Selective HER2 and HER2 mutation inhibitors

Abstract

A selective HER2 inhibitor compound represented by formula I or a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Selective HER2 and HER2 mutation inhibitors Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a selective HER2 and HER2 mutation inhibitor. Background Art

[0002] Currently, HER2 (also known as ErbB2) and HER2 mutations have become therapeutic targets for many cancers. HER2 small molecule kinase inhibitors, both marketed and under development, often also inhibit other pathways (such as EGFR). Consequently, they can cause side effects such as rash and diarrhea. HER2 inhibitors with brain penetration have particular applications for patients with brain metastases. Tucatinib, the only marketed selective HER2 small molecule kinase inhibitor, is undergoing numerous combination clinical studies due to its activity. Furthermore, new HER2-targeted ADCs, such as T-DM1 and T-DXd, while highly effective, inevitably develop drug resistance and have poor brain penetration.

[0003] In summary, there is an urgent need to develop small molecule kinase inhibitors for HER2 and HER2 mutations that have better performance, high selectivity, brain penetration, and no inhibitory effect on EGFR to meet clinical needs. Small molecule kinase inhibitors for HER3, 4 and HER3, 4 mutations are also needed to meet clinical needs.

[0004] Summary of the Invention

[0005] The present invention aims to provide novel selective HER2 inhibitors. Another object of the present invention is to provide methods of using the inhibitors or to provide uses of the inhibitors.

[0006] In the first aspect of the present invention, a compound or a pharmaceutically acceptable salt thereof is provided, wherein the compound is as shown in Formula I,

[0007] in,

[0008] Q 1 -CONR'-, Q 2 is a 4-6 membered monocyclic heterocyclic group containing one ring nitrogen (N) atom; or, -Q 1 -Q 2 - represents a fused ring or spiro ring formed by two identical or different 4-6 membered monocyclic heterocyclic groups containing one ring nitrogen atom; and the 4-6 membered monocyclic heterocyclic group is optionally substituted by one or more (such as 1, 2 or 3) R' groups; wherein R' is independently H or C 1-2 alkyl;

[0009] R 1Selected from the group consisting of H, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, C 1-4 alkoxy, and halogen;

[0010] R 2 Selected from the group consisting of H, substituted or unsubstituted C 1-4 Alkyl, and halogen;

[0011] R 3 Select from the following groups:

[0012] R 4 for

[0013] R 5 is H or substituted or unsubstituted C 1-4 alkyl;

[0014] R 6 Selected from the group consisting of H, substituted or unsubstituted C 1-4 Alkyl, -C 1-2 Alkylene-N(R")2; wherein R" is H or C 1-4 alkyl;

[0015] Unless otherwise specified, the substitution refers to the substitution of one or more (such as 1, 2 or 3) H atoms in the group by a substituent selected from the group consisting of deuterium (D), halogen, C1-4 alkyl, and C1-4 haloalkyl.

[0016] In another preferred embodiment, R' is H.

[0017] In another preferred embodiment, the 4-6 membered monocyclic heterocyclic group containing one ring nitrogen atom has carbon (C) atoms on the ring except the one ring nitrogen atom.

[0018] In another preferred embodiment, the 4-6 membered monocyclic heterocyclic group containing one ring nitrogen atom is saturated or unsaturated (eg, containing one double bond); preferably, it is saturated.

[0019] In another preferred embodiment, the fused ring or spiro ring formed by two identical or different 4-6 membered monocyclic heteroalkyl groups containing one ring nitrogen atom is saturated or unsaturated (eg, containing 1 or 2 double bonds); preferably, it is saturated.

[0020] In another preferred embodiment, -Q 1 -Q 2 - connected to the rest of the molecule via a N atom;

[0021] In another preferred embodiment, -Q 2 -Q1 -for

[0022] in,

[0023] represents a single bond or a double bond (preferably, is a single key);

[0024] *Represents the location in Q 1 The attachment site on

[0025] W 1 for -(CR'2) n1 -, W 2 for -(CR'2) n2 -; wherein n1=0, 1 or 2, n2=0, 1 or 2, and n1+n2≥1;

[0026] W 3 for -(CR'2) n3 -, W 4 for -(CR'2) n4 -; wherein n3=0, 1 or 2, n4=0, 1 or 2, and n3+n4≥1;

[0027] R' is each independently H or C 1-2 Alkyl (preferably, R' is H).

[0028] In another preferred embodiment, -Q 2 -Q 1 -for

[0029] In another preferred embodiment, n1+n2=1, 2 or 3, and n3+n4=1, 2 or 3.

[0030] In another preferred embodiment, n1+n2=1 or 2, and n3+n4=1 or 2.

[0031] In another preferred embodiment, n1+n2=1, 2 or 3, and n3+n4=2.

[0032] In another preferred embodiment, n1+n2=1 or 2, and n3+n4=2.

[0033] In another preferred embodiment, n1+n2=2, and n3+n4=1 or 2.

[0034] In another preferred example, n1=0, n2=2, n3=1 and n4=0. In another preferred example, n1=0, n2=1, n3=2 and n4=0. In another preferred example, n1=0, n2=1, n3=1 and n4=1. In another preferred example, n1=1, n2=1, n3=1 and n4=0. In another preferred example, n1=1, n2=1, n3=1 and n4=0. In another preferred example, n1=1, n2=1, n3=2 and n4=0. In another preferred example, n1=1, n2=1, n3=1 and n4=1. In another preferred example, n1=2, n2=0, n3=1 and n4=1. In another preferred example, n1=2, n2=0, n3=0 and n4=2. In another preferred example, n1=2, n2=1, n3=1 and n4=0.

[0035] In another preferred embodiment, -Q 2 -Q 1 -Selected from the group consisting of:

[0036] In another preferred embodiment, -Q 2 -Q 1 -for

[0037] in,

[0038] *Represents the location in Q 1 The attachment site on

[0039] W 5 for -(CR'2) n5 -, W 6 for -(CR'2) n6 -; wherein n5=0, 1, 2 or 3, n6=0, 1, 2 or 3 and 2≤n5+n6≤4;

[0040] W 7 for -(CR'2) n7 -, W 8 for -(CR'2) n8 -; wherein n7=0, 1, 2 or 3, n8=0, 1, 2 or 3 and 2≤n7+n8≤4;

[0041] R' is each independently H or C 1-2 Alkyl (preferably, R' is H).

[0042] In another preferred embodiment, n5=n6=1 or 2.

[0043] In another preferred example, n5=n6=2, and n7=n8=2.

[0044] In another preferred example, n5=n6=1, and one of n7 and n8 is 0, and the other is 1.

[0045] In another preferred embodiment, -Q 2 -Q 1 -for

[0046] in,

[0047] *Represents the location in Q 1 The attachment site on

[0048] W 9 for -(CR'2) n9 -; wherein n9=1, 2 or 3;

[0049] R' is each independently H or C 1-2 Alkyl (preferably, R' is H).

[0050] In another preferred embodiment, when the subscript n1, n2, n3, n4, n5, n6, n7, n8, or n9 is 0, correspondingly -(CR'2) n1 -、-(CR'2) n2 -、-(CR'2) n3 -、-(CR'2) n4 -、-(CR'2) n5 -、-(CR'2) n6 -、-(CR'2) n7 -、-(CR'2) n8 -, or -(CR'2) n9 - means none (single bond).

[0051] In another preferred embodiment, -Q 2 -Q 1 -Selected from the group consisting of:

[0052] In another preferred embodiment, the compound is as shown in Formula Ia

[0053] in,

[0054] represents a single bond or a double bond;

[0055] W 1 for -(CR'2) n1 -, W 2 for -(CR'2) n2 -; wherein subscript n1=0, 1 or 2, subscript n2=0, 1 or 2, and n1+n2≥1;

[0056] W 3 for -(CR'2) n3 -, W 4 for -(CR'2)n4 -; wherein subscript n3=0, 1 or 2, subscript n4=0, 1 or 2, and n3+n4≥1;

[0057] R 1 、R 2 、R 3 、R 4 and R' are as defined above.

[0058] In another preferred embodiment, W 1 、W 2 、W 3 、W 4 , subscript n1, subscript n2, subscript n3, and subscript n4 are as defined above.

[0059] In another preferred embodiment, the compound is as shown in Formula Ib

[0060] in,

[0061] W 5 for -(CR'2) n5 -, W 6 for -(CR'2) n6 -; wherein subscript n5=0, 1, 2 or 3, subscript n6=0, 1, 2 or 3, and 2≤n5+n6≤4;

[0062] W 7 for -(CR'2) n7 -, W 8 for -(CR'2) n8 -; wherein subscript n7=0, 1, 2 or 3, subscript n8=0, 1, 2 or 3, and 2≤n7+n8≤4;

[0063] R 1 、R 2 、R 3 、R 4 and R' are as defined above.

[0064] In another preferred embodiment, W 5 、W 6 、W 7 、W 8 , subscript n5, subscript n6, subscript n7, and subscript n8 are as defined above.

[0065] In another preferred embodiment, the compound is as shown in Formula Ic

[0066] in,

[0067] W 9 for -(CR'2) n9-; wherein subscript n9=1, 2 or 3;

[0068] R 1 、R 2 、R 3 、R 4 and R' are as defined above.

[0069] In another preferred embodiment, W 9 , subscript n9 is as defined above.

[0070] In another preferred embodiment, R 1 Selected from the group consisting of H, substituted or unsubstituted C 1-4 In another preferred embodiment, R 1 is substituted or unsubstituted C 1-4 In another preferred embodiment, R 1 C 1-4 In another preferred embodiment, R 1 is selected from the group consisting of methyl and ethyl. 1 It is a methyl group.

[0071] In another preferred embodiment, R 2 is selected from the group consisting of H, methyl, and ethyl. 2 For H.

[0072] In another preferred embodiment, R 3 for

[0073] In another preferred embodiment, R 5 C 1-4 In another preferred embodiment, R 5 It is a methyl group.

[0074] In another preferred embodiment, R 6 Selected from the group consisting of: H, -C 1-2 Alkylene-N(R")2; wherein R" is C 1-4 an alkyl group (preferably, a methyl group).

[0075] In another preferred embodiment, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 1 、Q1、Q2、R'、R",W 1 、W 2 、W 3 、W 4 、W 5 、W 6 、W 7、W 8 、W 9 , subscript n1, subscript n2, subscript n3, subscript n4, subscript n5, subscript n6, subscript n7, subscript n8, and subscript n9 are each independently the corresponding groups in the Example compounds or the compounds in Table A, Table B, and Table C.

[0076] In another preferred embodiment, the compound is selected from Table A, Table B and Table C:

[0077] Table A

[0078] Table B

[0079] Table C

[0080] In a second aspect of the present invention, a pharmaceutical composition is provided, comprising: (i) the compound according to the first aspect or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.

[0081] In the third aspect of the present invention, there is provided a use of the compound as described in the first aspect in the preparation of a medicament for treating or preventing a disease or condition, wherein the disease or condition is a disease or condition mediated by HER2, or a disease or condition that can be improved by inhibiting HER2.

[0082] In another preferred embodiment, the compound treats or prevents the disease or condition by selectively inhibiting HER2.

[0083] In another preferred embodiment, the disease or condition includes cancer.

[0084] In another preferred embodiment, the disease or condition comprises one or more of brain cancer, breast cancer, gallbladder cancer, bladder cancer, cervical cancer, colorectal cancer, gastric cancer, gastroesophageal junction cancer, endometrial cancer, skin cancer, esophageal cancer, head and neck cancer, astrocytic intestinal cancer, bile duct cancer, kidney cancer, liver cancer, ovarian cancer, pancreatic cancer, lung cancer or prostate cancer.

[0085] In a fourth aspect of the present invention, a method for inhibiting HER2 is provided, comprising: contacting a subject with the compound according to the first aspect, thereby inhibiting HER2.

[0086] In another preferred embodiment, the object is a cell.

[0087] In another preferred embodiment, the HER2 includes wild-type HER2, mutant HER2 (such as HER2YVMA), or a combination thereof.

[0088] In another preferred embodiment, the inhibition is selective inhibition of HER2.

[0089] In another preferred embodiment, the selective inhibition refers to substantially not inhibiting EGFR.

[0090] In another preferred embodiment, the substantially no inhibition means that the IC50 value of the inhibitory activity against EGFR is at least 20 times, preferably at least 50 times, the IC50 value of the inhibitory activity against HER2.

[0091] In another preferred embodiment, the method is non-therapeutic in vitro.

[0092] In a fifth aspect of the present invention, there is provided a method for treating or preventing a disease or condition, wherein the disease or condition is a disease or condition mediated by HER2, or a disease or condition ameliorated by inhibiting HER2, the method comprising the steps of:

[0093] A therapeutically effective amount of the compound of the first aspect or the pharmaceutical composition of the second aspect is administered to a subject in need thereof to treat or prevent the disease or disorder.

[0094] In another preferred embodiment, the disease or condition includes cancer.

[0095] In another preferred embodiment, the disease or condition includes one or more of brain cancer, breast cancer, gallbladder cancer, bladder cancer, cervical cancer, colorectal cancer, gastric cancer, gastroesophageal junction cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, stellate intestinal cancer, bile duct cancer, kidney cancer, liver cancer, ovarian cancer, pancreatic cancer, lung cancer or prostate cancer.

[0096] In another preferred embodiment, the subject is a mammal, preferably a human.

[0097] In another preferred embodiment, the compound treats or prevents the disease or condition by selectively inhibiting HER2.

[0098] In another preferred embodiment, the method further comprises administering to a subject in need thereof a therapeutically effective amount of an additional pharmaceutical agent.

[0099] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0100] After extensive and in-depth research, the inventors discovered that the compound represented by Formula I of the present application has excellent HER2 inhibitory activity and selectivity. Based on this, the inventors completed the present invention.

[0101] the term

[0102] As used herein, unless otherwise indicated, a single bond represented by a dashed line in a group definition represents the point at which the group is attached to another moiety.

[0103] In this document, unless otherwise defined, when a group is defined in a left-to-right writing manner, the writing manner does not mean that the group is connected to other parts of the molecule. In other words, when a group is defined in a left-to-right writing manner, it also includes groups written from right to left. For example, Q 1 When it is -CONR'-, 2 The connection can be made at either the CO terminal or the NR' terminal.

[0104] As used herein, the term "halogen" refers to F, Cl, Br, or I. Correspondingly, "halo" refers to a group in which a hydrogen atom is replaced by F, Cl, Br, or I.

[0105] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight-chain or branched hydrocarbon radical (i.e., C 1-6 represents 1-6 carbons). Alkyl (such as C 1-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0106] Unless otherwise specified, the term "cycloalkyl" refers to a group having the specified number of ring atoms (e.g., C 3-6 Cycloalkyl has 3-6 ring atoms) and is a fully saturated hydrocarbon ring, cycloalkyl (such as C 3-6 Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0107] Unless otherwise specified, the term "alkenyl" refers to an unsaturated alkyl group having one or more (preferably one) double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more (preferably one) triple bonds. Typically, an alkenyl group has 1-4 carbon atoms, i.e., C 1-4 Alkenyl and alkynyl groups have 1-4 carbon atoms, namely C 1-4 Examples of such unsaturated alkyl groups include ethenyl, 2-propenyl, ethynyl, 1- and 3-propynyl, and 3-butynyl.

[0108] Unless otherwise indicated, the term "alkoxy" is used in its conventional sense to refer to those alkyl groups having the specified number of carbon atoms attached to the remainder of the molecule via an oxygen atom, e.g., C 1-4 The alkoxy group may be methoxy (-OCH3), ethoxy, or the like.

[0109] As used herein, the term "alkylene," by itself or as part of another substituent, refers to a divalent radical derived from an alkane, for example -CH2-.

[0110] Unless otherwise specified, the term "heterocyclyl" refers to a cycloalkyl group containing 1 to 3 heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. In this context, a heterocyclyl group preferably refers to a saturated monocyclic heterocycle containing 4 to 6 ring atoms (i.e., 4-6 members) or containing one double bond. Preferably, in this context, a heterocyclyl group contains only one nitrogen heteroatom, and the remaining ring atoms are carbon atoms.

[0111] For the compounds provided herein, a bond from a substituent (typically an R group) to the center of a ring will be understood to refer to a bond to any available vertex of the ring.

[0112] As used herein, the terms "comprising", "including" or "comprising" indicate that various components can be used together in the mixture or composition of the present invention. Therefore, the terms "consisting essentially of" and "consisting of" are included in the term "comprising".

[0113] As used herein, the term "pharmaceutically acceptable" refers to substances that are suitable for use in humans and / or animals without excessive adverse side effects (such as toxicity, irritation, and allergic response), ie, at a reasonable benefit / risk ratio.

[0114] It should be understood that, unless otherwise specified, the description of each group name term covers the case where the number of carbon atoms / ring atoms is specified. For example, if the number of carbon atoms meets the requirement, the example / example of alkyl group can also be C 1-6 Examples / Instances of alkyl groups.

[0115] Unless otherwise specified, all compounds mentioned in the present invention are intended to include all possible optical isomers, such as single chiral compounds or mixtures of various chiral compounds (i.e., racemates). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0116] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S).

[0117] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) are intended to be encompassed within the scope of the present invention. When compounds provided herein have defined stereochemistry (denoted as R or S, or indicated by dashed or wedge-shaped bonds), those skilled in the art will understand that those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and up to 100% free of other isomers).

[0118] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the isotopic atoms that make up such compounds. An unnatural proportion of an isotope can be defined as the amount of the atom in question found in nature to 100% of that atom. For example, a compound may incorporate a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C) In addition to those uses described herein, such isotopic variants may provide additional uses. For example, isotopic variants of the compounds of the present invention may have additional uses, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic properties, thereby contributing to increased safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, whether or not radioactive, are intended to be encompassed by the present invention.

[0119] Active ingredient

[0120] As used herein, the term "compound of the present invention" or "compounds of the present invention" refers to compounds of Formula I, Formula Ia, Ib, or Ic herein. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates, or solvates of the compounds of Formula I, Formula Ia, Ib, or Ic.

[0121] The term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention with an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0122] The term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0123] In addition, the compounds of the present invention also include prodrugs of compounds represented by Formula I, Formula Ia, Ib, or Ic. The term "prodrug" includes compounds that may be biologically active or inactive, which, when administered by appropriate methods, undergo metabolic or chemical reactions in the human body to transform into a compound of Formula I, Formula Ia, Ib, or Ic, or a salt or solution of a compound of Formula I, Formula Ia, Ib, or Ic. Such prodrugs include, but are not limited to, carboxylate esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compounds.

[0124] Preparation method

[0125] Methods for preparing compounds of Formula I, Ia, Ib, or Ic of the present invention are specifically described herein, but these specific methods do not limit the present invention in any way. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art. Such combinations can be readily performed by those skilled in the art.

[0126] Pharmaceutical compositions and methods of administration

[0127] Because the compounds of the present invention have excellent selective inhibitory activity against HER2 and anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent, and ameliorate diseases associated with or mediated by HER2, or to treat, prevent, and ameliorate tumors. According to the prior art, the compounds of the present invention can be used to treat the following diseases: brain cancer, breast cancer, gallbladder cancer, bladder cancer. One or more of cervical cancer, colorectal cancer, gastric cancer, gastroesophageal junction cancer, endometrial cancer, skin cancer, esophageal tumors, head and neck tumors, astrocytic intestinal cancer, bile duct cancer, kidney cancer, liver cancer, ovarian cancer, pancreatic cancer, lung cancer, or prostate cancer.

[0128] As used herein, the term "selective" refers to an activity or potency (eg, inhibitory activity) against a given target (eg, HER2) that is greater than an activity or potency (eg, inhibitory activity) against other targets (eg, EGFR).

[0129] The pharmaceutical compositions of the present invention comprise a safe and effective amount or a therapeutically effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.01-500 mg of the compound of the present invention per dose, more preferably 0.01-100 mg per dose. Preferably, "one dose" refers to one capsule or tablet.

[0130] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0131] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0132] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0133] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0134] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0135] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0136] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0137] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0138] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0139] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. For example, the compounds of the present invention can be used as sensitizers for anti-tumor drugs and can be administered in combination with at least one other anti-tumor drug. The other anti-tumor drug can be a targeted drug or a drug for chemotherapy and radiotherapy (such as carboplatin, paclitaxel, temozolomide, etc.), and proton therapy.

[0140] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 0.01 to 500 mg, preferably 0.01 to 100 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0141] The main advantages of the present invention include:

[0142] 1. The compounds of the present invention have excellent selectivity and excellent inhibitory activity

[0143] 2. The compounds of the present invention have excellent selectivity. Therefore, the compounds of the present invention have lower toxicity and better safety.

[0144] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0145] A. Preparation Examples

[0146] Example 1: Synthesis of Compound 1

[0147] Step A

[0148] Compound 1a (2 g, 14.80 mmol), compound 1b (2.53 g, 16.28 mmol), and cesium carbonate (12.06 g, 37.00 mmol) were added sequentially to dimethyl sulfoxide (50 mL) and stirred at 80°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, and separated by medium-pressure flash preparative chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain Compound 1c (3.5 g, 87.50%) as an off-white solid. 1H NMR (400MHz, CDCl3): δppm 8.62(d,J=7.2Hz,1H),8.38(s,1H),8.27(d,J=2.4Hz,1H),8.17(dd,J=8.8,2.4Hz,1H),7.16(d,J =8.8Hz,1H),7.10(d,J=2.4Hz,1H),7.00(dd,J=7.6,2.4Hz,1H),2.36(s,3H).LCMS:271.2[M+H]+.

[0149] Step B

[0150] Compound 1c (3.5 g, 14.80 mmol) and reduced iron powder (3.62 g, 64.76 mmol) were added sequentially to ethanol (125 mL). Aqueous ammonium chloride (3.46 g, 64.76 mmol dissolved in 25 mL of water) was added, and the mixture was stirred at 70°C for 4 hours. The reaction was monitored by LCMS. Upon completion, the solvent was removed under reduced pressure, the mixture was diluted with water (100 mL), and extracted with ethyl acetate (200 mL x 3). The mixture was dried over anhydrous sodium sulfate and separated by medium-pressure flash preparative chromatography (eluent: petroleum ether / ethyl acetate, 3 / 1, v / v) to afford Compound 1d (2 g, 64.27%) as a pale yellow solid. 1H NMR (400MHz, CDCl3): δppm 8.44(d,J=7.6Hz,1H),8.19(s,1H),6.81–6.86(m,2H),6.77(d,J=2.4Hz,1H),6.6 0(d,J=2.4Hz,1H),6.56(dd,J=8.4,2.8Hz,1H),2.07(s,3H).LCMS:241.2[M+H]+.

[0151] Step C

[0152] Compound 1d (2 g, 8.32 mmol), compound 1e (1.94 g, 9.99 mmol), N,N-diisopropylethylamine (1.78 g, 13.73 mmol), and PyBOP (5.72 g, 9.99 mmol) were added sequentially to N,N-dimethylformamide (100 mL) and stirred at room temperature for 4 hours. The reaction was monitored by LCMS. Upon completion, the solvent was removed under reduced pressure, dissolved in water (100 mL), extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, and separated by medium-pressure flash preparative chromatography (eluent: dichloromethane / ethyl acetate, 1 / 10, v / v) to obtain compound 1f (2.5 g, 72.12%) as a light brown solid. LCMS: 417.0 [M+H]+.

[0153] Step D

[0154] Compound 1f (2.5 g, 6.00 mmol) was added to dichloromethane (50 mL), cooled to 0°C in an ice-water bath, and m-chloroperbenzoic acid (1.81 g, 8.40 mmol, 80%) was added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. After completion, the mixture was cooled to 0°C in an ice-water bath and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with dichloromethane (100 mL x 2), dried over anhydrous sodium sulfate, and separated by medium-pressure flash preparative chromatography (eluent: dichloromethane / methanol, 10 / 1, v / v) to obtain compound 1g (1 g, 38.52%) as a brown solid. LCMS: 432.9 [M+H]+.

[0155] Step E

[0156] Compound 1g (150 mg, 0.35 mmol), compound 1h (100 mg, 0.50 mmol), and N,N-diisopropylethylamine (135 mg, 1.04 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by medium-pressure flash preparative chromatography (eluent: dichloromethane / ethyl acetate, 1 / 1 to 1 / 10, v / v) to afford a yellow, viscous compound 1i (60 mg, 30.5%). LCMS: 567 [M+H]+.

[0157] Step F

[0158] Compound 1i (60 mg, 0.076 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure using LCMS to afford a crude, yellow, viscous compound 1j (40 mg). The crude product was used directly in the next step without purification. LCMS: 467.0 [M+H].

[0159] Step G

[0160] Compound 1j (40 mg, crude) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (0.5 M in DCM, 0.1 mL) was added dropwise at 0°C under nitrogen and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (30-50%) as eluents to afford Compound 1 (4.5 mg, 8.1%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.09(s,1H),8.77(d,J=7.6Hz,1H),8.55(d,J=2Hz,1H),8.34(s,1H),7.94–7.86( m,2H),7.24(d,J=8.8Hz,1H),7.11(dd,J=7.6,2.4Hz,1H),6.83–6.79(m,1H),6.5 8–6.25(m,2H),5.87–5.69(m,1H),5.43–5.08(m,2H),4.75–4.30(m,2H),4.06–3. 66(m,2H),2.63–2.40(m,1H),2.27(s,3H),2.25–2.10(m,1H).LCMS:521.2[M+H]+.

[0161] Example 2: Synthesis of Compound 2

[0162] Step A

[0163] Compound 1h (250 mg, 0.6 mmol) and N,N-diisopropylethylamine (324 mg, 2.51 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (170 mg, 1.88 mmol) was added dropwise at 0°C under nitrogen protection and stirred at room temperature for 1 hour. LCMS monitoring was performed. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous compound 2a (300 mg, 94.4%). This product was used directly in the next step without purification. LCMS: 253.1 [M+H]+.

[0164] Step B

[0165] Compound 2a (300 mg, 1.18 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure using LCMS to afford a crude, yellow, viscous compound 2b (170 mg). This product was used directly in the next step without purification. LCMS: 153.2 [M+H]+.

[0166] Step C

[0167] Compound 2b (32 mg, 0.21 mmol), compound 1g (60 mg, 0.14 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford compound 2 (8.5 mg, 11.75%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.99(d,J=3.0Hz,1H),8.72(d,J=7.5Hz,1H),8.44(d,J=2.4Hz,1H),8.27(s,1H),7.91–7.87( m,2H),7.17(d,J=8.6Hz,1H),7.05(dd,J=7.5,2.4Hz,1H),6.77–6.56(m,2H),6.34–6.30(m,1H ),5.85–5.73(m,1H),5.36–5.24(m,1H),4.93–4.86(m,1H),4.53–4.46(m,1H),4.33–4.17(m,1 H),4.00–3.62(m,2H),2.62–2.52(m,1H),2.23(s,3H),2.19–2.00(m,1H).LCMS:521.0[M+H]+.

[0168] Example 3: Synthesis of Compound 3

[0169] Step A

[0170] Compound 1g (200 mg, 0.46 mmol), compound 3a (183 mg, 0.92 mmol), and N,N-diisopropylethylamine (179 mg, 1.39 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by medium-pressure flash preparative chromatography (eluent: dichloromethane / ethyl acetate, 1 / 1 to 1 / 10, v / v) to afford a yellow, viscous compound 3b (150 mg, 56.5%). LCMS: 567.2 [M+H]+.

[0171] Step B

[0172] Compound 3b (150 mg, 0.26 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, as monitored by LCMS, to afford a crude, yellow, viscous compound 3c (90 mg). The crude product was used directly in the next step without purification. LCMS: 467.2 [M+H].

[0173] Step C

[0174] Compound 3c (90 mg, crude) and N,N-diisopropylethylamine (75 mg, 0.58 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (0.5 M in DCM, 0.38 mL) was added dropwise at 0°C under nitrogen and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford compound 3 (24 mg, 16.9% over two steps) as a yellow solid. 1H NMR (400MHz, DMSO-d6): δppm 9.64-9.59(m,1H),9.13(s,1H), 8.84(d,J=7.6Hz,1H),8.47(d,J=4.4Hz,1H),8.38(s,1H),8.01–7.96(m,2H),7.26– 7.23(m,1H).7.03(dd,J=7.2,2.4Hz,1H),6.80(d,J=2.4Hz,1H),6.54–6.24(m,1H),6 .18–6.08(m,1H),5.75–5.64(m,1H),5.23–4.95(m,1H),4.61–4.50(m,1H),4.40(t,J =8.4Hz,1H),4.13–3.89(m,1H),3.58–3.49(m,4H),2.21(s,3H).LCMS:521.2[M+H]+.

[0175] Example 4: Synthesis of Compound 4

[0176] Step A

[0177] Compound 3a (100 mg, 0.5 mmol) and N,N-diisopropylethylamine (259 mg, 2.0 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (136 mg, 1.5 mmol) was added dropwise at 0°C under nitrogen protection and stirred at room temperature for 1 hour. LCMS monitoring was used to quench the reaction after completion. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous compound 4a (120 mg, 94.4%). The product was used directly in the next step without purification. LCMS: 275.2 [M+Na]+.

[0178] Step B

[0179] Compound 4a (120 mg, 0.47 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure using LCMS to afford a crude, yellow, viscous compound 4b (70 mg). The crude product was used directly in the next step without purification. LCMS: 153.1 [M+H].

[0180] Step C

[0181] Compound 4b (70 mg, 0.46 mmol), compound 1g (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (94 mg, 0.92 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford compound 4 (29 mg, 28.64%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.08(d,J=4.4Hz,1H),8.85(d,J=7.2Hz,1H),8.63(s,1H),8.47(s,1H),7.92–7.73(m, 2H),7.30(d,J=8.8Hz,1H),7.18(d,J=7.2Hz,1H),6.88(s,1H),6.79–6.62(m,1H),6.32 –6.26(m,1H),5.83–5.71(m,1H),5.25(s,H),4.67–4.63(m,2H),4.34–4.32(m,1H),4.0 0–3.90(m,1H),3.65–3.61(m,1H),3.43–3.32(m,2H),2.31(s,3H).LCMS:521.0[M+H]+.

[0182] Example 5: Synthesis of Compound 5

[0183] Step A

[0184] Compound 1g (150 mg, 0.35 mmol), compound 5a (118 mg, 0.52 mmol), and N,N-diisopropylethylamine (135 mg, 1.04 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by medium-pressure flash preparative chromatography (eluent: dichloromethane / ethyl acetate, 1 / 1 to 1 / 10, v / v) to afford a yellow, viscous compound 5b (48 mg, 23.2%). LCMS: 595.1 [M+H]+.

[0185] Step B

[0186] Compound 5b (45 mg, 0.076 mmol) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (0.5 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, monitored by LCMS, to afford a crude, yellow, viscous compound 5c (40 mg). The crude product was used directly in the next step without purification. LCMS: 495.1 [M+H].

[0187] Step C

[0188] Compound 5c (35 mg, crude) and N,N-diisopropylethylamine (45 mg, 0.35 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (0.5 M in DCM, 0.17 mL) was added dropwise at 0°C under nitrogen and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 5 (8.7 mg, 20.9%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.94(s,1H),8.71(d,J=7.5Hz,1H),8.36(s,1H),8.26(s,1H),8.03–7.79(m,2H),7 .16(d,J=8.4Hz,1H),7.04(dd,J=7.5,2.4Hz,1H),6.76(d,J=2.3Hz,1H),6.40–6.37 (m,1H),6.24(dd,J=17.0,1.9Hz,1H),5.73(dd,J=10.3,1.8Hz,1H),4.10(s,2H),4 .04–4.02(m,4H),3.86(s,2H),2.22(s,3H),1.95–1.81(m,4H).LCMS:549.1[M+H]+.

[0189] Example 6: Synthesis of Compound 6

[0190] Step A

[0191] Compound 1g (150 mg, 0.347 mmol), compound 6a (95 mg, 0.420 mmol), and N,N-diisopropylethylamine (135 mg, 1.04 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by medium-pressure flash preparative chromatography (eluent: dichloromethane / ethyl acetate, 1 / 1 to 1 / 10, v / v) to afford a yellow, viscous compound 6b (80 mg, 38.78%). LCMS: 595.3 [M+H]+.

[0192] Step B

[0193] Compound 6b (80 mg, 0.134 mmol) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, as monitored by LCMS, to afford a crude, yellow, viscous compound 6c (50 mg). The crude product was used directly in the next step without purification. LCMS: 495.1 [M+H].

[0194] Step C

[0195] Compound 6c (50 mg, crude) and N,N-diisopropylethylamine (35 mg, 0.346 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (0.5 M in DCM, 0.11 mL) was added dropwise at 0°C under nitrogen and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (20-50%) as eluents to afford Compound 6 (8 mg, 14.42%) as a yellow solid. 1H NMR (400MHz, CD3OD): δppm 8.84(s,1H),8.63(d,J=7.6Hz,1H),8.31(s,1H),8.18(s,1H),7.82(s,1H),7.80(d,J=2.4Hz,1H),7.07(d,J=8.4Hz, 1H),6.96(dd,J=7.6,2.4Hz,1H),6.71–6.67(m,2H),6.10(dd,J=16.8,2Hz,1H),5.65(dd,J=10.4 ,1.6Hz,1H),3.97(s,4H),3.64–3.54(m,4H),2.14(s,3H),1.86–1.78(m,4H).LCMS:549.3[M+H]+.

[0196] Example 7: Synthesis of Compound 7

[0197] Step A

[0198] Compound 7a (100 mg, 0.5 mmol) and diisopropylethylamine (195 mg, 1.5 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (91 mg, 1.01 mmol) was added dropwise at 0°C under nitrogen protection and stirred at room temperature for 1 hour. LCMS monitoring was performed. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous compound 7b (100 mg, 78.7%). This product was used directly in the next step without purification. LCMS: 253.1 [M+H]+.

[0199] Step B

[0200] Compound 7b (100 mg, 1.16 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, as monitored by LCMS, to afford a crude yellow viscous product, Compound 7c (100 mg). This product was used directly in the next step without purification. LCMS: 153.2 [M+H].

[0201] Step C

[0202] Compound 7c (110 mg, crude), compound 1g (80 mg, 0.19 mmol), and N,N-diisopropylethylamine (120 mg, 0.9 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (20-50%) as eluents to afford compound 7 (11 mg, 11.1%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.04(s,1H),8.79(d,J=7.6Hz,1H),8.60(d,J=4.4Hz,1H),8.41(s,1H),7.89–7. 83(m,2H),7.25(d,J=8.4Hz,1H),7.13(dd,J=7.6,2.4Hz,1H),6.83(d,J=2.4Hz,1 H),6.55–6.21(m,1H),5.76–5.72(m,1H),5.01–4.98(m,2H),4.43(d,J=10.4Hz,2 H),4.24–4.20(m,2H),2.68–2.64(m,2H),2.26–2.23(m,4H).LCMS:521.2[M+H]+.

[0203] Example 8: Synthesis of Compound 8

[0204] Step A

[0205] Compound 8a (130 mg, 0.65 mmol) and N,N-diisopropylethylamine (337 mg, 2.6 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (177 mg, 1.95 mmol) was added dropwise at 0°C under nitrogen protection and stirred at room temperature for 1 hour. LCMS monitoring was performed. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous compound 8b (110 mg, 66.5%). The product was used directly in the next step without purification. LCMS: 253.1 [M+H]+.

[0206] Step B

[0207] Compound 8b (110 mg, 0.41 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure using LCMS to afford a crude yellow viscous product, Compound 8c (60 mg). This product was used directly in the next reaction without purification. LCMS: 153.2 [M+H].

[0208] Step C

[0209] Compound 8c (60 mg, 0.39 mmol), compound 1g (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (72 mg, 0.56 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford compound 8 (16 mg, 16.1%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.79(d,J=5.6Hz,1H),8.73(d,J=7.6Hz,1H),8.53(s,1H),8.37(s,1H),7.86 –7.74(m,2H),7.18–7.13(m,1H),7.08–7.06(m,1H),6.75(s,1H),6.41–6.28( m,1H),6.22–6.13(m,1H),5.69–5.65(m,1H),5.05–4.94(m,2H),4.46–4.42( m,1H),4.16–4.13(m,3H),2.70–2.66(m,H),2.18(S,3H).LCMS:521.0[M+H]+.

[0210] Example 9: Synthesis of Compound 9

[0211] Step A

[0212] Compound 9a (300 mg, 1.41 mmol) and triethylamine (285 mg, 2.81 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (191 mg, 2.11 mmol) was added dropwise at 0°C under nitrogen protection and stirred at room temperature for 1 hour. LCMS monitoring was used to quench the reaction after completion of the reaction. The mixture was concentrated under reduced pressure and diluted with ethyl acetate (30 mL). The residue was washed with water (20 mL x 2) and saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous compound 9b (300 mg, 82.9%). The product was used directly in the next step without purification. LCMS: 289.1 [M+Na]+.

[0213] Step B

[0214] Compound 9b (300 mg, 1.13 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, as monitored by LCMS, to afford a crude, yellow, viscous compound 9c (260 mg). This product was used directly in the next step without purification. LCMS: 167.1 [M+H].

[0215] Step C

[0216] Compound 9c (50 mg, crude), compound 1g (60 mg, 0.14 mmol), and N,N-diisopropylethylamine (90 mg, 0.69 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (20-50%) as eluents to afford compound 9 (30 mg, 40.4%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.06(s,1H),8.79(d,J=7.5Hz,1H),8.58(s,1H),8.38(s,1H),7.90–7.83(m,2 H),7.25(d,J=8.6Hz,1H),7.12(dd,J=7.5,2.4Hz,1H),6.82(d,J=2.3Hz,1H), 6.40–6.23(m,2H),5.74(dd,J=10.2,1.9Hz,1H),4.34(s,2H),4.15–3.95(m,4 H),3.91–3.79(m,2H),2.36(t,J=6.7Hz,2H),2.26(s,3H).LCMS:535.1[M+H]+.

[0217] Example 10: Synthesis of Compound 10

[0218] Step A

[0219] Compound 10a (50 mg, 0.24 mmol) and N,N-diisopropylethylamine (90 mg, 0.70 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (0.5 M in DCM, 0.35 mL) was added dropwise at 0°C under nitrogen and stirred at room temperature for 1 hour. After completion, the reaction was quenched by adding methanol (1 mL) and concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude, yellow, viscous compound 10b (55 mg). This product was used directly in the next step without purification. LCMS: 267.1 [M+H]+.

[0220] Step B

[0221] Compound 10b (55 mg, crude) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (2 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, as monitored by LCMS, to afford a crude, yellow, viscous compound 10c (70 mg). The product was used directly in the next step without purification. LCMS: 167.2 [M+H].

[0222] Step C

[0223] Compound 10c (50 mg, crude), compound 1g (60 mg, 0.14 mmol), and N,N-diisopropylethylamine (54 mg, 0.42 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (20-70%) as eluents to afford Compound 10 (4.8 mg, 6.4%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.02(s,1H),8.74(d,J=7.6Hz,1H),8.43(s,1H),8.29(s,1H),7.89–7.97(m,2H),7.19 (d,J=8.8Hz,1H),7.07(d,J=7.2Hz,1H),6.79(s,1H),6.68–6.62(m,1H),6.26–6.21(m ,1H),5.77–5.68(m,1H),3.99–3.81(m,4H),3.72–3.61(m,2H),3.22–3.13(m,1H),2.3 1–2.25(m,1H),2.25(s,3H),2.04–1.98(m,1H),1.33–1.28(m,2H).LCMS:535.2[M+H]+.

[0224] Example 11: Synthesis of Compound 11

[0225] Step A

[0226] Compound 11a (100 mg, 0.47 mmol) and N,N-diisopropylethylamine (243 mg, 1.89 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (128 mg, 1.41 mmol) was added dropwise at 0°C under nitrogen protection and stirred at room temperature for 1 hour. LCMS monitoring was performed. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous product, Compound 11b (110 mg, 87.7%). This product was used directly in the next step without purification. LCMS: 289.1 [M+Na]+.

[0227] Step B

[0228] Compound 11b (110 mg, 0.41 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, as monitored by LCMS, to afford a crude, yellow, viscous compound 11c (70 mg). This product was used directly in the next step without purification. LCMS: 167.1 [M+H].

[0229] Step C

[0230] Compound 11c (70 mg, 0.42 mmol), compound 1g (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (95 mg, 0.74 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 11 (20 mg, 19.8%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.96(d,J=4.0Hz,1H),8.69(d,J=7.2Hz,1H),8.48(s,1H),8.28(s,1H),7.82–7.79( m,2H),7.16(d,J=8.4Hz,1H),7.04–7.02(m,1H),6.74(s,1H),6.58–6.51(m,1H),6.2 9–6.20(m,1H),5.76–5.66(m,1H),4.74–4.60(m,1H),4.41–3.92(m,3H),3.76–3.69( m,3H),3.21–3.13(m,1H),2.20–2.13(m,4H),1.96–1.91(m,1H).LCMS:535.0[M+H]+.

[0231] Example 12: Synthesis of Compound 12

[0232] Step A

[0233] Compound 12a (100 mg, 0.47 mmol) and diisopropylethylamine (182 mg, 1.41 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (85 mg, 0.94 mmol) was added dropwise at 0°C under nitrogen protection and stirred at room temperature for 1 hour. LCMS monitoring was performed. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow viscous compound 12b (110 mg, 87.8%). The product was used directly in the next step without purification. LCMS: 267.1 [M+H]+.

[0234] Step B

[0235] Compound 12b (110 mg, 0.41 mmol) was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (1.5 mL) was added at 0°C under nitrogen and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, as monitored by LCMS, to afford a crude yellow viscous product, compound 12c (100 mg). This product was used directly in the next step without purification. LCMS: 167.1 [M+H].

[0236] Step C

[0237] Compound 12c (100 mg, crude), compound 1g (80 mg, 0.19 mmol), and N,N-diisopropylethylamine (120 mg, 0.9 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (20-50%) as eluents to afford Compound 12 (10.2 mg, 10.1%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.00(s,1H),8.71(d,J=7.6Hz,1H),8.40(s,1H),8.26(s,1H),7.92–7.88(m,2H),7.16(d ,J=8.8Hz,1H),7.04(dd,J=7.6,2.0Hz,1H),6.78–6.76(m,1H),6.74–6.61(m,1H),6.37–6 .26(m,1H),5.83–5.73(m,1H),5.01–4.92(m,1H),4.85–4.77(m,1H),4.23(s,1H),3.98–3 .88(m,1H),3.56–3.49(m,2H),2.42–2.37(m,2H),2.33–2.18(m,5H).LCMS:535.0[M+H]+.

[0238] Example 13: Synthesis of Compound 13

[0239] Step A

[0240] Compound 13a (235 mg, 0.864 mmol) and triethylamine (210 mg, 2.08 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 10 minutes. Compound 1g (150 mg, 0.347 mmol) was added, and the mixture was stirred at 70°C for 6 hours under nitrogen. The reaction was monitored by LCMS. After completion, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure flash chromatography (eluent: dichloromethane / methanol, 10 / 1, v / v) to obtain compound 13b (50 mg, 30.1%) as a pale yellow solid. LCMS: 479.2 [M+H]+.

[0241] Step B

[0242] Compound 13b (50 mg, 0.105 mmol) and N,N-diisopropylethylamine (32 mg, 0.319 mmol) were dissolved in dichloromethane (10 mL). Acryloyl chloride (0.5 M in DCM, 0.23 mL) was added dropwise at 0°C under nitrogen and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. After completion, methanol (1 mL) was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2) and saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 13 (4 mg, 7.19%) as a yellow solid. H NMR (400 MHz, DMSO-d6): δ ppm 9.50(s,1H),9.14(s,1H),8.94(d,J=7.6Hz,1H),8.47(s,1H),8.39(s,1H),8.04(d,J= 8.8Hz,1H),7.99(d,J=2.4Hz,1H),7.24(d,J=8.8Hz,1H),7.03(dd,J=7.6,2.4Hz,1H), 6.81(d,J=2Hz,1H),6.56–6.68(m,1H),6.23(dd,J=16.8,2Hz,1H),5.75(dd,J=10.4,2 .4Hz,1H),4.58–4.40(m,6H),4.28(d,J=13.6Hz,2H),2.21(s,3H).LCMS:533.0[M+H]+.

[0243] Example 14: Synthesis of Compound 14

[0244] Compound 14a (100 mg, 0.31 mmol, TFA salt), compound 1g (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (120 mg, 0.93 mmol) were added sequentially to 1,4-dioxane (6 mL) and stirred at 70°C for 4 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (10-40%) as eluents to afford Compound 14 (7.1 mg, 6.6%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.02(s,1H),8.74(d,J=7.2Hz,1H),8.43(s,1H),8.28(s,1H),7.96–7.91(m,2H),7.19( d,J=8.8Hz,1H),7.07(dd,J=7.2,2.4Hz,1H),6.86–6.74(m,2H),6.44–6.17(m,1H),5.3 5–5.24(m,0.5H),5.09–5.06(m,0.5H),4.77–4.65(m,1H),4.58–4.47(m,2H),4.26–3.9 6(m,1H),3.57–3.41(m,4H),2.41(s,2H),2.35(s,6H),2.25(s,3H).LCMS:578.1[M+H]+.

[0245] Example 15: Synthesis of Compound 15

[0246] Compound 15a (100 mg, 0.31 mmol, TFA salt), compound 1g (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (120 mg, 0.93 mmol) were added sequentially to 1,4-dioxane (6 mL) and stirred at 70°C for 4 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (10-40%) as eluents to afford Compound 15 (9.1 mg, 8.5%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.02(s,1H),8.74(d,J=7.2Hz,1H),8.43(s,1H),8.28(s,1H),7.96–7.91(m,2H),7.19( d,J=8.8Hz,1H),7.07(dd,J=7.2,2.4Hz,1H),6.86–6.74(m,2H),6.44–6.17(m,1H),5.3 5–5.24(m,0.5H),5.09–5.06(m,0.5H),4.77–4.65(m,1H),4.58–4.47(m,2H),4.26–3.9 6(m,1H),3.57–3.41(m,4H),2.41(s,2H),2.35(s,6H),2.25(s,3H).LCMS:578.1[M+H]+.

[0247] Example 16: Synthesis of Compound 16

[0248] Step A

[0249] Compound 16a (10.0 g, 67.5 mmol), compound 1b (11.5 g, 74.2 mmol), and cesium carbonate (44.0 g, 135.0 mmol) were added sequentially to dimethyl sulfoxide (200 mL) and stirred at 80°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was washed with water (100 mL x 3) and saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain Compound 16b (18.0 g, 84.7%) as a yellowish oil. 1H NMR (400MHz, DMSO-d6): δppm 8.28(s,1H),8.22(d,J=2.8Hz,1H),8.01(dd,J=9.1,2.9Hz,1H),7.68(d,J=8.7Hz,1H),7.44(d,J=2.2Hz,1 H),7.11(dd,J=8.7,2.2Hz,1H),6.69(d,J=9.1Hz,1H),3.89(s,3H),2.49–2.38(m,3H).LCMS:284.0[M+H]+.

[0250] Step B

[0251] Compound 16b (18.0 g, 63.5 mmol) and palladium-carbon catalyst (4.0 g) were sequentially added to methanol (200 mL) and stirred at room temperature under hydrogen for 14 hours. The reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was collected and concentrated under reduced pressure. The residue was diluted with water (100 mL), extracted with dichloromethane (200 mL x 3), dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: dichloromethane / methanol, 10 / 1, v / v) to obtain Compound 16c (7.2 g, 40.4%) as a pale yellow solid. 1H NMR (400MHz, CDCl3): δppm 7.83(s,1H),7.29–7.26(m,1H),7.17(d,J=2.2Hz,1H),7.01(dd,J=8.7,2.3Hz,1H),6.77(d,J=8.5Hz, 1H),6.60(d,J=2.7Hz,1H),6.51(dd,J=8.4,2.8Hz,1H),3.81(s,3H),2.14(s,3H).LCMS:254.1[M+H]+.

[0252] Step C

[0253] Compound 16c (7.2 g, 28.5 mmol), compound 1e (6.6 g, 34.2 mmol), N,N-diisopropylethylamine (14.7 g, 114.0 mmol), and PyBOP (21.4 g, 41.0 mmol) were added sequentially to N,N-dimethylformamide (110 mL) and stirred at room temperature for 14 hours. The reaction was monitored by LCMS. After completion, the reaction solution was added dropwise to 500 mL of water and stirred for 10 minutes. After complete dispersion, the solid was collected by filtration and concentrated under reduced pressure to remove moisture. Ether and a small amount of acetonitrile were added to the solid to slurry it, and the mixture was filtered again to obtain a light brown solid, compound 16d (10.46 g, 85.6%). LCMS: 430.1 [M+H]+.

[0254] Step D

[0255] Compound 16d (10.46 g, 24.4 mmol) was added to dichloromethane (100 mL), cooled to 0°C in an ice-water bath, and m-chloroperbenzoic acid (6.3 g, 36.6 mmol, 80%) was added. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by LCMS. Upon completion, the mixture was cooled to 0°C in an ice-water bath and quenched with saturated aqueous sodium bicarbonate (200 mL). The mixture was extracted with dichloromethane (200 mL x 2), dried over anhydrous sodium sulfate, and separated by column chromatography (eluent: dichloromethane / methanol, 10 / 1, v / v) to obtain Compound 16e (4.23 g, 38.93%) as a brown solid. 1H NMR (400MHz, CDCl3) δppm9.62(s,1H),9.42(s,1H),8.87(s,1H),8.12(s,1H),7.82(d,J=2.4Hz,1H),7.70(dd,J=8.8,2.8Hz,1H), 7.39–7.33(m,2H),7.11(dd,J=8.8,2.2Hz,1H),6.91(d,J=8.7Hz,1H),3.90(s,3H),3.07(s,3H),2.35(s,3H).LCMS:446.0[M+H]+.

[0256] Step E

[0257] Compound 14a (100 mg, crude, TFA salt), compound 16e (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (15-40%) as eluents, to afford compound 16 (7.8 mg, 7.4%) as a yellow solid. NMR (400MHz, CD3OD): δppm8.97(s,1H),8.37(s,1H),8.10(s,1H),7.80–7.79(m,1H),7.74–7. 69(m,1H),7.53(d,J=8.4Hz,1H),7.11–7.06(m,2H),6.88(d,,J=8.8Hz,1H),6.85–6.73(m,1H) ,6.41–6.16(m,1H),5.26–5.04(m,1H),4.77–4.63(m,1H),4.55–4.45(m,2H),4.23–3.95(m,1H ),3.90(s,3H),3.53–3.37(m,4H),2.43(s,2H),2.37(s,6H),2.29(s,3H).LCMS:591.0[M+H]+.

[0258] Example 17: Synthesis of Compound 17

[0259] Compound 15a (100 mg, crude, TFA salt), compound 16e (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) were sequentially added to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (15-40%) as eluents, to afford compound 17 (10 mg, 9.6%) as a yellow solid. NMR (400MHz, CD3OD): δppm8.97(s,1H),8.37(s,1H),8.10(s,1H),7.80–7.79(m,1H),7.74–7. 69(m,1H),7.53(d,J=8.4Hz,1H),7.11–7.06(m,2H),6.88(d,,J=8.8Hz,1H),6.85–6.73(m,1H) ,6.41–6.16(m,1H),5.26–5.04(m,1H),4.77–4.63(m,1H),4.55–4.45(m,2H),4.23–3.95(m,1H ),3.90(s,3H),3.53–3.37(m,4H),2.43(s,2H),2.37(s,6H),2.29(s,3H).LCMS:591.0[M+H]+.

[0260] Example 18: Synthesis of Compound 18

[0261] Step A

[0262] Compound 1f (100 mg, 0.24 mmol) was added to dichloromethane (5 mL), and sulfonyl chloride (81 mg, 0.6 mmol) was added dropwise at 0°C. The mixture was stirred under nitrogen for 1 hour. LCMS monitoring was performed. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by medium-pressure flash chromatography (eluent: dichloromethane / ethyl acetate, 1 / 4, v / v) to obtain Compound 18a (60 mg, 55.56%) as a yellow solid. LCMS: 405.1 [M+H]+.

[0263] Step B

[0264] Compound 18b (67 mg, 0.37 mmol), compound 18a (50 mg, 0.12 mmol), XPhos Pd G2 (9.7 mg, 0.012 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg, 0.037 mmol) and cesium carbonate (80 mg, 0.25 mmol) were added sequentially to dioxane (10 mL) and stirred at 90 °C for 16 hours under nitrogen protection. After completion of the reaction, the reaction was monitored by LCMS and concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 18 (5.0 mg, 6.96%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.26(s,1H),8.82–8.79(m,1H),8.67(s,1H),8.46(s,1H),7.96–7.91(m,2H) ,7.23–7.21(m,1H),7.16–7.12(m,1H),6.89–6.79(m,2H),6.24–6.19(m,1H) ,5.78–5.76(m,1H),5.37(d,J=4.0Hz,1H),4.10–4.07(m,1H),3.67–3.62(m, 1H),2.24(s,3H),1.93–1.76(m,4H),1.64–1.59(m,2H).LCMS:551.0[M+H]+.

[0265] Example 19: Synthesis of Compound 19

[0266] Step A

[0267] Compound 19a (67 mg, 0.37 mmol), compound 18a (50 mg, 0.12 mmol), XPhos Pd G2 (9.7 mg, 0.012 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg, 0.037 mmol) and cesium carbonate (80 mg, 0.25 mmol) were added sequentially to dioxane (10 mL) and stirred at 90 °C for 16 hours under nitrogen protection. After completion of the reaction, the reaction was monitored by LCMS and concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL × 2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 19 (3.5 mg, 4.88%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.29(s,1H),8.85–8.80(m,1H),8.69(s,1H),8.49–8.25(m,1H),7.24(d,J =8.4Hz,1H),7.17(d,J=7.6Hz,1H),6.92–6.85(m,2H),6.27–6.22(m,1H),5 .81–5.78(m,1H),5.40(d,J=4.0Hz,1H),4.13–4.09(m,1H),3.70–3.64(m,1 H),2.27(s,3H),1.86–1.78(m,4H),1.67–1.61(m,2H).LCMS:551.0[M+H]+.

[0268] Example 20: Synthesis of Compound 20

[0269] Compound 20a (150 mg, crude), compound 1g (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (71.7 mg, 0.55 mmol) were added sequentially to 1,4-dioxane (6 mL) and stirred at 70°C for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (30-50%) as eluents) to afford Compound 20 (4.8 mg, 5.0%) as a yellow solid. 1H NMR (400MHz, CD3OD): δppm 8.98(s,1H),8.69(d,J=7.6Hz,1H),8.47(s,1H),8.27(s,1H),7.83–7.77(m ,2H),7.15(d,J=8.4Hz,1H),7.02(dd,J=7.2,1.5Hz,1H),6.73(s,1H),6.22 6.16(m,2H),5.72–5.60(m,1H),5.19–4.98(m,1H),4.73–4.65(m,1H),4.42–4.3 8(m,2H),4.18–3.86(m,1H),3.50–3.31(m,4H),2.17(s,3H).LCMS:521.0[M+H]+.

[0270] Example 21: Synthesis of Compound 21

[0271] Compound 21a (35 mg, 0.23 mmol), compound 1g (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (45 mg, 0.35 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 48 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 21 (7 mg, 12.23%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.02(s,1H),8.73(d,J=7.2Hz,1H),8.44(s,1H),8.28(s,1H),7.94–7.91( m,2H),7.13(d,J=8.8Hz,1H),7.08–7.05(m,1H),6.79–6.78(m,1H),6.51– 6.25(m,2H),5.82–5.72(m,1H),5.41–5.06(m,2H),4.59–4.38(m,2H),3.9 9–3.69(m,2H),2.59–2.41(m,1H),2.34–2.13(m,4H).LCMS:521.0[M+H]+.

[0272] Example 22: Synthesis of Compound 22

[0273] Compound 22a (35 mg, 0.23 mmol), compound 1g (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (60 mg, 0.46 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 48 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 22 (7 mg, 12.23%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.03(s,1H),8.74(d,J=7.2Hz,1H),8.45(s,1H),8.28(s,1H),7.95–7.91( m,2H),7.19(d,J=8.4Hz,1H),7.08–7.06(m,1H),6.79–6.78(m,1H),6.51– 6.28(m,2H),5.81–5.72(m,1H),5.41–5.11(m,2H),4.59–4.39(m,2H),3.9 9–3.69(m,2H),2.59–2.54(m,1H),2.41–2.17(m,4H).LCMS:521.0[M+H]+.

[0274] Example 23: Synthesis of Compound 23

[0275] Compound 23a (35 mg, crude), compound 1g (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (71 mg, 0.55 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (10-40%) as eluents, to afford Compound 23 (4.0 mg, 7.0%) as a yellow solid. 1H NMR(400MHz,MeOD)δppm 9.04(s,1H),8.74(d,J=7.6Hz,1H),8.43(s,1H),8.28(s,1H),7.98–7.88 (m,2H),7.19(d,J=8.6Hz,1H),7.07(dd,J=7.6,2.4Hz,1H),6.80–6.62(m, 2H),6.39–6.28(m,1H),5.88–5.78(m,1H),4.26(s,1H),4.01–3.90(m,1H ),3.70–3.50(m,2H),2.58–2.05(m,8H),1.28(s,1H).LCMS:535.0[M+H]+.

[0276] Example 24: Synthesis of Compound 24

[0277] Compound 24a (35 mg, crude), compound 1g (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (71 mg, 0.55 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (10-40%) as eluents to afford Compound 24 (4.0 mg, 7.0%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 9.05(s,1H),8.74(d,J=7.6Hz,1H),8.45(s,1H),8.29(s,1H),7.97–7.87(m,2H ),7.20(d,J=8.6Hz,1H),7.07(dd,J=7.6,2.4Hz,1H),6.79(t,J=4.2Hz,1H),6. 76–6.62(m,1H),6.39–6.28(m,1H),5.85–5.76(m,1H),4.77(m,1H),4.27(s,1H ),4.00–3.90(m,1H),3.65–3.45(m,2H),2.54–2.07(m,8H).LCMS:535.0[M+H]+.

[0278] Example 25: Synthesis of Compound 25

[0279] Compound 23a (35 mg, crude), compound 16e (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (71 mg, 0.55 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (10-40%) as eluents to afford Compound 25 (4.0 mg, 7.0%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 8.99(s,1H),8.37(s,1H),8.18(s,1H),7.80(s,1H),7.72(d,J=8.6Hz,1H),7 .56(d,J=8.6Hz,1H),7.14–7.05(m,2H),6.90(d,J=8.8Hz,1H),6.78–6.63(m ,1H),6.38–6.27(m,1H),5.84–5.73(m,1H),4.77(m,1H),4.28–4.21(m,1H), 4.01–3.92(m,4H),3.68–3.50(m,2H),2.57–2.04(m,8H).LCMS:548.1[M+H]+.

[0280] Example 26: Synthesis of Compound 26

[0281] Compound 24a (35 mg, crude), compound 16e (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (71 mg, 0.55 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (10-40%) as eluents to afford compound 26 (4.4 mg, 7.2%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 9.04(d,J=2.2Hz,1H),8.88(d,J=5.4Hz,1H),8.41(s,1H),7.86(s,1H),7.80(dd,J=12. 6,6.0Hz,2H),7.28(d,J=8.8Hz,1H),7.16(d,J=2.2Hz,1H),7.02(d,J=8.8Hz,1H),6.70 –6.55(m,1H),6.35–6.28(m,1H),5.80–5.65(m,1H),4.77(m,1H),4.31–4.23(m,1H),4. 05(s,3H),3.97–3.89(m,1H),3.68–3.55(m,2H),2.55–2.25(m,8H).LCMS:548.0[M+H]+.

[0282] Example 27: Synthesis of Compound 27

[0283] Compound 16e (80 mg, 0.18 mmol), compound 7c (50 mg, crude), and N,N-diisopropylethylamine (120 mg, 0.93 mmol) were added sequentially to 1,4-dioxane (10 mL) and stirred at 70°C for 4 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Xbridge-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.05% TFA) and MeCN (20-60%) as eluents to afford Compound 27 (4.3 mg, 4.49%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.94–8.36(m,1H),8.46–8.38(m,1H),8.34–8.28(m,1H),7.73(d,J=2.4Hz,1H),7.66(dd,J=8.4,2 .4Hz,1H),7.57(dd,J=8.8,3.2Hz,1H),7.11–7.07(m,1H),7.04(d,J=2.0Hz,1H),6.86(d,J=8.8Hz ,1H),6.35–6.07(m,2H),5.70–5.62(m,1H),4.89(d,J=10Hz,1H),4.29(d,J=10.4Hz,2H),4.14(t, J=7.4Hz,2H),3.89(s,3H),2.63–2.51(m,2H),2.18(s,3H),1.23–1.19(m,2H).LCMS:534.2[M+H]+.

[0284] Example 28: Synthesis of Compound 28

[0285] Compound 1g (80 mg, 0.18 mmol), compound 28a (100 mg, crude), and N,N-diisopropylethylamine (120 mg, 0.93 mmol) were added sequentially to 1,4-dioxane (10 mL) and stirred at 70°C for 4 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Xbridge-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (25-50%) as eluents to afford compound 28 (4.3 mg, 4.49%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.00(s,1H),8.72(d,J=7.6Hz,1H),8.41(s,1H),8.26(s,1H),7.95–7.87(m,2 H),7.17(d,J=8.8Hz,1H),7.07–7.02(m,1H),6.7-6.15(m,1H),6.31–6.21(m,2 H),5.08–5.66(m,1H),5.34–5.02(m,1H),4.73(d,J=13.2Hz,1H),4.58–4.42( m,2H),4.00–3.66(m,1H),3.54–3.40(m,3H),2.23(m,4H).LCMS:521.0[M+H]+.

[0286] Example 29: Synthesis of Compound 29

[0287] Compound 29a (98 mg, 0.65 mmol), compound 1g (100 mg, 0.23 mmol), and N,N-diisopropylethylamine (150 mg, 1.15 mmol) were added sequentially to 1,4-dioxane (10 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (25-55%) as eluents, to afford Compound 29 (55 mg, 45.9%) as a yellow solid. NMR (400MHz, CD3OD): δppm8.96(s,1H),8.75(s,1H),8.42–8.32(m,2H),7.89–7.87(m, 2H),7.15(d,J=8.4Hz,1H),7.03(d,J=7.6Hz,1H),6.77–6.57(m,2H),6.35–6.29(m,1H) ,5.79(d,J=10.4Hz,1H),5.34–5.22(m,1H),4.50–4.44(m,1H),4.27–4.19(m,1H),3.9 0–3.36(m,2H),2.60–2.51(m,1H),2.21(s,3H),2.15–1.99(m,2H).LCMS:521.0[M+H]+.

[0288] Example 30: Synthesis of Compound 30

[0289] Compound 30a (98 mg, 0.65 mmol), compound 1g (100 mg, 0.23 mmol), and N,N-diisopropylethylamine (150 mg, 1.15 mmol) were added sequentially to 1,4-dioxane (10 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 30 (45 mg, 37.6%) as a yellow solid. NMR (400MHz, CD3OD): δppm8.96(s,1H),8.74(s,1H),8.42–8.31(m,2H),7.89–7.87(m, 2H),7.15(d,J=8.4Hz,1H),7.03(d,J=7.6Hz,1H),6.77–6.56(m,2H),6.35–6.29(m,1H) ,5.79(d,J=10.4Hz,1H),5.34–5.22(m,1H),4.50–4.44(m,1H),4.26–4.19(m,1H),3.9 3–3.36(m,2H),2.61–2.51(m,1H),2.21(s,3H),2.16–1.99(m,2H).LCMS:521.0[M+H]+.

[0290] Example 31: Synthesis of Compound 31

[0291] Compound 22a (40 mg, 0.27 mmol), compound 16e (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (72 mg, 0.56 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 48 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford compound 31 (12 mg, 20.46%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.95(s,1H),8.35(s,1H),8.07(s,1H),7.77(s,1H),7.68(d,J=8.4Hz,1H),7 .50(d,J=8.8Hz,1H),7.09–7.04(m,2H),6.85(d,J=8.4Hz,1H),6.50–6.21(m ,2H),5.78–5.68(m,1H),5.35–5.04(m,2H),4.55–4.35(m,2H),3.95–3.65(m ,5H),2.55–2.49(m,1H),2.27(s,3H),2.15–2.11(m,1H).LCMS:534.0[M+H]+.

[0292] Example 32: Synthesis of Compound 32

[0293] Compound 21a (35 mg, 0.22 mmol), compound 16e (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (72 mg, 0.56 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 48 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (25-55%) as eluents) to afford Compound 32 (9 mg, 15.35%) as a yellow solid. 1H NMR (400MHz, CD3OD): δppm 8.98(s,1H),8.38(s,1H),8.15(s,1H),7.79(s,1H),7.72–7.69(m,1H),7.56(s,1H),6.8-7.2(m,3H),6.49–6.24(m,2H),5.81–5.71(m ,1H),5.38–5.08(m,2H),4.58–4.36(m,2H),3.97–3.68(m,5H),2.57–2.52(m,1H),2.29(s,3H),2.19–2.17(m,1H).LCMS:534.1[M+H]+.

[0294] Example 33: Synthesis of Compound 33

[0295] Compound 20a (150 mg, crude), compound 16e (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (70 mg, 0.54 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (10-40%) as eluents to afford compound 33 (6.2 mg, 6.5%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.98(s,1H),8.37(s,1H),8.1(s,1H),7.80–7.79(m,1H),7.74–7.69(m,1H),7.54(d ,J=8.8Hz,1H),7.12(s,1H),7.09–7.06(m,1H),6.88(d,J=8.8Hz,1H),6.31–6.21(m ,2H),5.81–5.68(m,1H),5.26–5.06(m,1H),4.73–4.64(m,1H),4.54–4.45(m,2H),4 .26–3.96(m,1H),3.90(s,3H),3.53–3.36(m,3H),2.29(s,3H).LCMS:534.2[M+H]+.

[0296] Example 34: Synthesis of Compound 34

[0297] Compound 28a (100 mg, crude), compound 16e (80 mg, 0.18 mmol), and N,N-diisopropylethylamine (75 mg, 0.58 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (15-40%) as eluents to afford compound 34 (3.6 mg, 3.76%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.02(s,1H),8.64(d,J=7.6Hz,1H),8.40(s,1H),8.0–7.6(m,4H),7.22(d,J=9 .2Hz,1H),7.15(s,1H),6.98(d,J=8.8Hz,1H),6.34–6.25(m,2H),5.82–5.69( m,1H),5.36–5.23(m,1H),4.77–4.66(m,1H),4.60–4.42(m,2H),4.28–4.20(m ,1H),4.04–3.95(m,3H),3.56–3.39(m,3H),2.29(s,3H).LCMS:534.2[M+H]+.

[0298] Example 35: Synthesis of Compound 35

[0299] Compound 29a (102 mg, 0.67 mmol), compound 16e (100 mg, 0.22 mmol), and N,N-diisopropylethylamine (145 mg, 1.12 mmol) were added sequentially to 1,4-dioxane (10 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (25-55%) as eluents) to afford compound 35 (60 mg, 51.1%) as a yellow solid. NMR (400MHz, MeOD) δppm8.99(d,J=3.0Hz,1H),8.57(s,1H),8.40(d,J=3.1Hz,1H),7.82(s,1H),7.75(d,J=8. 9Hz,1H),7.68(d,J=8.9Hz,1H),7.19(d,J=8.9Hz,1H),7.14(s,1H),6.95(d,J=8.7Hz,1H),6.78–6.59(m,1H) ,6.37–6.32(m,1H),5.81(d,J=10.6Hz,1H),5.36–5.24(m,1H),4.54–4.44(m,1H),4.32–4.19(m,1H),3.99(s ,3H),3.95–3.90(m,1H),3.76–3.63(m,1H),2.58(s,1H),2.28(s,3H),2.24–1.96(m,2H).LCMS:534.0[M+H]+.

[0300] Example 36: Synthesis of Compound 36

[0301] Compound 30a (102 mg, 0.67 mmol), compound 16e (100 mg, 0.22 mmol), and N,N-diisopropylethylamine (145 mg, 1.12 mmol) were added sequentially to 1,4-dioxane (10 mL) and stirred at 70°C for 6 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (25-55%) as eluents) to afford compound 36 (53 mg, 45.1%) as a yellow solid. NMR (400MHz, MeOD) δppm8.99(d,J=3.0Hz,1H),8.57(s,1H),8.40(d,J=3.1Hz,1H),7.82(s,1H),7.75(d,J=8. 9Hz,1H),7.68(d,J=8.9Hz,1H),7.19(d,J=8.9Hz,1H),7.14(s,1H),6.95(d,J=8.7Hz,1H),6.78–6.59(m,1H) ,6.37–6.32(m,1H),5.81(d,J=10.6Hz,1H),5.36–5.24(m,1H),4.54–4.44(m,1H),4.32–4.19(m,1H),3.99(s ,3H),3.95–3.90(m,1H),3.76–3.63(m,1H),2.58(s,1H),2.28(s,3H),2.24–1.96(m,2H).LCMS:534.0[M+H]+.

[0302] Example 37: Synthesis of Compound 37

[0303] Compound 37a (10 mg, 0.59 mmol), compound 18a (40 mg, 0.1 mmol), XPhos Pd G2 (8 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.03 mmol), and cesium carbonate (64 mg, 0.2 mmol) were added sequentially to dioxane (10 mL) and stirred at 90°C under nitrogen for 16 hours. LCMS monitoring was used. After completion, the reaction was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 37 (10 mg, 8.1%) as a yellow solid. 1H NMR (400MHz, CD3OD): δppm 9.29(s,1H),8.84–8.82(m,2H),8.70–8.58(m,1H),8.47(s,1H),7.98–7.93( m,2H),7.25–7.23(m,1H),7.18–7.16(m,1H),6.88–6.81(m,1H),6.75–6.69(m ,1H),6.33–6.29(m,1H),5.82–5.79(m,1H),4.91–4.81(m,1H),3.88–3.78(m ,2H),2.39–2.37(m,1H),2.28(s,3H),2.20–2.03(m,3H).LCMS:537.0[M+H]+.

[0304] Example 38: Synthesis of Compound 38

[0305] Compound 38a (50 mg, 0.3 mmol), compound 18a (40 mg, 0.1 mmol), XPhos Pd G2 (8 mg, 0.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.03 mmol), and cesium carbonate (64 mg, 0.2 mmol) were added sequentially to dioxane (10 mL) and stirred at 90°C under nitrogen for 16 hours. LCMS monitoring was performed. After completion, the reaction was concentrated under reduced pressure. The residue was diluted with ethyl acetate (30 mL), washed with water (20 mL x 2), washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 38 (5 mg, 8.1%) as a yellow solid. 1H NMR (400MHz, CD3OD): δppm 9.26(s,1H),8.78(d,J=7.6Hz,1H),8.66(s,1H),8.37(s,1H),7.99–7.93(m, 2H),7.21(d,J=8.4Hz,1H),7.12–7.10(m,1H),6.84(d,J=2.0Hz,1H),6.75–6 .69(m,1H),6.28(m,1H),5.82–5.79(m,1H),4.88–4.81(m,1H),3.88–3.77(m ,2H),2.39–2.34(m,1H),2.26(s,3H),2.19–2.09(m,3H).LCMS:537.0[M+H]+.

[0306] Example 39: Synthesis of Compound 39

[0307] Compound 39a (40 mg, 0.23 mmol), compound 1g (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (60 mg, 0.46 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 16 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 39 (10 mg, 17.02%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.98(s,1H),8.74(d,J=8.0Hz,1H),8.40(s,1H),8.28(s,1H),8.14(s,1H), 7.95–7.91(m,1H),7.19(d,J=8.0Hz,1H),7.07–7.06(m,1H),6.80–6.79(m,1 H),6.15–6.07(m,2H),5.69–5.21(m,3H),4.32–4.28(m,2H),3.94–3.64(m, 3H),3.13–3.10(m,1H),2.17–2.14(m,4H),2.03(s,1H).LCMS:535.0[M+H]+.

[0308] Example 40: Synthesis of Compound 40

[0309] Compound 39a (40 mg, 0.23 mmol), compound 16e (50 mg, 0.11 mmol), and N,N-diisopropylethylamine (60 mg, 0.46 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and separated by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length), using water (0.1% TFA) and MeCN (25-55%) as eluents) to afford Compound 40 (11 mg, 18.25%) as a yellow solid. 1H NMR (400MHz, CD3OD): δppm 8.96(s,1H),8.46–8.43(m,1H),8.35(s,1H),8.08–8.07(m,1H),7.83– 7.63(m,2H),7.18–7.14(m,2H),6.96–6.94(m,1H),6.21–6.07(m,2H), 5.68–5.19(m,3H),4.31–4.02(m,3H),3.97(s,3H),3.80–3.63(m,2H), 3.13–3.09(m,1H),2.33–2.23(m,4H),2.03(s,1H).LCMS:548.0[M+H]+.

[0310] Example 41: Synthesis of Compound 41

[0311] Compound 41a (20 mg, 0.12 mmol), compound 1g (30 mg, 0.07 mmol), and N,N-diisopropylethylamine (27 mg, 0.21 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 16 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford Compound 41 (4 mg, 10.7%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.13–8.99(m,1H),8.84–8.82(m,1H),8.62(s,1H),8.45(s,1H),8.11–8.07(m,1H),7.91–7 .86(m,1H),7.29(d,J=8.4Hz,1H),7.18(s,1H),6.87(s,1H),6.18–6.04(m,2H),5.64–5.55 (m,1H),5.40–5.20(m,1H),4.81–4.78(m,1H),4.35–4.23(m,3H),4.16–3.84(m,1H),3.75– 3.67(m,1H),3.15–3.04(m,1H),2.34–2.23(m,4H),2.09–2.03(m,1H).LCMS:535.0[M+H]+.

[0312] Example 42: Synthesis of Compound 42

[0313] Compound 41a (20 mg, 0.12 mmol), compound 16e (30 mg, 0.07 mmol), and N,N-diisopropylethylamine (27 mg, 0.21 mmol) were added sequentially to 1,4-dioxane (5 mL) and stirred at 70°C for 16 hours. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and separated by preparative HPLC using a Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using water (0.1% TFA) and MeCN (25-55%) as eluents to afford compound 42 (5 mg, 13.05%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ ppm 9.31(s,1H),9.08–8.97(m,1H),8.57–8.55(m,1H),8.06–7.98(m,1H),7.92–7.91(m,1H),7.86–7. 79(m,1H),7.39(d,J=8.8Hz,1H),7.26(s,1H),7.10(d,J=8.8Hz,1H),6.17–6.04(m,2H),5.64–5.5 4(m,1H),5.39–5.18(m,2H),4.90–4.78(m,1H),4.35–4.31(m,2H),4.14(s,3H),3.90–3.84(m,1H) ,3.69–3.66(m,1H),3.14–3.09(m,1H),2.33–2.26(m,4H),2.09–2.03(m,1H).LCMS:548.0[M+H]+.

[0314] B. Test Examples

[0315] 1 Experimental Purpose

[0316] This experiment used the CellTiter-Glo (CTG) kit provided by Promega, a homogenous cell viability assay that measures cell viability in cultured cells by quantifying ATP. The goal of this experiment was to use the CTG assay to evaluate the effects of test compounds on cell proliferation in the BAF3-HER2 cell line.

[0317] 2 Experimental materials and equipment

[0318] 2.1 Experimental Reagents and Consumables

[0319] 2.2 Experimental instruments and equipment

[0320] 3 Experimental methods

[0321] 3.1 Cell culture

[0322] 1) Cell lines: Ba / F3-HER2WT, Ba / F3-HER2A775_G776ins YVMA clone#5, Ba / F3-EGFR WT

[0323] 2) Complete culture medium: RPMI 1640 + 10% fetal bovine serum + 1X penicillin-streptomycin, RPMI 1640 + 10% fetal bovine serum + 1X penicillin-streptomycin + 2 μg / mL puromycin, RPMI 1640 + 10% fetal bovine serum + 1X penicillin-streptomycin + 100 ng / mL EGF

[0324] 3) Cell inoculation medium: RPMI 1640 + 10% fetal bovine serum + 1X penicillin-streptomycin, RPMI 1640 + 10% fetal bovine serum + 1X penicillin-streptomycin, RPMI 1640 + 10% fetal bovine serum + 1X penicillin-streptomycin + 100 ng / mL EGF

[0325] 3.2. Proliferation assay of HER2 and EGFR wild-type and mutant cell lines

[0326] 1) Ba / F3-HER2WT, Ba / F3-HER2_A775_G776ins YVMA clone#5 & Ba / F3-EGFR WT cell lines were cultured in complete medium at 37°C and 5% CO2.

[0327] 2) Dilute the reference compound stock solution and the test compound stock solution to 1 mM, and then perform 3-fold serial dilutions, 10 doses, two replicates, and set aside.

[0328] 3) Then, use Echo to transfer 30 nL of each serially diluted compound to a 384-well cell plate and centrifuge at 200 g for 3-5 seconds at room temperature.

[0329] 4) Collect the cells, resuspend them in inoculation medium, and inoculate them into the corresponding experimental wells of a 384-well cell culture plate. For HER2WT and HER2A775_G776ins YVMA, 30 μL is inoculated per well for a total of 600 cells, and for EGFRWT, 30 μL is inoculated per well for a total of 800 cells.

[0330] 5) The cell culture plate was then incubated at 37°C for 72 hours.

[0331] 6) Prepare CTG detection reagent working solution and set aside.

[0332] 7) After incubation, the cell culture plate was equilibrated to room temperature, and then 30 μL of CTG reagent was added to all experimental wells of the cell plate.

[0333] 8) Place the cell culture plate on a shaker for 3 minutes, and then place it in the dark at room temperature for 30 minutes.

[0334] 9) Use Envision to read the chemiluminescence signal value and collect data.

[0335] Data analysis

[0336] 1)Z'factor=1-3*(SDMax+SDMin) / (MeanMax-MeanMin)

[0337] 2)Z'factor=1-3*(SDMax+SDMin) / (MeanMax-MeanMin)

[0338] 3)CVMax=(SDMax / MeanMax)*100%

[0339] 4)CVMin=(SDMin / MeanMin)*100%

[0340] 5) Experimental window = signal value / background value

[0341] 6) Negative control: 0.1% DMSO

[0342] 7) Positive control: 1,000 nM neratinib

[0343] 8) Calculate the compound IC50 using the GraphPad nonlinear fitting formula:

[0344] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0345] X: log value of compound concentration; Y: percentage of inhibition rate

[0346] 9) Inhibition (%) = (1-(Cpd-MeanMin) / (MeanMax-MeanMin))×100%

[0347] 100% inhibition rate: 1,000 nM neratinib; 0% inhibition rate: 0.1% DMSO

[0348] 4 IC50 values ​​of compounds

[0349] In the table, NA means not tested.

[0350] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is as shown in Formula I, in, Q 1 -CONR'-, Q 2 is a 4-6 membered monocyclic heterocyclic group containing one ring nitrogen atom; or, -Q 1 -Q 2 - represents a fused ring or spiro ring formed by two identical or different 4-6 membered monocyclic heterocyclic groups containing one ring nitrogen atom; and the 4-6 membered monocyclic heterocyclic group is optionally substituted by one or more R' groups; wherein R' is independently H or C 1-2 alkyl; R 1 Selected from the group consisting of H, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, C 1-4 alkoxy, and halogen; R 2 Selected from the group consisting of H, substituted or unsubstituted C 1-4 Alkyl, and halogen; R 3 Select from the following groups: R 4 for R 5 is H or substituted or unsubstituted C 1-4 alkyl; R 6 Selected from the group consisting of H, substituted or unsubstituted C 1-4 Alkyl, -C 1-2 Alkylene-N(R")2; wherein R" is H or C 1-4 alkyl; Unless otherwise specified, the substitution refers to the substitution of one or more (such as 1, 2 or 3) H atoms in the group by a substituent selected from the group consisting of deuterium (D), halogen, C1-4 alkyl, and C1-4 haloalkyl.

2. The compound according to claim 1, wherein The compound is shown in Formula Ia in, represents a single bond or a double bond; W 1 for -(CR'2) n1 -, W 2 for -(CR'2) n2 -; wherein subscript n1=0, 1 or 2, subscript n2=0, 1 or 2, and n1+n2≥1; W 3 for -(CR'2) n3 -, W 4 for -(CR'2) n4 -; wherein subscript n3=0, 1 or 2, subscript n4=0, 1 or 2, and n3+n4≥1; R 1 、R 2 、R 3 、R 4 and R' is as defined in claim 1.

3. The compound according to claim 1, wherein -Q 2 -Q 1 -for 4. The compound according to claim 1, wherein The compound is shown in Formula Ib in, W 5 for -(CR'2) n5 -, W 6 for -(CR'2) n6 -; wherein subscript n5=0, 1, 2 or 3, subscript n6=0, 1, 2 or 3, and 2≤n5+n6≤4; W 7 for -(CR'2) n7 -, W 8 for -(CR'2) n8 -; wherein subscript n7=0, 1, 2 or 3, subscript n8=0, 1, 2 or 3, and 2≤n7+n8≤4; R 1 、R 2 、R 3 、R 4 and R' is as defined in claim 1.

5. The compound according to claim 1, wherein n5=n6=1 or 2.

6. The compound according to claim 1, wherein The compound is shown in formula Ic in, W 9 for -(CR'2) n9 -; wherein subscript n9=1, 2 or 3; R 1 、R 2 、R 3 、R 4 and R' is as defined in claim 1.

7. The compound according to claim 1, wherein R 1 is substituted or unsubstituted C 1-4 Alkyl; and / or, R 2 Selected from the group consisting of H, methyl, and ethyl.

8. The compound according to claim 1, wherein The compound is selected from Table A, Table B and Table C: Table A Table B Table C 9. A pharmaceutical composition, characterized in that include: (i) the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient.

10. Use of the compound of claim 1 in the preparation of a medicament for treating or preventing a disease or condition, wherein the disease or condition is a disease or condition mediated by HER2, or a disease or condition that can be ameliorated by inhibiting HER2.

11. The use according to claim 10, characterized in that The diseases or conditions include cancer.

12. The use according to claim 10, characterized in that The disease or condition includes one or more of brain cancer, breast cancer, gallbladder cancer, bladder cancer, cervical cancer, colorectal cancer, stomach cancer, gastroesophageal junction cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, astrocytic intestinal cancer, bile duct cancer, kidney cancer, liver cancer, ovarian cancer, pancreatic cancer, lung cancer or prostate cancer.

13. A method for inhibiting HER2, comprising: Contacting a subject with the compound of claim 1, thereby inhibiting HER2, wherein the method is non-therapeutic in vitro.

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