 7.52 (s, 1 H), 7.15 (dd, J=8.6, 4.5 Hz, 1 H), 6.89 - 6.99 (m, 1 H), 6.78 (d, J=5.4 Hz, 1 H), 6.73 (s, 1 H), 4.09 (t, J=7.2 Hz, 2 H), 3.83 - 3.90 (m, 3 H), 3.30 (t, J=7.4 Hz, 2 H), 2.98 (t, J=6.9 Hz, 2 H) 2.65 - 2.73 (m, 4 H), 2.38 - 2.48 (m, 2 H ), 2.23 - 2.30 (m, 6 H).

Example 13I.

N-[2-[2-(dimethylamino)ethyl-methyl-amino]-5-[[4-(6-fluoro-2,3-dihydro-1H-pyrrolo[1,2- a] Ind-4-yl)pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 13H. The title compound (FA salt, 13.60 mg, yield 7.53%) was obtained. LCMS (ESI) (0-60 AB) : m / z: 544.2 [M + 1] RT: 2.075min / 4 min; 1 H-NMR (400 MHz, DMSO) δ 10.08 (s, 1 H), 8.61 ( s, 1 H), 8.27 (br. s., 1 H), 8.24 (d, J=5.4 Hz, 1 H), 8.17 (s, 1 H), 8.01 (d, J = 10.9 Hz, 1 H) , 7.34 (dd, J=8.7, 4.7 Hz, 1 H), 7.00 (s, 1 H), 6.93 (td, J=9.1, 2.64 Hz, 1 H), 6.89 (d, J=5.5 Hz, 1 H ), 6.43 (dd, J=17.0, 10.1 Hz, 1 H), 6.15 (dd, J=17.0, 1.88 Hz, 1 H), 5.66 - 5.72 (m, 1 H), 4.12 (t, J=7.1 Hz) , 2 H), 3.78 (s, 3 H), 3.27 (t, J=7.4 Hz, 3 H), 2.93 (t, J=5.5 Hz, 2 H), 2.69 (s, 3 H), 2.59 (quin , J = 7.2 Hz, 2 H), 2.44 (t, J = 5.6 Hz, 2 H).

Process 6.

Example 14.

N-[5-[[4-(7,7-Difluoro-8,9-dihydro-6H-pyrido[1,2-a]indole-10-yl)pyrimidin-2-yl]amino] -2-[2-(Dimethylamino)ethyl-methyl-amino]-4-methoxyphenyl]prop-2-enylamine.

Example 14A.

Ethyl (E)-3-(1H-indol-2-yl)prop-2-enoate.

2 - Formaldehyde hydrazine (5.00 g, 51.66 mmol) was added to THF (30 mL) at 25 ° C, and 2 -diethoxyphosphonium ethyl acetate (11.58 g) was slowly added to the mixture. , 51.66 mmol, and NaH (2.76 g, 68.88 mmol), after nitrogen displacement, stirred for 3 hours. TLC showed the reaction was complete, the reaction mixture was slowly added saturated NH (15mL) aqueous ₄ Cl, extracted with DCM (20mL × 3), the organic phase with saturated saline water (10mL), dried with anhydrous sodium sulfate, concentrated, Column chromatography (PE/EA = 20:1 - 10:1) ¹ H NMR (400 MHz, CDCl3) δ 8.33 (br. s., 1H), 7.69 (d, J = 16.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.34 - 7.39 (m, 1H), 7.26 - 7.30 (m, 1H), 7.09 - 7.15 (m, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.22 (d, J=16.0 Hz, 1H), 4.28 (q, J =7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H), 1.35 (t, J=7.15 Hz, 3H).

Example 14B.

Ethyl (E)-3-[1-(2-tert-butoxy-2-oxoethyl)indol-2-yl]prop-2-enoate.

Example 14A (7.00 g, 32.52 mmol) was added to DMF (100 mL). To this mixture was added 2 - butyl bromoacetate (12.69 g, 65.04 mmol) and Cs ₂ CO ₃ (21.19) Gram, 65.04 mmol, and warmed to 50 ° C for 12 hours. TLC showed the reaction was completed. EtOAc m. The rate is 73.80%). ¹ H-NMR (400 MHz, CDCl3): δ 7.61 - 7.73 (m, 2 H), 7.29 - 7.31 (m, 1 H), 7.24 - 7.28 (m, 1 H), 7.16 (ddd, J = 7.9, 6.0, 1.8 Hz, 1 H) , 7.03 (s, 1 H), 6.49 (d, J = 15.8 Hz, 1 H), 4.25 - 4.34 (m, 2 H), 1.46 (s, 9 H), 1.36 ( t, J = 7.1 Hz, 3 H).

Example 14C.

3-[1-(2-Tertiarybutoxy-2-oxoethyl)indol-2-yl]propanoate.

Example 14B (8.50 g, 25.81 mmol) was dissolved in MeOH (100 mL) at 20 &lt;0&gt;C, and Pd/C (10%, &lt H ₂ of mixture (a pressure of 15 Psi), stirred for 12 hours. </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI></RTI><RTIgt;

Example 14D.

7-Oxo-8,9-dihydro-6H-pyrido[1,2-a]indole-6-carboxylate.

At 0 ° C, the embodiment of Example 14C (8.00 g, 24.14 mmol) was added to (60 mL) in of THF, To this mixture, t -BuOK (5.42 g, 48.28 mmol), and stirred for 2 hours. TLC showed the reaction was completed and dilute hydrochloric acid (0.5 M) was added to the reaction mixture to pH 6-7. After additional EA (150 mL) and water (30 mL), EtOAc (EtOAc) The rate is 98.59%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.59 (d, J = 7.1 Hz, 1 H), 7.13 - 7.26 (m, 3 H), 6.39 (s, 1 H), 5.42 (s, 1 H ), 3.25 - 3.41 (m, 2 H), 2.95 (dt, J = 16.3, 4.1 Hz, 1 H), 2.62 - 2.75 (m, 1 H), 1.41 (s, 9 H).

Example 14E.

8,9-Dihydro-6H-pyrido[1,2-a]indol-7-one.

Example 14D (7.00 g, 24.53 mmol) was added to toluene (100 mL). To this mixture was added SiO ₂ (7.00 g, 116.52 mmol), and the mixture was replaced with nitrogen and warmed to 110 ° C for 12 hours. . TLC showed the reaction was completed. The title compound was obtained (jjjjjjjj ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.60 (d, J = 7.6 Hz, 1 H), 7.19 - 7.26 (m, 2 H), 7.13 - 7.19 (m, 1 H), 6.38 (s, 1 H), 4.69 (s, 2 H), 3.28 (t, J = 6.5 Hz, 2 H), 2.74 - 2.86 (m, 2 H).

Example 14F.

7,7-Dichloro-8,9-dihydro-6H-pyrido[1,2-α]indole.

Example 14E (1.70 g, 9.18 mmol) was added to DCM (20 mL), and DAST (5.92 g, 36.72 m. TLC showed completion of the reaction, saturated NaHCO aqueous ₃ (10mL) added to the reaction mixture was added DCM (50mL) and extracted, the organic phase was washed with water (15 mL), concentrated and purified by column chromatography (PE / EA = 30: 1 - 10: 1) Isolation and purification gave the title compound (yellow solid, 1.17 g, yield: 59.66%). ¹ H-NMR (400 MHz, CDCl3): δ 7.56 (d, J = 7.6 Hz, 1 H), 7.12 - 7.26 (m, 3 H), 6.31 (s, 1 H), 4.35 (t, J =12.7) Hz, 2 H), 3.20 (t, J = 6.8 Hz, 2 H), 2.38 (tt, J = 13.4, 6.7 Hz, 2 H).

Example 14G.

10-(2-chloropyrimidin-4-yl)-7,7-difluoro-8,9-dihydro-6H-pyrido[1,2-α]indole.

This example was prepared according to the method of Example A, replacing Example A6 with Example 14F. The title compound was obtained (yellow solid, 600.00 mg, yield 49.25%). ¹ H-NMR (400 MHz, CDCl3): δ 8.52 - 8.56 (m, 1 H), 8.03 - 8.10 (m, 1 H), 7.58 (d, J = 5.4 Hz, 1 H), 7.30 - 7.37 (m , 3 H), 4.43 (t, J = 12.3 Hz, 2 H), 3.69 (t, J = 6.8 Hz, 2 H), 2.47 (tt, J = 13.4, 6.7 Hz, 2 H).

Example 14H.

4-(7,7-Dichloro-8,9-dihydro-6H-pyrido[1,2-a]indole-10-yl)-N-(4-fluoro-2-methoxy-5 -Nitro-phenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example B, replacing Example A with Example 14G. The title compound (yellow solid, 1.06 g, yield 78.01%) was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.96 (m, 1 H), 8.26 - 8.60 (m, 2 H), 8.08 (m, 1 H) , 7.54 (m, 1 H), 7.12 - 7.44 (m, 4 H), 4.65 (m, 2 H), 4.02 (m., 3 H) 3.49 (m, 2 H) 2.52 (m, 2 H).

Example 14I.

N1-[4-(7,7-Difluoro-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]-N4-[2- (Dimethylamino)ethyl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 1A, and Example B was replaced with Example 14I. The title compound (brown solid, 1.05 g, yield: 75.98%). LCMS (ESI) (5-95): m/z:

Example 14J.

N4-[4-(7,7-Difluoro-8,9-dihydro-6H-pyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]-N 1 - [2 -(Dimethylamino)ethyl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 14I. The title compound (pink solid, 491.00 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 14K.

N-[5-[[4-(7,7-Difluoro-8,9-dihydro-6H-pyrido[1,2-a]indole-10-yl)pyrimidin-2-yl]amino] -2-[2-(Dimethylamino)ethyl-methyl-amino]-4-methoxyphenyl]prop-2-enylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 14J. The title compound (FA salt, 141.90 mg, yield 23.81%) was obtained. ¹ H-NMR (400 MHz, MeOD): δ 8.56 (s, 2 H), 8.39 (d, J = 5.4 Hz, 1 H), 8.07 (d, J = 7.15 Hz, 1 H), 7.43 (d, J = 7.1 Hz, 1 H), 7.15 - 7.28 (m, 3 H), 6.96 (s, 1 H), 6.38 - 6.54 (m, 2 H), 5.85 (dd, J = 9.0, 2.7 Hz, 1 H ), 4.50 (t, J = 12.6 Hz, 2 H), 4.00 (s, 3 H), 3.54 (t, J = 6.8 Hz, 2 H), 3.43 (t, J = 5.5 Hz, 2 H), 3.17 (d, J = 5.2 Hz, 2 H), 2.79 (s, 6 H) 2.71 (s, 3 H), 2.42 (tt, J = 13.5, 6.9 Hz, 2 H). LCMS (ESI) (0-60.): m/z:

Example 15.

N-(2-((2-dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyridyl) [1,2-a]non-10-yl)pyrimidin-2-yl)amino)phenyl)propenylamine.

Example 15A.

6,7,8,9-tetrahydropyrido[1,2-α]fluorene.

This example was prepared according to the procedure of Example 13D, and Example 13C was replaced with 8,9-dihydropyrido[1,2-a]indole-7(6H)one. The title compound was obtained (brown solid, 182. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.57-7.60 (m, 1H), 7.31-7.33 (m, 1H), 7.13-7.19 (m, 2H), 6.25 (s, 1H), 4.06-4.11 ( m, 2H), 3.01-3.04 (m, 2H), 2.11-2.15 (m, 2H), 1.92-1.97 (m, 2H).

Example 15B.

10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-α]indole.

This example was prepared according to the method of Example A, replacing Example A6 with Example 15A. The title compound (brown oil, 100.00 mg, yield 18.44%) was obtained. LCMS (ESI) (5-95_AB): m/z:

Example 15C.

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(6,7,8,9-tetrahydropyrido[1,2-a]indole-10-yl) Pyrimidin-2-amine.

This example was prepared according to the method of Example B, replacing Example A with Example 15B. The title compound was obtained (yield: EtOAc, EtOAc (EtOAc)

Example 15D.

N1-(2-(Dimethylamino)ethyl)-5-methoxy-N1-methyl-2-nitro-N4-(4-(6,7,8,9-tetrahydropyrido[1] , 2-a] fluoren-10-yl)pyrimidin-2-yl)benzene-1,4-diamine.

This example was prepared according to the method of Example 1A, and Example B was replaced with Example 15C. The title compound was obtained (brown solid, 300.00 mg, yield: LCMS (ESI) (5-95_AB): m.

Example 15E.

N1-(2-(Dimethylamino)ethyl)-5-methoxy N1 methyl N4-(4-(6,7,8,9-tetrahydropyrido[1,2-a]fluorene -10-yl)pyrimidin-2-yl)benzene-1,2,4-triamine.

This example was prepared according to the method of Example 1B, replacing Example 1A with Example 15D. The title compound was obtained (yellow solid, 250.00 mg, crude).

Example 15F.

N-(2-((2-dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(6,7,8,9-tetrahydropyridyl) [1,2-a]non-10-yl)pyrimidin-2-yl)amino)phenyl)propenylamine.

This example was prepared according to the method of Example 1C, and Example 1B was replaced with Example 15E. The title compound was obtained (FA salt, 46.00 mg, yield 11.64%). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.60 (s, 1H), 8.48 (s, 1H), 8.35 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.12-7.20 (m, 3H), 6.97 (s, 1H), 6.48-6.50 (m, 2H), 5.88 (t, J = 5.8 Hz, 1H), 4.16 (t, J = 5.8 Hz, 2H), 4.03 (s, 3H), 3.49 (t, J = 5.4 Hz, 2H), 3.24-3.30 (m, 4H), 2.86 (s, 6H), 2.72 (s, 3H), 2.08-2.19 (m, 2H), 1.98-1.88 (m, 2H). LCMS (ESI) (5-95_AB): m/z:

Process 7.

General preparation methods for intermediates C and D:

Example C1.

2-bromoethyl trifluoromethanesulfonate.

To a mixture of pyridine (20 mL) and DCM (70 mL (7.60 g, 60.82 mmol), stirred for 10 minutes and allowed to bring the temperature to 10 °C. The reaction mixture was filtered and EtOAc EtOAc (EtOAcjjjjjjjj ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.61 (t, J = 6.0 Hz, 2 H) 4.75 (t, J = 6.0 Hz, 2 H).

Example C2.

(2-Bromoethyl)diphenylphosphonium.

Example C1 (17.90 g, 69.64 mmol) was added to toluene (40 mL) at 25 ° C. To the mixture was added diphenyl sulfide (13.81 g, 69.64 mmol) and warmed to 100 ° C, stirred for 5 hours under nitrogen. The reaction mixture was cooled to 25 ° C, EtOAc (EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.64-3.74 (t, J = 6.0 Hz 2 H) 4.87 (t, J = 6.0 Hz, 2 H) 7.69-7.82 (m, 6 H) 8.09 (d, J = 8.0 Hz, 4 H).

Example C3.

Diphenyl (vinyl) fluorene.

Example C2 (11.20 g, 25.27 mmol) was added to THF/H ₂ O (2:1, 36 mL) at 25 ° C, and KHCO ₃ (3.04 g, 30.32 m. And stir for 20 minutes. The reaction mixture was concentrated (2°C, EtOAc) (m. The title compound (brown oil, 6.20 g, yield 54.16%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 6.50 (dd, J = 16.0, 4 Hz, 1 H) 6.71 (dd, J = 8.0, 4 Hz, 1 H) 7.53 (dd, J = 16.0, 8.0 Hz , 1 H) 7.65-7.78 (m, 2 H) 7.83-7.93 (m, 1 H).

Example C4.

3,4-Dihydro-1H-[1,4]oxazine [4,3-a]indole.

2-Hydroxymethyl-hydrazine (2.50 g, 16.99 mmol) was added to DCM (250 mL) at 0 ° C. KOH (1.14 g, 20.39 mmol) was added to the mixture and stirred 30 minute. A solution of Example C3 (6.16 g, 16.99 mmol) in DCM (50 mL) was then added dropwise to the mixture and warmed to 20 ° C and stirred for 11.5 hours. The reaction mixture was concentrated and purified with EtOAcjjjjjjjjj ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.59 (d, J = 8.0 Hz, 1H), 7.34-7.29 (m, 1H), 7.21 (dt, J = 1.2, 7.6 Hz, 1H), 7.17-7.12 (m, 1H), 6.24 (d, J = 0.8Hz, 1H), 5.01 (d, J = 0.8Hz, 2H), 4.22-4.17 (m, 2H), 4.13-4.08 (m, 2H).

Example C.

10-(2-chloropyrimidin-4-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

This example was prepared according to the method of Example A, replacing Example A6 with Example C4. The title compound (brown solid, 1.30 g, crude) was obtained. LCMS (ESI) (10-80): m/z:

Example D.

4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-N-(4-fluoro-2-methoxy-5- Nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example B, and Example A was replaced with Example C. The title compound (yellow solid, 311.00 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Process 8.

Example 16.

N-(2-((2-ethylamino)ethyl)(methyl)amino)-5 - ((4-(3,4-dihydro-1H-[1,4]oxazino[4] , 3-a] 吲哚-10-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) acrylamide.

Example 16A.

N1-(2-(Diethylamino)ethyl)-N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10- 5-)-5-methoxy-N 1 -methyl-2-nitrobenzene-1,4-diamine.

Intermediate D (150.00 mg, 344.50 micromoles) was dissolved with N,N-diethyl-N-methylethane-1,2-diamine (134.59 mg, 1.03 mmol) under N2. To DMA (5 mL), DIEA (133.57 mg, 1.03 mmol) was added to the mixture, and the mixture was warmed to 90 ° C and stirred for 12 hours. </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; . LCMS (ESI) (0-60): m/z:

Example 16B.

N1-(2-(Diethylamino)ethyl)-N4-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10- Pyrimido-2-yl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

Example 16A (300.00 mg, 549.82 micromoles) was dissolved in MeOH (5 mL) at 25 &lt;0&gt;C and Pd/C (10%, 0.20 g). The mixture was replaced with H _{2 for} 3 times and then stirred under a pressure of 15 Psi for 2 hours. TLC (DCM: MeOH = 20:1) EtOAc (EtOAc) LCMS (ESI) (0-60.).

Example 16C.

N-(2-((2-ethylamino)ethyl)(methyl)amino)-5 - ((4-(3,4-dihydro-1H-[1,4]oxazino[4] , 3-a] 吲哚-10-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl) acrylamide.

Example 16B (200.00 mg, 387.86 micromoles) was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and water (1 mL) at 0 ° C, and 3 - chloropropyl chloride (73.87 mg, 581.79 micromoles, stirred for 0.5 hours, then sodium hydroxide (62.06 mg, 1.55 mmol) was added to the mixture and the mixture was warmed to 70 ° C and stirred for 12 hours. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; . ¹ H NMR (400MHz, CD ₃ OD): δ 8.53 (br. s., 1 H), 8.28- 8.30 (m, 2 H), 8.01 - 8.03 (m, 1 H), 7.39 - 7.40 (m, 1 H), 7.21-7.23(m, 2 H), 7.09 (d, J=5.20 Hz, 1 H), 6.95 (s, 1 H), 6.53 - 6.55 (m, 1 H), 6.40 - 6.44 (m, 1 H), 5.84 - 5.87 (m, 1 H), 5.14 (s, 2 H), 4.09 (s, 4 H), 4.00 (s, 3 H), 3.29 - 3.51 (m, 2 H), 3.27 ( t, J = 5.60 Hz, 2 H), 3.20 (q, J = 7.20 Hz, 4 H), 2.74 (s, 3 H), 1.25 (t, J = 7.20 Hz, 6 H). LCMS (ESI) (0-60): m/z:

Example 17.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 17A.

4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-N-(4-fluoro-2-methoxy-5- Nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N',N'-trimethyl-1,2 - Ethylenediamine. The title compound was obtained (yellow solid, 230.00 mg, yield: 87.95%). LCMS (0-60AB):m/z: 518.2 [M+1].

Example 17B.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N 1 - (2- (Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 17A. The title compound (yellow solid, 170.00 mg, yield 72.96%) was obtained. LCMS (0-60AB): m/z: 488.2 [M+1].

Example 17C.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 17B. The title compound (FA salt, 20.00 mg, yield 10.29%) was obtained. ¹ H NMR (400MHz, CD ₃ OD): δ 8.49 (br. s., 1H), 8.33 (d, J = 4.0Hz, 1H), 8.29 (s, 1H), 8.08-8.01 (m, 1H), 7.46-7.40 (m, 1H), 7.26-7.20 (m, 2H), 7.17 (d, J = 4.0Hz, 1H), 6.95 (s, 1H), 6.59-6.38 (m, 2H), 5.84 (dd, J = 2.0, 8.0Hz, 1H), 5.18 (s, 2H), 4.17-4.11 (m, 4H), 3.97 (s, 3H), 3.45 (t, J = 6.0Hz, 2H), 3.20 (t, J = 6.0Hz, 2H), 2.81 (s, 6H), 2.72 (s, 3H). LCMS (0-60): m/z: 542.2 [M+1].

Example 18.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 18A.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-2-methoxy- N 4 -Methyl-N 4 -(2-(methylamino)ethyl)-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N1,N2-dimethylethane-1,2-di amine. The title compound was obtained (yellow solid, 160.00 mg, yield: 85.24%). LCMS (ESI) (0-60.).

Example 18B.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N4-(2-( Ethyl (methyl)amino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

Example 18A (100.00 mg, 198.59 micromoles), MeCHO (26.24 mg, 595.77 micromoles) and acetic acid (5.96 mg, 99.30 micromoles) were dissolved in DCE (5 mL) and the mixture was warmed to 40. C was stirred for 2 hours. Then, NaBH(OAc) ₃ (126.27 mg, 595.77 micromolar) was added to the reaction mixture, and the resulting mixture was stirred at 40 ° C for 2 hours. </RTI><RTIID=0.0></RTI><RTIID=0.0></RTI></RTI></RTI> LCMS (ESI) (0-60.).

Example 18C.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N 1 - (2- (Ethyl(methyl)amino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 18B. The title compound (yellow solid, 100.00 mg, crude) was obtained. LCMS (ESI) (0-60): m.

Example 18D.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 18C. The title compound (FA salt, 38.3 mg, yield 31.89%) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.46 (br. s., 1 H), 8.34 (s, 1 H), 8.23 (br. s., 1 H), 7.96 (d, J = 4.80 Hz , 1 H), 7.33 - 7.34 (m, 1 H), 7.17 - 7.19 (m, 2 H), 7.01 (d, J=5.20 Hz, 1 H), 6.94 (s, 1 H), 6.56 - 6.63 ( m, 1 H), 6.41 - 6.45 (m, 1 H), 5.85 (d, J=10.40 Hz, 1 H), 5.06 (br. s., 2 H), 4.01 (br. S., 4 H) , 3.98(s, 3 H), 3.48 (br. s., 2 H), 3.26 (br. s., 2 H), 3.12 - 3.21 (m, 2 H), 2.82 (s, 3 H), 2.72 (s, 3 H), 1.25 (t, J = 7.20 Hz, 3 H). LCMS (ESI) (0-60): m/z:

Example 19.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 19A.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N4-(2-( Dimethylamino)ethyl)-N 4 -ethyl-2-methoxy-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N1 ethyl-N2,N2-dimethylethane-1 , 2-diamine. The title compound (yellow solid, 80 mg, crude) was obtained. LCMS (ESI) (0-60): m/z:

Example 19B.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N 1 - (2- (Dimethylamino)ethyl)-N1ethyl-5-methoxybenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 19A. The title compound (yellow solid, 80 mg, crude) was obtained. LCMS (ESI) (0-60): m/z:

Example 19C.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 19B. The title compound (FA salt, 13.40 mg, yield 13.79%) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.49 (br. s., 1 H), 8.32 (d, J = 5.60 Hz, 1 H), 8.28 (s, 1H), 8.04 (d, J = 8.80) Hz, 1 H), 7.41 - 7.44 (m, 1 H), 7.23 - 7.25 (m, 2 H), 7.14 (d, J=5.60 Hz, 1 H), 6.96 (s, 1 H), 6.48 - 6.54 (m, 2 H), 5.83 - 5.92 (m, 1 H), 5.16 (s, 2 H), 4.12 (s, 3 H), 3.99 (s, 2 H), 3.52 (t, J = 5.80 Hz, 1 H), 3.25 (t, J=5.60 Hz, 1 H), 3.08 (d, J=6.80 Hz, 1 H), 2.85 (s, 2 H), 1.06 (t, J=7.20 Hz, 1 H) . LCMS (ESI) (0-60.).

Example 20.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((1-(Dimethylamino)propan-2-yl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 20A.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N4-(1-( Dimethylamino)propan-2-yl)-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N',N'-trimethyl 1-methyl -1,2-ethylenediamine. The title compound was obtained as a red oil (270.00 mg, yield: 48.90%). LCMS (ESI) (0-60): m/z:

Example 20B.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N 1 - (1- (Dimethylamino)propan-2-yl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 20A. The title compound (brown oil, 227.00 mg, yield 75.03%) was obtained. LCMS (ESI) (0-60.).

Example 20C.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((1-(Dimethylamino)propan-2-yl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 20B. The title compound (FA salt, 7.71 mg, 2.83%) was obtained. ¹ H NMR (400MHz, CD ₃ OD): δ 8.29 (s, 2H), 8.22 (d, J = 5.2 Hz, 1H), 8.08 (s, 1H), 7.94-7.97 (m, 1H), 7.32-7.34 (m, 1H), 7.12-7.16 (m, 2H), 7.06 (d, J = 5.2 Hz, 1H), 6.71-6.74 (m, 1H), 6.36-6.43 (m, 2H), 5.73-5.76 (m , 1H), 5.06-5.08 (m, 2H), 3.97-4.07 (m, 5H), 3.85-3.87 (m, 3H), 3.10-3.16 (m, 1H), 2.91-2.95 (m, 1H), 2.77 (s, 6H), 2.55-2.58 (m, 3H), 1.29-1.33 (m, 3H), 1.12-1.16 (m, 1H). LCMS (ESI) (0-60): m/z:

Process 9.

Example 21.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-(Ethyl(2-(methylamino)ethyl)amino)-4-methoxyphenyl)propenylamine.

Example 21A.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N 4 -ethyl- N 4 -(2-(methylamino)ethyl)-2-methoxy-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N1,N2-diethylethane-1,2-di amine. The title compound (red oil, 520 mg, crude) was obtained. LCMS (ESI) (0-60): m/z:

Example 21B.

Tertiary butyl (2-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidine-2) -Amino)amino)-5-methoxy-2-nitrophenyl)(ethyl)amino)methyl)(ethyl)carbamic acid tert-butyl ester.

Example 21A (260.00 mg, 489.09 micromoles), (Boc) ₂ O (260.00 mg, 489.09 micromoles) and potassium carbonate (101.40 mg, 733.63 micromoles) were dissolved in THF (5 mL) and water (1 mL) ). The mixture was stirred at 25 ° C for 12 hours. The reaction was completed with EtOAc (EtOAc) (EtOAc) , 230 mg, yield 71.98%). LCMS (ESI) (0-60): m/z:

Example 21C.

Third butyl (2-((2-amino-4-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl) Pyrimidin-2-yl)amino)-5-methylphenyl)(ethyl)amino)methyl)(ethyl)carbamic acid tert-butyl ester.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 21B. The title compound (brown oil, mp. LCMS (ESI) (0-60): m/z:

Example 21D.

Third butyl (2-((2-propenylamino)-4((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10) -yl)pyrimidin-2-yl)amino)-5-methylphenyl)(ethyl)amino)methyl)(ethyl)carbamic acid tert-butyl ester.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 21C. The title compound (brown oil, mp. LCMS (ESI) (0-60).

Example 21E.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-(Ethyl(2-(methylamino)ethyl)amino)-4-methoxyphenyl)propenylamine.

Example 21D (180 mg, 273.64 micromoles) was dissolved in DCM (5 mL). EtOAc (EtOAc) After the completion of the addition, the reaction solution was stirred at 25 ° C for 12 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated, the crude product was dissolved in DCM (20mL) and washed with saturated NaHCO ₃ adjusted to pH 9 to 10. The organic phase was separated and concentrated to give a crude material. mjjjjjjjjj ¹ H NMR (400MHz, CD3OD): δ 8.23 (d, J=5.5Hz, 1H), 8.09 (s, 1H), 7.95 (d, J=8.2Hz, 1H), 7.31 - 7.37 (m, 1H), 7.10 - 7.18 (m, 2H), 7.07 (d, J=5.5Hz, 1H), 6.82 (s, 1H), 6.38 - 6.48 (m, 1H), 6.26 - 6.34 (m, 1H), 5.74 (d, J=10.1Hz, 1H), 5.07 (s, 2 H), 4.04 (br. s., 4H), 3.87 (s, 3H), 3.38 (br. s., 2H), 3.04 (d, J=5.0 Hz, 2H), 2.87 - 3.01 (m, 4H), 1.22 - 1.33 (m, 3H), 0.94 (t, J = 7.0Hz, 3H). LCMS (ESI) (0-60): m/z:

Example 22.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-(Ethyl (2-(ethyl(methyl)amino)).

Example 22A.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N 4 -ethyl- N4-(2-(ethyl(methyl)amino)ethyl)-2-methoxy-5-nitrobenzene-1,4-diamine.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl) at 25 ° C -N 4 -ethyl-N 4 -(2-(methylamino)ethyl)-2-methoxy-5-nitrobenzene-1,4-diamine (260.00 mg, 489.09 micromolar), HCHO (44.06 mg, 1.47 mmol, 40.42 uL) and HOAc (2.94 mg, 2.80 uL) were dissolved in MeOH (5 mL) and stirred for 0.5 h. NaBH(OAc) ₃ (310.97 mg, 1.47 mmol) was added to the reaction mixture, and the obtained mixture was stirred at 25 ° C for 12 hours. LCMS showed the reaction was completed. Aqueous NaHCO ₃ (10 mL) was added toEtOAc. The crude product was purified with EtOAc EtOAcjjjjjjj LCMS (ESI) (0-60): m/z:

Example 22B.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N1ethyl N1-( 2-(Ethyl(methyl)amino)ethyl)-5-methoxybenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 22A. The title compound (brown oil, 155 mg, crude). LCMS (ESI) (0-60): m/z:

Example 22C.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-(Ethyl(2-(ethyl(methyl)amino)ethyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 22B. The title compound (FA salt, 38.72 mg, yield 19.93%) was obtained. ¹ H NMR (400MHz, CD ₃ OD): δ 8.50 (br. s., 1H), 8.21 - 8.29 (m, 2H), 7.93 - 7.99 (m, 1H), 7.31 - 7.36 (m, 1H), 7.14 - 7.22 (m, 2H), 7.02 (d, J=5.4Hz, 1 H), 6.92 (s, 1H), 6.48 - 6.59 (m, 1H), 6.37 - 6.45 (m, 1H), 5.84 (dd, J=10.0, 1.6Hz, 1H), 5.07 (s, 2H), 4.02 (s, 4H), 3.92 - 3.99 (m, 3H), 3.51 (t, J=5.33 Hz, 2H), 3.23 (br. s ., 2H), 2.99 - 3.18 (m, 4H), 2.79 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H). LCMS (ESI) (0-60.).

Example 23.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Isopropylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 23A.

Tert-butyl (2-hydroxyethyl)(isopropyl)carbamic acid tert-butyl ester.

2-(Isopropylamino)ethanol (18.30 g, 177.39 mmol) and K ₂ CO ₃ (49.04 g, 354.78 mmol) were dissolved in THF (100 mL) and H ₂ O at 25 °C. To 20 mL), (Boc) ₂ O (58.07 g, 266.09 mmol) was added to the mixture and stirred for 3 hours. TLC (PE: EtOAc = 2: 1) showed the reaction was completed. Water (50 mL) was added to the mixture and the mixture was evaporated. The organic phases were combined, dried over anhydrous Na ₂ SO _4, filtered off with suction and concentrated. The crude product was purified by column chromatography _{(SiO 2, PE: EtOAc =} 50: 1 to 2: 1) , yielding the title compound (yellow oil, 24.00 g, 59.90% yield). ¹ H NMR (400MHz, CDCl ₃ ): δ 4.28-4.06 (m, 1H), 3.78-3.65 (m, 2H), 3.31 (br. s., 2H), 1.50-1.48 (s, 9H), 1.14 ( d, J = 6.8 Hz, 6H).

Example 23B.

Third butyl-N-isopropyl-N-(2-oxoethyl)carbamic acid.

Example 23A (10.00 g, 49.19 mmol) was dissolved in DCM (100 mL). Dess-martin reagent (31.30 g, 73.79 mmol) was added to the reaction mixture and stirred for 2 hours. TLC (PE: EtOAc = 3: 1) showed the reaction was completed. The reaction was filtered, the filtrate was concentrated to give the residue was dissolved in EtOAc (50mL), washed with saturated aqueous NaHCO ₃ (50mL x 2), and dried over anhydrous Na ₂ SO _4, filtered off with suction and concentrated. The crude product The crude product was purified by column chromatography _{(SiO 2: PE: EtOAc =} 100: 1 to 10: 1) , yielding the title compound (yellow oil, 7.90 g, yield 71.82%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.53 (br. s., 1H), 4.63-4.21 (m, 1H), 3.86-3.61 (m, 2H), 1.50-1.39 (m, 9H), 1.12 ( d, J = 6.8 Hz, 6H).

Example 23C.

Third butyl-N-isopropyl-N-[2-(dimethylamino)ethyl]carbamic acid.

Example 23B (1.80 g, 8.94 mmol) and methylamine hydrochloride (1.21 g, 17.89 mmol) were dissolved in MeOH (200 mL), and then argon was added and then Pd/C (10%, 100.00 mg) And replaced with H2 3 times. The reaction solution was heated to 50 ° C under a pressure of 50 psi and stirred for 24 hours. After TLC (DCM: MeOH = 20:1), EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) dried over anhydrous Na ₂ SO _4, filtered off with suction and concentrated to give the title compound (yellow oil, 600.00 mg, 26.37% yield). ¹ H NMR (300MHz, CDCl ₃ ): δ 4.24-4.07 (m, 1H), 3.20-3.15 (m, 2H), 2.77-2.66 (m, 2H), 2.52-2.42 (m, 3H), 1.48 (s , 9H), 1.13 (d, J = 6.8Hz, 6H).

Example 23D.

Tertiary butyl (2-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidine-2) -Methylamino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl)(isopropyl)carbamic acid tert-butyl ester.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with Example 23C. The title compound was obtained (yellow solid, 200 mg, yield 88.4%). LCMS (ESI) (5-95): m/z:

Example 23E.

Third butyl (2-((2-amino-4-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl) Pyrimidin-2-yl)amino)-5-methoxyphenyl)(methyl)amino)ethyl)(isopropyl)carbamic acid tert-butyl ester.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 23D. The title compound (brown solid, 180 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 23F.

(2-((2-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidine) 2-Benzylamino)-5-methoxyphenyl)(methyl)amino)ethyl)(isopropyl)carbamic acid tert-butyl ester.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 23E. The title compound (180 mg, crude) was obtained and used directly to the next.

Example 23G.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-(Ethyl(2-(isopropylamino)ethyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 21E, replacing Example 21D with Example 23F. The title compound (yellow solid FA salt, 24.30 mg, yield 14.34%) was obtained. ¹ H NMR (400MHz, CD ₃ OD): δ 8.33 (d, J = 4.0 Hz, 1H), 8.27 (s, 1H), 8.08-8.03 (m, 1H), 7.46-7.42 (m, 1H), 7.28 -7.20 (m, 2H), 7.15 (d, J = 4.0 Hz, 1H), 6.92 (s, 1H), 6.58-6.49 (m, 1H), 6.44-6.37 (m, 1H), 5.84 (dd, J = 2.0, 8.0 Hz, 1H), 5.19 (s, 2H), 4.14 (s, 4H), 3.98 (s, 3H), 3.44 (t, J = 6.0 Hz, 2H), 3.39-3.33 (m, 1H) , 3.15 (t, J = 6.0 Hz, 2H), 2.72 (s, 3H), 1.35 (d, J = 8.0 Hz, 6H). LCMS (ESI) (0-60): m/z:

Example 24.

N-(2-((2-(t-butylamino)ethyl)(methyl)amino)-5-((4-(3,4-dihydro-1H-[1,4]oxazine) [4,3-a]Indol-1-ylpyrimidin-2-yl)amino)-4-methoxyphenyl)propenylamine.

Example 24A.

Third butyl (2-(tert-butylamino)ethyl)(methyl)carbamic acid.

2-Methylpropan-2-amine (844.04 mg, 11.54 mmol) and tert-butyl-N-methyl-N-(2-oxoethyl)carbamic acid (1.00) at 20 °C g, 5.77 mmol) was dissolved in MeOH (30mL), purged with argon was added Pd / C (10%, 200.00 mg) and replaced with H _2. The reaction solution was stirred under a pressure of 50 Psi in H ₂ for 16 hours. LCMS showed complete consumption of the reaction and the desired MS was detected. The reaction mixture was filtered and evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal ¹ H NMR (400MHz, CDCl ₃ ): δ 3.28 (t, J = 6.7 Hz, 2H), 2.92 - 2.82 (m, 3H), 2.75 - 2.65 (m, 2H), 1.53 - 1.39 (m, 10H), 1.08 (s, 9H).

Example 24B.

N1-(Tert-butyl)-N2-dimethylethane-1,2-diamine.

Example 24A (200.00 mg, 868.24 micromolar) was dissolved in EA (30 mL) at 20 ° C. HCl / EtOAc (4 m/l, 2. Stir for 4 hours. TLC (DCM / MeOH = 10/1) showed starting material consumption. The reaction mixture was concentrated to give the title compound ( white powder, m. _{^{1 H NMR (400MHz, D 2}} O): δ 3.60 - 3.39 (m, 4H), 3.00 - 2.79 (m, 3H), 1.60 - 1.37 (m, 9H).

Example 24C.

N4-[2-(Tertiary butylamino)ethyl]-N 1 -[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]吲哚- 10-yl)pyrimidin-2-yl]-2-methoxy-N-4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with Example 24B. The title compound was obtained (120.00 mg, crude). LCMS (ESI) (5-95): m/z:

Example 24D.

N1-[2-(Tertiary butylamino)ethyl]-N4-[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10 -yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 24C. The title compound (orange powder, 100 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 24E.

N-(2-((2-(t-butylamino)ethyl)(methyl)amino)-5-((4-(3,4-dihydro-1H-[1,4]oxazine) [4,3-a]Indol-1-ylpyrimidin-2-yl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 24D. The title compound (FA salt, 46.82 mg, yield 39.41%) was obtained. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.73 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.13 - 8.00 ( m, 2H), 7.50 (d, J = 7.0 Hz, 1H), 7.29 - 7.16 (m, 2H), 7.10 (d, J = 5.5 Hz, 1H), 6.94 (s, 1H), 6.80 (dd, J = 10.3, 16.8 Hz, 1H), 6.22 (d, J = 16.8 Hz, 1H), 5.72 (d, J = 11.0 Hz, 1H), 5.13 (s, 2H), 4.15 (d, J = 4.8 Hz, 2H ), 4.08 (d, J = 4.8 Hz, 2H), 3.85 (s, 3H), 3.22 (br. s., 2H), 2.93 (br. s., 2H), 2.60 (s, 3H), 1.35 - 1.03 (m, 9H). LCMS (ESI) (5-95): m/z: 57.

Example 25.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 25A.

1-Chloro-N,N,2-trimethylpropan-2-amine.

2-(Dimethylamino)-2-methylpropan-1-ol (10.00 g, 85.33 mmol) was dissolved in toluene (100 mL), and SOCl ₂ (20.30 g, 170.66 mmol) was added to the mixture. ear). After the addition was completed, the reaction solution was heated to 100 ° C and stirred for 3 hours. TLC (DCM / MeOH = 10/1) was monitored to show complete starting material consumption. The reaction mixture was concentrated to give the title compound (yield: _{^{1 H NMR (400MHz, CD 3}} OD): δ 3.65 - 3.56 (m, 2H), 3.05 (s, 6H), 1.77 - 1.68 (m, 6H).

Example 25B.

N1, N2, N2, 2-tetramethylpropane-1,2-diamine.

Dissolving 1-chloro-N,N,2-trimethylpropan-2-amine (1.00 g, 5.81 mmol, hydrochloride) in H ₂ O (10 mL) at 20 ° C Methylamine (1.80 g, 17.43 mmol) was slowly added to the mixture and stirred for 2 hours. LCMS showed the reaction was completed. NaOH solid (2 g) was slowly added to the reaction mixture. After the reaction mixture was cooled, extracted with MTBE (20 mL x 2). The separated organic phase was concentrated to 5 mL, then HCl/EA (5 mL) Compound (orange powder, 1.00 g, crude, hydrochloride). _{^{1 H NMR (400MHz, D 2}} O): δ 3.57 - 3.48 (m, 2H), 3.01 (s, 6H), 2.81 - 2.75 (m, 3H), 1.53 (s, 6H).

Example 25C.

N1-[4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl]-N4-[2-( Dimethylamino)-2-methylpropyl]-2-methyl-N--4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with Example 25B. The title compound was obtained (red powder, 100.00 mg, crude). LCMS (ESI) (5-95): m/z:

Example 25D.

N4-[4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl]-N 1 - [2- (Dimethylamino)-2-methylpropyl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 25C. The title compound (yellow gum, 70 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 25E.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 25D. The title compound (formate, 50.92 mg, yield 58.97%) was obtained. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 10.59 (br. s., 1H), 8.53 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.28 (s, 2H), 8.12 - 8.03 (m, 2H), 7.54 - 7.45 (m, 1H), 7.26 - 7.19 (m, 2H), 7.15 - 7.06 (m, 2H), 6.48 (dd, J = 10.0, 16.8 Hz, 1H), 6.23 (dd, J = 1.4, 16.9 Hz, 1H), 5.75 (d, J = 11.5 Hz, 1H), 5.06 (s, 2H), 4.24 - 4.14 (m, 2H), 4.05 (d, J = 4.8 Hz, 2H), 3.87 - 3.83 (m, 3H), 3.12 (br. s., 2H), 2.69 (s, 3H), 2.35 (s, 6H), 1.07 - 0.89 (m, 6H). LCMS (ESI) (5-95): m/z: 57.

Example 26.

N-(2 - ((2-(aziridine-1-yl)ethyl)(methyl)amino)-5 - ((4-(3,4-dihydro-1H-[1,4]) Pyrazino[4,3-a]indol-10-ylpyrimidin-2-yl)amino)-4-methoxyphenyl)propenylamine.

Example 26A.

N4-[2-(Aziridine-1-yl)ethyl]-N 1 -[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]吲哚-10-yl)pyrimidin-2-yl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing N,N-diethyl-N-methylethane-1,2-diamine with 2-(aziridine-1-yl)-N- Methylamine. The title compound (red powder, 150.00 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 26B.

N1-[2-(aziridine-1-yl)ethyl]-N4-[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]吲哚-10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 26A. The title compound (brown powder, 130.00 mg, crude) was obtained.

Example 26C.

N-(2-((2-(aziridin-1-yl)ethyl)(methyl)amino)-5 - ((4-(3,4-dihydro-1H-[1,4]) Pyrazino[4,3-a]indol-10-ylpyrimidin-2-yl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 26B. The title compound (FA salt, 57.26 mg, yield 39.64%) was obtained. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 9.28 (s, 1H), 8.36 - 8.31 (m, 2H), 8.30 (s, 1H), 8.11 - 7.98 (m, 2H), 7.55 - 7.44 (m , 1H), 7.27 - 7.16 (m, 2H), 7.11 - 7.05 (m, 1H), 6.88 (s, 1H), 6.68 (dd, J = 10.2, 16.9 Hz, 1H), 6.20 (dd, J = 1.3 , 17.1 Hz, 1H), 5.72 (d, J = 10.8 Hz, 1H), 5.11 (s, 2H), 4.15 (d, J = 5.0 Hz, 2H), 4.08 (d, J = 4.8 Hz, 2H), 3.82 (s, 3H), 3.23 (br. s., 2H), 3.10 (t, J=5.3 Hz, 2H), 3.00 (br. s., 4H), 2.55 (s, 3H), 1.97 (br. s., 2H). LCMS (ESI) (5-95): m/z:

Example 27.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 4-methoxy-2-(methyl(2-(methylamino)ethylamino)phenyl)propenylamine.

The synthesis process of this embodiment is the same as the process 9.

Example 27A.

Tertiary butyl (2-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidine-2) -yl)amino)-5-methoxy-2-nitrophenyl)(methyl)amino)ethyl)(methyl)carbamic acid.

This example was prepared according to the method of Example 21B, replacing Example 21A with N1-(4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole- 10-yl)pyrimidin-2-yl)-2-methoxy-N 4 -methyl-N 4 -(2-(methylamino)ethyl)-5-nitrobenzene-1,4-diamine . The title compound (yellow solid, 150.00 mg, crude) was obtained. LCMS (ESI) (0-60): m/z:

Example 27B.

Third butyl (2-((2-amino-4-((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl) Pyrimidin-2-yl)amino)-5-methoxyphenyl)(methyl)amino)ethyl)(methyl)carbamic acid.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 27A. The title compound (yellow solid, 100.00 mg, crude) was obtained. LCMS (ESI) (0-60): m/z:

Example 27C.

Third butyl (2-((2-propenylamino)-4((4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10) -yl)pyrimidin-2-yl)amino)-5-methoxyphenyl)(methyl)amino)ethyl)(methyl)carbamic acid.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 27B. The title compound (yellow solid, 150.00 mg, crude) was obtained. LCMS (ESI) (0-60): m/z:

Example 27D.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 4-methoxy-2-(methyl(2-(methylamino)ethylamino)phenyl)propenylamine.

This example was prepared according to the method of Example 21E, replacing Example 21D with Example 27C. The title compound (formate, 9.26 mg, 6.65%) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.44 (br. s., 1 H), 8.31 - 8.35 (m, 2 H), 8.03 - 8.06 (m, 1 H), 7.42 (s, 1 H) , 7.21 - 7.28 (m, 2 H), 7.16 (d, J=5.60 Hz, 1 H), 6.94 (s, 1 H), 6.54 - 6.60 (m, 1 H), 6.40 - 6.45 (m, 1 H ), 5.84 - 5.87 (m, 1 H), 5.17 (s, 2 H), 4.13 (s, 4 H), 3.98 (s, 3 H), 3.43 (t, J=5.20 Hz, 2 H), 3.17 (t, J = 5.20 Hz, 2 H), 2.72 (d, J = 1.20 Hz, 6 H). LCMS (ESI) (0-60): m/z: 528.4 [M+1].

Example 28.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methylamino)-4-ethoxyphenyl)propenylamine.

Example 28A.

4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-N-(2-methoxy-4-fluoro-5- Nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the procedure of Example D, replacing 4-fluoro-2-methoxy-5-nitroaniline with 2-ethyl-4-fluoro-5-nitroaniline. The title compound (yellow solid, 300.00 mg, crude) was obtained.

Example 28B.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N4-(2-( Dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example 28A, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound (yellow solid, 230.00 mg, crude). LCMS (ESI) (5-95): m/z:

Example 28C.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N 1 - (2- (Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 28B. The title compound (brown powder, 200.00 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 28D.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methylamino)-4-ethoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 28C. The title compound was obtained (FA salt, 125.00 mg, yield 50.65%). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.46 (br. s., 1H), 8.35 (d, J = 4.0 Hz, 1H), 8.32 (s, 1H), 8.09-8.05 (m, 1H), 7.49-7.42 (m, 1H), 7.28-7.21 (m, 2H), 7.19 (d, J = 4.0 Hz, 1H), 6.95 (s, 1H), 6.57-6.42 (m, 2H), 5.86 (dd, J = 2.0, 8.0 Hz, 1H), 5.20 (s, 2H), 4.22 (q, J = 8.0 Hz, 2H), 4.16 (br. s., 4H), 3.46 (t, J=6.0 Hz, 1H) , 3.25 - 3.20 (m, 1H), 2.84 (s, 2H), 2.73 (s, 1H), 1.49 (t, J = 8.0 Hz, 1H). LCMS (ESI) (0-60): m/z:

Example 29.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methylamino)-4-isopropylphenyl)propenylamine.

Example 29A.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N4-(2-( Dimethylamino)ethyl)-2-isopropoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

Intermediate C (200 mg, 699.96 micromoles) and N4-[2-(dimethylamino)ethyl]-2-isopropoxy-N 4 -methyl-5-nitro group under N2 - Benzene-1,4-diamine (207.44 mg, 699.96 micromoles) in 10 mL of 1,4-dioxane solution was added Pd(OAc) ₂ (15.71 mg, 70.00 micromoles), K ₃ PO ₄ ( 297.16 mg, 1.40 mmol, and XPhos (33.37 mg, 70.00 micromoles), and warmed to 90 ° C for 10 hours. LCMS showed the reaction was complete, the mixture was filtered, concentrated and the crude product purified by preparative plate _{(SiO 2, DCM: 1:} MeOH = 10) , yielding the title compound (yellow solid, 130.00 mg, 26.45% yield). LCMS (ESI) (5-95): m/z:

Example 29B.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)-N 1 - (2- (Dimethylamino)ethyl)-5-isopropyl N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 29A. The title compound (light yellow solid, 120.00 mg, crude) was obtained. LCMS (ESI) (5-95): m/z:

Example 29C.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)pyrimidin-2-yl)amino)- 2-((2-(Dimethylamino)ethyl)(methylamino)-4-isopropylphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 29B. The title compound (FA salt, 20.00 mg, yield 13.96%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.44 (br. s., 1H), 9.37 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.07-7.99 (m, 1H), 7.60 (s, 1H), 7.38-7.33 (m, 1H), 7.31-7.27 (m, 2H), 7.19 (d, J = 4.0 Hz, 1H), 6.80 (dd, J = 4.0, 16.0 Hz, 1H), 6.72 (s, 1H), 6.41 (dd, J = 4.0, 16.0 Hz, 1H), 5.74-5.65 (m, 1H), 5.39 (s, 2H), 4.50 (spt, J = 6.0 Hz, 1H), 4.16 (s, 4H), 3.18 (t, J = 6.0 Hz, 2H), 2.95 (t, J = 6.0 Hz, 2H), 2.67-2.64 (m, 9H), 1.39 (d, J = 6.0 Hz, 6H) . LCMS (ESI) (0-60): m/z:

Process 10.

Example 30.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl) Amino)-2 - ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 30A.

10-(2-Chloro-5-fluoro-pyridin-4-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

2,4-Dichloro-5-fluoropyrimidine (23.14 g, 138.56 mmol) was dissolved in DME (400 mL) at 25 ° C, and AlCl ₃ (30.79 g, 230.94 mmol) was added portionwise to the mixture. Ears, 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole (20.00 g, 115.47 mmol) was then added portionwise and stirred for 12 hours. TLC showed the reaction was complete. The reaction solution was poured into water (1200 mL) with stirring, and the solid was filtered, and then filtered and evaporated. The obtained solid was dried <RTI ID=0.0> ¹ H NMR (400MHz, CDCl ₃ ): δ 8.41 (d, J = 2.80 Hz, 1 H), 7.94 - 7.98 (m, 1 H), 7.30 - 7.41 (m, 3 H), 5.26 (s, 2 H ), 4.17 - 4.29 (m, 4 H).

Example 30B.

4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoro-N-(4-fluoro-2-methoxy 5--5-nitrophenyl)pyrimidine-2-amine.

Example 30A (28.00 g, 92.19 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (18.02 g, 96.80 mmol) were dissolved in 1,4-diox under nitrogen. To a mixture of six rings (300 mL), K ₃ PO ₄ (39.14 g, 184.38 mmol), XPhos (4.39 g, 9.22 mmol) and Pd ₂ (dba) ₃ (8.44 g, 9.22 m) were added to the mixture. Mohr), and the temperature was raised to 120 ° C and stirred for 10 hours. </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; ¹ H NMR (400MHz, DMSO-d ₆ ): δ 8.89 (d, J = 8.40 Hz, 1 H), 8.59 (d, J = 3.20 Hz, 1 H), 8.50 (s, 1 H), 7.78 (dd , J = 7.60, 3.51 Hz, 1 H), 7.55 (d, J = 8.00 Hz, 1 H), 7.37 (d, J = 13.20 Hz, 1 H), 7.25 (d, J = 7.20 Hz, 1 H) , 7.20 (d, J = 7.20 Hz, 1 H), 5.11 (s, 2 H), 4.20 (d, J = 8.00 Hz, 4 H), 4.02 (s, 3 H). LCMS (ESI) (5-95): m/z:

Example 30C.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl)-N4- (2-(Dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example 30B, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound was obtained (red solid, 35.50 g, yield 87.43%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.06 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.88 - 7.93 (m, 1 H), 7.54 (s, 1 H), 7.38 (s, 1 H), 7.32 (s, 2 H), 6.69 (s, 1 H), 5.29 (s, 2 H), 4.30 (d, J = 5.60 Hz, 2 H), 4.23 (d, J = 5.60 Hz, 2 H), 4.00 (s, 3 H), 3.25 - 3.31 (m, 2 H), 2.89 (s, 3 H), 2.53 - 2.61 (m, 2 H), 2.28 (s, 6 H ). LCMS (ESI) (0-60): m/z:

Example 30D.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl)-N 1 - (2-(Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 30C. The title compound was obtained (red solid, 26.50 g, yield 79.32%). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.31 (d, J = 2.80 Hz, 1 H), 8.06 - 8.10 (m, 1 H), 8.03 (s, 1 H), 7.62 (s, 1 H), 7.39 (d, J = 4.80 Hz, 1 H), 7.29 - 7.34 (m, 2 H), 6.72 (s, 1 H), 5.20 (s, 2 H), 4.24 (dd, J = 16.40, 5.20 Hz, 4 H), 3.86 (s, 3 H), 2.98 (s, 2 H), 2.69 (s, 3 H), 2.39 - 2.46 (m, 2 H), 2.29 (s, 6 H). LCMS (ESI) (0-60): m/z:

Example 30E.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl) Amino)-2 - ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 30D. The title compound (23.20 g, yield 79.02%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 10.09 - 10.17 (m, 1 H), 9.46 (s, 1 H), 8.39 (d, J = 3.20 Hz, 1 H), 7.89 - 7.94 (m, 1 H ), 7.55 (s, 1 H), 7.34 - 7.38 (m, 1 H), 7.29 (s, 1 H), 7.24 - 7.28 (m, 1 H), 6.81 (s, 1 H), 6.26 - 6.43 ( m, 2 H), 5.65 - 5.71 (m, 1 H), 5.31 (s, 2 H), 4.22 - 4.27 (m, 2 H), 4.20 (d, J = 5.60 Hz, 2 H), 3.90 (s , 3 H), 2.86 - 2.94 (m, 2 H), 2.73 (s, 3 H), 2.23 - 2.33 (m, 8 H). LCMS (ESI) (0-60): m/z:

Example 31.

N-[5 - [[4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl) Amino]-4-methoxy-2-[methyl[2-(dimethylamino)ethyl]amino]phenyl]prop-2-enylamine.

The synthesis process of this embodiment is the same as the process 9.

Example 31A.

N1-[4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl]-2- Methoxy-N 4 -methyl-N 4 -[2-(methylamino)ethyl]-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with 4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10- 5-)fluoro-N-(4-fluoro-2-methoxy-5-nitro-phenyl)pyrimidine-2-amine, N,N-diethyl-N-methylethane- The 1,2-diamine is replaced by N1,N2-dimethylethane-1,2-diamine. The title compound (yellow solid, 1.50 g, yield 93.08%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.07 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.90 (m, 1 H), 7.56 (s, 1 H), 7.36 - 7.42 (m, 1 H), 7.29 - 7.35 (m, 2 H), 6.67 (s, 1 H), 5.29 (s, 2 H), 4.18 - 4.35 (m, 5 H), 4.00 (s, 2 H ), 3.37 (t, J = 6.00 Hz, 2 H), 2.78 - 2.87 (m, 4 H), 2.46 (s, 3 H). LCMS (ESI) (5-95): m/z:

Example 31B.

Third butyl-N-[2-[4 - [[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)- 3-Fluoropyridin-2-yl]amino]-5-methoxy-N-methyl-2-nitroaniline]ethyl]-N-methylcarbamic acid tert-butyl ester.

This example was prepared according to the method of Example 21B, and Example 21A was replaced with Example 31A. The title compound was obtained (yellow solid, 1.45 g, yield: 80.99%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.07 (s, 1 H), 8.35 (d, J = 2.80 Hz, 1 H), 7.90 (m, 1 H), 7.56 (s, 1 H), 7.36 - 7.42 (m, 1 H), 7.29 - 7.35 (m, 2 H), 6.67 (s, 1 H), 5.29 (s, 2 H), 4.18 - 4.35 (m, 5 H), 4.00 (s, 2 H ), 3.37 (t, J = 6.00 Hz, 2 H), 2.78 - 2.87 (m, 4 H), 2.46 (s, 3 H). LCMS (ESI) (5-95): m/z:

Example 31C.

Tert-butyl-N-[2-[2-amino-4 - [[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10) -yl)-5-fluoro-pyridin-2-yl]amino]-5-methoxy-N-methylanilino]ethyl]-N-methylcarbamic acid tert-butyl ester.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 31B. The title compound (yellow solid, 1.30 g, yield 94.30%) was obtained. LCMS (ESI) (5-95): m/z:

Example 31D.

Third butyl-N-[2-[4 - [[4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)- 5-fluoropyridin-2-yl]amino]-5-methoxy-N-methyl-2-(prop-2-enylamino)-anilino]ethyl]-N-methylcarbamic acid Tributyl ester.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 31C. The title compound was obtained (yellow solid, 1.2 g, yield: 84.47%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.28 - 9.47 (m, 1 H), 8.29 (d, J = 2.80 Hz, 1 H), 7.82 (d, J = 5.20 Hz, 1 H), 7.47 (s , 1 H), 7.27 - 7.30 (m, 1 H), 7.15 - 7.22 (m, 3 H), 6.69 (s, 1 H), 6.30 (d, J = 4.40 Hz, 2 H), 5.60 - 5.67 ( m, 1 H), 5.22 (d, J = 2.80 Hz, 2 H), 4.07 - 4.21 (m, 4 H), 3.82 (s, 3 H), 3.24 - 3.34 (m, 2 H), 2.90 (br s., 2 H), 2.77 (s, 3 H), 2.61 (s, 3 H), 1.39 (s, 8 H). LCMS (ESI) (5-95): m/z:

Example 31E.

N-[5 - [[4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl) Amino]-4-methoxy-2-[methyl[2-(dimethylamino)ethyl]amino]phenyl]prop-2-enylamine.

This example was prepared according to the method of Example 21E, replacing Example 21D with Example 31D. The title compound (body formate, 235.20 mg, yield 20.76%) was obtained. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.51 - 8.55 (m, 1 H), 8.42 (s, 1 H), 8.36 - 8.40 (m, 1 H), 7.84 - 7.92 (m, 1 H), 7.47 (d, J = 7.60 Hz, 1 H), 7.13 - 7.30 (m, 2 H), 6.93 (s, 1 H), 6.37 - 6.53 (m, 2 H), 5.80 - 5.88 (m, 1 H) , 5.10 (s, 2 H), 4.21 (s, 4 H), 4.00 (s, 3 H), 3.39 - 3.45 (m, 3 H), 3.15 (br. s., 2 H), 2.71 (s, 3 H), 2.70 (s, 3 H). LCMS (ESI) (0-60): m/z: 546.2.

Example 32.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl) Amino)-2 -((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 32A.

N1-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl)-N4- (2-(Dimethylamino)-2-methylpropyl)-2-methyl-N--4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with 4-(3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl. -5-fluoro-N-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2-amine, N,N-diethyl-N-methylethane-1, The 2-diamine is replaced by N1,N2,N2,2-tetramethylpropane-1,2-diamine. The title compound (red solid, 200.00 mg, yield 80.44%). ¹ H NMR (400MHz, CDCl ₃ ) : δ 9.02 (s, 1H), 8.28 (d, J=4.0 Hz, 1H), 7.85-7.79 (m, 1H), 7.61 (s, 1H), 7.33 - 7.29 ( m, 1H), 7.29 - 7.26 (m, 1H), 7.25 - 7.20 (m, 2H), 5.23 (s, 2H), 5.19 (s, 2H), 4.24 - 4.18 (m, 2H), 4.16 - 4.11 ( m, 2H), 4.09 (s, 3H), 2.93 (s, 3H), 2.68 (s, 6H), 1.34 (s, 6H).

Example 32B.

N4-(4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl)-N 1 - (2-(Dimethylamino)-2-methylpropyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 32A. The title compound was obtained (220.00 mg, yield 92.94%). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.23 (d, J=4.0 Hz, 1H), 8.02 - 7.94 (m, 1H), 7.91 (s, 1H), 7.54 (s, 1H), 7.32 - 7.27 ( m, 1H), 7.26 - 7.20 (m, 2H), 6.57 - 6.54 (m, 1H), 5.08 (s, 2H), 4.22 - 4.15 (m, 2H), 4.14 - 4.09 (m, 2H), 3.77 ( s, 3H), 3.21 (s, 2H), 2.72 (s, 3H), 2.67 (s, 6H), 1.33 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 32C.

N-(5-((4-(3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl) Amino)-2 -((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 32B. The title compound (brown solid, 50.00 mg, yield 20.38%) was obtained. ¹ H NMR (400MHz, CD ₃ OD): δ 8.39 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.32 (d, J =8.0 Hz, 1H), 7.15 - 7.09 (m, 1H), 7.09 - 7.03 (m, 1H), 7.01 (s, 1H), 6.43 - 6.33 (m, 2H), 5.82 - 5.72 (m, 1H), 4.92 (s, 2H), 4.06 (s, 4H), 3.89 (s, 3H), 3.66 - 3.27 (m, 2H), 2.67 (s, 3H), 2.63 (s, 6H), 1.22 (s, 6H) . LCMS (ESI) (5-95): m/z: 588.3 [M+1].

Example 33.

N-[2-[2-(Dimethylamino)ethyl-methyl-amino]-5-[[5-fluoro-4-(7-fluoro-3,4-dihydro-1H-[1, 4] Oxazino[4,3-a]indole-10-ylpyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enylamine.

The synthesis process of this embodiment is the same as the process 10.

Example 33A.

6-fluoro-1-(p-toluenesulfonyl)hydrazine.

6-Fluoro-1H-indole (18.00 g, 133.20 mmol) was dissolved in N,N-dimethylformamide (400 mL) at 0 ° C, and NaH (6.39) was added portionwise to the mixture. Gram, 60% w, 159.84 mmol, stirred for 1 hour. Then, 4 - methylbenzenesulfonium chloride (30.47 g, 159.84 mmol) was slowly added to the mixture, and the mixture was heated to 15 ° C and stirred for 11 hours. LCMS showed the reaction was complete, the addition of saturated NH ₄ Cl solution (500 mL) to the mixture, and the precipitated solid was filtered and concentrated to give the title compound (yellow solid, 39.80 g, crude). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.71 - 7.81 (m, 3 H), 7.56 (d, J = 3.60 Hz, 1 H), 7.46 (dd, J = 8.40, 5.20 Hz, 1 H), 7.26 (d, J = 8.00 Hz, 2 H), 7.00 (m, 1 H), 6.64 (d, J = 3.60 Hz, 1 H), 2.37 (s, 3 H).

Example 33B.

6-Fluoro-1-(p-toluenesulfonyl)indole-2-carboxylic acid.

6-Fluoro-1-(p-toluenesulfonyl) hydrazine (39.80 g, 132.06 mmol) was dissolved in tetrahydrofuran (400 mL) at -70 ° C, and n-butyllithium was added dropwise to the mixture. 2.5 mol, 52.82 mL), stirred for 1 hour. Dry ice (58.11 g, 1.32 mmol) was then slowly added to the mixture and stirred for 1.5 hours. TLC showed the reaction was complete, the addition of saturated NH ₄ Cl solution (200mL) added to the mixture and extracted with EA (200mL x2), aqueous phase was adjusted with concentrated hydrochloric acid to pH = 1, (200mL x3) extracted, concentrated and then DCM, to give the title Compound (yellow solid, 32.75 g, yield 74.40%). ^{1 H NMR (400MHz, DMSO-} d 6): δ 7.96 (d, J = 8.40 Hz, 1 H), 7.80 (d, J = 10.40 Hz, 1 H), 7.72 (dd, J = 8.80, 6.00 Hz, 1 H), 7.44 (d, J = 8.00 Hz, 2 H), 7.34 (s, 1 H), 7.23 (br. s., 1 H), 2.37 (s, 3 H).

Example 33C.

(6-Fluoro-1H-indol-2-yl)methanol.

6-Fluoro-1-(p-toluenesulfonyl)indole-2-carboxylic acid (32.75 g, 98.25 mmol) was dissolved in tetrahydrofuran (400 mL) at 0 ° C, and the mixture was added portionwise. Lithium tetrahydrogen aluminum (9.32 g, 245.63 mmol) was stirred at 25 ° C for 16 hours. TLC showed the reaction was completed. Water (9.5 mL), 15% NaOH (9.5 mL), and water (28 mL) were sequentially added to the reaction mixture, and the mixture was filtered, and the filtrate was concentrated to give a crude product. : MeOH = 20:1, 3:1) ¹ H NMR (400MHz, CDCl ₃ ): δ 8.37 (br. s., 1 H), 7.50 (dd, J = 8.40, 5.20 Hz, 1 H), 7.06 (dd, J = 9.60, 1.60 Hz, 1 H ), 6.90 (td, J = 9.20, 2.00 Hz, 1 H), 6.41 (s, 1 H), 4.84 (s, 2 H).

Example 33D.

7-Fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

(6-Fluoro-1H-indol-2-yl)methanol (5.11 g, 30.94 mmol) and potassium hydroxide (4.34 g, 77.35 mmol) were dissolved in dichloromethane at 0 °C. 300 mL), phenylvinylhydrazine (14.02 g, 37.13 mmol) was added dropwise to the mixture, and stirred at 20 ° C for 12 hours. TLC showed the reaction was completed, EtOAc (EtOAc:EtOAc: The yield was 61.70%). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.49 (dd, J = 8.40, 5.20 Hz, 1 H), 6.99 (dd, J = 9.20, 2.00 Hz, 1 H), 6.91 (ddd, J = 9.60, 8.40 , 2.00 Hz, 1 H), 6.22 (s, 1 H), 4.98 (s, 2 H), 4.16 - 4.24 (m, 2 H), 4.01 - 4.09 (m, 2 H).

Example 33E.

Tetrahydro-1H-[1,4]oxazino[4,3-a] in 10-(2-chloro-5-fluoro-pyridin-4-yl)-7-fluoro-3,4,5a,9a Hey.

This example was prepared according to the method of Example 30A, replacing 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole with Example 33D. The title compound was obtained (yellow solid, 3.40 g, yield: 64.79%). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.44 (d, J = 2.80 Hz, 1 H), 7.85 - 7.96 (m, 1 H), 6.98 - 7.13 (m, 2 H), 5.24 (s, 2 H ), 4.22 - 4.30 (m, 2 H), 4.10 - 4.20 (m, 2 H).

Example 33F.

5-fluoro-4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-N-(4-fluoro- 2-methoxy-5-nitro-phenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 30B, replacing Example 30A with Example 33E. The title compound (yellow solid, 5.10 g, crude) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.37 (d, J = 8.00 Hz, 1 H), 8.40 (d, J = 2.40 Hz, 1 H), 7.81 - 7.88 (m, 1 H), 7.67 (s , 1 H), 7.44 (m, 1 H), 7.05 - 7.11 (m, 2 H), 6.79 (d, J = 12.00 Hz, 1 H), 5.25 (s, 2 H), 4.27 - 4.33 (m, 2 H), 4.15 - 4.20 (m, 3 H), 4.06 (s, 3 H).

Example 33G.

N4-[2-(Dimethylamino)ethyl]-N 1 -[5-fluoro-4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazine[4, 3-a] 吲哚-10-yl)pyrimidin-2-yl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example 33F, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound (yellow solid, 4.20 g, crude) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.01 (s, 1 H), 8.33 (d, J = 2.80 Hz, 1 H), 7.76 - 7.86 (m, 1 H), 7.53 (s, 1 H), 6.97 - 7.08 (m, 2 H), 6.68 (s, 1 H), 5.23 (s, 2 H), 4.24 - 4.30 (m, 2 H), 4.10 - 4.17 (m, 2 H), 3.99 (s, 3 H), 3.26 (t, J = 7.20 Hz, 2 H), 2.88 (s, 3 H), 2.55 (t, J = 7.20 Hz, 2 H), 2.26 (s, 6 H). LCMS (ESI) (5-95): m/z:

Example 33H.

N1-[2-(Dimethylamino)ethyl]-N4-[5-fluoro-4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazine[4,3- a] 吲哚-10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 33G. The title compound was obtained (yellow solid, 1.23 g, yield: 30.95%). ¹ H NMR (400MHz, CDCl ₃ ): δ. 8.32 (d, J = 2.40 Hz, 1 H), 8.00 (s, 1 H), 7.64 (s, 1 H), 6.99 - 7.13 (m, 2 H) , 6.68 (s, 1 H), 5.15 (s, 2 H), 4.26 (d, J = 5.20 Hz, 2 H), 4.15 (d, J = 5.20 Hz, 2 H), 3.87 (s, 3 H) , 3.35 (br. s., 2 H), 3.08 (br. s., 2 H), 2.84 (s, 6 H), 2.73 (s, 3 H). LCMS (ESI) (0-60): m/z:

Example 33I.

N-[2-[2-(Dimethylamino)ethyl-methyl-amino]-5-[[5-fluoro-4-(7-fluoro-3,4-dihydro-1H-[1, 4] Oxazino[4,3-a]indole-10-ylpyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 33H. The title compound was obtained (281.50 g, yield 24.41%). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.54 (br. s., 1 H), 8.48 (br. s., 1 H), 8.38 (br. s., 1 H), 7.81 - 7.90 (m , 1 H), 7.17 - 7.25 (m, 1 H), 6.97 (s, 2 H), 6.41 - 6.52 (m, 2 H), 5.86 (m, 1 H), 5.07 (br. s., 3 H ), 4.17 (d, J = 14.00 Hz, 4 H), 4.00 (s, 3 H), 3.41 (br. s., 3 H), 3.12 (br. s., 2 H), 2.76 (br. s ., 6 H), 2.72 (s, 3 H). LCMS (ESI) (0-60): m/z: 578.3 [M+1].

Example 34.

N-(5-((4-(7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridine -2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

The synthesis process of this embodiment is the same as the process 10.

Example 34A.

(6-Chloro-1H-indol-2-yl)methanol.

This example was prepared according to the method of Example 33C, replacing 6-fluoro-1-(p-toluenesulfonyl)indole-2-carboxylic acid with 6-chloro-1-toluenesulfonyl-1H-indole- 2-carboxylic acid. The title compound (brown solid, 3.50 g, yield: 79.30%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.50 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.09 (dd, J=4.0, 8.0 Hz, 1H), 6.40 (s, 1H) , 4.85 (s, 2H).

Example 34B.

7-Chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

This example was prepared according to the method of Example 33D, replacing 33C with 34A. The title compound (brown solid, 1.30 g, yield 29.17%) was obtained. 1H NMR (400MHz, CDCl3): δ 7.49 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.11 (dd, J=0.8, 8.0 Hz, 1H), 6.22 (d, J=4.0 Hz , 1H), 4.99 (s, 2H), 4.26 - 4.14 (m, 2H), 4.10 - 4.04 (m, 2H). LCMS (ESI) (5-95): m/z:21.

Example 34C.

7-Chloro-10-(2-chloro-5-fluoropyridin-4-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

This example was prepared according to the method of Example 30A, replacing 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole with 34B. The title compound was obtained (yellow solid, 480.00 <RTIgt; ¹ H NMR (400MHz, CDCl ₃ ): δ 8.44 (d, J=4.0 Hz, 1H), 7.88 (dd, J=4.0, 8.0 Hz, 1H), 7.39 (s, 1H), 7.31 - 7.29 (m, 1H), 5.25 (s, 2H), 4.31 - 4.14 (m, 4H). LCMS (ESI) (5-95): m/z:

Example 34D.

4-(7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoro-N-(4-fluoro- 2-methoxy-5-nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 30B, replacing 30A with 34C. The title compound (yellow solid, 450.00 mg, yield 66.11%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.25 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 4.0 Hz, 1H), 7.71 (dd, J=4.0, 8.0 Hz, 1H), 7.57 (s, 1H), 7.30 (d, J=4.0 Hz, 1H), 7.17 (dd, J=4.0, 8.0 Hz, 1H), 6.69 (d, J=12.0 Hz, 1H), 5.16 (s, 2H) , 4.23 - 4.17 (m, 2H), 4.11 - 4.07 (m, 2H), 3.96 (s, 3H). LCMS (ESI) (5-95): m/z:

Example 34E.

N1-(4-(7-Chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl -N4-(2-(Dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example 34D, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound (red solid, 300.00 mg, yield 85.58%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.02 (s, 1H), 8.35 (d, J=4.0 Hz, 1H), 7.84 - 7.75 (m, 1H), 7.53 (s, 1H), 7.38 (d, J=4.0 Hz, 1H), 7.25 (dd, J=4.0, 8.0 Hz, 1H), 6.69 (s, 1H), 5.26 (s, 2H), 4.33 - 4.24 (m, 2H), 4.20-4.14 (m , 2H), 4.00 (s, 3H), 3.28 (t, J=8.0 Hz, 2H), 2.90 (s, 3H), 2.57 (t, J=8.0 Hz, 2H), 2.28 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 34F.

N4-(4-(7-Chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridin-2-yl )-N 1 -(2-(Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 34E. The title compound (brown solid, 200.00 mg, yield 70.37%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.22 (d, J = 2.8 Hz, 1H), 7.91 - 7.86 (m, 2H), 7.52 (s, 1H), 7.29 (d, J=4.0 Hz, 1H) , 7.16 (dd, J=4.0, 8.0 Hz, 1H), 6.63 (s, 1H), 5.08 (s, 2H), 4.19 - 4.15 (m, 2H), 4.10 - 4.06 (m, 2H), 3.77 (s , 3H), 2.88 (t, J=8.0 Hz, 2H), 2.60 (s, 3H), 2.33 (t, J=8.0 Hz, 2H), 2.19 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 34G.

N-(5-((4-(7-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridine -2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 34F. The title compound was obtained (65.50 mg, yield 29.27%). ¹ H NMR (400MHz, CD ₃ OD): δ 8.98 (s, 1H), 8.36 (d, J=4.0 Hz, 1H), 7.82 (dd, J=4.0, 8.0 Hz, 1H), 7.50 (d, J =0.8 Hz, 1H), 7.16 (dd, J=0.8, 8.0 Hz, 1H), 6.98 (s, 1H), 6.52 (dd, J=12.0, 20.0 Hz, 1H), 6.28 (dd, J=0.8, 20.0 Hz, 1H), 5.77 (dd, J=0.8, 8.0 Hz, 1H), 5.10 (s, 2H), 4.17 (s, 4H), 3.94 (s, 3H), 3.06 (t, J=4.0 Hz, 2H), 2.71 (s, 3H), 2.44 (t, J=4.0 Hz, 2H), 2.30 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 35.

N-[2-[2-(Dimethylamino)ethyl-methylamino]-5-[[5-fluoro-4-(6-methoxy-3,4-dihydro-1H-[1 4] Oxazino[4,3-a]indole-10-ylpyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enylamine.

The synthesis process of this embodiment is the same as the process 10.

Example 35A.

(7-Methoxy-1H-indol-2-yl)methanol.

Ethyl ethyl 7-methoxy-1H-indole-2-carboxylate (11.00 g, 50.17 mmol) was dissolved in THF (100 mL) at 0 ° C. Lithium tetrahydrogenate (2.86 g, 75.26 mmol) was heated to 25 ° C for 3 hours. LCMS showed the reaction was complete, H ₂ O (1mL) and NaOH (1mL) to the reaction mixture, followed by addition of H2O (3mL), filtered and the filtrate concentrated to give the title compound (brown oil, 10.00 g). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.57 (br. s., 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 7.03 (t, J = 8.0 Hz, 1 H), 6.65 ( d, J=8.0 Hz, 1 H), 6.40 (d, J=4.0 Hz, 1 H), 4.84 (d, J=4.0 Hz, 2 H), 3.97 (s, 3 H). LCMS (ESI) (5-95): m/z: 178.1 [M+1].

Example 35B.

6-Methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

(7-Methoxy-1H-indol-2-yl)methanol (10.00 g, 56.43 mmol) and sodium hydroxide (7.92 g, 141.08 mmol) were dissolved in dichlorobenzene at 0 °C. Methane (300 mL) was added dropwise a solution of phenyl vinylhydrazine (24.54 g, 67.72 mmol) in dichloromethane (200 mL), and then warmed to 25 ° C and stirred for 3 hours under N ₂ . After TLC showed complete reaction, and extracted (500mLx2) with dichloromethane H ₂ O (700mL) was added to the reaction mixture, the organic layer was washed with saturated aqueous sodium chloride (1000mL), dried over anhydrous sodium sulfate (10 g) was dried, concentrated, The title compound (brown solid, 5.80 g, 50.58% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.18 (d, J = 8.0 Hz, 1 H), 7.02 (t, J = 8.0 Hz, 1 H), 6.63 (d, J = 8.0 Hz, 1 H) , 6.20 (s, 1 H), 4.99 (s, 2 H), 4.50-4.57 (m, 2 H), 4.10-4.17 (m, 2 H), 3.94 (s, 3 H).

Example 35C.

10-(2-chloro-5-fluoro-pyridin-4-yl)-6-methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole .

This example was prepared according to the method of Example 30A, replacing 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole with 35B. The title compound (brown solid, 5.80 g, 50.58% yield) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.41 (d, J = 4.0 Hz, 1 H), 7.48 (dd, J=8.0, 4.00 Hz, 1 H) 7.17 (t, J=8.00 Hz, 1 H 6.73 (d, J=8.00 Hz, 1 H), 5.22 (s, 2 H), 4.65 (t, J=4.00 Hz, 2 H), 4.17 (t, J=4.00 Hz, 2 H), 3.96 ( s, 3 H). LCMS (ESI) (5-95): m/z:

Example 35D.

5-fluoro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(6-methoxy-3,4-dihydro-1H-[1,4]oxazine And [4,3-a] 吲哚-10-yl)pyrimidine-2-amine.

This example was prepared according to the method of Example 30B, replacing 30A with 35C. The title compound was obtained (yellow solid, 3.2 g). ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.37 (d, J = 8.00 Hz, 1 H), 8.36 (d, J = 2.00 Hz, 1 H), 7.64 (br. s., 1 H), 7.40 - 7.46 (m, 1 H), 7.14 (t, J=8.00 Hz, 1 H), 6.67-6.78 (m, 2 H), 5.21 (s, 2 H), 4.63 (t, J=4.00 Hz, 2 H), 4.20 (t, J=4.00 Hz, 2 H), 4.03 (s, 3 H), 3.96 (s, 3 H). LCMS (ESI) (5-95): m/z:

Example 35E.

N4-[2-(Dimethylamino)ethyl]-N 1 -[5-fluoro-4-(6-methoxy-3,4-dihydro-1H-[1,4]oxazino[ 4,3-a]吲哚-10-yl)pyrimidin-2-yl]-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamino].

This example was prepared according to the method of Example 16A, replacing Example D with Example 35D, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound was obtained (yellow solid, 3.2 g). LCMS (ESI) (5-95): m/z:

Example 35F.

N1-[2-(Dimethylamino)ethyl]-N4-[5-fluoro-4-(6-methoxy-3,4-dihydro-1H-[1,4]oxazine[4, 3-a] 吲哚-10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 35E. The title compound (brown oil, 500 mg) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.28 (d, J = 4.00 Hz, 1 H), 8.03 (s, 1 H), 7.58 - 7.63 (m, 2 H), 7.14 (t, J = 8.00 Hz, 1 H), 6.67 – 6.72 (m, 2 H), 5.13 (s, 2 H), 4.62 (t, J=4.00 Hz, 2 H), 4.16 (t, J=8.00 Hz, 2 H), 3.95 (s, 3 H), 3.84 (s, 3 H), 2.95 (t, J=8.00 Hz, 2 H), 2.67 (s, 3 H), 2.39 (t, J=4.00 Hz, 2 H), 2.26 (s, 6 H). LCMS (ESI) (5-95): m/z:

Example 35G.

N-[2-[2-(Dimethylamino)ethyl-methylamino]-5-[[5-fluoro-4-(6-methoxy-3,4-dihydro-1H-[1 4] Oxazino[4,3-a]indole-10-ylpyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 35F. The title compound was obtained (210.00 mg, 330.35 micromoles, 58.98% yield). ¹ H NMR (400 MHz, CD ₃ OD) : δ 8.46 - 8.57 (m, 2 H), 8.37 (d, J = 3.00 Hz, 1 H), 7.40 (dd, J = 8.00, 3.45 Hz, 1 H) 7.06 (t, J=8.00 Hz, 1 H) 6.96 (s, 1 H) 6.75 (d, J=8.00b Hz, 1 H) 6.39 - 6.54 (m, 2 H) 5.82 - 5.90 (m, 1 H) 5.05 (s, 2 H) 4.58 (t, J=5.00 Hz, 2 H) 4.13 (t, J=5.00 Hz, 2 H) 4.00 (s, 3 H) 3.96 (s, 3 H) 3.39 (d, J =8.00 Hz, 2 H) 3.06 - 3.18 (m, 2 H) 2.70 - 2.77 (m, 9 H). LCMS (ESI) (5-95): m/z:

Example 36.

N-(5-((4-(4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-) 5-Fluoropyridin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine methanesulfonate.

The synthesis process of this embodiment is the same as the process 10.

Example 36A.

Ethyl 1-(2-ethoxy-2-oxoethyl)-1H-indole-2-carboxylate.

Ethyl phthalate-2-carboxylate (32.00 g, 169.12 mmol), ethyl bromoacetate (70.61 g, 422.80 mmol) and potassium carbonate (70.12 g, 507.36 mmol) mixed with acetonitrile (400 mL) The mixture was stirred at 80 ° C for 20 hours. LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate (500 mL) and water (500 mL) and then evaporated. The organic phase was concentrated and purified with EtOAc EtOAc EtOAc EtOAc ¹ H NMR (400MHz, CDCl ₃ ): δ 7.72 (d, J = 8.1 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.34 - 7.29 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H), 5.34 (s, 2H), 4.38 (q, J=7.2 Hz, 2H), 4.24 (q, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H). LCMS (ESI) (5-95): m/z:

Example 36B.

Ethyl ethyl 1-(1-methoxy-2-methyl-1-oxopropan-2-yl)-1H-indole-2-carboxylate.

Potassium bis(trimethylsulfonium)amide (1 M, 334.18 mL) was added dropwise to tetrahydrofuran (300 mL) dissolved in Example 36A (46.00 g, 167.09 mmol) at -70 °C. The mixture was stirred at -70 ° C for 0.5 hours and then iodomethane (47.43 g, 334.18 mmol) was added dropwise. The mixture was stirred at 5-15 °C for 12 hours. TLC showed no reaction. The mixture was diluted with water (500 mL) and ethyl acetate (500 mL) and then evaporated. The organic phase was concentrated and purified by chromatography (PE: EA = 40:1, 20:1). The obtained product (48 g) was dissolved in tetrahydrofuran (200 mL), and then bis(trimethylsulfonium)amino potassium (1M, 497.70 mL) was added dropwise at -70 °C. The mixture was stirred at -70 ° C for 0.5 hours and then methyl iodide (70.64 g, 497.70 mmol) was added dropwise. The resulting mixture was stirred at 0 ° C for 3 hours. LCMS showed the reaction was complete. The mixture was diluted with water (300 mL) and ethyl acetate (300 mL) and then evaporated. The organic phase was concentrated and purified with EtOAc (EtOAc:EtOAc:EtOAc ¹ H NMR (400MHz, CDCl ₃ ): δ 7.67 (dd, J=7.6, 13.6 Hz, 2H), 7.36 (s, 1H), 7.26 (s, 1H), 7.15 (t, J = 7.2 Hz, 1H) , 4.34 (q, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 2.10 (s, 6H), 1.41 (t, J=7.2 Hz, 3H), 1.18 (t, J= 7.2 Hz, 3H). LCMS (ESI) (5-95): m.

Example 36C.

2-(2-(Hydroxymethyl)-1H-indol-1-yl)-2-methylpropan-1-ol.

Lithium tetrahydroaluminum (3.75 g, 98.91 mmol) was added portionwise to tetrahydrofuran (100 mL) dissolved in Example 36B (10.00 g, 32.97 mmol). The mixture was stirred at 40 ° C for 1 hour. TLC showed the reaction was complete. Water (3.75 mL) and 15% aqueous sodium hydroxide solution (3.75 mL) were added dropwise to the mixture at 0 ° C, and then filtered. The filtrate was concentrated to give the title compound (m. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.52 (d, J = 7.2 Hz, 2H), 7.13 (t, J = 6.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.22 (s , 1H), 4.51 (s, 2H), 3.55 (s, 2H), 3.39 (s, 2H), 1.64 (s, 6H).

Example 36D.

4,4-Dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

Methanesulfonium chloride (3.16 g, 27.59 mmol) was added dropwise to dissolve in Example 36C (5.50 g, 25.08 mmol), triethylamine (3.81 g, 37.62 mmol) at 0 °C. The mixture was stirred with DMF (100 mL). Sodium hydrogen (2.01 g, 50.16 mmol) was added. The mixture was stirred at 70 ° C for 4 hr. MS was obtained from the title compound. The chloroform (100 mL) was washed with EtOAc (EtOAc)EtOAc. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.56 (t, J = 8.6 Hz, 2H), 7.20 - 7.05 (m, 2H), 6.20 (s, 1H), 4.97 (s, 2H), 3.80 (s, 2H), 1.68 (s, 6H). LCMS (ESI) (5-95AB): m/z: 202.0 [M+1].

Example 36E.

10-(2-chloro-5-fluoro-pyridin-4-yl)-4,4-dimethyl-1,3-dihydro-[1,4]oxazino[4,3-a]吲哚.

This example was prepared according to the method of Example 30A, replacing 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole with 36D. The title compound was obtained (yellow solid, 1.30 g, yield: 87.66%). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.35 (d, J = 2.8 Hz, 1H), 7.87 - 7.77 (m, 1H), 7.61 - 7.51 (m, 1H), 7.25 - 7.13 (m, 2H), 5.10 (s, 2H), 3.78 (s, 2H), 1.67 (s, 6H).

Example 36F.

4-(4,4-Dimethyl-1,3-dihydro-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoro-N-(4- Fluor-2-methoxy-5-nitro-phenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 30B, replacing Example 30A with Example 36E. The title compound was obtained (deep yellow solid, 1.30 g, yield 68.88%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.38 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 7.89 - 7.81 (m, 1H), 7.70 - 7.59 (m, 2H), 7.32 - 7.19 (m, 1H), 6.76 (d, J=12.0 Hz, 1H), 5.21 (s, 2H), 4.03 (s, 3H), 3.90 (s, 2H), 1.76 (s, 6H ). LCMS (ESI) (5-95): m/z:

Example 36G.

N1-(4-(4,4-Dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridine 2-yl)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example 36F, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound (red solid, 750.00 mg, 80.16% yield) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.07 (s, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.91 - 7.79 (m, 1H), 7.70 - 7.60 (m, 1H), 7.56 ( s, 1H), 7.25 (dd, J=3.2, 5.6 Hz, 1H), 6.68 (s, 1H), 5.21 (s, 2H), 3.98 (s, 3H), 3.90 (s, 2H), 3.27 (t , J = 6.8 Hz, 2H), 2.88 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.27 (s, 6H), 1.75 (s, 6H).

Example 36H.

N4-(4-(4,4-Dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridine 2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 36G. The title compound (dark yellow solid, 600.00 mg, crude) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.30 (d, J = 2.5 Hz, 1H), 8.04 (s, 2H), 7.67 - 7.58 (m, 2H), 7.25 (dd, J=3.2, 6.4 Hz, 2H), 6.71 (s, 1H), 5.10 (s, 2H), 3.93 - 3.76 (m, 5H), 2.96 (t, J=6.8 Hz, 2H), 2.67 (s, 3H), 2.40 (t, J =6.8 Hz, 2H), 2.26 (s, 6H), 1.75 (s, 6H).

Example 36I.

N4-(4-(4,4-Dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-5-fluoropyridine 2-yl)-N 1 -(2-(dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 36H. The title compound (dark yellow solid, 330.00 mg, 59.93% yield) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.40 (br. s., 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.91 - 7.77 (m, 1H), 7.65 - 7.52 (m, 2H) , 7.21 (dd, J=2.8, 6.0 Hz, 2H), 6.69 (s, 1H), 6.36 (d, J=16.4 Hz, 1H), 5.68 (d, J=11.2 Hz, 1H), 5.20 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.17 (br. s., 2H), 2.76 - 2.43 (m, 9H), 1.73 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 36J.

N-(5-((4-(4,4-dimethyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-) 5-Fluoropyridin-2-yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine methanesulfonate.

To a solution of EA (0.66 mL Micro-mole) solution. After the addition was completed, stirring was continued at this temperature for 1 hour. A red precipitate precipitated. The mixture was filtered, and EtOAc EtOAcjjjjjjj ¹ H NMR (400 MHz, CD ₃ OD): δ 8.39 (d, J = 5.2 Hz, 1H), 7.94 - 7.85 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.38 - 7.21 (m , 2H), 7.10 (s, 1H), 6.70 - 6.58 (m, 1H), 6.51 - 6.38 (m, 1H), 5.87 (d, J = 10.8 Hz, 1H), 5.00 (s, 2H), 3.99 ( s, 3H), 3.85 (s, 2H), 3.59 (t, J=5.2 Hz, 2H), 3.37 (t, J=5.2 Hz, 2H), 2.93 (s, 6H), 2.83 (s, 3H), 2.73 (s, 4H), 1.74 (s, 6H). LCMS (ESI) (5-95): m/z:

Process 11.

Example 37A.

(5-Fluoro-1H-indol-2-yl)methanol.

5-Fluoro-1H-indole-2-carboxylic acid (10.00 g, 55.82 mmol) was dissolved in THF (100 mL) at 0 ° C. To this mixture was added LAH (3.18 g, 83.79 mmol) Ear) and stir at 0~25 °C for 4 hours. TLC (PE: EtOAc = 1:1) EtOAc (EtOAc: EtOAc) (Yellow solid, 9.00 g, yield 85.91%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.44 (br. S,, 1H), 7.20-7.27 (m, 2H), 6.97-6.92 (m, 1H), 6.38 (s, 1H), 4.83 (s , 3H), 2.09 (br. s., 1H).

Example 37B.

8-Fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

This example was prepared according to the method of Example C4, replacing 2-hydroxymethyl-hydrazine with (5-fluoro-1H-indol-2-yl)methanol. The title compound (light yellow solid, 1.30 g, yield 50.54%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.18-7.27 (m, 2H), 6.95-6.93 (m, 1H), 6.21 (s, 1H), 5.00 (s, 2H), 4.17-4.22 (m, 2H), 4.06-4.11 (m, 2H).

Example 37C.

10-bromo-8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

Example 37B (5.00 g, 26.15 mmol) was dissolved in THF (100 mL) at -70 ° C, and NBS (5.12 g, 28.77 mmol) was added to the mixture at -70. C was stirred for 1 hour. TLC (PE: EtOAc = 10: 1) showed the reaction completed, the reaction solution (20mL) and quenched with saturated NaHCO ₃ solution, and extracted with EtOAc (30mL * 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated The residue was purified with EtOAc EtOAcjjjjjjjj ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.27-7.17 (m, 1H), 7.02-6.99 (m, 1H), 4.93 (s, 2H), 4.22-4.14 (m, 2H), 4.12-4.03 ( m, 2H).

Example 37D.

8-fluoro-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-[1,4] Oxazine and [4,3-a]吲哚.

Example 37C (5.50 g, 20.36 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborane (5.21 g, 40.72 mmol, 5.92 mL) were dissolved. To the mixture was added Pd ₂ (dba) ₃ (372.93 mg, 407.20 micromoles), Et ₃ N (6.18 g, 61.08 mmol, 8.47 mL) and X-PHOS (388.29 mg) in toluene (100 mL). After 814.40 micromolar, and after replacing N ₂ , the temperature was raised to 110 ° C and stirred for 3 hours. TLC (PE: DCM = 10: 1). Gram, yield 90.59%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.67 (dd, J1 = 2.4 Hz, J2 = 10 Hz, 1H), 7.19 (dd, J1 = 4.4 Hz, J2 = 8.8 Hz, 1H), 6.97-6.94 ( m, 1H), 5.17 (s, 2H), 4.21-4.15 (m, 2H), 4.11-4.05 (m, 2H), 1.36 (s, 12H).

Example 37E.

10-(2-chloropyrimidin-4-yl)-8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

Example 37D (1.50 g, 4.73 mmol) and 2,4 - dichloro-pyrimidine (1.41 g, 9.46 mmol) was dissolved in THF (20mL) and water (3mL), to this mixture was added Na ₂ CO ₃ (1.00 mg, 9.46 mmol) and Pd(dppf)Cl2.CH 2 Cl 2 (200.00 mg, 244.91 μmol) were warmed to 50 ° C under nitrogen for 8 hours. TLC (PE: EtOAc = 5:1) EtOAc (EtOAc: EtOAc = EtOAc (EtOAc) The title compound (white solid, 700.00 g, 38.98%). ^{1 H NMR (300 MHz, CDCl} 3): δ 8.53 (d, J = 5.4Hz, 1H), 7.71 (dd, J1 = 2.4Hz, J2 = 9.9Hz, 1H), 7.49 (d, J = 5.4Hz, 1H), 7.34-7.31 (m, 1H), 7.10-7.08 (m, 1H), 5.41 (s, 2H), 4.30-4.14 (m, 4H). LCMS (ESI) (5-95): m/z: 304.0.

Example 37F.

4-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-N-(4-fluoro-2-methoxy 5--5-nitro-phenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example D, replacing Example C with Example 37E. The title compound (gray solid, 700.00 mg, crude) was obtained. ¹ H NMR (300MHz, CDCl ₃ ): δ 9.40 (d, J = 8.1Hz, 1H), 8.49 (d, J = 5.7Hz, 1H), 7.72 (d, J = 9.9Hz, 1H), 7.57 (s , 1H), 7.15 (d, J = 5.4Hz, 1H), 7.08-7.06 (m, 1H), 6.79 (d, J = 12.3Hz, 1H), 6.65 (d, J = 12.0Hz, 1H), 5.42 (s, 2H), 4.27-4.25 (m, 2H), 4.21-4.19 (m, 2H), 4.06 (s, 3H). LCMS (ESI) (5-95): m/z: 454.2 [M+1].

Example 37G.

N4-[2-(Dimethylamino)ethyl]-N 1 -[4-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]吲哚-10-yl)pyrimidin-2-yl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example 37F, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound (brown solid, 140.00 mg, yield: 88.89%). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.96 (s, 1H), 8.35 (d, J = 5.2Hz, 1H), 7.62 (dd, J1 = 2.4Hz, J2 = 10.0Hz, 1H), 7.36 (s , 1H), 7.22 (dd, J1 = 4.4Hz, J2 = 9.0Hz, 1H), 7.00-6.91 (m, 2H), 6.63 (s, 1H), 6.64-6.60 (m, 1H), 5.33 (s, 2H), 4.21-4.15 (m, 2H), 4.12-4.06 (m, 2H), 3.92 (s, 3H), 3.25-3.18 (m, 2H), 2.82 (s, 3H), 2.54 (t, J = 7.2 Hz, 2H), 2.25 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 37H.

N1-[2-(Dimethylamino)ethyl]-N4-[4-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]吲哚-10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 37G. The title compound (brown solid, 160.00 mg, crude) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.41 (d, J = 5.6 Hz, 1H), 7.95 (s, 1H), 7.85-7.82 (m, 1H), 7.80-7.71 (m, 1H), 7.48 ( s, 1H), 7.07-7.02 (m, 1H), 6.93 (d, J = 5.6Hz, 1H), 6.73 (s, 1H), 5.38 (s, 2H), 4.27-4.22 (m, 2H), 4.21 -4.16 (m, 2H), 3.86 (s, 3H), 3.04-3.00 (m, 2H), 2.70 (s, 3H), 2.49-2.46 (m, 2H), 2.32 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 37I.

N-[2-[2-(Dimethylamino)ethyl-methyl-amino]-5-[4-(8-fluoro-3,4-dihydro-1H-[1,4]oxazine [4,3-a]Indol-1-ylpyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 37H. The title compound (formate, 73.00 mg, yield 37.33%) was obtained. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 10.13 (s, 1H), 8.60 (s, 1H), 8.33 (d, J = 5.2Hz, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.85 (dd, J1 = 2.0Hz, J2 = 10.4Hz, 1H), 7.51 (dd, J1 = 4.6Hz, J2 = 8.8Hz, 1H), 7.13-6.97 (m, 3H), 6.44 (dd, J1 = 10.0Hz, J2 = 16.8Hz, 1H), 6.19 (dd, J1 = 2.0Hz, J2 = 16.8z, 1H), 5.78-5.67 (m, 1H), 5.07 (s, 2H), 4.18-4.11 ( m, 2H), 4.10-4.00 (m, 2H), 3.80 (s, 3H), 2.94 (t, J = 5.2Hz, 2H), 2.70(s, 3H), 2.44 (t, J = 5.6Hz, 2H ), 2.29 (s, 6H). LCMS (ESI) (5-95.): m/z:

Example 38.

N-[2-[2-(Dimethylamino)ethyl-methyl-amino]-5-[[4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazine And [4,3-a]indole-10-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enylamine.

The synthesis process of this embodiment is the same as the process 11.

Example 38A.

Ethyl methyl-6-fluoro-1H-indole-2-carboxylate.

2-Bromo-4-fluoro-benzaldehyde (20.00 g, 98.52 mmol) and methyl-2-aminoacetic acid (18.55 g, 147.78 mmol, hydrochloride) were dissolved in NMP (500 mL) Cs ₂ CO ₃ (64.20 g, 197.04 mmol) and Cu ₂ O (1.41 g, 9.85 mmol) were added to the mixture, and the mixture was warmed to 100 ° C under nitrogen atmosphere and stirred for 16 hours. TLC (PE: DCM = 10: 1), EtOAc (EtOAc: EtOAc (EtOAc) and concentrated and the resulting residue was purified by column chromatography _{(SiO 2, PE: EtOAc =} 500: 1 to 20: 1) to give the title compound (yellow solid, 5.00 g, yield 26.27%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.20 (br. s., 1H), 7.62 (dd, J1 = 5.2Hz, J2 = 8.8Hz, 1H), 7.21 (d, J = 1.2Hz, 1H), 7.10 (dd, J1 = 2.0Hz, J2 = 9.6Hz, 1H), 6.94 (dt, J1 = 2.4Hz, J2 = 9.2Hz, 1H), 3.95 (s, 3H).

Example 38B.

(6-Fluoro-1H-indol-2-yl)methanol.

This example was prepared according to the method of Example 37A, replacing 5-fluoro-1H-indole-2-carboxylic acid with ethyl methyl-6-fluoro-1H-indole-2-carboxylate. The title compound (yellow oil, 4.50 g, 89.49%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.54 (br. s., 1H), 7.56-7.44 (m, 1H), 7.07-7.00 (m, 1H), 6.91-6.88 (m, 1H), 6.39 ( s, 1H), 4.81 (s, 2H).

Example 38C.

7-Fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

This example was prepared according to the method of Example 37B, substituting (5-fluoro-1H-indol-2-yl)methanol with (6-fluoro-1H-indol-2-yl)methanol. The title compound (brown solid, 1.20 g, 31.10%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.49 (dd, J1 = 8.8 Hz, J2 = 5.2 Hz, 1H), 6.84-7.03 (m, 2 H), 6.22 (s, 1H), 4.98 (s, 2 H), 4.17-4.22 (m, 2 H), 4.02-4.07 (m, 2 H).

Example 38D.

10-bromo-7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

This example was prepared according to the method of Example 37C, replacing 37B with 38C. The title compound (white solid, 2.20 g, 53.69%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.42-7.31 (m, 1H), 6.95-6.81 (m, 2H), 4.84-4.73 (m, 2H), 4.11-4.03 (m, 2H), 3.97-3.85 (m, 2H).

Example 38E.

7-Fluoro-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H- [1,4] Oxazine and [4,3-a]吲哚.

This example was prepared according to the method of Example 37D, replacing 37C with 38D. The title compound (light yellow solid, 2.50 g, 96.72%). ¹ H NMR (300MHz, CDCl ₃ ): δ 7.93-7.83 (m, 1H), 6.99-6.89 (m, 2H), 5.15 (s, 2H), 4.20-4.13 (m, 2H), 4.07-4.00 (m , 2H), 1.34 (s, 12H).

Example 38F.

10-(2-chloropyrimidin-4-yl)-7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole.

This example was prepared according to the method of Example 37E, replacing 37D with 38E. The title compound (light yellow solid, 1.10 g, 47.45%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.53 (d, J = 5.4Hz, 1H), 7.98 (dd, J = 5.2Hz, J2 = 9.2Hz, 1H), 7.53 (d, J = 5.2Hz, 1H ), 7.14-7.05 (m, 2H), 5.43-5.35 (m, 2H), 4.26-4.21 (m, 2H), 4.18-4.13 (m, 2H). LCMS (ESI) (5-95): m/z: 304.0.

Example 38G.

4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole-10-yl)-N-(4-fluoro-2-methoxy 5--5-nitrophenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example D, replacing Example C with Example 38F. The title compound (brown solid, 2.00 g, crude). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.39 (d, J = 8.4Hz, 1H), 8.48 (d, J = 5.2Hz, 1H), 7.97 (dd, J1 = 5.2Hz, J2 = 8.8Hz, 1H ), 7.57 (s, 1H), 7.19 (d, J = 5.2Hz, 1H), 7.11-7.03 (m, 2H), 6.79 (d, J = 12.0Hz, 1H), 5.40 (s, 2H), 4.30 -4.24 (m, 2H), 4.20-4.11 (m, 2H), 4.06 (s, 3H). LCMS (ESI) (5-95): m/z:

Example 38H.

N4-[2-(Dimethylamino)ethyl]-N 1 -[4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]吲哚-10-yl)pyrimidin-2-yl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example 38G, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound (brown solid, 1.60 g, yield 71.70%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.06 (s, 1H), 8.44 (d, J = 5.2Hz, 1H), 8.02-7.92 (m, 1H), 7.66-7.37 (m, 2H), 7.15- 7.01 (m, 3H), 6.76 (s, 1H), 5.43 (s, 2H), 4.31-4.23 (m, 2H), 4.19-4.10 (m, 2H), 3.99 (s, 3H), 3.36-3.28 ( m, 2H), 2.91 (s, 3H), 2.64-2.61 (m, 2H), 2.32 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 38I.

N1-[2-(Dimethylamino)ethyl]-N4-[4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-[1吲哚-10-yl)pyrimidin-2-yl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 38H. The title compound (brown solid, 1.50 g, yield 89.30%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.41 (d, J = 5.2Hz, 1H), 8.09 (dd, J1 = 5.2Hz, J2 = 9.6 Hz, 1H), 7.97 (s, 1H), 7.64-7.57 (m, 1H), 7.49 (s, 1H), 7.09-7.06 (m, 1H), 6.97 (d, J = 5.2Hz, 1H), 6.73 (s, 1H), 5.37 (s, 2H), 4.27- 4.20 (m, 2H), 4.17-4.10 (m, 2H), 3.86 (s, 3H), 3.04-2.97 (m, 2H), 2.70 (s, 3H), 2.52-2.43 (m, 3H), 2.32 ( s, 6H). LCMS (ESI) (5-95): m/z:

Example 38J.

N-[2-[2-(Dimethylamino)ethyl-methyl-amino]-5-[[4-(7-fluoro-3,4-dihydro-1H-[1,4]oxazine And [4,3-a]indole-10-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl]-prop-2-enylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 38I. The title compound (formate, 90.00 mg, yield 39.84%) was obtained. ¹ H NMR (400MHz, DMSO-d ₆ ): δ 10.14 (s, 1H), 8.61 (s, 1H), 8.34 (d, J = 5.2Hz, 1H), 8.26 (s, 1H), 8.16-8.03 ( m, 2H), 7.38 (dd, J1 = 2.4Hz, J2 = 9.6Hz, 1H), 7.08-6.94 (m, 3H), 6.44 (dd, J1 = 10.0Hz, J2 = 16.8Hz, 1H), 6.19 ( Dd, J1 = 2.0Hz, J2 = 16.8Hz, 1H), 5.76-5.65 (m, 1H), 5.04 (s, 2H), 4.14-4.00 (m, 4H), 3.80 (s, 3H), 2.94 (t , J = 5.6Hz, 2H), 2.70 (s, 3H), 2.42 (t, J = 5.6Hz, 2H), 2.28 (s, 6H). LCMS (ESI) (5-95): m/z:

Example 39.

N-[5 - [[4-(8,9-Dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5-) Fluoridin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxyphenyl]prop-2-enylamine.

The synthesis process of this embodiment is the same as the process 11.

Example 39A.

1H-pyrrolo[2,3-b]pyridin-2-ylmethanol.

1-(p-Toluenesulfonyl)pyrrolo[2,3-b]pyridine-2-carboxylic acid (26.00 g, 82.19 mmol) was dissolved in tetrahydrofuran (300 mL) at 0 ° C to the mixture Lithium tetrahydroaluminum (12.48 g, 328.76 mmol) was added portionwise and stirred at 20 ° C for 32 hours. TLC showed the completion of the reaction. Water (13 mL), 15% NaOH (13 mL) and water (39 mL) were sequentially added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated to give a crude product which was purified by column chromatography (DCM) The title compound (yellow solid, 2.90 g, yield: 23.81%). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.14 (dd, J = 4.80, 1.20 Hz, 1 H), 7.94 (d, J = 7.60 Hz, 1 H), 7.08 (dd, J = 8.00, 4.80 Hz , 1 H), 6.42 (s, 1 H), 4.77 (s, 3 H).

Example 39B.

8,9-Dihydro-6H-pyrido[3,4]pyrrolo[3,5-α][1,4]oxazine.

1H-pyrrolo[2,3-b]pyridin-2-ylmethanol (2.50 g, 16.87 mmol) and potassium hydroxide (2.37 g, 42.18 mmol) were dissolved in dichlorobenzene at 0 °C. Methane (900 mL), a solution of phenyl vinyl hydrazine (7.34 g, 20.24 mmol) in DCM (100 mL) was added dropwise to the mixture, and the mixture was stirred at 20 ° C for 12 hours. TLC showed the reaction was completed, EtOAc (EtOAc) (EtOAc) 27.90%).

Example 39C.

5-bromo-8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazine.

This example was prepared according to the method of Example 37C, replacing Example 37B with Example 39B. The title compound (yellow solid, 180.00 mg, yield 45.99%) was obtained. LCMS (ESI) (5-95AB): m/z: 253.

Example 39D.

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-6H-pyrido[3,4]pyrrole [3,5-α][1,4]oxazine.

This example was prepared according to the method of Example 37D, replacing Example 37C with Example 39C. The title compound (yellow solid, 170.00 mg, yield 73.97%) was obtained. LCMS (ESI) (5-95): m/z:

Example 39E.

5-(2-chloro-5-fluoro-pyridin-4-yl)-8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazine .

This example was prepared according to the method of Example 37E, replacing Example 37D with Example 39D. The title compound (yellow solid, 90.00 mg, yield 60.29%) was obtained. _{^{1 H NMR (400MHz, CDCl 3}} ): δ 8.12 - 8.58 (m, 4 H), 5.35 (. Br s, 2 H.), 4.09 - 4.59 (m, 4 H). LCMS (ESI) (5-95): m/z:

Example 39F.

4-(8,9-dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5-fluoro-N-(4- Fluor-2-methoxy-5-nitro-phenyl)pyrimidine-2-amine.

This example was prepared according to the method of Example 30B, replacing Example 30A with Example 39E. The title compound was obtained (yellow solid, 88.00 mg, yield 65.71%). ¹ H NMR (400MHz, CDCl ₃ ): δ. 9.36 (br. s., 1 H), 8.08 - 8.58 (m, 2 H), 7.66 (br. s., 1 H), 7.35 - 7.52 (m, 1 H), 6.68 - 6.88 (m, 1 H), 5.34 (br. s., 2 H), 4.21 - 4.55 (m, 4 H), 4.08 (br. s., 3 H). LCMS (ESI) (5-95): m/z:

Example 39G.

N1-[4-(8,9-Dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5-fluoropyridine-2 -yl]-N4-[2-(dimethylamino)ethyl]-2-methoxy-N 4 -methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example 39F, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound was obtained (yellow solid, 55.00 mg, yield 43.19%). LCMS (ESI) (5-95): m/z:

Example 39H.

N4-[4-(8,9-Dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5-fluoropyridine-2 -yl]-N1-[2-(dimethylamino)ethyl]-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 39G. The title compound was obtained (yellow solid, 420.00 mg, yield: 99.13%). LCMS (ESI) (5-95): m/z: 507.2.

Example 39I.

N-[5 - [[4-(8,9-Dihydro-6H-pyrido[2,3]pyrrolo[4,5-α][1,4]oxazin-5-yl)-5-) Fluoridin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxyphenyl]prop-2-enylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 39H. The title compound was obtained (8.60 mg, yield 17.44%). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.54 (br. s., 1 H), 8.48 (br. s., 1 H), 8.38 (br. s., 1 H), 7.81 - 7.90 (m , 1 H), 7.17 - 7.25 (m, 1 H), 6.97 (s, 2 H), 6.41 - 6.52 (m, 2 H), 5.86 (m, 1 H), 5.07 (br. s., 3 H ), 4.17 (d, J = 14.00 Hz, 4 H), 4.00 (s, 3 H), 3.41 (br. s., 3 H), 3.12 (br. s., 2 H), 2.76 (br. s ., 6 H), 2.72 (s, 3 H). LCMS (ESI) (0-60): m/z: 578.3 [M+1].

Process 12.

Example E1.

7-(3-Bromopropyl)-1hydro-indole.

7-Hydroxyindole (2.60 g, 19.49 mmol) was dissolved in THF (10.00 mL) and triphenylphosphine (10.22 g, 38.98 mmol) and 3-bromopropanol (5.42) were added at 10 °C. g, 38.98 mmol, then DIAD (7.88 g, 38.98 mmol) was slowly added dropwise, and the mixture was stirred at 30 ° C for 12 hours. TLC showed the reaction was completed. After concentrating, the title compound was obtained (jjjjjjjjj ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.29 (br. s., 1 H) , 7.18 (d, J = 2.13 Hz, 1 H), 7.11 (t, J = 2.70 Hz, 1 H) , 6.91 - 6.98 (m, 1 H) , 6.59 (d, J=7.65 Hz, 1 H), 6.47 (dd, J=3.01, 2.26 Hz, 1 H), 4.16 - 4.28 (m, 2 H), 3.52 - 3.63 (m, 2 H) , 2.27 - 2.41 (m, 2 H).

Example E2.

4-fluoro- 2 -methoxy- 5 -nitroaniline.

Example E1 (2.07 g, 8.15 mmol) was dissolved in DMF (10 mL) at 0 ° C then NaH (0.652 g, 16.30 m. The mixture was stirred at 30 ° C for 2 hours. TLC showed the reaction was complete, H ₂ O (10mL) added to the reaction mixture, and the mixture was added EA (200mL) and extracted, the organic phase was concentrated and purified by column chromatography (PE: 1 EA = 30: : 1,20) , yielding The title compound (white solid, 1.13 g, yield 80.05%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.27 - 7.33 (m, 1 H) , 7.09 (d, J = 3.14 Hz, 1 H), 7.00 - 7.06 (m, 1 H) , 6.81 - 6.87 (m , 1 H), 6.58 (d, J = 3.01 Hz, 1 H), 4.31 - 4.38 (m, 2 H) , 4.18 - 4.25 (m, 2 H) , 2.36 - 2.44 (m, 2 H).

Example E.

7-(2-Chloropyrimidin-4-yl)-3,4-dihydro-2H-[1,4]oxazine [2,3,4-hi]indole.

AlCl ₃ (3.7 g, 27.72 mmol) was dissolved in DME (20 mL) at 10 ° C, 2,4-dichloropyrimidine (2.75 g, 18.48 mmol) was added to the mixture and stirred for 0.5 hour. . Further, Example E2 (1.6 g, 9.24 mmol) was added portionwise, and the mixture was warmed to 80 ° C and stirred for 2 hours. TLC showed the completion of the reaction. EtOAc (EtOAc) was evaporated. The title compound (yellow solid, 1.3 g, yield 49.24%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.45 - 8.52 (m, 1 H), 7.90 - 8.01 (m, 2 H), 7.52 (d, J = 5.40 Hz, 1 H), 7.17 - 7.27 (m , 1 H), 6.94 (d, J = 7.78 Hz, 1 H), 4.26 - 4.46 (m, 4 H) , 2.35 - 2.50 (m, 2 H).

Example F.

4-(3,4-Dihydro-2H-[1,4]oxazine [2,3,4-hi]indol-7-yl)-N-(4-fluoro-2-methoxy-5 -Nitrophenyl)pyrimidine-2-amine.

Example E (2.4 g, 8.40 mmol) and 4-fluoro-2-methoxy-5-nitro-phenylamine (1.64 g, 8.82 mmol), p-toluenesulfonic acid 1.76 g, 1.1 mmol) was added to a solution of 1,4-dioxane (90 mL), warmed to 110 ° and stirred for 12 hours. LCMS showed the reaction was completed, aqueous ammonia (50 mL) was added to the mixture and the mixture was adjusted to pH = 8. The mixture was cooled to 20 and filtered. The solid was washed with EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.10 (d, J = 8.41 Hz, 1 H), 8.28 - 8.48 (m, 3 H), 8.07 (d, J = 7.78 Hz, 1 H), 7.26 - 7.42 (m, 2 H), 7.01 (t, J=7.84 Hz, 1 H), 6.78 (d, J=7.53 Hz, 1 H) , 4.34 (d, J=4.64 Hz, 4 H) , 4.02 (s , 3 H), 2.34 (br. s., 2 H).

Example 40.

N-(5-((4-(3,4-Dihydro-2H-[1,4]oxazine [2,3,4-hi]吲哚-7-yl)pyrimidin-2-yl)amino) 2-(-(2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 40A.

N1-(4-(3,4-Dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)pyrimidin-2-yl)-N4-(2- (Dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

This example was prepared according to the method of Example 16A, replacing Example D with Example F, replacing N,N-diethyl-N-methylethane-1,2-diamine with N,N', N'-trimethyl-1,2-ethanediamine. The title compound was obtained (yellow solid, 1.00 g, yield: 82.15%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.62 (s, 1 H) , 8.42 (d, J = 5.27 Hz, 1 H) , 8.32 (s, 1 H), 7.80 (d, J = 7.91 Hz, 1 H), 7.52 - 7.61 (m, 1 H) , 7.14 - 7.25 (m, 2 H) , 6.91 (d, J = 7.65 Hz, 1 H), 6.70 (s, 1 H) , 4.35 - 4.51 (m, 4 H) , 4.01 (s, 3 H) , 3.33 (t, J=7.09 Hz, 2 H), 2.93 (s, 3 H), 2.63 (t, J=7.09 Hz, 2 H) , 2.45 (dt, J = 10.29, 5.40 Hz, 2 H), 2.32 (s, 6 H).

Example 40B.

N4-(4-(3,4-Dihydro-2H-[1,4]oxazine [2,3,4-hi]indol-7-yl)pyrimidin-2-yl)-N 1 - (2 -(Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This example was prepared according to the method of Example 16B, replacing Example 16A with Example 40A. The title compound was obtained (yellow solid, 0.8 g, yield: 85.01%). ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.27 (d, J = 5.27 Hz, 1 H), 8.08 (t, J = 3.95 Hz, 2 H), 7.70 (s, 1 H), 7.53 (s, 1 H), 7.10 (t, J=7.91 Hz, 1 H), 6.94 (d, J=5.27 Hz, 1 H), 6.83 (d, J=7.65 Hz, 1 H), 6.61 - 6.66 (m, 1 H) , 4.20 - 4.34 (m, 4 H), 3.75 - 3.80 (m, 3 H) , 2.94 (t, J = 6.78 Hz, 2 H), 2.62 (s, 3 H) , 2.42 (t, J= 6.59 Hz, 2 H), 2.30 - 2.38 (m, 2 H), 2.26 (s, 6 H).

Example 40C.

N-(5-((4-(3,4-Dihydro-2H-[1,4]oxazine [2,3,4-hi]吲哚-7-yl)pyrimidin-2-yl)amino) 2-(-(2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This example was prepared according to the method of Example 16C, replacing Example 16B with Example 40B. The title compound was obtained (120.00 mg, yield 71.15%). ¹ H NMR (400MHz, CDCl ₃ ): δ 10.21 (br. s., 1H), 9.84 (s, 1H), 9.07 (br. s., 1H), 8.40 (d, J=2.0 Hz, 1H), 7.81 - 7.68 (m, 2H), 7.22 (d, J=4.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.81 (s, 1H) ), 6.48 - 6.31 (m, 2H), 5.78 - 5.64 (m, 1H), 4.64 - 4.52 (m, 2H), 4.45 - 4.36 (m, 2H), 3.90 (s, 3H), 2.90 (t, J =4.0 Hz, 2H), 2.72 (s, 3H), 2.48 - 2.36 (m, 2H), 2.33 - 2.21 (m, 8H). LCMS (ESI) (5-95): m/z:

Example 41.

N-(5-((4-(3,3-Dimethyl-3,4-dihydro-2H-[1,4]oxazine [2,3,4-hi]吲哚-7-yl)) Amino)-2 - ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) acrylamide.

Example 41A.

7-(3-Chloro-2,2-dimethylpropyl)-1H-indole.

7-hydroxyindole (5.00 g, 37.55 mmol), 3-chloro-2,2-dimethyl-propan-1-ol (6.91 g, 56.33 mmol) at 20 ° C, three Phenylphosphine (1.57 g, 6.00 mmol) was dissolved in THF (150 mL). After nitrogen was applied, DIAD (15.19 g, 75.10 mmol) was added dropwise to the mixture. The mixture was stirred at 70 ° C for 12 hours. TLC showed the reaction was completed, EtOAcqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ ¹ H NMR (400MHz, CDCl ₃ ): δ 7.29 (s, 1H), 7.21 (t, J=4.0 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz , 1H), 6.58 - 6.53 (m, 1H), 3.96 (s, 2H), 3.65 (s, 2H), 1.20 (s, 6H). LCMS (ESI) (5-95): m/z: 238.1 [M+1].

Example 41B.

3,3-Dimethyl-3,4-dihydro-2H-[1,4]oxazine [2,3,4-hi]吲哚.

Example 41A (3.50 g, 14.72 mmol) was dissolved in DMF (50 mL) EtOAc. TLC showed the reaction was completed. Water (50 mL) was added to the mixture, which was extracted with EA (50 mL×2). The organic layer was dried over anhydrous sodium sulfate, and concentrated, and then purified by column chromatography (PE: EA = 20:1, 10:1) Purification gave the title compound (m.j. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.28 (d, J = 1.0 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.03 - 6.97 (m, 2H), 6.79 (dd, J=0.8, 7.7 Hz, 1H), 6.52 (d, J=3.1 Hz, 1H), 4.05 - 3.98 (m, 2H), 3.87 (s, 2H), 1.17 (s, 6H). LCMS (ESI) (5-95): m/z: 2021.

Example 41C.

7-(2-Chloropyrimidin-4-yl)-3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine [2,3,4-hi]indole.

This embodiment replaces the embodiment E2 with the embodiment 41B according to the method of the embodiment E. The title compound was obtained (yellow solid, 2.30 g, yield: 64.13%). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.47 (d, J=4.0 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.49 (d, J=4.0 Hz , 1H), 7.19 (t, J=9.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.05 (s, 2H), 4.00 (s, 2H), 1.17 (s, 6H). LCMS (ESI) (5-95): m/z: 314.0.

Example 41D.

4-(3,3-Dimethyl-3,4-dihydro-2H-[1,4]oxazine [2,3,4-hi]indol-7-yl)-N-(4-fluoro 2-methoxy-5-nitrophenyl)pyrimidine-2-amine.

This embodiment replaces the embodiment E with the embodiment 41C according to the method of the embodiment F. The title compound was obtained (yellow solid, 3.00 g, yield 88.31%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.85 (d, J=8.0 Hz, 1H), 8.45 (d, J=4.0 Hz, 1H), 8.20 (s, 1H), 7.78 (d, J=8.0 Hz , 1H), 7.64 (s, 1H), 7.26 (br. s., 1H), 7.18 (t, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.77 (d, J =12.0 Hz, 1H), 4.11 (s, 2H), 4.08 (s, 2H), 4.05 (s, 3H), 3.71 (s, 2H), 1.21 (s, 6H). LCMS (ESI) (5-95): m/z: 464.0

Example 41E.

N1-(4-(3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)pyrimidin-2- -N4-(2-(Dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

In this example, according to the method of Example 16A, Example D was replaced with Example 41D, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with N,N',N. '-Trimethyl-1,2-ethanediamine. The title compound was obtained (yellow solid, 1.70 g, yield: 96.16%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.55 (s, 1H), 8.41 (d, J=4.0 Hz, 1H), 8.20 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.60 - 7.50 (m, 1H), 7.23 - 7.13 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 4.11 (s, 2H), 4.07 (s, 2H), 4.00 (s, 3H), 3.36 - 3.26 (m, 2H), 2.92 (s, 3H), 2.61 (t, J=8.0 Hz, 2H), 2.35 - 2.24 (m, 6H), 1.21 (s, 6H) . LCMS (ESI) (5-95): m/z:

Example 41F.

N4-(4-(3,3-dimethyl-3,4-dihydro-2H-[1,4]oxazine[2,3,4-hi]indol-7-yl)pyrimidin-2- -N 1 -(2-(Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This embodiment replaces Embodiment 16A with Embodiment 41E in accordance with the method of Embodiment 16B. The title compound (yellow solid, 1.50 g, yield 93.24%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 8.35 (d, J = 4.0 Hz, 1H), 8.18 - 8.08 (m, 2H), 7.76 - 7.69 (m, 1H), 7.60 (s, 1H), 7.17 ( t, J=8.0 Hz, 1H), 7.02 (d, J=4.0 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 4.06 (s, 2H), 4.00 ( s, 2H), 3.86 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.69 (s, 3H), 2.49 - 2.39 (m, 2H), 2.28 (s, 6H), 1.19 (s , 6H). LCMS (ESI) (5-95): m/z:

Example 41G.

N-(5-((4-(3,3-Dimethyl-3,4-dihydro-2H-[1,4]oxazine [2,3,4-hi]吲哚-7-yl)) Amino)-2 - ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) acrylamide.

This embodiment replaces Embodiment 16B with Embodiment 41F in accordance with the method of Embodiment 16C. The title compound (brown solid, 1.30 g, yield 95.57%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 10.24 (s, 1H), 9.85 (s, 1H), 9.08 (s, 1H), 8.40 (d, J=4.0 Hz, 1H), 7.74 (s, 1H) , 7.68 (d, J=8.0 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.87 - 6.79 (m, 2H), 6.50 - 6.32 ( m, 2H), 5.72 (dd, J=2.0, 8.0 Hz, 1H), 4.26 (s, 2H), 4.07 (s, 2H), 3.89 (s, 3H), 2.92 - 2.85 (m, 2H), 2.71 (s, 3H), 2.29 (br. s., 2H), 2.27 (s, 6H), 1.18 (s, 6H). LCMS (ESI) (5-95): m/z: 570.2 [M+1].

Example 41H.

N-(5-((4-(3,3-Dimethyl-3,4-dihydro-2H-[1,4]oxazine [2,3,4-hi]吲哚-7-yl)) Amino)-2 - ((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) acrylamide methanesulfonate.

This embodiment replaces Embodiment 36I with Embodiment 41G in accordance with the method of Embodiment 36J. The title compound (1.36 g, yield 89.43%) was obtained. ¹ H NMR (400MHz, CD ₃ OD): δ 8.68 (s, 1H), 8.29 (d, J=4.0 Hz, 1H), 8.10 (s, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.97 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.60 - 6.42 (m, 2H) ), 5.93 - 5.82 (m, 1H), 4.06 (s, 2H), 4.03 (s, 2H), 4.02 (s, 3H), 3.48 (t, J=6.0 Hz, 2H), 3.30 - 3.24 (m, 2H), 2.88 (s, 6H), 2.72 (s, 3H), 2.70 (s, 3H), 1.15 (s, 6H). LCMS (ESI) (0-60): m/z:

Example 42.

N-(5-((4-(3H-spiro[[1,4]oxazine[2,3,4-hi]吲哚-2,1'-cyclopropyl]-6-yl)pyrimidine-2 -yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 42A.

1-(2-Nitrophenoxy)cyclopropanecarboxylic acid.

1-Fluoro-2-nitrobenzene (10.37 g, 73.47 mmol) and 1-hydroxycyclopropanecarboxylic acid (5.00 g, 48.98 mmol) were dissolved in DMF (100 mL). NaH (4.90 g, 122.45 mmol) was added portionwise, and the mixture was stirred at 80 ° C for 12 hours. TLC showed that the reaction was almost complete. Water (20 mL) was added thereto, and the mixture was extracted with EA (100 mL EtOAc). EtOAc (EtOAc (EtOAc) Compound (yellow solid, 6.00 g, yield 54.89%). ¹ H NMR (400MHz, CDCl ₃ ): δ 7.84 (dd, J=2.0, 8.0 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 1.80 - 1.73 (m, 2H), 1.55 - 1.49 (m, 2H).

Example 42B.

4-Siro[benzo[b][1,4]oxazine-2,1'-cyclopropyl]-3(4H)-one.

Example 42A (11.00 g, 49.29 mmol), NH4Cl (10..55 g, 197.15 mmol), iron powder (11.01 g, 197.15 mmol) dissolved in ethanol (15 mL) and water (2 mL) in. The reaction solution was replaced with nitrogen, and the mixture was heated to 90 ° C and stirred for 12 hours. TLC showed the reaction was complete. The reaction mixture was cooled and filtered. EtOAc EtOAcjjjjjj _{^{1 H NMR (400MHz, CDCl 3}} ): δ 9.43, 7.12 - 6.65 (m, 1H), 1.62 - 1.02 (m, 4H) (br s, 1H..). LCMS (ESI) (5-95): m/z:

Example 42C.

6-3,4-Dihydrospiro[benzo[b][1,4]oxazin-2,1'-cyclopropane].

Example 42B (8.50 g, 48.52 mmol) was dissolved in THF (100 mL), and LiAlH4 (4.60 g, 121.30 mmol) was added at 70 ° C and stirred for 2 hours. LCMS monitored the reaction to completion. Water (4.6 mL), a 15% NaOH (4.6 mL) solution and water (13.8 mL) were added to the mixture, and the mixture was stirred for 30 min. , yield 98.89%). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.85 - 6.77 (m, 1H), 6.77 - 6.72 (m, 1H), 6.71 - 6.65 (m, 2H), 3.86 (br. s., 1H), 3.33 ( d, J = 2.0 Hz, 2H), 1.11 - 1.03 (m, 2H), 0.74 - 0.67 (m, 2H). LCMS (ESI) (5-95): m/z: 1621.

Example 42D.

8-4-(2,2-Dimethoxyethyl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane].

Example 42C (7.50 g, 46.53 mmol), K ₂ CO ₃ (9.65 g, 69.8 mmol), KI (772.33 mg, 4.65 mmol) and 2-bromo-1,1-diethoxy Ethyl ethane (18.34 g, 93.06 mmol) was dissolved in DMF (50 mL). After nitrogen replacement, it was heated to 130 ° C and stirred for 12 hours. TLC showed a small amount of material remaining, water (150 mL) was added to the mixture, and the mixture was extracted with DCM (100 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was applied to column chromatography (PE: EA = 1000:1, 100:1) The title compound (yellow oil, 8.0 g, yield: 61.99%). ¹ H NMR (400MHz, CDCl ₃ ): δ 6.90 - 6.82 (m, 1H), 6.72 (d, J = 8.0 Hz, 2H), 6.63 - 6.56 (m, 1H), 4.79 - 4.66 (m, 1H), 3.80 - 3.69 (m, 2H), 3.64 - 3.53 (m, 2H), 3.46 - 3.38 (m, 4H), 1.28 - 1.17 (m, 6H), 1.05 - 0.97 (m, 2H), 0.73 - 0.61 (m , 2H).

Example 42E.

10--3H-spiro[[1,4]oxazine [2,3,4-hi]indole-2,1'-cyclopropane].

AlCl ₃ (10.1 g, 75.72 mmol) was added to DCM (50 mL) at 0 ° C, and then applied to DCM (130 mL). In the mixture. After stirring at 0 ° C for 10 minutes, TLC showed a small amount of material remaining. The mixture was slowly poured into ice water (300 mL), EtOAc (EtOAc) (EtOAc) Purification gave the title compound (yel. ¹ H NMR (400MHz, CDCl ₃ ): δ 7.26 - 7.23 (m, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.62 (d, J= 8.0 Hz, 1H), 6.51 (d, J=2.0 Hz, 1H), 4.19 (s, 2H), 1.27 - 1.19 (m, 2H), 0.88 - 0.81 (m, 2H).

Example 42F.

6-(2-Chloropyrimidin-4-yl)-3H-spiro[[1,4]oxazine [2,3,4-hi]indole-2,1'-cyclopropane].

This embodiment replaces the embodiment E2 with the embodiment 42E according to the method of the embodiment E. The title compound was obtained (yellow solid, 1.30 g, yield 67.38%). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.49 (d, J=4.0 Hz, 1H), 8.02 (s, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.54 (d, J=4.0 Hz , 1H), 7.19 (t, J=8.0 Hz, 1H), 6.76 - 6.71 (m, 1H), 4.27 (s, 2H), 1.28 - 1.23 (m, 2H), 0.91 - 0.85 (m, 2H). LCMS (ESI) (5-95): m/z:

Example 42G.

N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(3H-spiro[[1,4]oxazine[2,3,4-hi]吲哚-2,1 'Cyclopropyl]-6-yl)pyrimidin-2-amine.

This embodiment replaces the embodiment E with the embodiment 42F according to the method of the embodiment F. The title compound (yellow solid, 1.80 g, yield 92.06%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 9.90 (d, J = 8.0 Hz, 1H), 8.48 - 8.42 (m, 1H), 8.33 (s, 1H), 7.71 - 7.58 (m, 2H), 7.28 ( s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.82 - 6.67 (m, 2H), 4.40 - 4.26 (m, 2H), 4.08 - 3.99 (m, 3H), 1.31 - 1.17 (m, 2H), 1.02 - 0.82 (m, 2H). LCMS (ESI) (5-95): m/z: 448.1 [M+1].

Example 42H.

N1-(4-(3H-spiro[[1,4]oxazine[2,3,4-hi]吲哚-2,1'-cyclopropyl]-6-yl)pyrimidin-2-yl)- N4-(2-(Dimethylamino)ethyl)-2-methoxy-N--4-methyl-5-nitrobenzene-1,4-diamine.

In this example, according to the method of Example 16A, Example D was replaced with Example 42G, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with N,N',N. '-Trimethyl-1,2-ethanediamine. The title compound was obtained (yellow solid, 1.80 g, yield 84.55%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.63 (s, 1H), 8.42 (d, J=4.0 Hz, 1H), 8.35 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.73 - 6.67 (m, 2H), 4.42 - 4.31 (m, 2H), 4.00 (s, 3H), 3.36 - 3.26 (m, 2H), 2.91 (s, 3H), 2.61 (t, J=8.0 Hz, 2H), 2.33 - 2.26 (m, 6H), 1.25 - 1.19 (m, 2H), 0.92 - 0.84 (m, 2H). LCMS (ESI) (5-95): m/z:

Example 42I.

N4-(4-(3H-spiro[[1,4]oxazine[2,3,4-hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidin-2-yl)- N 1 -(2-(Dimethylamino)ethyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This embodiment replaces Embodiment 16A with Embodiment 42H in accordance with the method of Embodiment 16B. The title compound (yellow solid, 1.60 g, yield 94.12%). ¹ H NMR (400MHz, CDCl ₃ ): δ 8.41 - 8.32 (m, 1H), 8.18 - 8.13 (m, 1H), 7.91 - 7.82 (m, 2H), 7.60 (s, 1H), 7.18 - 7.12 (m , 1H), 7.06 (d, J=4.0 Hz, 1H), 6.76 - 6.67 (m, 2H), 4.27 (s, 2H), 3.86 - 3.84 (m, 3H), 3.00 - 2.93 (m, 2H), 2.69 (s, 3H), 2.42 (t, J=8.0 Hz, 2H), 2.29 - 2.25 (m, 6H), 1.26 - 1.21 (m, 2H), 0.92 - 0.83 (m, 2H). LCMS (ESI) (5-95): m/z:

Example 42J.

N-(5-((4-(3H-spiro[[1,4]oxazine[2,3,4-hi]吲哚-2,1'-cyclopropyl]-6-yl)pyrimidine-2 -yl)amino)-2 -((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This embodiment replaces Embodiment 16B with Embodiment 42I in accordance with the method of Embodiment 16C. The title compound (1.25 g, yield 85.09%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ): δ 10.23 (br. s., 1H), 9.85 (s, 1H), 9.21 (br. s., 1H), 8.40 (d, J=4.0 Hz, 1H), 7.75 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.20 (d, J=4.0 Hz, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.35 (d, J=4.0 Hz, 2H), 5.68 (t, J=6.0 Hz, 1H), 4.39 (s, 2H), 3.90 (s, 3H), 2.98 - 2.85 (m, 2H), 2.71 (s, 3H), 2.30 - 2.22 (m, 8H), 1.25 - 1.19 (m, 2H), 0.87 (s, 2H). LCMS (ESI) (5-95): m/z:

Example 43.

N-(5-((4-(3H-spiro[[1,4]oxazine[2,3,4-hi]吲哚-2,1'-cyclopropyl]-6-yl)pyrimidine-2 -yl)amino)-2 -((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

Example 43A.

N1-(4-(3H-spiro[[1,4]oxazine[2,3,4-hi]吲哚-2,1'-cyclopropyl]-6-yl)pyrimidin-2-yl)- N4-(2-(Dimethylamino)-2-methylpropyl)-2-methyl-N--4-methyl-5-nitrobenzene-1,4-diamine.

In this example, according to the method of Example 16A, Example D was replaced with Example 42G, and N,N-diethyl-N-methylethane-1,2-diamine was replaced with N1, N2, N2. 2-tetramethylpropane-1,2-diamine. The title compound (yellow solid, 500 mg, yield 39.01%). ¹ H NMR (400MHz, CDCl ₃ ): δ 9.61 (s, 1H), 8.43 (d, J =4.0 Hz, 1H), 8.27 (s, 1H), 7.74 - 7.58 (m, 2H), 7.31 (s, 1H), 7.23 (d, J = 4.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 4.34 (s, 2H), 4.22 - 4.11 ( m, 3H), 3.86 (br. s., 2H), 3.03 (s, 3H), 2.73 (s, 6H), 1.43 (s, 6H), 1.28 - 1.22 (m, 2H), 0.91 - 0.86 (m , 2H). LCMS (ESI) (5-95): m/z:

Example 43B.

N4-(4-(3H-spiro[[1,4]oxazine[2,3,4-hi]indole-2,1'-cyclopropyl]-6-yl)pyrimidin-2-yl)- N 1 -(2-(Dimethylamino)-2-methylpropyl)-5-methoxy N1 methylbenzene-1,2,4-triamine.

This embodiment replaces Embodiment 16A with Embodiment 43A in accordance with the method of Embodiment 16B. The title compound (yellow solid, 300.00 mg, yield 63.41%). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.31 (d, J = 4.0 Hz, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 4.0 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.65 - 6.62 (m, 1H), 4.37 (s, 2H), 3.92 (s , 3H), 3.29 (s, 2H), 2.83 (s, 3H), 2.74 (s, 6H), 1.24 (s, 6H), 1.16 - 1.12 (m, 2H), 0.95 - 0.92 (m, 2H). LCMS (ESI) (5-95): m/z: 528.3 [M+1].

Example 43C.

N-(5-((4-(3H-spiro[[1,4]oxazine[2,3,4-hi]吲哚-2,1'-cyclopropyl]-6-yl)pyrimidine-2 -yl)amino)-2 -((2-(dimethylamino)-2-methylpropyl)(methyl)amino)-4-methoxyphenyl)propenylamine.

This embodiment replaces Embodiment 16B with Embodiment 43B in accordance with the method of Embodiment 16C. The title compound was obtained (230.00 mg, yield 69.54%). ¹ H NMR (400MHz, CD ₃ OD): δ 8.56 (br. s., 1H), 8.29 (d, J=4.0 Hz, 1H), 8.09 (br. s., 1H), 7.82 (d, J= 8.0 Hz, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.14 (s, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.60 - 6.49 (m, 3H), 5.90 (dd, J=4.0, 7.9 Hz, 1H), 4.34 (s, 2H), 4.03 (s, 3H), 3.69 - 3.41 (m, 2H), 2.80 (s, 3H), 2.75 (s, 6H), 1.34 (s , 6H), 1.16 - 1.11 (m, 2H), 0.95 - 0.90 (m, 2H). LCMS (ESI) (5-95): m/z:

Biochemical experiment.

Experimental Materials.

Enzymes: EGFR wild type, EGFR T790M/L858R, EGFR T790M and INSR were purchased from Life technology (Madison, WI), and EGFR d746-750/T790M was purchased from Carna Biosciences (Japan).

HTRF kit: purchased from Cis-Bio International containing Eu-labeled TK1 antibody, XL665 and biotin-tagged TK1 polypeptide substrate.

Testing equipment: Envision (PerkinElmer).

Experimental method: The test compound was diluted 3-fold to obtain a final concentration of 10 doses from 300 nM to 0.015 nM.

Wild type EGFR enzyme reaction mixture system: 0.05 nM wild type EGFR, 1 uM biotin-TK1 peptide, 25 uM ATP enzyme buffer total 10 uL. The reaction plate was white Proxiplate 384-Plus plate (PerkinElmer), 23 °C reaction 60 minute.

EGFR T790M/L858R enzyme reaction mixture system: 0.04 nM EGFR T790M/L858R, 1 uM biotin-TK1 peptide, 20 uM ATP enzyme buffer total 10 uL. The reaction plate is white Proxiplate 384-Plus plate (PerkinElmer), 23 °C Reaction for 60 minutes.

EGFR d746-750/T790M enzyme reaction mixture system: 0.025 nM EGFR d746-750/T790M, 1 uM biotin-TK1 peptide, 40 uM ATP enzyme buffer total 10 uL. Reaction plate is white Proxiplate 384-Plus plate (PerkinElmer) , reaction at 23 ° C for 60 minutes.

EGFR T790M enzyme reaction mixture system: 0.03 nM EGFR T790M, 1 uM biotin-TK1 peptide, 10 uM ATP enzyme buffer total 10 uL. The reaction plate was white Proxiplate 384-Plus plate (PerkinElmer), and reacted at 23 ° C for 60 minutes.

INSR enzyme reaction mixture system: 0.5 nM INSR, 1 uM biotin-TK1 peptide, 35 uM ATP enzyme buffer total 10 uL. The reaction plate was white Proxiplate 384-Plus plate (PerkinElmer), and reacted at 23 ° C for 60 minutes.

Detection reaction: 10 ul of detection reagent contained Antibody 2 nM and added XL665 62.5 nM. Incubate at 23 °C for 60 minutes. Envision reads the board.

Data Analysis: The readings were converted to inhibition (%) (Min-Ratio) / (Max-Min) * 100% by the following formula. 4 parameter curve fitting (Model 205 in XLFIT5, iDBS) measured IC50 data.

Cell experiment.

Experimental materials: RPMI 1640, fetal bovine serum, penicillin/streptomycin solution, all purchased from Life Technology (Madison, WI). Cell Titer-Glo luminescent cell viability reagents were purchased from Promega (Madison, WI). Both A431 cell line and NCI-H1975 cell line were purchased from the European Collection of Cell Cultures (ECACC). Plate reading instrument: Envision (PerkinElmer).

Experimental method: 384-well plates, 300 A431 cells and NCI-H1975 cells per well, 45 ul volume. Incubate overnight at 37 ° C in a CO 2 incubator. The test compound was diluted 3-fold to obtain 10 dose concentrations from 10 uM to 0.508 nM, two duplicate wells. The intermediate plate was added with 49 ul of medium per well. Transfer 1 ul of the compound from the gradient-diluted compound plate to the intermediate plate and mix well. Transfer 5 ul of liquid from the middle plate to the cell plate. The cells were further cultured for 6 days in a CO2 incubator. After 6 days, 25 ul of detection reagent was added. Incubate for 10 minutes at room temperature and Envision reads the plate.

Data Analysis: The reading was converted to inhibition rate (%) (Max-Sample) / (Max-Min) * 100% by the following formula. 4 parameter curve fitting (Model 205 in XLFIT5, iDBS) measured IC 50 data.

The wild type EGFR enzyme of the compound of the present invention inhibits IC 50, EGFR L858R/T790M enzyme inhibits IC 50 , EGFR d746-750/T790M enzyme inhibits IC 50 , NCI-H1975 cell IC 50 of EGFR L858R/T790M and IC50 of EGFR WT of A431 cell The data is shown in Table 1 below. Table 1

The IC50 data for INSR enzyme inhibition of the compounds of the invention are shown in Table 2 below. Table 2

In vivo pharmacodynamic studies.

The following in vivo pharmacodynamic data indicate that the compounds of the present invention exhibit strong antitumor activity and reduced tumor volume in a NCI-H1975 non-small cell lung cancer patient-derived xenograft (CDX) model (BALB/c nude mouse) model. . For example, representative compounds 30, 33, 34, 40, 42 and 43 reduced the tumor volume from a first of about 149 mm ³ to 3-39 mm ³ after 21 days of dosing.

In vivo pharmacodynamic experiments were performed on subcutaneously implanted NCI-H1975 lung cancer-derived xenograft (CDX) BALB/c nude mice: BALB/c nude mice, female, 6-8 weeks, weighing approximately 18-22 g, will Mice were maintained in a special pathogen-free environment and in a single ventilated cage (5 mice per cage). All cages, bedding and water are disinfected prior to use. All animals are free to access a standard certified commercial laboratory diet. A total of 100 mice purchased from Beijing Vitallihua were used for the study. Tumor tissue (20-30 mm 3 ) was implanted subcutaneously into the right flank of each mouse for tumor growth. The experiment was started when the average tumor volume reached approximately 150-200 cubic millimeters. The test compound was orally administered daily (compound 30 was administered at 10 mg/kg, compounds 33, 34, 40, 42 and 43 were administered at 20 mg/kg, and compound AZD9291 was administered at 5 mg/kg for 21 consecutive days. The data is listed in Table 3). The tumor volume was measured twice a week using a two-dimensional caliper. The volume was measured in cubic millimeters and was calculated by the following formula: V = V = 0.5 ax b2, where a and b are the long and short diameters of the tumor, respectively. The anti-tumor efficacy is determined by dividing the average tumor-increased volume of the treated animals by the average tumor-increased volume of the untreated animals. table 3

In vivo selective studies.

The following in vivo selective experimental data indicates that the compounds of the present invention exhibit good in vivo selectivity in a model of a human xenograft (CDX) model (BALB/c nude mouse) derived from A431 human squamous cell carcinoma. In this model, the weaker inhibition of tumors indicates that the selectivity in vivo is better. For example, representative compounds 17, 30, 37, and 38 (Experiment 1, results are shown in Table 4) After 21 days of dosing (20 mg/kg), tumor volume increased from approximately 175 mm ³ at the beginning to 1201 to 1434. Mm ³ , while Afatinib (7.5 mg/kg) only increased to 479 mm ³ . Representative compounds 33, 34 and 40 (Experiment 2, results are shown in Table 5) After 21 days of administration (20 mg/kg), the tumor volume increased from approximately 144 mm ³ at the beginning to 1135 to 1708 mm ³ , while AZD9291 ( 5 mg / kg) only increased to 321 mm ³ .

In vivo selective experiments were performed on subcutaneously implanted human squamous cell A431 xenograft (CDX) BALB/c nude mice: BALB/c nude mice, female, 6-8 weeks, weighing approximately 18-20 g, will be small Rats were maintained in a special pathogen-free environment and in a single ventilated cage (5 mice per cage). All cages, bedding and water are disinfected prior to use. All animals are free to access a standard certified commercial laboratory diet. All experimental mice were purchased from mice of Shanghai BK Laboratory Animal Co., LTD for research. Tumor tissue (20-30 mm 3 ) was implanted subcutaneously into the right flank of each mouse for tumor growth. The experiment was started when the average tumor volume reached approximately 150-200 cubic millimeters. The test compound was orally administered (compounds 17, 30, 37 and 38 were administered once daily at 20 mg/kg, compound AZD9291 was administered once daily at 5 mg/kg, and compound CO-1686 was administered at 50 mg/kg daily. For two doses, the compound Erlotinib was administered once daily at 75 mg/kg, and the compound Afatinib was administered once daily at 7.5 mg/kg for 21 consecutive days. The data are listed in Table 4; Compounds 33, 34, 40, 42 and 43 were administered once daily at 20 mg/kg, and compound AZD9291 was administered once daily at 5 mg/kg for 21 consecutive days. The data is shown in Table 5). The tumor volume was measured twice a week using a two-dimensional caliper. The volume was measured in cubic millimeters and was calculated by the following formula: V = V = 0.5 ax b2, where a and b are the long and short diameters of the tumor, respectively. The anti-tumor efficacy is determined by dividing the average tumor-increased volume of the treated animals by the average tumor-increased volume of the untreated animals. Table 4 table 5

Clinical data from EGFR TKIs suggest that non-selective inhibition of wild-type EGFR has side effects, including rash and diarrhea; inhibition of insulin receptor (INSR) leads to hyperglycemia and high insulin. Tables 1 to 5 show that many of our compounds not only have excellent in vitro activity and selectivity for L858R/EGFR T790M and EGFR790M, but also have good pharmacodynamics and in vivo selectivity in vivo, with selectivity from wild-type EGFR ( A431) and low inhibitory activity against the insulin receptor (INSR) can be demonstrated. These in vitro and in vivo selective data show that our compounds will be safer.

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Claims (10)

a compound of the formula (I) or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, Where W is: n=1; Y ₁ , Y ₂ and Y ₃ are both -C(R) ₂ -; X _{1 is} selected from CR _X1 , N; X _{2 is} selected from CR _X2 , N; X _{3 is} selected from CR _X3 , N; R _X1 , R _X2 and R _X3 are each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH ₂ , or R _X1 , R _X2 , R _X3 are each independently selected from the group consisting of 2, 3 or 4 R substituted: C _1-6 alkyl, C _1-6 heteroalkyl; R _{1 is} selected from H, F, Cl, Me, CN, CF ₃ ; R _{2 is} selected from R ₀₂ , OR ₀₂ , SR ₀₂ ; R _{02 is} independently selected from the group consisting of 1, 2, 3 or 4 R: C _1-4 alkyl, C _1-4 heteroalkyl, C _3-5 cycloalkyl-( CH ₂ ) _0-3 -; R _{3 is} selected from C _{1 1-6} alkyl, C _1-6 heteroalkyl, C _{2 -4} alkynyl, 3 optionally substituted by 1, 2, 3 or 4 R ～7-membered cycloalkyl, 3- to 7-membered cycloalkyl-L-, 3- to 7-membered heterocycloalkyl, 3- to 7-membered heterocycloalkyl-L-; L is selected from —O—, —S—, -C(=O)-, -S(=O) ₂ -, -S(=O)-, or L is selected from the group consisting of 1, 2, 3 or 4 R: NH, C _1-4 Alkyl, C _1-4 heteroalkyl; "hetero" represents a hetero atom or a hetero atom selected from: -C(=O)NH-, -NH-, -O-, -S-, N, =O , =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O ₂ -; the number of heteroatoms or heteroatoms is independently selected from 0, 1, 2, 3; R is selected from H, F, Cl, Br, I, OH, CN, or R is selected from the group consisting of 2, 3 or 4 R' substituted: NH ₂ , C _1-4 alkyl, C _1-4 heteroalkyl, 3 to 7 membered cycloalkyl, or 3 to 7 membered heterocycloalkyl; R' selected From F, Cl, Br, I, CN, OH, NH ₂ , CF ₃ , NHCH ₃ , CH ₂ OCH ₃ , N(CH ₃ ) ₂ . The compound of claim 1, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R is selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN , Me, Et, CF ₃ , N(CH ₃ ) ₂ , N(CD ₃ ) ₂ , NHCH ₃ , , , , , , , , , . The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the structural unit From: , . The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R _{3 is} selected from optionally substituted by 1, 2, 3 or 4 R :-C _1-4 alkyl, -NH-C _1-4 alkyl, -NH-C(=O)-C _1-4 alkyl, -OC _1-4 alkyl, -SC _1-4 alkane Base, -S(=O)-C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, C _{2 -3} alkynyl, 3- to 6-membered cycloalkyl, 3 to 6 a cycloalkyl-L-, a 3- to 6-membered heterocycloalkyl group, and a 3- to 6-membered heterocycloalkyl-L-, said "hetero" representing a hetero atom or a hetero atom selected from: -C(=O) NH-, -NH-, -O-, -S-, N, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S (=O)-, -S(=O) ₂ -, the number of heteroatoms or heteroatoms is independently selected from 0, 1, 2, 3; specifically, R _{3 is} selected from optionally 1, 2, 3 Or 4 R substituted: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , More specifically, R _{3 is} selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R _{02 is} selected from the group consisting of Me, CHF ₂ , CH ₂ CH ₃ , CH (CH) ₃ ) ₂ . The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, selected from the group consisting of: with . The method for producing a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, the method comprising: Wherein R ₁ , W, R ₂ and R _{3 are} as described in claims 1-6. A pharmaceutical composition comprising a compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer, solvate, crystal thereof or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating a tumor Applications. A method of treating a tumor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt, isomer, solvate, crystal or as The pharmaceutical composition of claim 8.