Arylamide compound, pharmaceutical composition containing same, preparation method and use thereof

Abstract

#imgabs0#The present invention relates to an arylamide compound of formula (I′), a pharmaceutical composition comprising the same, a method for preparing the same, and use thereof in preventing or treating tumor-related diseases or conditions.

Description

Technical Field

[0001] The present invention relates to arylamide compounds, pharmaceutical compositions comprising the same, methods for their preparation, and their use in preventing or treating diseases or conditions associated with RAF and / or RAS kinase activity. Background Art

[0002] Protein kinases are enzymes that catalyze protein phosphorylation reactions. By mediating cell signaling, protein phosphorylation regulates cellular physiological activities, such as cell survival, proliferation, differentiation, apoptosis, and metabolism. Dysfunction of protein kinases is closely associated with numerous diseases, including tumors, autoimmune diseases, inflammatory responses, central nervous system disorders, cardiovascular disease, and diabetes.

[0003] RAF belongs to ATP kinase and is an important component of the RAS-RAF-MEK signaling pathway. It is divided into three subtypes, A, B, and C, with high homology and similar domains. RAF exists in the cytoplasm as an inactive monomer. After being stimulated by upstream growth factors, RAS changes from an inactive conformation (GDP binding) to an active conformation (GTP binding), thereby recruiting intracellular RAF to the cell membrane and promoting its dimerization and phosphorylation. The activated RAF phosphorylates and activates MEK and ERK in turn, ultimately regulating cell proliferation, differentiation, apoptosis, and metastasis (Karoulia Z et al., Nat Rev Cancer. 2017 Nov; 17 (11): 676-691). Mutated B-RAF can continuously activate the MAPK signaling pathway in the form of monomers (V600 mutation) or dimers (non-V600 mutations) independent of RAS. RAF inhibitors inhibit the RAS-RAF-MEK signaling pathway by suppressing the activity of RAF monomers and dimers. They are used to treat tumors with RAS or RAF mutations, accounting for approximately one-third of cancer patients. Applicable tumor types mainly include melanoma, NSCLC, CRC, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, and others.

[0004] αC-OUT RAF inhibitors, such as Vemurafenib, can effectively inhibit the kinase activity of BRAF with V600 point mutations. However, αC-OUT inhibitors are ineffective in inhibiting RAF activation in tumors driven by RAS mutations, wild-type B-RAF, and non-V600 point mutations, and drug resistance has emerged after clinical use. Summary of the Invention

[0005] The present invention provides novel arylamide compounds that exhibit potent inhibitory effects on RAF and / or RAS kinases and possess favorable pharmacokinetic and other properties. These compounds can inhibit RAF dimer activity, overcome the dimer resistance mechanism induced by existing RAF inhibitors, and reduce the toxicity of paradoxical ERK activation. They are therefore suitable for the treatment of tumors harboring RAS or RAF mutations.

[0006] One aspect of the present invention provides a compound of Formula I' or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof:

[0007]

[0008] in:

[0009] Ring A is selected from a benzene ring and a 5-6 membered heteroaromatic ring;

[0010] Ring B is selected from C 6-10 aromatic rings, 5-10 membered heteroaromatic rings and 4-10 membered heterocyclic rings;

[0011] X 1 and X 2 are each independently selected from C and N;

[0012] X 3 and X 4 are each independently selected from CH and N;

[0013] Y is selected from -O-, -NH-, -C(=O)-, -CR 5 R 6 -、-CR 5 R 6 O-and-CR 5 R 6 NH-; provided that, when ring A is a thiophene ring, Y is not -O- or -NH-;

[0014] R 1 Selected from H, C 1-6 Alkyl and C 3-6 cycloalkyl, said alkyl and cycloalkyl are each optionally substituted with one or more halogens;

[0015] R 2 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, said alkyl and alkoxy are each optionally substituted with one or more halogens;

[0016] R 3 For LR 3 ';

[0017] L is independently a direct bond or -(CH2) n -;

[0018] R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl and 4-10 membered heterocyclic group; or when L is a direct bond and m is greater than 1, two R 3 'Together with the group to which it is connected, it forms a 4-10 membered heterocyclic ring;

[0019] R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NH2, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups;

[0020] R 5 and R 6 Each independently selected from H, hydroxy, halogen, -NH2, -NHCH3, -N(CH3)2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy), C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy and 4-10 membered heterocyclic group, or R 5 With R 6 Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy and heterocyclyl groups is optionally substituted with one or more halogens;

[0021] R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R25b Each independently selected from H, OH, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; said alkyl, alkoxy, cycloalkyl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and 4-10 membered heterocyclic group;

[0022] R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl and heterocyclyl being each optionally substituted with one or more halogens;

[0023] m is 0, 1, 2, 3, 4 or 5;

[0024] n is 1 or 2; and

[0025] p is 0, 1, 2 or 3.

[0026] Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof and one or more pharmaceutically acceptable carriers.

[0027] Another aspect of the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a disease or condition associated with RAF and / or RAS kinase activity.

[0028] Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention for use in preventing or treating a disease or condition associated with RAF and / or RAS kinase activity.

[0029] Another aspect of the present invention provides a method for preventing or treating a disease or condition associated with RAF and / or RAS kinase activity, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention.

[0030] Another aspect of the present invention provides methods of preparing the compounds of the present invention.

[0031] definition

[0032] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0033] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps, even though the additional unrecited elements or method steps are not necessarily present (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of.").

[0034] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 Alkyl" and "C 1-4 "Alkyl" refers to a linear or branched group having 1 to 6 carbon atoms and 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0035] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more backbone atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, in the backbone carbon atoms of the alkyl group. Numerical ranges (e.g., C 1-6 Assorted alkyl) refers to the number of carbons in the chain, which in this example includes 1-6 carbon atoms. For example, a -CH2OCH2CH3 group is referred to as a C3 assorted alkyl. Connection to the rest of the molecule can be through heteroatoms or carbon atoms in the assorted alkyl chain.

[0036] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-8 Halogenated alkyl, "C 1-6 Haloalkyl" and "C 1-4 The term "haloalkyl" refers to a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0037] As used herein, the term "hydroxyalkyl" refers to a group in which a hydrogen atom in an alkyl group is replaced by one or more hydroxyl groups, for example, C 1-4 Hydroxyalkyl or C 1-3 Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, and the like.

[0038] As used herein, the term "alkoxy" refers to a group having an oxygen atom inserted into an alkyl group (as defined above) at any reasonable position, preferably a C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH2-OCH3, and the like, wherein the alkoxy groups are optionally substituted with one or more (such as 1 to 3) identical or different substituents. For example, the term "haloalkoxy" refers to an alkoxy group wherein the hydrogen atoms are substituted with one or more (such as 1 to 3) identical or different halogen atoms.

[0039] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group containing one or more double bonds, such as "C 2-6"Alkenyl" is an alkenyl radical having 2 to 6 carbon atoms. Such alkenyl radicals are, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds according to the invention contain an alkenyl radical, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0040] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0041] As used herein, the term "paracyclic" or "fused ring" refers to a ring system formed by two or more cyclic structures that share two adjacent atoms.

[0042] As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.

[0043] As used herein, the term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other.

[0044] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including but not limited to monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl, including spirocyclic, annular (condensed) or bridged ring systems (i.e., spirocyclic alkyl, annular (condensed) alkyl and bridged cycloalkyl, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.). In the present invention, cycloalkyl is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl are optionally substituted with oxo (oxo) groups (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 ring carbon atoms, such as C 3-6 Cycloalkyl, which may be a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic alkyl, such as C 5-8 Spiroalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Condensed cycloalkyl, C 5-6 Spiroalkyl, C5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl.

[0045] As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined above. Representative examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0046] As used herein, the term "heterocyclyl" or "heterocycle" refers to an aliphatic monocyclic or polycyclic (e.g., cyclic, spirocyclic or bridged) group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms, including but not limited to oxygen atoms, nitrogen atoms and sulfur atoms, wherein the carbon atoms and heteroatoms on the heterocyclyl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or are optionally substituted with one or more (e.g., 1 to 3) independently selected from halogen and C 1-3 The alkyl group is substituted with a substituent.

[0047] As used herein, the term "4-11 membered heterocyclyl" means a heterocyclyl containing 4-11 ring atoms, including but not limited to 4-10 membered heterocyclyl, 4-9 membered heterocyclyl, 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 4-7 membered nitrogen-containing heterocyclyl, 4-7 membered oxygen-containing heterocyclyl, 4-7 membered sulfur-containing heterocyclyl, 5-6 membered nitrogen-containing heterocyclyl, 5-6 membered oxygen-containing heterocyclyl, 5-6 membered sulfur-containing heterocyclyl, etc., wherein the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 4-11 membered heterocyclyls include but are not limited to oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (such as ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl.

[0048] In the present invention, the heterocyclic group can form a parallel ring structure with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other groups can be on any heterocyclic group or cycloalkyl group. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic and heterocyclic groups, heterocyclic and cycloalkyl groups, monoheterocyclic and monoheterocyclic groups, and monoheterocyclic and monocycloalkyl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and (mono) cycloalkyl groups, 3-7 membered (mono) heterocyclic groups and C 4-6(Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0049] In the present invention, the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.

[0050] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example The “nitrogen-containing bridged heterocycle”, “oxygen-containing bridged heterocycle” and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0051] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated rings sharing a ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc., for example The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle" and "sulfur-containing spiroheterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.

[0052] Examples of the group obtained by condensing a heterocyclic group with an aryl group include, but are not limited to:

[0053] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π electron system. 6-12 "Aryl (aromatic ring)" means an aromatic group (aromatic ring) containing 6 to 12 carbon atoms, preferably C 6-10 Aryl (aromatic ring), preferably phenyl (phenyl ring) or naphthyl (naphthalene ring). Aryl is optionally substituted with one or more (such as 1 to 3) identical or different substituents (such as halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0054] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which can have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom can be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl are optionally substituted with oxo groups (for example, to form C=O, S(=O) or S(=O)2).

[0055] As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" means a heteroaryl group (heteroaromatic ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including a 5-10 membered nitrogen-containing heteroaryl group, a 5-10 membered oxygen-containing heteroaryl group, a 5-10 membered sulfur-containing heteroaryl group, a 5-6 membered nitrogen-containing heteroaryl group, a 5-6 membered oxygen-containing heteroaryl group, a 5-6 membered sulfur-containing heteroaryl group, etc. The "nitrogen-containing heteroaryl group," "oxygen-containing heteroaryl group," and "sulfur-containing heteroaryl group" each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., as well as 5-10 membered cyclic groups containing these groups.

[0056] In the present invention, a heteroaryl group (e.g., a monoheteroaryl group) can share two adjacent atoms with an aryl group (e.g., a monocyclic aryl group, such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group) or another heteroaryl group (e.g., another monoheteroaryl group) to form a parallel ring structure, and the connection point can be on any heteroaryl ring or on other rings, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (mono)heterocyclic group and (mono)heteroaryl and (mono)cycloalkyl, such as a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heteroaryl, a 5-6-membered (mono)heteroarylphenyl group, a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heterocyclic group or a 5-6-membered (mono)heteroaryl and C 4-6 (mono)cycloalkyl (e.g., 5-6 membered heteroarylcyclobutyl, 5-6 membered heteroarylcyclopentyl or 5-6 membered heteroarylcyclohexyl), examples of which are not limited to indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, wait.

[0057] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0058] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0059] If a substituent is described as being "optionally substituted with one or more...", the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0060] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0061] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0062] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0063] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0064] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0065] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a separate diastereomer. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oxime can exist in the following tautomeric form equilibrium in solution:

[0066]

[0067] It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0068] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0069] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0070] A cocrystal refers to a drug active molecule and other physiologically acceptable acid, base, salt, or non-ionic compound molecules bound in the same crystal lattice by hydrogen bonds, π-π stacking, van der Waals forces, and other non-covalent bonds.

[0071] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0072] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0073] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate salts and meglumine salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0074] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0075] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0076] Those skilled in the art will appreciate that, because nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles can form N-oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. The synthetic method for preparing the N-oxide of heterocycles and tertiary amines is well known to those skilled in the art, including but not limited to oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0077] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0078] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0079] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0080] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0081] Compound

[0082] In some embodiments, the present invention provides a compound of Formula I′ or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide, or prodrug thereof:

[0083]

[0084] in:

[0085] Ring A is selected from a benzene ring and a 5-6 membered heteroaromatic ring;

[0086] Ring B is selected from C 6-10aromatic rings, 5-10 membered heteroaromatic rings and 4-10 membered heterocyclic rings;

[0087] X 1 and X 2 are each independently selected from C and N;

[0088] X 3 and X 4 are each independently selected from CH and N;

[0089] Y is selected from -O-, -NH-, -C(=O)-, -CR 5 R 6 -、-CR 5 R 6 O-and-CR 5 R 6 NH-; provided that, when ring A is a thiophene ring, Y is not -O- or -NH-;

[0090] R 1 Selected from H, C 1-6 Alkyl and C 3-6 cycloalkyl, said alkyl and cycloalkyl are each optionally substituted with one or more halogens;

[0091] R 2 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, said alkyl and alkoxy are each optionally substituted with one or more halogens;

[0092] R 3 For LR 3 ';

[0093] L is independently a direct bond or -(CH2) n -;

[0094] R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl and 4-10 membered heterocyclic group; or when L is a direct bond and m is greater than 1, two R 3 'Together with the group to which it is connected, it forms a 4-10 membered heterocyclic ring;

[0095] R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b, wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NH2, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups;

[0096] R 5 and R 6 Each independently selected from H, hydroxy, halogen, -NH2, -NHCH3, -N(CH3)2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy), C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy and 4-10 membered heterocyclic group, or R 5 With R 6 Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy and heterocyclyl groups is optionally substituted with one or more halogens;

[0097] R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each independently selected from H, OH, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; said alkyl, alkoxy, cycloalkyl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and 4-10 membered heterocyclic group;

[0098] R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl and heterocyclyl being each optionally substituted with one or more halogens;

[0099] m is 0, 1, 2, 3, 4 or 5;

[0100] n is 1 or 2; and

[0101] p is 0, 1, 2 or 3.

[0102] In some embodiments, the compounds of the present invention have the structure shown in Formula I'-A:

[0103]

[0104] in:

[0105] The groups are as defined above for formula I'.

[0106] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NH2, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C3-6 cycloalkyl and 4-6 membered heterocyclic groups.

[0107] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, -NR 20a R 20b 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy, heterocyclyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy and 4-6 membered heterocyclic groups.

[0108] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, -NR 20a R 20b 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b, wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy, heterocyclyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 Halogenated alkoxy.

[0109] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from H, hydroxy, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 alkoxy), 4-6 membered heterocyclyl, 5-6 membered heteroaryl and -NR 20a R 20b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), heterocyclyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy and 4-6 membered heterocyclic groups.

[0110] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 alkoxy), 4-6 membered heterocyclyl, 5-6 membered heteroaryl and -NR 20a R 20b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), heterocyclyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 Halogenated alkoxy.

[0111] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from hydroxy, F, methyl, -CH2CH2NH2,

[0112] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from hydroxy, F, methyl, -CH2CH2NH2,

[0113] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from F, methyl, -CH2CH2NH2,

[0114] In certain embodiments, the present invention provides compounds of Formula I' or Formula I'-A, wherein p is 0 or 1.

[0115] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide, or prodrug thereof:

[0116]

[0117] in:

[0118] Ring A is selected from a benzene ring and a 5-6 membered heteroaromatic ring;

[0119] Ring B is selected from C 6-10 aromatic rings, 5-10 membered heteroaromatic rings and 4-10 membered heterocyclic rings;

[0120] X 1 and X 2 are each independently selected from C and N;

[0121] X 3 and X 4 are each independently selected from CH and N;

[0122] Y is selected from -O-, -NH-, -C(=O)-, -CR 5 R 6 -、-CR 5 R 6 O-and-CR 5 R 6 NH-; provided that, when ring A is a thiophene ring, Y is not -O- or -NH-;

[0123] R 1 Selected from H, C 1-6 Alkyl and C 3-6 cycloalkyl, said alkyl and cycloalkyl are each optionally substituted with one or more halogens;

[0124] R 2 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, said alkyl and alkoxy are each optionally substituted with one or more halogens;

[0125] R 3For LR 3 ';

[0126] L is independently a direct bond or -(CH2) n -;

[0127] R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic group, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl and 4-10 membered heterocyclic group; or when L is a direct bond and m is greater than 1, two R 3 'Together with the group to which it is connected, it forms a 4-10 membered heterocyclic ring;

[0128] R 5 and R 6 Each independently selected from H, hydroxy, halogen, -NH2, -NHCH3, -N(CH3)2, CN, C 1-6 Alkyl, C 1-6Heteroalkyl (e.g. C 1-6 Alkoxy), C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy and 4-10 membered heterocyclic group, or R 5 With R 6 Together with the atoms to which it is attached, it forms C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy and heterocyclyl groups is optionally substituted with one or more halogens;

[0129] R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each independently selected from H, OH, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; said alkyl, alkoxy, cycloalkyl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and 4-10 membered heterocyclic group;

[0130] R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl and heterocyclyl being each optionally substituted with one or more halogens;

[0131] m is 0, 1, 2, 3, 4 or 5; and

[0132] n is 1 or 2.

[0133] In some embodiments, the compounds of the present invention have the structure shown in Formula IA:

[0134]

[0135] in:

[0136] Each group is as defined above for formula I;

[0137] In some embodiments, the compounds of the present invention have the structure shown in Formula IB:

[0138]

[0139] in:

[0140] Each group is as defined above for formula I;

[0141] In some embodiments, the compounds of the present invention have the structure shown in Formula IC:

[0142]

[0143] in:

[0144] Each group is as defined above for formula I;

[0145] In some embodiments, the compounds of the present invention have the structure shown in Formula ID:

[0146]

[0147] in:

[0148] The groups are as defined above for formula I.

[0149] In certain embodiments, in the compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID provided herein, Ring A is a benzene ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring or a pyridine ring.

[0150] In certain embodiments, in the compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID provided herein, Ring A is a benzene ring, a thiophene ring, a pyrazole ring, an imidazole ring, or a pyridine ring.

[0151] In certain embodiments, in the compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID provided herein, Ring A is a benzene ring, a thiophene ring, a pyrrole ring, an imidazole ring, or a pyridine ring.

[0152] In certain embodiments, in the compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID provided herein, Ring A is a benzene ring, a thiophene ring, an imidazole ring, or a pyridine ring.

[0153] In certain embodiments, in the compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID provided by the present invention, ring A is a benzene ring or a 5-membered heteroaromatic ring; preferably, ring A is a benzene ring, a thiophene ring, a pyrrole ring, a pyrazole ring or an imidazole ring; more preferably, ring A is a benzene ring, a thiophene ring, a pyrrole ring or an imidazole ring.

[0154] In certain embodiments, in the compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID provided by the present invention, Ring A is a benzene ring or a 5-membered heteroaromatic ring; preferably, Ring A is a benzene ring, a thiophene ring, a pyrazole ring or an imidazole ring; more preferably, Ring A is a benzene ring, a thiophene ring or an imidazole ring.

[0155] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein ring B is C 6-10 aromatic ring or a 5-10 membered heteroaromatic ring; preferably, ring B is a C6 aromatic ring or a 6 membered heteroaromatic ring; more preferably, ring B is a benzene ring or a pyridine ring.

[0156] In certain embodiments, the present invention provides compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID, wherein X 1 is C and X 2 C; or X 1 is C and X 2 N; or X 1 N and X 2 is C; preferably, X 1 is C and X 2 C; or X 1 is C and X 2 is N.

[0157] In certain embodiments, the present invention provides compounds of formula I' or formula I, wherein X 3 is CH and X 4 is N.

[0158] In certain embodiments, in the compound of formula I' or formula I provided by the present invention, Y is selected from -NH-, -C(=O)-, -CR 5 R 6 -、-CR 5 R 6 O-and-CR 5 R 6 NH-; provided that, when ring A is a thiophene ring, Y is not -NH-.

[0159] In certain embodiments, in the compound of formula I' or formula I provided by the present invention, Y is selected from -NH-, -C(=O)-, -CH2-, -CHOH- and -CH(CH3)O-; provided that, when ring A is a thiophene ring, Y is not -NH-.

[0160] In certain embodiments, in the compound of formula I' or formula I provided by the present invention, Y is selected from -NH-, -C(=O)-, -CH2- and -CHOH-; provided that, when ring A is a thiophene ring, in the compound of formula I' or formula I provided by the present invention, Y is not -NH-.

[0161] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 1 H or C 1-3 Alkyl; preferably, R 1 For H.

[0162] In certain embodiments, the present invention provides compounds of formula I' or formula I, wherein R 2 Selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, said alkyl and alkoxy are each optionally substituted with one or more halogens; preferably, R 2 Selected from halogen and C 1-3 Alkyl; preferably, R 2 is F or -CH3; more preferably, R 2 is -CH3.

[0163] In certain embodiments, the present invention provides compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID, wherein each occurrence of L is independently a direct bond or -CH2-.

[0164] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 cycloalkyl and 4-6 membered heterocyclic groups.

[0165] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -NR 20a R 20b 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy, C 1-3 Heteroalkyl (e.g. C 1-3 Alkoxy), C 3-6 cycloalkyl and 4-6 membered heterocyclic groups.

[0166] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -NR20a R 20b 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy, C 1-3 Heteroalkyl (e.g. C 1-3 Alkoxy), C 3-6 cycloalkyl and 4-6 membered heterocyclic groups.

[0167] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, -NR 20a R 20b 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy, and heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 heteroalkyl and 4-6 membered heterocyclyl.

[0168] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, -NR 20a R 20b 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy, and heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 Halogenated alkoxy.

[0169] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, halogen, CN, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), -NR 20a R 20b 、-S(=O)2R 22 and C(=O)R 21 , wherein the alkyl and heteroalkyl (eg alkoxy) groups are each optionally substituted by one or more groups independently selected from halogen, C 1-3 The substituents of the heteroalkyl and 4-6 membered heterocyclic groups are substituted.

[0170] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, halogen, CN, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), -NR 20a R 20band C(=O)R 21 , wherein the alkyl and heteroalkyl (eg, alkoxy) groups are each optionally substituted with one or more halogens.

[0171] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy) and -NR 20a R 20b , wherein the alkyl and heteroalkyl (eg, alkoxy) groups are each optionally substituted with one or more halogens.

[0172] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 'is independently F, Cl, Br, CN, methyl, trifluoromethyl, methoxy, ethoxy, -C(=O)CH3, -N(CH3)2, -S(=O)2CH3,

[0173] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 'is independently F, Cl, Br, CN, methyl, trifluoromethyl, methoxy, ethoxy, -C(=O)CH3, -N(CH3)2, -S(=O)2CH3,

[0174] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently F, Cl, CN, methyl, trifluoromethyl, methoxy, ethoxy, -C(=O)CH3, -N(CH3)2 or

[0175] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently F, Cl, trifluoromethyl, methoxy, -N(CH3)2 or

[0176] In certain embodiments, when L is a direct bond and m is greater than 1, any two R 3 'Together with the groups to which they are connected, they constitute a 4-6 membered heterocyclic ring. Preferably, they constitute

[0177] In certain embodiments, the present invention provides compounds of formula I' or formula I, wherein R 5 and R 6 Each independently selected from H, hydroxyl, -NH2, -NHCH3, -N(CH3)2, CN, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy) and C 3-6 Cycloalkyl, or R 5 With R 6 Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, wherein the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl and heterocyclyl are each optionally substituted with one or more halogens.

[0178] In certain embodiments, the present invention provides compounds of formula I' or formula I, wherein R 5 and R 6 Each independently selected from H, hydroxyl, -NH2 and C 1-4 Alkyl, or R 5 With R 6 Together with the atoms to which it is attached, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, said alkyl, cycloalkyl and heterocyclyl are each optionally substituted by one or more halogens.

[0179] In certain embodiments, the present invention provides compounds of formula I' or formula I, wherein R 5 and R 6 are each independently selected from H, hydroxyl and methyl.

[0180] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each independently selected from H, -NHCH3, -N(CH3)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl; each of the alkyl, alkoxy, cycloalkyl and heterocyclyl groups is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 alkyl and 4-6 membered heterocyclic groups.

[0181] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy and 4-6 membered heterocyclyl; said alkyl, alkoxy and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 alkyl and 4-6 membered heterocyclic groups.

[0182] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each is independently H, methyl, ethyl, propyl or oxetanyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, methyl and oxetanyl.

[0183] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 21 and R 22 Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are each optionally substituted with one or more halogens.

[0184] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 21 and R 22 Each independently is C 1-4 In a preferred embodiment, R 21 and R 22 are each independently methyl.

[0185] In certain embodiments, the present invention provides compounds of Formula I', Formula I'-A, Formula I, Formula IA to Formula ID, wherein m is 0, 1, 2 or 3.

[0186] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NH2, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups;

[0187] R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each independently selected from H, -NHCH3, -N(CH3)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl; each of the alkyl, alkoxy, cycloalkyl and heterocyclyl groups is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 alkyl and a 4-6 membered heterocyclyl; and

[0188] R 21 and R 22 Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6 Cycloalkyl, said alkyl, alkoxy and cycloalkyl are each optionally substituted with one or more halogens.

[0189] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, -NR 20a R 20b 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy, heterocyclyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Haloalkoxy and 4-6 membered heterocyclic groups;

[0190] R 20a 、R 20b 、R 23a and R 23b Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy and 4-6 membered heterocyclyl; said alkyl, alkoxy and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 alkyl and a 4-6 membered heterocyclyl; and

[0191] R 21 C 1-4 alkyl.

[0192] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4Each occurrence is independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 alkoxy), hydroxy, 4-6 membered heterocyclyl, 5-6 membered heteroaryl and -NR 20a R 20b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), heterocyclyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy, 4-6 membered heterocyclyl; and

[0193] R 20a and R 20b Each is independently H, methyl, ethyl, propyl or oxetanyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, methyl and oxetanyl.

[0194] In certain embodiments, the present invention provides compounds of formula I' or formula I'-A, wherein R 4 Each occurrence is independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 alkoxy), 4-6 membered heterocyclyl, 5-6 membered heteroaryl and -NR 20a R 20b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), heterocyclyl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 haloalkoxy; and

[0195] R 20a and R 20b Each is independently H, methyl, ethyl, propyl or oxetanyl, each of which is optionally substituted with one or more substituents independently selected from F, Cl, Br, methyl and oxetanyl.

[0196] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups;

[0197] R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each independently selected from H, -NHCH3, -N(CH3)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl; each of the alkyl, alkoxy, cycloalkyl and heterocyclyl groups is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 alkyl and a 4-6 membered heterocyclyl; and

[0198] R 21 and R 22 Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy and C 3-6Cycloalkyl, said alkyl, alkoxy and cycloalkyl are each optionally substituted with one or more halogens.

[0199] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -NR 20a R 20b 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy, C 1-3 Heteroalkyl (e.g. C 1-3 Alkoxy), C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups;

[0200] R 20a 、R 20b 、R 23a and R 23b Each independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy and 4-6 membered heterocyclyl; said alkyl, alkoxy and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 alkyl and a 4-6 membered heterocyclyl; and

[0201] R 21 C 1-4 alkyl.

[0202] In certain embodiments, the present invention provides compounds of formula I', formula I'-A, formula I, formula IA to formula ID, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, -NR 20a R 20b 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl (eg, alkoxy), cycloalkyl, cycloalkoxy, and heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl and C 1-3 haloalkoxy;

[0203] R 20a 、R 20b 、R 23a and R 23b are each independently H, methyl, ethyl, propyl, or oxetanyl, each optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, methyl, and oxetanyl; and

[0204] R 21 C 1-4 alkyl.

[0205] The present invention covers any combination of the above embodiments.

[0206] In some embodiments, compounds of the present invention include, but are not limited to:

[0207]

[0208]

[0209]

[0210]

[0211] Preparation method

[0212] In certain embodiments, the present invention provides a method for preparing a compound of Formula IA comprising the steps of:

[0213] Route A

[0214]

[0215] in:

[0216] PG is an amino protecting group, preferably 2,4-dimethoxybenzyl;

[0217] The remaining groups are as defined above;

[0218] The reaction conditions of each step are as follows:

[0219] Step 1: Compounds IA-1 and IA-2 undergo a substitution reaction or coupling reaction (such as Buchwald or Ullman reaction) to produce compound IA-3;

[0220] For the substitution reaction, the reaction can be carried out in an acid (e.g., trifluoroacetic acid, hydrochloric acid, etc.) or a base (e.g., t BuONa, t BuOK, t The reaction is carried out in the presence of BuOLi, Cs2CO3, DIPEA, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3); the solvent that can be used is, for example, isopropanol, tert-butanol, toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40°C to 140°C.

[0221] For the Buchwald reaction, the catalyst that can be used is, for example, Pd(OAc)2, Pd2(dba)3, Pd(dba)2, PdCl2, Pd(PPh3)4, Pd(dppf)Cl2, Pd(acac)2 or Pd(allyl)2; the ligand that can be used is PPh3, XPhos, SPhos, RuPhos, XantPhos, dppf, BINOL, BINAP or PCy3; the base that can be used is, for example, t BuONa, t BuOK, t BuOLi, Cs2CO3, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3; solvents that can be used include toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40°C to 140°C.

[0222] For the Ullmann reaction, the catalyst that can be used is, for example, CuCl, CuBr, CuI or Cu2O; the ligand that can be used is, for example, salicylaldehyde oxime, cyclohexanediamine, N,N'-dimethylethylenediamine, TMEDA or ethylenediamine; the base that can be used is, for example, t BuONa, t BuOK, t BuOLi, Cs2CO3, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3; solvents that can be used include toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40°C to 140°C.

[0223] Step 2: Compound IA-3 is reduced to generate compound IA-4;

[0224] Reducing agents that can be used in the reduction reaction include, for example, zinc powder / acetic acid, iron powder / ammonium chloride solution, iron powder / hydrochloric acid solution, palladium carbon / hydrogen, etc.; solvents that can be used include, for example, water, ethanol, methanol, or mixtures thereof; and the reaction temperature is 0°C to 90°C, for example, room temperature, 60°C, 70°C, 80°C, or 90°C.

[0225] Step 3: Compound IA-4 and IA-5 undergo condensation reaction to produce compound IA-6;

[0226] The condensation reaction is preferably carried out in the presence of a condensing agent and a base. Available condensing agents include T3P, HATU, CDI, HOBt, DMAP, DCC, DIC, EDC, HBTU, HCTU or PyBOP. Available bases include pyridine, TEA, DIPEA, t BuOK, t BuONa, t BuOLi, NaH, NaOH, Cs2CO3, K3PO4 or Na2CO3, etc. Available solvents include THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, acetone, CH3CN, 1,4-dioxane or toluene, etc. The reaction temperature is 0°C to 120°C, for example, room temperature.

[0227] Alternatively, compound IA-5 can be first prepared as an acyl halide using acyl halide reagents such as thionyl chloride and oxalyl chloride. This reaction can be carried out in the presence of a small amount of DMF or in the absence of DMF. The reaction temperature is 0°C to 120°C. The resulting acyl halide is then reacted with compound IA-4 in the presence of a base to produce compound IA-6. Suitable bases include TEA or DIPEA. Suitable solvents include THF, DCM, DCE, CH3CN, 1,4-dioxane, or toluene. The reaction can be carried out at a temperature between 0°C and 120°C.

[0228] Step 4: Compound IA-6 is deprotected under acidic conditions to generate a compound of formula IA.

[0229] The reaction can be carried out in a solvent such as trifluoroacetic acid at a temperature of 25°C to 120°C, for example 70°C or 100°C.

[0230] In certain embodiments, the present invention provides a method for preparing a compound of Formula IA comprising the steps of:

[0231] Route A-1

[0232]

[0233] in:

[0234] PG is an amino protecting group, preferably 2,4-dimethoxybenzyl;

[0235] The remaining groups are as defined above;

[0236] The reaction conditions of each step are as follows:

[0237] Step 1: Compound IA-5 and IA-7 are condensed to form compound IA-8;

[0238] The condensation reaction is preferably carried out in the presence of a condensing agent and a base. Available condensing agents include T3P, HATU, CDI, HOBt, DMAP, DCC, DIC, EDC, HBTU, HCTU or PyBOP. Available bases include pyridine, TEA, DIPEA, t BuOK, t BuONa, t BuOLi, NaH, NaOH, Cs2CO3, K3PO4 or Na2CO3, etc. Available solvents include THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, acetone, CH3CN, 1,4-dioxane or toluene, etc. The reaction temperature is 0°C to 120°C, for example, room temperature.

[0239] Alternatively, compound IA-5 can be first prepared as an acyl halide using acyl halide reagents such as thionyl chloride and oxalyl chloride. This reaction can be carried out in the presence of a small amount of DMF or in the absence of DMF. The reaction temperature is 0°C to 120°C. The resulting acyl halide is then reacted with compound IA-4 in the presence of a base to produce compound IA-6. Suitable bases include TEA or DIPEA. Suitable solvents include THF, DCM, DCE, CH3CN, 1,4-dioxane, or toluene. The reaction can be carried out at a temperature between 0°C and 120°C.

[0240] Step 2: Compounds IA-1 and IA-8 undergo a substitution reaction or coupling reaction (such as Buchwald or Ullman reaction) to produce compound IA-6;

[0241] For the substitution reaction, the reaction can be carried out in an acid (e.g., trifluoroacetic acid, hydrochloric acid, etc.) or a base (e.g., t BuONa, t BuOK, t The reaction is carried out in the presence of BuOLi, Cs2CO3, DIPEA, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3); the solvent that can be used is, for example, isopropanol, tert-butanol, toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40°C to 140°C.

[0242] For the Buchwald reaction, the catalyst that can be used is, for example, Pd(OAc)2, Pd2(dba)3, Pd(dba)2, PdCl2, Pd(PPh3)4, Pd(dppf)Cl2, Pd(acac)2 or Pd(allyl)2; the ligand that can be used is PPh3, XPhos, SPhos, RuPhos, XantPhos, dppf, BINOL, BINAP or PCy3; the base that can be used is, for example, t BuONa, t BuOK, t BuOLi, Cs2CO3, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3; solvents that can be used include toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40°C to 140°C.

[0243] For the Ullmann reaction, the catalyst that can be used is, for example, CuCl, CuBr, CuI or Cu2O; the ligand that can be used is, for example, salicylaldehyde oxime, cyclohexanediamine, N,N'-dimethylethylenediamine, TMEDA or ethylenediamine; the base that can be used is, for example, t BuONa, t BuOK, t BuOLi, Cs2CO3, LiHMDS, LDA, NaHMDS, KHMDS, K3PO4, Na2CO3, KOAc, NaHCO3 or K2CO3; solvents that can be used include toluene, xylene, THF, DME, 1,4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40°C to 140°C.

[0244] Step 3: Compound IA-6 is deprotected under acidic conditions to generate a compound of formula IA.

[0245] The reaction can be carried out in a solvent such as trifluoroacetic acid at a temperature of 25°C to 120°C, for example 70°C or 100°C.

[0246] In certain embodiments, the present invention provides a method for preparing a compound of Formula IB comprising the steps of:

[0247] Route B-1

[0248]

[0249] in:

[0250] PG is an amino protecting group, preferably 2,4-dimethoxybenzyl;

[0251] The remaining groups are as defined above;

[0252] The reaction conditions of each step are as follows:

[0253] Step 1: Compound IB-1 reacts with a boron-containing reagent to produce compound IB-2;

[0254] Examples of acceptable boron-containing reagents include B2(pin)2. Examples of acceptable catalysts include Pd(OAc)2, Pd(PPh3)4, and Pd(dppf)Cl2. Examples of acceptable ligands include PPh3, dppf, BINOL, BINAP, or PCy3. Examples of acceptable bases include Cs2CO3, K3PO4, Na2CO3, KOAc, NaHCO3, and K2CO3. Examples of acceptable solvents include 1,4-dioxane, DMF, DMSO, and CH3CN. The reaction temperature may be between 50°C and 120°C.

[0255] Step 2: Compound IB-2 and IA-2 undergo coupling reaction to generate compound IB-3;

[0256] The catalyst that can be used in the coupling reaction is, for example, Pd(OAc)2, Pd(PPh3)4 or Pd(dppf)Cl2; the base that can be used is, for example, Cs2CO3, K3PO4, Na2CO3, AcOK, NaHCO3 or K2CO3; the ligand that can be used is, for example, PPh3, DPPF, BINOL, BINAP or PCy3; the solvent that can be used is, for example, toluene / H2O, 1,4-dioxane / H2O, DMF / H2O, DMSO / H2O or CH3CN / H2O, and the reaction temperature can be 60°C to 120°C.

[0257] Step 3: Compound IB-3 is reduced to generate compound IB-4;

[0258] The reaction conditions are as described in the second step of the preparation of the compound of formula IA (Route A).

[0259] Step 4: Compound IB-4 and IA-5 are condensed to form compound IB-5;

[0260] The reaction conditions are the same as those described in the third step of the preparation method of the compound of formula IA (Route A).

[0261] Step 5: Compound IB-5 is deprotected under acidic conditions to generate a compound of formula IB;

[0262] The reaction conditions are the same as those described in the fourth step of the preparation method of the compound of formula IA (Route A).

[0263] In certain embodiments, the present invention provides a method for preparing a compound of Formula IB comprising the steps of:

[0264] Route B-2

[0265]

[0266] in:

[0267] PG is an amino protecting group, preferably 2,4-dimethoxybenzyl;

[0268] The remaining groups are as defined above;

[0269] The reaction conditions of each step are as follows:

[0270] Step 1: Compound IB-6 and IB-7 undergo coupling reaction to generate compound IB-8;

[0271] The catalyst that can be used in the coupling reaction is, for example, Pd(TFA)2, Pd(OAc)2, Pd(PPh3)4 or Pd(dppf)Cl2; the ligand that can be used is, for example, PPh3, DPPF, BINOL, BINAP or PCy3; the base that can be used is, for example, Cs2CO3, K3PO4, Na2CO3, AcOK, NaHCO3 or K2CO3; the solvent that can be used is, for example, toluene, xylene, 1,4-dioxane, DMF, DMSO or CH3CN; and the reaction temperature can be 60°C to 120°C.

[0272] Step 2: Compound IB-8 and IA-5 undergo condensation reaction to generate compound IB-5;

[0273] The reaction conditions are the same as those described in the third step of the preparation method of the compound of formula IA (Route A).

[0274] Step 3: Compound IB-5 is deprotected under acidic conditions to generate a compound of formula IB;

[0275] The reaction conditions are the same as those described in the fourth step of the preparation method of the compound of formula IA (Route A).

[0276] In certain embodiments, the present invention provides a method for preparing a compound of Formula IC comprising the steps of:

[0277] Route C

[0278]

[0279] in:

[0280] Each group is as defined above;

[0281] The method comprises subjecting compound IB to a catalytic oxidation reaction to produce a compound of formula IC;

[0282] The catalyst that can be used is, for example, NIS, NBS, I2, etc.; the solvent that can be used is, for example, DMSO; and the reaction temperature can be 25°C to 120°C, for example, 100°C.

[0283] In certain embodiments, the present invention provides a method for preparing a compound of formula ID comprising the steps of:

[0284] Route D-1

[0285]

[0286] in:

[0287] Each group is as defined above;

[0288] The method comprises subjecting compound IB to a catalytic oxidation reaction to produce a compound of formula ID;

[0289] The catalyst that can be used is, for example, NIS, NBS, I2, etc.; the solvent that can be used is, for example, DMSO; and the reaction temperature can be 25°C to 120°C, for example, 100°C.

[0290] In certain embodiments, the present invention provides a method for preparing a compound of formula ID comprising the steps of:

[0291] Route D-2

[0292]

[0293] in:

[0294] Each group is as defined above;

[0295] The method comprises subjecting compound IC to a reduction reaction to produce a compound of formula ID;

[0296] The reducing agent that can be used is, for example, sodium borohydride or borane; the solvent that can be used is THF, DCM, DCE or MeOH; and the reaction temperature can be -20°C to 60°C, for example, room temperature.

[0297] Pharmaceutical compositions, preparations and methods of treatment

[0298] In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof and one or more pharmaceutically acceptable carriers.

[0299] In some embodiments, the present invention provides a pharmaceutical formulation, which is preferably a solid formulation, a semisolid formulation, a liquid formulation, or a gaseous formulation.

[0300] In some embodiments, the pharmaceutical composition or pharmaceutical formulation is preferably administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0301] In some embodiments, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention in the preparation of a medicament for preventing or treating a disease or condition associated with RAF and / or RAS kinase activity.

[0302] In some embodiments, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention in the preparation of a medicament for modulating (e.g., reducing or inhibiting) the activity of RAF and / or RAS kinase.

[0303] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention, for use in preventing or treating a disease or condition associated with RAF and / or RAS kinase activity.

[0304] In some embodiments, the present invention provides a method for preventing or treating a disease or condition associated with RAF and / or RAS kinase activity, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, metabolite, isotopically labeled compound, N-oxide or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention.

[0305] In some embodiments, the disease or condition associated with RAF and / or RAS kinase activity is preferably cancer or tumor.

[0306] In some embodiments, the cancer or tumor is preferably lung cancer (e.g., non-small cell lung cancer), breast cancer, ovarian cancer, gastric cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, intestinal cancer, pancreatic cancer, head and neck cancer, uterine cancer, esophageal cancer, thyroid cancer, bladder cancer, blood cancer, lymphoma, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.

[0307] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0308] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0309] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by any suitable route.

[0310] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0311] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[0312] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0313] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50 mg per kg body weight per day. In some cases, the dosage level not higher than the lower limit of the aforementioned range can be enough, and in other cases, still can adopt larger doses when not causing any harmful side effects, condition is first divided into several smaller doses to be administered throughout the day.

[0314] The compound of the present invention may be contained in a pharmaceutical composition or formulation in an amount ranging from about 0.01 mg to about 1000 mg.

[0315] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0316] The term "prevention" refers to the fact of preventing or delaying the occurrence or reducing the intensity of clinical or biochemical manifestations associated with the disease, and includes not only prevention before the development of the disease but also prevention of recurrence of the disease after treatment.

[0317] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0318] In some embodiments, the pharmaceutical compositions or pharmaceutical formulations of the present invention may further comprise one or more additional therapeutic or prophylactic agents (e.g., other drugs used to treat cancer or tumor diseases). In some embodiments, the therapeutic methods of the present invention may further comprise administering one or more additional therapeutic or prophylactic agents (e.g., other drugs used to treat cancer or tumor diseases). DETAILED DESCRIPTION

[0319] Example

[0320] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0321] The abbreviations used in this document have the following meanings:

[0322]

[0323]

[0324] The compounds of the present invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography (Flash column chromatography). 1 The reaction was confirmed by H NMR and / or MS. Reaction monitoring was performed by TLC or LC-MS.

[0325] 1 H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).

[0326] LC / MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0327] TLC used silica gel GF 254 as the stationary phase.

[0328] Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0329] Flash column chromatography was performed using a Biotage flash column chromatograph.

[0330] Prep-HPLC used Agilent 1260 and Waters 2489.

[0331] Microwave reactions were performed using a BiotageInitiator microwave reactor.

[0332] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0333] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Teber Chemical Company.

[0334] Example 1: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 1)

[0335]

[0336] Step 1: Preparation of 8-bromoquinazolin-4(3H)-one (Compound 1b)

[0337] Compound 1a (1.0 g, 4.63 mmol) was added to formamide (15 mL) under nitrogen protection and heated to 135°C for 2 hours. A large amount of solid precipitated after the reaction was completed. This was diluted with 60 mL of water and filtered under reduced pressure. The filter cake was washed with clean water and the resulting solid was dried under reduced pressure at 50°C to yield compound 1b (800 mg). MS m / z (ESI): 224.9 [M+H] + .

[0338] Step 2: Preparation of methyl 4-oxo-3,4-dihydroquinazoline-8-carboxylate (Compound 1c)

[0339] Compound 1b (780 mg, 3.47 mmol), TEA (1.75 g, 17.33 mmol, 2.41 mL), Pd(dppf)Cl2·DCM (283.05 mg, 346.60 μmol), and MeOH (25 mL) were added to an autoclave. After sealing, carbon monoxide was introduced to 1.0-1.2 MPa, and then heated to 120°C for 5 hours. After completion of the reaction, 60 mL of water was added for dilution, and the mixture was filtered under reduced pressure. The filter cake was washed with clean water, and the resulting solid was dried under reduced pressure at 50°C. The mixture was then slurried with methanol (5 mL) and filtered to dryness to obtain compound 1c (400 mg). MS m / z (ESI): 205.0 [M+H] + .

[0340] Step 3: Preparation of methyl 4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxylate (Compound 1e)

[0341] Compound 1c (430.0 mg, 2.11 mmol) and BOP (558.8 mg, 2.74 mmol) were dissolved in DMF (10 mL), followed by the dropwise addition of DBU (1.06 g, 4.21 mmol, 1.04 mL). After stirring for 10 min, compound 1d (528.19 mg, 3.16 mmol, 474.56 μL) was added, and the mixture was stirred at 25°C for 16 hours. After the reaction was complete as monitored by LC-MS, the reaction was quenched with water and extracted three times with EA. The organic phases were combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 1e (570 mg, 1.61 mmol). MS m / z (ESI): 354.1 [M+H] + .

[0342] Step 4: Preparation of 4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxylic acid (Compound 1f)

[0343] Compound 1e (570 mg, 1.61 mmol) was dissolved in THF (15 mL) and MeOH (5 mL). Aqueous sodium hydroxide (193.56 mg, 4.84 mmol) (5 mL) was added and stirred at 25°C for 16 hours. After the reaction was complete as monitored by LC-MS, the solvent was removed under reduced pressure and the resulting solid residue was dissolved in 20 mL of water. The residue was washed twice with EA. The aqueous phase was adjusted to a pH of approximately 3 with 2M hydrochloric acid and concentrated under reduced pressure. The resulting solid residue was dissolved in methanol. The insoluble solid was filtered off and the filtrate was concentrated to give compound 1f (460 mg). MS m / z (ESI): 340.1 [M+H] + .

[0344] Step 5: Preparation of N-(3-chloro-2-fluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 1i)

[0345] Compound 1g (3.92 g, 26.95 mmol) and 1h (5 g, 22.46 mmol) were added to isopropanol (25 mL), followed by the addition of TFA (3.07 g, 26.95 mmol, 2.00 mL). The mixture was stirred in a sealed container at 100°C for 18 hours. LC-MS confirmed the complete reaction. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with isopropanol, and the resulting solid was dried under reduced pressure to yield compound 1i (7 g). MS m / z (ESI): 332.0 [M+H] + .

[0346] Step 6: N 1 Preparation of -(3-chloro-2-fluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 1j)

[0347] Compound 1i (3.5 g, 10.55 mmol) was added to ethanol (50 mL) and water (15 mL). Iron powder (2.95 g, 52.75 mmol) and concentrated hydrochloric acid (12 M, 3 mL) were then added. The mixture was heated to 90°C and stirred for 3.5 hours. LC-MS confirmed the reaction was complete. The mixture was filtered through celite while hot. The filtrate was concentrated under reduced pressure to remove most of the solvent. A mixed solvent of chloroform and isopropanol (chloroform / isopropanol = 4 / 1, 200 mL) and saturated sodium carbonate solution (50 mL) were then added and stirred thoroughly. The mixture was allowed to stand for separation, and the lower organic phase was collected. The aqueous phase was extracted twice with chloroform / isopropanol = 4 / 1. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (eluent: 100% DCM) to obtain compound 1j (1.7 g). MS m / z (ESI): 302 [M+H]. + .

[0348] Step 7: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 1k)

[0349] Compounds 1f (130 mg, 383.09 μmol) and 1j (115.60 mg, 383.09 μmol) were added to pyridine (9 mL), followed by the addition of T3P (3 mL, 50% in DMF). The mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was directly dried, diluted with 60 mL of water, and extracted with EA (30 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to yield compound 1k (110.0 mg). MS m / z (ESI): 623.2 [M+H] + .

[0350] Step 8: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 1)

[0351] Compound 1k (125 mg, 200.62 μmol) was added to trifluoroacetic acid (5.0 mL) and reacted at 70°C for 2 hours. After the reaction, the reaction solution was concentrated to dryness and basified by adding saturated sodium bicarbonate solution. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 1 (35.0 mg). MS m / z (ESI): 472.6 [M+H] + .

[0352] 1 H NMR (400MHz, DMSO-d6) δ13.20(s,1H),9.24(s,1H),8.66(dd,J=7.6,1.6Hz,1H),8.62(s,1H),8.53(dd,J=8.4,1.6Hz,1H),8.44–8.32(m,2H),8.23( br,1H),7.90(d,J=6.0Hz,1H),7.69(t,J=7.6Hz,1H),7.62(d,J=8.8Hz,1 H),7.59–7.53(m,1H),7.40–7.31(m,1H),7.28–7.20(m,2H),2.45(s,3H).

[0353] Example 2: 4-amino-N-(1-(2-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 2)

[0354]

[0355] Step 1: Preparation of 7-bromo-N-(2,4-dimethoxybenzyl)thieno[3,2-d]pyrimidin-4-amine (Compound 2b)

[0356] Compound 2a (3 g, 12.02 mmol) was dissolved in DMF (15 mL), and compound 1d (2.11 g, 12.62 mmol) and DIPEA (2.33 g, 18.03 mmol) were added sequentially. The mixture was stirred at 20°C for 16 hours. After the reaction was complete as monitored by LC-MS, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 2b (4.46 g). MS m / z (ESI): 379.9 [M+H] + .

[0357] Step 2: Preparation of methyl 4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidine-7-carboxylate (Compound 2c)

[0358] Compound 2b (2 g, 5.26 mmol), Pd(dppf)Cl2·DCM (429.52 mg, 525.96 μmol), MeOH (25 mL), and TEA (2.66 g, 26.30 mmol, 3.66 mL) were added sequentially to an autoclave. The atmosphere was purged with nitrogen three times, and carbon monoxide was introduced to 2.3 MPa. The mixture was stirred at 120°C for 5 hours. LC-MS monitored the complete reaction. After cooling, the reaction solution was isolated and purified by silica gel flash column chromatography (DCM / MeOH = 93 / 7) to obtain compound 2c (1.82 g). MS m / z (ESI): 360.0 [M+H] + .

[0359] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidine-7-carboxylic acid (Compound 2d)

[0360] Compound 2c (1.82 g, 5.06 mmol) was added to a mixture of THF (60 mL), MeOH (15 mL), and water (15 mL). NaOH (607.68 mg, 15.19 mmol) was then added and stirred at 25°C for 4 hours. LC-MS confirmed the complete reaction. The reaction mixture was diluted with a small amount of water and extracted with ethyl acetate. The aqueous phase was collected and the pH was adjusted to 3 with dilute hydrochloric acid. The solvent was removed under reduced pressure, and the resulting crude solid product was reconstituted with dichloromethane and methanol (10:1). The insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by slurrying with MTBE and methanol to yield compound 2d (1.4 g). MS m / z (ESI): 346.0 [M+H]. + .

[0361] Step 4: Preparation of 1-(2-fluorobenzyl)-6-methyl-5-nitroisoquinoline (Compound 2f)

[0362] Compound 2e (1.06 g, 4.49 mmol) and 1h (200 mg, 898.36 μmol) were dissolved in toluene (10.0 mL). Palladium acetate (40.34 mg, 179.67 μmol), potassium phosphate (667.43 mg, 3.14 mmol), tricyclohexylphosphine (50.39 mg, 179.67 μmol), and water (1.5 mL) were then added. The atmosphere was purged with nitrogen three times and the temperature was raised to 120°C for 12 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, washed once with water, and once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (DCM / MeOH = 98 / 2) to yield compound 2f (220.0 mg). MS m / z (ESI): 297.0 [M+H] + .

[0363] Step 5: Preparation of 1-(2-fluorobenzyl)-6-methylisoquinolin-5-amine (Compound 2g)

[0364] Compound 2f (50 mg, 168.75 μmol) was added to ethanol (6.0 mL) and water (2.0 mL). Iron powder (47.12 mg, 843.75 μmol) and concentrated hydrochloric acid (12 M, 0.5 mL) were then added. The temperature was raised to 90°C and the reaction was allowed to react for 3.5 hours. After completion of the reaction, the mixture was filtered through celite while hot and diluted with saturated sodium carbonate solution. The mixture was then extracted with a 4 / 1 chloroform / isopropanol mixture (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 2g (44 mg). MS m / z (ESI): 267.0 [M+H]. + .

[0365] Step 6: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-(2-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 2h)

[0366] Compounds 2g (44.0 mg, 165.2 μmol) and 2d (60.0 mg, 173.72 μmol) were dissolved in pyridine (4.0 mL) and T3P (3.0 mL, 50% in DMF) was added dropwise. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, as monitored by LC-MS. The reaction solution was diluted with ethyl acetate and the pH was adjusted to approximately 13 with saturated aqueous sodium bicarbonate. The mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 2h (100 mg). MS m / z (ESI): 594.0 [M+H] + .

[0367] Step 7: Preparation of 4-amino-N-(1-(2-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 2)

[0368] Compound 2h (100 mg, 168.44 μmol) was added to trifluoroacetic acid (3.0 mL) and reacted at 70°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness, added with saturated sodium bicarbonate solution, and extracted three times with EA. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 50 mg of crude product. 20 mg of the crude product was separated and purified by Prep-HPLC to obtain compound 2 (6.0 mg). MS m / z (ESI): 444.0 [M+H] + .

[0369] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.95(s,1H),8.58(s,1H),8.38(d,J=6.0Hz,1H),8.22(d,J=8.7Hz,1H),7.97(s,2H),7. 68(s,1H),7.66(d,J=2.5Hz,1H),7.31-7.24(m,1H),7.22-7.13(m,2H),7.09(td,J=7.5,1.2Hz,1H),4.69(s,2H),2.44(s,3H).

[0370] Example 3: 4-amino-N-(1-(2-fluorobenzoyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 3)

[0371]

[0372] Compound 2 (30 mg, 67.64 μmol) was dissolved in DMSO (2.0 mL), and NIS (15.22 mg, 67.64 μmol) was added. The reaction was allowed to proceed at 100°C for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature and directly purified by Prep-HPLC to obtain compound 3 (7.57 mg). MS m / z (ESI): 458.1 [M+H] + .

[0373] 1 HNMR (400MHz, DMSO-d6) δ11.74(s,1H),8.98(s,1H),8.60(s,1H),8.54(d,J=5.8Hz,1H),8.31(d,J=8.7Hz,1H),8.01(d,J=5.9Hz,1H),7.98(s,2H ),7.85(td,J=7.5,1.7Hz,1H),7.78(d,J=8.8Hz,1H),7.76–7.70(m,1H),7.43(td,J=7.7,0.7Hz,1H),7.31(dd,J=10.5,8.6Hz,1H),2.49(s,3H).

[0374] Example 4: 4-amino-N-(1-((2-fluorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 4)

[0375]

[0376] Compound 3 (7 mg, 15.30 μmol) was added to MeOH (4 mL), and NaBH4 (8.68 mg, 229.52 μmol) was added under ice bath. The temperature was naturally raised to room temperature and stirring was continued at room temperature for 1 hour. After the reaction was completed as monitored by LC-MS, the solvent was concentrated to dryness, diluted with water, and extracted three times with EA. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by Prep-HPLC to obtain compound 4 (2.27 mg). MS m / z (ESI): 460.1 [M+H] + .

[0377] 1 HNMR (400MHz, DMSO-d6) δ11.64(s,1H),8.95(s,1H),8.58(s,1H),8.41(d,J=5.9Hz,1H),8.32(d,J=8.7Hz,1H),7.97(s,2H),7.73(d,J=5.9Hz, 1H),7.68–7.58(m,2H),7.35-7.31(m,1H),7.22(t,J=7.4Hz,1H),7.14– 7.06(m,1H),6.74(d,J=6.4Hz,1H),6.40(d,J=6.4Hz,1H),2.43(s,3H).

[0378] Example 5: 4-amino-N-(1-(4-methoxybenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 5)

[0379]

[0380] Step 1: Preparation of 1-(4-methoxybenzyl)-6-methyl-5-nitroisoquinoline (Compound 5b)

[0381] Compound 1h (100 mg, 449.18 μmol), 5a (668.72 mg, 2.70 mmol), palladium acetate (20.17 mg, 89.84 μmol), potassium phosphate (333.72 mg, 1.57 mmol), and tricyclohexylphosphine (25.19 mg, 89.84 μmol) were added to toluene (5.0 mL) and water (1.0 mL). The atmosphere was purged with nitrogen three times and stirred at 120°C for 12 hours. After completion of the reaction, the mixture was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (DCM / MeOH = 98 / 2) to give compound 5b (110.0 mg). MS m / z (ESI): 309.1 [M+H] + .

[0382] Step 2: Preparation of 1-(4-methoxybenzyl)-6-methylisoquinolin-5-amine (Compound 5c)

[0383] Compound 5b (260 mg, 843.25 μmol) was added to EtOH (5 mL) and stirred thoroughly. Concentrated hydrochloric acid (12 M, 1.05 mL) was then added. The temperature was raised to 60°C, and iron powder (235.48 mg, 4.22 mmol) was slowly added. After the addition was complete, the temperature was raised to 90°C and the reaction mixture was allowed to react for 2 hours. After the reaction was completed, the reaction solution was spin-dried, diluted with 60 mL of water, and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 5c (250 mg). MS m / z (ESI): 279.1 [M+H] + .

[0384] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-(4-methoxybenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 5d)

[0385] Compound 2d (49.63 mg, 143.71 μmol) and 5c (50 mg, 143.71 μmol) were added to pyridine (4 mL). After stirring to dissolve, T3P (3 mL, 50% in EA) was added and the mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was directly spin-dried, 60 mL of water was added, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (EA / PE = 1 / 1) to obtain compound 5d (51.0 mg). MS m / z (ESI): 606.3 [M+H] + .

[0386] Step 4: Preparation of 4-amino-N-(1-(4-methoxybenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 5)

[0387] Compound 5d (35 mg, 57.78 μmol) was added to trifluoroacetic acid (3.0 mL) and reacted at 70°C for 3 hours. After the reaction, the reaction solution was concentrated to dryness and basified by adding saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 5 (15.0 mg). MS m / z (ESI): 456.1 [M+H] + .

[0388] 1H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.42(d,J=5.6Hz,1H),8.23(d,J=8.4Hz,1H),7.97(s,2H), 7.65(d,J=6.0Hz,1H),7.60(d,J=8.8Hz,1H),7.24–7.18(m,2H),6.84–6.78(m,2H),4.58(s,2H),3.68(s,3H),2.41(s,3H).

[0389] Example 6: 4-amino-N-(1-(4-(methoxybenzoyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 7)

[0390]

[0391] Compound 5 (10.0 mg, 21.95 μmol) and NIS (4.94 mg, 21.95 μmol) were dissolved in DMSO (2.0 mL) and reacted at 100°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and directly separated and purified by Prep-HPLC to obtain compound 7 (5.0 mg). MS m / z (ESI): 470.1 [M+H] + .

[0392] 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.98(s,1H),8.61(s,1H),8.58(d,J=6.0Hz,1H),7.99(s,2H),7.97–7.94(m, 1H),7.87(d,J=8.8Hz,1H),7.84–7.79(m,2H),7.68(d,J=8.8Hz,1H),7.11–7.06(m,2H),3.86(s,3H),2.47(s,3H).

[0393] Example 7: 4-amino-N-(1-(hydroxy(4-methoxyphenyl)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 6)

[0394]

[0395] Compound 5 (35 mg, 76.83 μmol) and NIS (17.29 mg, 76.83 μmol) were dissolved in DMSO (3.0 mL) and reacted at 100°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and directly separated and purified by Prep-HPLC to obtain compound 6 (8.0 mg). MS m / z (ESI): 472.1 [M+H] + ;

[0396] 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),8.94(s,1H),8.57(s,1H),8.47(d,J=6.0Hz,1H),8.31(d,J=8.8Hz,1H),7.96(s,2H),7.72(d,J=6.0H z,1H),7.53(d,J=8.8Hz,1H),7.32–7.27(m,2H),6.86–6.82(m,2H),6.36(d,J=5.6Hz,1H),6.30(d,J=5.2Hz,1H),3.69(s,3H),2.39(s,3H).

[0397] Example 8: 4-amino-N-(1-(2-chlorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 10)

[0398]

[0399] Step 1: Preparation of 2-(2-chlorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 10c)

[0400] Compound 10a (1.25 g, 6.08 mmol), 10b (1.70 g, 6.69 mmol), Pd(dppf)Cl2·DCM (496.40 mg, 608.33 μmol), and potassium acetate (1.49 g, 15.21 mmol) were added to 1,4-dioxane (4 mL). The nitrogen atmosphere was replaced three times and the mixture was heated to 100°C for 3 hours. After completion of the reaction, the mixture was filtered through celite, diluted with 100 ml of water, and extracted with EA (50 ml x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain compound 10c (800 mg).

[0401] Step 2: Preparation of 1-(2-chlorobenzyl)-6-methyl-5-nitroisoquinoline (Compound 10d)

[0402] Compound 1h (100 mg, 449.18 μmol), 10c (340.31 mg, 1.35 mmol), palladium acetate (20.17 mg, 89.84 μmol), potassium phosphate (333.72 mg, 1.57 mmol), and tricyclohexylphosphine (25.19 mg, 89.84 μmol) were added to toluene (5 mL) and water (1 mL). After nitrogen substitution three times, the mixture was stirred at 120°C for 12 hours. After completion of the reaction, the mixture was diluted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 95 / 5) to obtain compound 10d (120.0 mg). MS m / z (ESI): 313.0 [M+H] + .

[0403] Step 3: Preparation of 1-(2-chlorobenzyl)-6-methylisoquinolin-5-amine (Compound 10e)

[0404] Compound 10d (90 mg, 287.77 μmol) was added to EtOH (5 mL) and stirred thoroughly. HCl (12 M, 0.36 mL) was then added. The temperature was then raised to 60°C and iron powder (80.36 mg, 1.44 mmol) was slowly added. After the addition was complete, the temperature was raised to 90°C and the reaction was allowed to proceed for 2 hours. After the reaction was complete, the reaction solution was spin-dried, diluted with 60 mL of water, and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 10e (95 mg). MS m / z (ESI): 283.1 [M+H] + .

[0405] Step 4: Preparation of N-(1-(2-chlorobenzyl)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 10f)

[0406] Compound 2d (103.82 mg, 300.60 μmol) and 10e (85 mg, 300.60 μmol) were added to pyridine (3 mL). After stirring to dissolve, T3P (2 mL, 50% in EA) was added and the mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was directly spin-dried, diluted with 60 mL of water, and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (EA / PE = 1 / 1) to obtain compound 10f (127 mg). MS m / z (ESI): 610.2 [M+H] + .

[0407] Step 5: Preparation of 4-amino-N-(1-(2-chlorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 10)

[0408] Compound 10f (125 mg, 204.88 μmol) was added to trifluoroacetic acid (5.0 mL) and reacted at 70°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness, basified by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 85 mg of crude product. 20 mg of the product was separated and purified by Prep-HPLC to obtain compound 10 (4.04 mg). MS m / z (ESI): 460.0 [M+H] + .

[0409] 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.95(s,1H),8.58(s,1H),8.36(d,J=6.0Hz,1H),8.19(d,J=8.8Hz,1H),7. 97(s,2H),7.70–7.64(m,2H),7.51–7.46(m,1H),7.30–7.20(m,2H),7.13–7.08(m,1H),4.77(s,2H),2.44(s,3H).

[0410] Example 9: 4-amino-N-(1-(2-chlorobenzoyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 11)

[0411]

[0412] Compound 10 (20.0 mg, 43.48 μmol) and NIS (24.5 mg, 108.71 μmol) were dissolved in DMSO (2.0 mL) and reacted at 100°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and directly separated and purified by Prep-HPLC to obtain compound 11 (8.0 mg). MS m / z (ESI): 474.0 [M+H] + .

[0413] 1H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.97(s,1H),8.60–8.56(m,2H),8.53(d,J=5.6Hz,1H),8.05–8.02(m,1H),7 .98(s,2H),7.84(d,J=8.8Hz,1H),7.71(dd,J=7.6,1.6Hz,1H),7.64–7.58(m,1H),7.56–7.50(m,2H),2.50(s,3H).

[0414] Example 10: 4-amino-N-(1-((2-chlorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 14)

[0415]

[0416] Compound 10 (25.0 mg, 54.35 μmol) and NIS (13.5 mg, 59.79 μmol) were dissolved in DMSO (2.0 mL) and reacted at 100°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and directly separated and purified by Prep-HPLC to obtain compound 14 (4.0 mg). MS m / z (ESI): 476.0 [M+H] + .

[0417] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.95(s,1H),8.58(s,1H),8.38(d,J=8.4Hz,1H),8.34(d,J=6.0Hz,1H),7.97(s,2 H),7.75–7.65(m,3H),7.44–7.36(m,2H),7.34–7.29(m,1H),6.82(d,J=5.6Hz,1H),6.40(d,J=5.6Hz,1H),2.45(s,3H).

[0418] Example 11: 4-amino-N-(1-(2-chlorobenzyl)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 25)

[0419]

[0420] Step 1: Preparation of N-(1-(2-chlorobenzyl)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 25a)

[0421] Compound 10e (60 mg, 212.19 μmol) and 1f (72 mg, 212.19 μmol) were added to pyridine (3 mL). After stirring to dissolve, T3P (2 mL, 50% in DMF) was added and the mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was directly spin-dried, diluted with 60 mL of water, and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 25a (45 mg). MS m / z (ESI): 604.1 [M+H] + .

[0422] Step 2: Preparation of 4-amino-N-(1-(2-chlorobenzyl)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 25)

[0423] Compound 25a (45 mg, 74.49 μmol) was added to trifluoroacetic acid (5.0 mL) and reacted at 70°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 25 (3.21 mg). MS m / z (ESI): 454.1 [M+H] + .

[0424] 1 H NMR (400MHz, DMSO-d6) δ13.26(s,1H),8.67–8.60(m,2H),8.53(dd,J=8.0,1.6Hz,1H),8.46–8.13(m,4H),7.76(d,J=6.0Hz,1 H),7.72–7.64(m,2H),7.48(dd,J=7.6,1.6Hz,1H),7.31–7.19(m,2H),7.10(dd,J=7.2,2.0Hz,1H),4.77(s,2H),2.46(s,3H).

[0425] Example 12: 4-amino-N-(1-((2-chlorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 24)

[0426]

[0427] Step 1: Preparation of 4-amino-N-(1-(2-chlorobenzoyl)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 24a)

[0428] Compound 25 (20 mg, 44.06 μmol) and NIS (10.41 mg, 46.26 μmol) were dissolved in DMSO (3.0 mL) and reacted at 100°C for 3 hours. The mixture was diluted with 20 mL of water and extracted with EA (15 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 24a (15 mg). MS m / z (ESI): 468.0 [M+H] + .

[0429] Step 2: Preparation of 4-amino-N-(1-((2-chlorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 24)

[0430] Compound 24a (20 mg, 42.74 μmol) was dissolved in methanol (3.0 mL). NaBH4 (14.37 mg, 213.72 μmol) was added under ice-water bath and allowed to react at 0°C for 2 hours. After completion of the reaction, the reaction solution was directly separated and purified by Prep-HPLC to obtain compound 24 (8 mg). MS m / z (ESI): 470.0 [M+H] + .

[0431] 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),8.66–8.60(m,2H),8.55–8.50(m,1H),8.42–8.32(m,3H),8.30–8.16(m,1H),7.80(d,J=6 .0Hz,1H),7.73–7.66(m,3H),7.43–7.36(m,2H),7.34–7.28(m,1H),6.82(d,J=5.6Hz,1H),6.39(d,J=6.8Hz,1H),2.47(s,3H).

[0432] Example 13: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 30)

[0433]

[0434] Step 1: Preparation of methyl 4-aminoimidazo[2,1-f][1,2,4]triazine-7-carboxylate (Compound 30b)

[0435] Compound 30a (200 mg, 0.934 mmol), TEA (472.8 mg, 4.67 mmol), Pd(dppf)Cl2·DCM (76.31 mg, 93.45 μmol), and MeOH (5 mL) were added to an autoclave. After sealing, carbon monoxide was introduced to 1.0-1.2 MPa and heated to 120°C for 5 hours. After the reaction, the reaction solution was cooled to room temperature. A large amount of solid precipitated and was filtered under reduced pressure. The filter cake was washed with clean water and dried under reduced pressure at 50°C. The mixture was then slurried with 5 mL of methanol and filtered to obtain compound 30b (160 mg). MS m / z (ESI): 194.0 [M+H] + .

[0436] Step 2: Preparation of 4-aminoimidazo[2,1-f][1,2,4]triazine-7-carboxylic acid (Compound 30c)

[0437] 30b (50 mg, 258.85 μmol) was added to MeOH (3 mL), followed by a solution of NaOH (51.77 mg, 1.29 mmol) in water (0.5 mL). The mixture was allowed to react overnight at room temperature. After completion of the reaction, the pH of the reaction solution was adjusted to 5-6 with dilute hydrochloric acid. The MeOH was evaporated under reduced pressure to remove the precipitated solid, which was filtered. The filter cake was washed with water and dried under reduced pressure to yield compound 30c (40 mg). MS m / z (ESI): 180.1 [M+H] + .

[0438] Step 3: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 30)

[0439] Compounds 1j (50 mg, 165.70 μmol) and 30c (78.11 mg, 165.70 μmol) were added to pyridine (3 mL). After stirring to dissolve, T3P (2 mL, 50% in DMF) was added and the mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was directly spin-dried, diluted with 60 mL of water, and extracted with EA (30 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Pre-HPLC to yield compound 30 (55.0 mg). MS m / z (ESI): 463.0 [M+H] + .

[0440] 1H NMR (400MHz, DMSO-d6) δ10.38(s,1H),9.25(s,1H),8.69(s,1H),8.61(s,1H),8.39–8.34(m,2H),8.24(s,1H),7. 90(d,J=6.0Hz,1H),7.62(d,J=8.8Hz,1H),7.58–7.51(m,1H),7.39–7.33(m,1H),7.26–7.18(m,2H),2.44(s,3H).

[0441] Example 14: 4-amino-N-(1-(3-chloro-2-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 8)

[0442]

[0443] Step 1: Preparation of 2-(3-chloro-2-fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 8b)

[0444] Compound 8a (2.0 g, 8.9 mmol), 10b (3.4 g, 13.3 mmol), palladium acetate (121.8 mg, 531.6 μmol), 1,1'-bis(diphenylphosphino)ferrocene (312.8 mg, 531.6 μmol), and potassium acetate (1.33 g, 13.3 mmol) were added to 1,4-dioxane (30.0 mL). The mixture was reacted at 100°C under nitrogen for 4 hours, then the temperature was lowered to 65°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was isolated and purified by silica gel column chromatography (PE / EA = 19 / 1) to obtain compound 8b (1.0 g).

[0445] Step 2: Preparation of 1-(3-chloro-2-fluorobenzyl)-6-methyl-5-nitroisoquinoline (Compound 8c)

[0446] Compound 8b (721.8 mg, 2.7 mmol), 1h (200 mg, 889.4 μmol), palladium acetate (40.3 mg, 177.9 μmol), potassium phosphate (667.4 mg, 3.1 mmol), tricyclohexylphosphine (50.4 mg, 177.9 μmol), water (1.5 mL), and toluene (10.0 mL) were added to a reaction flask, the atmosphere was replaced with nitrogen, and the reaction was carried out at 120°C for 12 hours. After the reaction, the reaction solution was concentrated to dryness, and the crude product was separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 8c (140 mg). MS m / z (ESI): 331.1 [M+H] + .

[0447] Step 3: Preparation of 1-(3-chloro-2-fluorobenzyl)-6-methylisoquinolin-5-amine (Compound 8d)

[0448] Compound 8c (130 mg, 393.1 μmol) was dissolved in glacial acetic acid (10.0 mL), the atmosphere was replaced with nitrogen, and zinc powder (311.5 mg, 4.72 mmol) was added portionwise. The reaction was allowed to react at 25°C for 30 minutes. After completion of the reaction, the mixture was filtered and concentrated. The mixture was basified with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 8d (118 mg). MS m / z (ESI): 301.1 [M+H] + .

[0449] Step 4: Preparation of N-(1-(3-chloro-2-fluorobenzyl)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 8e)

[0450] Compounds 8d (110 mg, 365.7 μmol) and 2d (126.3 mg, 365.7 μmol) were dissolved in pyridine (5.0 mL), the atmosphere was replaced with nitrogen, and T3P (2.1 g, 3.34 mmol) was added. The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the mixture was concentrated, basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH = 19 / 1) to obtain compound 8e (176 mg). MS m / z (ESI): 628.2 [M+H] + .

[0451] Step 5: Preparation of 4-amino-N-(1-(3-chloro-2-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 8)

[0452] Compound 8e (176 mg, 280.2 μmol) was added to trifluoroacetic acid (5.0 mL) and reacted at 70°C for 3 hours. After the reaction, the reaction solution was concentrated to dryness, then methanol and potassium carbonate were added and stirred for 10 minutes to alkalize. The mixture was filtered and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 8 (120.0 mg). MS m / z (ESI): 478.0 [M+H] + .

[0453] 1H NMR (400MHz, DMSO-d6) δ11.65(br,1H),8.95(s,1H),8.58(s,1H),8.36(d,J=6.0Hz,1H),8.26(d,J=8.8Hz,1H),7.97(s,2H ),7.70(d,J=8.8Hz,1H),7.67(d,J=6.0Hz,1H),7.46(td,J=7.6,1.6Hz,1H),7.21–7.12(m,2H),4.76(s,2H),2.45(s,3H).

[0454] Example 15: 4-amino-N-(1-((3-chloro-2-fluorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 9)

[0455]

[0456] Compound 8 (100 mg, 209.2 μmol) and NIS (47.6 mg, 209.2 μmol) were dissolved in DMSO (4.0 mL) and reacted at 100°C for 4 hours. After the reaction, the reaction solution was cooled to room temperature and directly separated and purified by Prep-HPLC to obtain compound 9 (1.7 mg). MS m / z (ESI): 494.0 [M+H] + .

[0457] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.95(s,1H),8.58(s,1H),8.38(d,J=6.0Hz,2H),7.97(s,2H),7.73(d,J=5.9Hz,1H),7.6 9(d,J=8.7Hz,1H),7.64(t,J=6.9Hz,1H),7.50(t,J=7.0Hz,1H),7.28(t,J=7.9Hz,1H),6.79(s,1H),6.57(s,1H),2.45(s,3H).

[0458] Example 16: 4-amino-N-(1-((4-((dimethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 40)

[0459]

[0460] Step 1: Preparation of N-(4-((dimethylamino)methyl)phenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 40b)

[0461] Compound 40a (121.46 mg, 808.53 μmol) and 1h (150 mg, 673.77 μmol) were added to isopropanol (5 mL), followed by the addition of TFA (92 mg, 808.53 μmol). The mixture was stirred at 100°C for 18 hours. After the reaction, the reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with isopropanol, and the resulting solid was dried under reduced pressure to yield compound 40b (170 mg). MS m / z (ESI): 337.2 [M+H] + .

[0462] Step 2: N 1 Preparation of -(4-((dimethylamino)methyl)phenyl)-6-methylisoquinoline-1,5-diamine (Compound 40c)

[0463] Compound 40b (170 mg, 505.37 μmol) was added to ethanol (8 mL) and water (0.5 mL), followed by iron powder (141.12 mg, 2.53 mmol) and concentrated hydrochloric acid (12 M, 630 μL). The mixture was heated to 90°C and stirred for 2 hours. After the reaction, the solvent was concentrated under reduced pressure to remove most of the solvent. The reaction mixture was diluted with water and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 40c (120 mg). MS m / z (ESI): 307.2 [M+H] + .

[0464] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((4-((dimethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 40d)

[0465] Compound 1f (50 mg, 147.34 μmol) and 40c (45.15 mg, 147.34 μmol) were added to pyridine (3 mL), followed by T3P (2 mL, 50% in DMF). The mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was directly dried, basified by adding saturated sodium bicarbonate solution, and extracted with EA. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 40d (110.0 mg). MS m / z (ESI): 628.2 [M+H] + .

[0466] Step 4: Preparation of 4-amino-N-(1-((4-((dimethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 40)

[0467] Compound 40d (100 mg, 159.30 μmol) was added to trifluoroacetic acid (5.0 mL) and reacted at 70°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated sodium bicarbonate solution. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 40 (8.0 mg). MS m / z (ESI): 478.2 [M+H] + .

[0468] 1 H NMR(400MHz,DMSO-d6)δ13.27–12.46(br,1H),10.21–9.56(m,2H),8.94–8.21(m,5H),8.00–7.67(m,5H) ,7.50(d,J=8.4Hz,2H),7.34(d,J=6.4Hz,1H),4.28(d,J=4.8Hz,2H),2.76(d,J=4.8Hz,6H),2.48(s,3H).

[0469] Example 17: 4-amino-N-(1-(4-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 13)

[0470]

[0471] Step 1: Preparation of 1-(4-fluorobenzyl)-6-methyl-5-nitroisoquinoline (Compound 13b)

[0472] Compound 1h (200 mg, 898.36 μmol), 13a (1.7 g, 7.19 mmol), palladium acetate (40.34 mg, 179.67 μmol), tricyclohexylphosphine (25.19 mg, 89.84 μmol), and potassium phosphate (667.43 mg, 3.14 mmol) were added to toluene (3.0 mL) and water (1 mL). The atmosphere was purged with nitrogen three times and the mixture was reacted at 120°C for 12 hours. After completion of the reaction, the mixture was filtered through celite, 200 mL of water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM:MeOH = 20:1) to afford compound 13b (165 mg). MS m / z (ESI): 297.1 [M+H] + .

[0473] Step 2: Preparation of 1-(4-fluorobenzyl)-6-methylisoquinolin-5-amine (Compound 13c)

[0474] Compound 13b (210 mg, 708.75 μmol) was added to ethanol (3.0 mL) and water (1 mL), followed by the addition of iron powder (197.92 mg, 3.54 mmol) and concentrated hydrochloric acid (12 M, 2 mL). The atmosphere was purged with nitrogen three times and the reaction was continued at 90°C for 3.5 hours. After completion of the reaction, the mixture was filtered through celite, 200 mL of water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM / MeOH = 20 / 1) to obtain compound 13c (165 mg). MS m / z (ESI): 267.2 [M+H] + .

[0475] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-(4-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 13d)

[0476] Compound 13c (36 mg, 135.18 μmol) and 2d (56.02 mg, 162.22 μmol) were added to pyridine (3.0 mL), followed by T3P (129.03 mg, 405.54 μmol), and the mixture was allowed to react at room temperature for 1 hour. After the reaction, 50 mL of water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM / MeOH = 20:1) to obtain compound 13d (51 mg). MS m / z (ESI): 594.2 [M+H] + .

[0477] Step 4: Preparation of 4-amino-N-(1-(4-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 13)

[0478] Compound 13d (101 mg, 170.13 μmol) was added to trifluoroacetic acid (3.0 mL) and reacted at 70°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated sodium bicarbonate solution. The organic phase was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The organic phase was separated and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 13 (1.3 mg). MS m / z (ESI): 444.1 [M+H] + .

[0479] 1H NMR (400MHz, DMSO-d6) δ11.61(s,1H),9.04(s,1H),8.59(s,1H),8.51(d,J=4Hz,1H),8.45(d,J=8.8Hz,1H),8.24(br s,2H),7.97(d,J=6.4Hz,1H),7.82(d,J=8.8Hz,1H),7.42-7.36(m,2H),7.17-7.10(m,2H),4.82(s,2H),2.49(s,3H).

[0480] Example 18: 4-amino-N-(1-((4-fluorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 15)

[0481]

[0482] Compound 13 (20 mg, 45.1 μmol) and NIS (10.15 mg, 45.10 μmol) were dissolved in DMSO (3.0 mL) and reacted at 100°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and directly purified by Prep-HPLC to obtain compound 15 (2.5 mg). MS m / z (ESI): 460.1 [M+H] + .

[0483] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.47(d,J=6.0Hz,1H),8.34(d,J=8.8Hz,1H),7.97(s,2 H),7.74(d,J=5.6Hz,1H),7.56(d,J=4.8Hz,1H),7.47-7.40(m,2H),7.15-7.07(m,2H),6.51-6.39(m,2H),2.40(s,3H).

[0484] Example 19: 4-amino-N-(1-(3-chlorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 16)

[0485]

[0486] Step 1: Preparation of 2-(3-chlorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 16b)

[0487] Compound 16a (1 g, 4.87 mmol), 10b (1.36 g, 5.35 mmol), Pd(dppf)Cl2 (397.12 mg, 486.67 μmol), and KOAc (1.19 g, 12.17 mmol) were added to 1,4-dioxane (3.0 mL). The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 3 hours. After completion of the reaction, the mixture was filtered through celite, 200 mL of water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM / MeOH = 20 / 1) to obtain compound 16b (623 mg).

[0488] Step 2: Preparation of 1-(3-chlorobenzyl)-6-methyl-5-nitroisoquinoline (Compound 16c)

[0489] Compound 16b (1.36 g, 5.39 mmol), 1h (400 mg, 1.80 mmol), Pd(OAc)2 (80.68 mg, 359.34 μmol), tricyclohexylphosphine (50.39 mg, 179.67 μmol), and K3PO4 (1.33 g, 6.29 mmol) were added to toluene (3.0 mL) and water (1 mL). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 120°C for 12 hours. After completion of the reaction, the mixture was filtered through celite, 200 mL of water was added, and the mixture was extracted with EA and washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM / MeOH = 60 / 1) to afford compound 16c (412 mg). MS m / z (ESI): 313.1 [M+H] + .

[0490] Step 3: Preparation of 1-(3-chlorobenzyl)-6-methylisoquinolin-5-amine (Compound 16d)

[0491] Compound 16c (400 mg, 1.28 mmol) was added to ethanol (3.0 mL) and water (1 mL), followed by the addition of iron powder (357.15 mg, 6.39 mmol) and concentrated hydrochloric acid (12 M, 4 mL). The atmosphere was purged with nitrogen three times and the reaction was continued at 90°C for 3 hours. After completion of the reaction, the mixture was filtered through celite, 200 mL of water was added, and the mixture was extracted with a mixed solvent of chloroform and isopropanol (volume ratio 4:1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 16d (325 mg). MS m / z (ESI): 283.1 [M+H] + .

[0492] Step 4: Preparation of N-(1-(3-chlorobenzyl)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 16e)

[0493] Compounds 16d (91 mg, 321.82 μmol) and 2d (133.38 mg, 386.18 μmol) were added to pyridine (2.0 mL), followed by T3P (307.19 mg, 965.46 μmol), and the mixture was allowed to react at 25°C for 2 hours. After the reaction, 100 mL of water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM / MeOH = 40 / 1) to obtain compound 16e (85 mg). MS m / z (ESI): 610.0 [M+H] + .

[0494] Step 5: Preparation of 4-amino-N-(1-(3-chlorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 16)

[0495] Compound 16e (80 mg, 131.12 μmol) was added to trifluoroacetic acid (2.0 mL) and reacted at 70°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness, alkalized by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The product was separated and purified by Prep-HPLC to obtain compound 16 (6.1 mg). MS m / z (ESI): 460.2 [M+H] + .

[0496] 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),8.95(s,1H),8.58(s,1H),8.44(d,J=6.0Hz,1H),8.29(d,J=8.8Hz,1H),7.9 8(s,2H),7.69(d,J=6.0Hz,1H),7.64(d,J=12.4Hz,1H),7.49(s,1H),7.32–7.19(m,3H),4.68(s,2H),2.42(s,3H).

[0497] Example 20: 4-amino-N-(1-((3-chlorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 17)

[0498]

[0499] Compound 16 (54 mg, 117.40 μmol) and NIS (26.41 mg, 117.40 μmol) were dissolved in DMSO (2.0 mL) and reacted at 100°C for 1 hour. After the reaction, the reaction solution was cooled to room temperature and directly separated and purified by Prep-HPLC to obtain compound 17 (13.3 mg). MS m / z (ESI): 476.0 [M+H] + .

[0500] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.47(d,J=6Hz,1H),8.38(d,J=4.8Hz,1H),7.97(s,2H),7.74(d,J=6.0Hz ,1H),7.59(d,J=8.8Hz,1H),7.50(s,1H),7.36–7.32(m,2H),7.30–7.26(m,1H),6.58(d,J=5.4Hz,1H),6.45(d,J=4.4Hz,1H),2.40(s,3H).

[0501] Example 21: 4-amino-N-(6-methyl-1-(2-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 29)

[0502]

[0503] Step 1: Preparation of 4,4,5,5-tetramethyl-2-(2-(trifluoromethyl)benzyl)-1,3,2-dioxaborolane (Compound 29b)

[0504] Compound 29a (2.0 g, 8.2 mmol), 10b (2.55 g, 9.8 mmol), potassium carbonate (3.47 g, 24.6 mmol), and tetrakis(triphenylphosphine)palladium (478.6 mg, 410.0 μmol) were added to 1,4-dioxane (50.0 mL), the atmosphere was replaced with nitrogen, and the reaction was carried out at 95°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was isolated and purified by silica gel column chromatography (PE / EA = 19 / 1) to obtain compound 29b (1.3 g).

[0505] Step 2: Preparation of 6-methyl-5-nitro-1-(2-(trifluoromethyl)benzyl)isoquinoline (Compound 29c)

[0506] Compound 29b (1.1 g, 3.8 mmol), 1h (200 mg, 889.4 μmol), palladium acetate (40.3 mg, 177.9 μmol), potassium phosphate (667.4 mg, 3.1 mmol), and tricyclohexylphosphine (50.4 mg, 177.9 μmol) were added to a mixture of water (1.5 mL) and toluene (10.0 mL). The atmosphere was replaced with nitrogen and the mixture was reacted at 120°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 29c (91 mg). MS m / z (ESI): 347.0 [M+H] + .

[0507] Step 3: Preparation of 6-methyl-1-(2-(trifluoromethyl)benzyl)isoquinolin-5-amine (Compound 29d)

[0508] Compound 29c (91 mg, 262.8 μmol), iron powder (44.9 mg, 788.3 μmol), and ammonium chloride (28.7 mg, 525.3 μmol) were added to a mixture of ethanol (6.0 mL) and water (2.0 mL). The atmosphere was replaced with nitrogen and the mixture was allowed to react at 80°C for 3 hours. After completion of the reaction, the mixture was filtered and concentrated. The mixture was basified with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by reverse-phase column chromatography on a C18 column (0.05% aqueous ammonium bicarbonate solution / acetonitrile = 60 / 40) to yield compound 29d (20 mg). MS m / z (ESI): 317.1 [M+H] + .

[0509] Step 4: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(6-methyl-1-(2-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 29e)

[0510] Compound 29d (20.0 mg, 63.2 μmol) and 2d (21.8 mg, 63.2 μmol) were dissolved in pyridine (2.0 mL), the atmosphere was replaced with nitrogen, and T3P (0.5 mL) was added. The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by reverse-phase chromatography on a C18 column (0.05% aqueous ammonium bicarbonate / acetonitrile = 60 / 40) to obtain compound 29e (18 mg). MS m / z (ESI): 644.0 [M+H] + .

[0511] Step 5: Preparation of 4-amino-N-(6-methyl-1-(2-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 29)

[0512] Compound 29e (18 mg, 28.0 μmol) was added to trifluoroacetic acid (2.0 mL) and reacted at 70°C for 3 hours. After the reaction, the reaction solution was concentrated to dryness, and then methanol and potassium carbonate were added and stirred thoroughly. The mixture was filtered and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 29 (3.0 mg). MS m / z (ESI): 494.1 [M+H] + .

[0513] 1 H NMR (400MHz, DMSO-d6) δ11.67(s,1H),8.95(s,1H),8.58(s,1H),8.36(d,J=6.0Hz,1H),8.13(d,J=8.7Hz,1H),7.97(s,2H),7.77(d, J=7.5Hz,1H),7.68(t,J=6.9Hz,2H),7.54(t,J=7.5Hz,1H),7.46(t,J=7.6Hz,1H),7.11(d,J=7.7Hz,1H),4.86(s,2H),2.44(s,3H).

[0514] Example 22: 4-amino-N-(1-(4-fluoro-2-(trifluoromethyl)benzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 31)

[0515]

[0516] Step 1: Preparation of 1,6-dimethyl-5-nitroisoquinoline (Compound 31b)

[0517] Compound 1h (3.0 g, 13.3 mmol), 31a (16.8 g, 66.7 mmol), palladium acetate (605.1 mg, 2.7 mmol), potassium phosphate (10.0 g, 46.7 mmol), and tricyclohexylphosphine (755.8 mg, 2.7 mmol) were added to a mixture of water (15.0 mL) and toluene (85.0 mL). The atmosphere was replaced with nitrogen and the mixture was reacted at 100°C for 16 hours. After the reaction, the reaction solution was concentrated to dryness, and the crude product was separated and purified by silica gel column chromatography (PE / EA = 40 / 60) to obtain compound 31b (2.69 g). MS m / z (ESI): 203.1 [M+H] + .

[0518] Step 2: Preparation of 1,6-dimethylisoquinolin-5-amine (Compound 31c)

[0519] Compound 31b (2.69 g, 13.3 mmol), iron powder (2.27 g, 39.9 mmol), and ammonium chloride (1.45 g, 26.6 mmol) were added to a mixture of ethanol (90.0 mL) and water (30.0 mL). The atmosphere was replaced with nitrogen and the mixture was allowed to react at 80°C for 3 hours. After the reaction, the mixture was filtered and concentrated. The mixture was basified with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (100% EA) to yield compound 31c (2.25 g). MS m / z (ESI): 173.1 [M+H] + .

[0520] Step 3: Preparation of 3-((5-amino-6-methylisoquinolin-1-yl)methyl)-2,4-dimethylpentyl-3-ol (Compound 31e)

[0521] Compound 31c (2.69 g, 13.3 mmol) was dissolved in tetrahydrofuran (50.0 mL) and cooled to -60°C under nitrogen. n-Butyllithium (20 mL, 49.6 mmol, 2.5 M in n-hexane) was slowly added dropwise while maintaining this temperature. The mixture was allowed to react at -60°C for 1 hour. Compound 31d (4.87 g, 41.8 mmol) was then slowly added dropwise. The mixture was allowed to react at -60°C for 3 hours. After the reaction, ice water was slowly added dropwise in an ice-water bath to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (100% EA) to yield compound 31e (3.33 g). MS m / z (ESI): 287.1 [M+H] + .

[0522] Step 4: Preparation of 1-(4-fluoro-2-(trifluoromethyl)benzyl)-6-methylisoquinolin-5-amine (Compound 31g)

[0523] Compound 31e (100 mg, 349.2 μmol), 31f (173.2 mg, 698.3 μmol), palladium trifluoroacetate (11.8 mg, 34.9 μmol), cesium carbonate (229.8 mg, 698.3 μmol), and tricyclohexylphosphine (19.8 mg, 69.8 μmol) were added to toluene (10.0 mL), the atmosphere was replaced with nitrogen, and the mixture was reacted at 120°C for 3 hours. After the reaction, the reaction solution was concentrated to dryness, and the crude product was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 31g (100 mg). MS m / z (ESI): 335.1 [M+H] + .

[0524] Step 5: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-(4-fluoro-2-(trifluoromethyl)benzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 31h)

[0525] Compound 31g (115.0 mg, 344.0 μmol) and 2d (118.8 mg, 344.0 μmol) were dissolved in pyridine (5.0 mL), the atmosphere was purged with nitrogen, and T3P (3.0 mL, 50% in DMF) was added. The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, basified with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by reverse-phase column chromatography on a C18 column (0.05% aqueous ammonium bicarbonate / acetonitrile = 60 / 40) to yield compound 31h (200 mg). MS m / z (ESI): 662.1 [M+H] + .

[0526] Step 6: Preparation of 4-amino-N-(1-(4-fluoro-2-(trifluoromethyl)benzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 31)

[0527] Compound 31h (200 mg, 302.3 μmol) was added to trifluoroacetic acid (5.0 mL) and reacted at 70°C for 3 hours. After the reaction, the reaction solution was concentrated to dryness, and then methanol and potassium carbonate were added, stirred for 10 minutes, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 31 (130.0 mg). MS m / z (ESI): 512.1 [M+H] + .

[0528] 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.95(s,1H),8.58(s,1H),8.33(d,J=6.0Hz,1H),8.17(d,J=8.7Hz,1H),7. 96(s,2H),7.71–7.63(m,3H),7.45(td,J=8.5,2.7Hz,1H),7.24(dd,J=8.5,5.6Hz,1H),4.85(s,2H),2.45(s,3H).

[0529] Example 23: 4-amino-N-(6-methyl-1-(3-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 19)

[0530]

[0531] Step 1: Preparation of 6-methyl-5-nitro-1-(3-(trifluoromethyl)benzyl)isoquinoline (Compound 19b)

[0532] Compound 19a (300.0 mg, 1.35 mmol), 1h (424.08 mg, 1.48 mmol), Pd(OAc)2 (60.51 mg, 269.51 μmol), tricyclohexylphosphine (75.58 mg, 269.51 μmol), and K3PO4 (858.13 mg, 4.04 mmol) were added to toluene (5.0 mL) and water (1.0 mL). After nitrogen substitution three times, the mixture was reacted at 120°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to dryness, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain compound 19b (322.0 mg). MS m / z (ESI): 347.0 [M+H] + .

[0533] Step 2: Preparation of 6-methyl-1-(3-(trifluoromethyl)benzyl)isoquinolin-5-amine (Compound 19c)

[0534] Compound 19b (300.0 mg, 866.29 μmol) was added to ethanol (6.0 mL) and water (2.0 mL). Iron powder (145.15 mg, 2.60 mmol) and ammonium chloride (92.68 mg, 1.73 mmol) were added sequentially. The mixture was reacted at 80°C for 3 hours. After the reaction, the reaction solution was filtered and the filtrate was concentrated to obtain compound 19c (270.0 mg). MS m / z (ESI): 317.1 [M+H] + .

[0535] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(6-methyl-1-(3-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 19d)

[0536] Compound 19c (16.5 mg, 108.0 μmol) was added to pyridine (5.0 mL), followed by compound 2d (324.28 mg, 938.92 μmol) and T3P (2.0 mL, 50% in DMF). The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, basified by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 19d (370.0 mg). MS m / z (ESI): 644.1 [M+H] + .

[0537] Step 4: Preparation of 4-amino-N-(6-methyl-1-(3-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 19)

[0538] Compound 19d (50.0 mg, 77.68 μmol) was added to trifluoroacetic acid (2.0 mL) and reacted at 80°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 19 (12.3 mg). MS m / z (ESI): 494.1 [M+H] + .

[0539] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.94(s,1H),8.58(s,1H),8.44(d,J=5.92Hz,1H),8.32(d,J=8.72Hz,1H) ,7.97(s,2H),7.73(s,1H),7.70–7.64(m,2H),7.62-7.59(m,1H),7.57-7.48(m,2H),4.79(s,2H),2.43(s,3H).

[0540] Example 24: 4-amino-N-(6-methyl-1-(3-(trifluoromethyl)benzoyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 22) and 4-amino-N-(1-(hydroxy(3-(trifluoromethyl)phenyl)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 23)

[0541]

[0542] Compound 19 (60.0 mg, 121.58 μmol) and NIS (27.35 mg, 121.58 μmol) were dissolved in DMSO (1.0 mL) and reacted at 100°C for 1.5 hours. After the reaction, the reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was first purified by silica gel column chromatography (DCM / MeOH = 95 / 5) to obtain crude products of compound 22 and compound 23, respectively. These products were then separated and purified by Prep-HPLC to obtain compound 22 (10.26 mg). MS m / z (ESI): 508.1 [M+H] + ; and compound 23 (10.35 mg), MS m / z (ESI): 510.1 [M+H] + .

[0543] Compound 22: 1 H NMR(400MHz,DMSO-d6)δ11.76(s,1H),8.98(s,1H),8.64-8.61(m,2H),8.21-8.14(m,3H),8.12-8.08(m,1H ),8.05(dd,J=5.8,0.92Hz,1H),7.99(s,2H),7.82(t,J=7.84Hz,1H),7.75(d,J=8.76Hz,1H),2.49(s,3H).

[0544] Compound 23: 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.47(d,J=5.88Hz,1H),8.40(d,J=8.76Hz,1H),7.97(s,2H),7.85(s,1H),7.74(dd, J=5.84,0.84Hz,1H),7.65(d,J=7.72Hz,1H),7.62-7.58(m,2H),7.53(t,J =7.68Hz,1H),6.66(d,J=5.68Hz,1H),6.57(d,J=5.68Hz,1H),2.41(s,3H).

[0545] Example 25: 4-amino-N-(1-(4-chloro-2-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 26)

[0546]

[0547] Step 1: Preparation of 2-(4-chloro-2-fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Compound 26b)

[0548] Compound 26a (1.5 g, 6.71 mmol), 10b (2.05 g, 8.05 mmol), Pd(OAc)2 (150.70 mg, 671.23 μmol), dppf (387.0 mg, 671.23 μmol), and KOAc (988.12 mg, 10.07 mmol) were added to 1,4-dioxane (20.0 mL). The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 4 hours, followed by a further reaction at 65°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain compound 26b (850.0 mg).

[0549] Step 2: Preparation of 1-(4-chloro-2-fluorobenzyl)-6-methyl-5-nitroisoquinoline (Compound 26c)

[0550] Compound 26b (850.0 mg, 3.14 mmol), 1h (350.0 mg, 1.57 mmol), Pd(OAc)2 (70.59 mg, 314.43 μmol), tricyclohexylphosphine (88.17 mg, 314.43 μmol), and K3PO4 (1.0 g, 4.72 mmol) were added to toluene (10.0 mL) and water (2.0 mL). After nitrogen substitution three times, the mixture was reacted at 120°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to dryness, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain compound 26c (270.0 mg). MS m / z (ESI): 331.0 [M+H] + .

[0551] Step 3: Preparation of 1-(4-chloro-2-fluorobenzyl)-6-methylisoquinolin-5-amine (Compound 26d)

[0552] Compound 26c (270.0 mg, 816.35 μmol) was added to ethanol (6.0 mL) and water (2.0 mL). Iron powder (136.78 mg, 2.45 mmol) and ammonium chloride (43.67 mg, 816.35 μmol) were then added sequentially. The mixture was reacted at 80°C for 2 hours. After completion of the reaction, the reaction solution was filtered and concentrated to yield compound 26d (200.0 mg). MS m / z (ESI): 301.1 [M+H] + .

[0553] Step 4: Preparation of N-(1-(4-chloro-2-fluorobenzyl)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 26e)

[0554] Compound 26d (200.0 mg, 664.99 μmol) was added to pyridine (10.0 mL), followed by compound 2d (229.67 mg, 664.99 μmol) and T3P (3.0 mL, 50% in DMF). The mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness, basified by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 26e (400.0 mg). MS m / z (ESI): 628.0 [M+H] + .

[0555] Step 5: Preparation of 4-amino-N-(1-(4-chloro-2-fluorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 26)

[0556] Compound 26e (400.0 mg, 636.83 μmol) was added to trifluoroacetic acid (5.0 mL) and reacted at 80°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 26 (240.0 mg). MS m / z (ESI): 478.0 [M+H] + .

[0557] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),8.95(s,1H),8.58(s,1H),8.36(d,J=6.0Hz,1H),8.24(d,J=8.64Hz,1H) ,7.97(s,2H),7.69–7.66(m,2H),7.42(dd,J=10.32,2.0Hz,1H),7.25-7.18(m,2H),4.69(s,2H),2.45(s,3H).

[0558] Example 26: 4-amino-N-(1-(4-chloro-2-fluorobenzoyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 27) and 4-amino-N-(1-((4-chloro-2-fluorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 28)

[0559]

[0560] Compound 26 (80.0 mg, 167.38 μmol) and NIS (37.66 mg, 167.38 μmol) were dissolved in DMSO (2.0 mL) and reacted at 100°C for 1.5 hours. After the reaction, the reaction solution was cooled to room temperature, added with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 27 (19.26 mg) was separated and purified by Prep-HPLC. MS m / z (ESI): 492.0 [M+H] + ; and compound 28 (15.38 mg), MS m / z (ESI): 494.0 [M+H] + .

[0561] Compound 27: 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H),8.98(s,1H),8.60(s,1H),8.55(d,J=5.8Hz,1H),8.37(d,J=8.76Hz,1H),8.03(d,J=5.84Hz,1H),7 .99(s,2H),7.87(t,J=8.08Hz,1H),7.80(d,J=8.84Hz,1H),7.60(dd,J=10.36,1.96Hz,1H),7.52(dd,J=8.36,1.96Hz,1H),2.50(s,3H).

[0562] Compound 28: 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.96(s,1H),8.58(s,1H),8.39-8.33(m,2H),7.98(s,2H),7. 75(d,J=5.92Hz,1H),7.70-7.65(m,2H),7.36-7.31(m,2H),6.75(s,1H),6.55(s,1H),2.45(s,3H).

[0563] Example 27: 4-amino-N-(1-(4-chlorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 18)

[0564]

[0565] Step 1: Preparation of 1-(4-chlorobenzyl)-6-methyl-5-nitroisoquinoline (Compound 18b)

[0566] Compound 18a (510.5 mg, 2020.0 μmol), 1h (300.0 mg, 1350.0 μmol), palladium acetate (60.5 mg, 269.5 μmol), potassium phosphate (1000.0 mg, 4720.0 μmol), and tricyclohexylphosphine (75.6 mg, 269.5 μmol) were added to toluene (12.0 mL) and water (2.0 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 120°C for 12 hours. After the reaction, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain compound 18b (310.0 mg). MS m / z (ESI): 313.0 [M+H] + .

[0567] Step 2: Preparation of 1-(4-chlorobenzyl)-6-methylisoquinolin-5-amine (Compound 18c)

[0568] Compound 18b (310.0 mg, 991.2 μmol) was dissolved in ethanol (12.0 mL), followed by the addition of iron powder (276.8 mg, 4960.0 μmol), concentrated hydrochloric acid (12 M, 0.6 mL), and water (3.0 mL). The temperature was raised to 90°C and the reaction mixture was allowed to react for 3.5 hours. After the reaction, saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to alkaline. The solid was removed by filtration through celite, and the filter cake was washed with ethyl acetate. The liquid was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 18c (190.0 mg). MS m / z (ESI): 283.1 [M+H] + .

[0569] Step 3: Preparation of N-(1-(4-chlorobenzyl)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 18d)

[0570] Compound 18c (190.0 mg, 671.9 μmol) and 2d (232.1 mg, 671.9 μmol) were dissolved in pyridine (10.0 mL), and 1-propylphosphoric anhydride (427.6 mg, 1340.0 μmol) was added dropwise. The mixture was allowed to react at 25°C for 12 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The reaction solution was diluted with ethyl acetate and washed three times with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 3 / 2) to obtain compound 18d (215.0 mg). MS m / z (ESI): 610.2 [M+H] + .

[0571] Step 4: Preparation of 4-amino-N-(1-(4-chlorobenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 18)

[0572] Compound 18d (215.0 mg, 352.4 μmol) was added to trifluoroacetic acid (10.0 mL) and reacted at 70°C for 4 hours. After completion of the reaction, the reaction solution was concentrated to dryness, redissolved in dichloromethane, and basified with triethylamine. The crude product was concentrated to obtain a crude product, which was separated and purified by Prep-HPLC to obtain compound 18 (66.0 mg). MS m / z (ESI): 460.0 [M+H] + .

[0573] 1 HNMR (400MHz, DMSO-d6) δ11.63(s,1H),8.94(s,1H),8.57(s,1H),8.43(d,J=6.0Hz,1H),8.24(d,J=8.7H z,1H),7.97(s,2H),7.68(d,J=6.0Hz,1H),7.63(d,J=8.8Hz,1H),7.32(s,4H),4.66(s,2H),2.42(s,3H).

[0574] Example 28: 4-amino-N-(1-((4-chlorophenyl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 20) and 4-amino-N-(1-(4-chlorobenzoyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 21)

[0575]

[0576] Compound 18 (57.0 mg, 123.9 μmol) and NIS (30.7 mg, 136.3 μmol) were dissolved in DMSO (3.0 mL) and reacted at 100°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and directly separated and purified by Prep-HPLC to obtain compound 20 (16.0 mg). MS m / z (ESI): 476.0 [M+H] + ; and compound 21 (10.0 mg), MS m / z (ESI): 474.0 [M+H] + .

[0577] Compound 20: 1 HNMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.47(d,J=5.7Hz,1H),8.33(d,J=8.8Hz,1H),7.97(s,2H),7. 75(d,J=5.6Hz,1H),7.57(d,J=8.7Hz,1H),7.42(d,J=8.2Hz,2H),7.36(d,J=8.3Hz,2H),6.55(s,1H),6.43(s,1H),2.40(s,3H).

[0578] Compound 21: 1 HNMR (400MHz, DMSO-d6) δ11.75(s,1H),8.98(s,1H),8.61(s,1H),8.60(d,J=6.0Hz,1H),8.02(d,J=3.6Hz,1H ),8.00(s,1H),7.99(s,2H),7.88(d,J=8.4Hz,2H),7.72(d,J=8.8Hz,1H),7.65(d,J=8.6Hz,2H),2.48(s,3H).

[0579] Example 29: 4-amino-N-(6-methyl-1-(4-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 34)

[0580]

[0581] Step 1: Preparation of 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)benzyl)-1,3,2-dioxaborolane (Compound 34b)

[0582] Compound 34a (3000.0 mg, 12550.0 μmol), 10b (3820.0 mg, 15060.0 μmol), potassium carbonate (5200.0 mg, 37650.0 μmol), and tetrakis(triphenylphosphine)palladium (725.2 mg, 627.5 μmol) were added to 1,4-dioxane (50.0 mL). The atmosphere was purged with nitrogen three times and the temperature was raised to 95°C for 16 hours. After completion of the reaction, the reaction mixture was filtered to remove the solids, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated and separated and purified by silica gel column chromatography (PE / EA = 19 / 1) to obtain compound 34b (470.0 mg). MS m / z (ESI): 287.0 [M+H] + .

[0583] Step 2: Preparation of 6-methyl-5-nitro-1-(4-(trifluoromethyl)benzyl)isoquinoline (Compound 34c)

[0584] The preparation method of compound 18b was followed by reference to the first step of Example 27 except that compound 18a was replaced by compound 34b to obtain compound 34c (165.0 mg). MS m / z (ESI): 347.0 [M+H] + .

[0585] Step 3: Preparation of 6-methyl-1-(4-(trifluoromethyl)benzyl)isoquinolin-5-amine (Compound 34d)

[0586] Compound 34c (165.0 mg, 476.5 μmol) was dissolved in methanol (10.0 mL), followed by the addition of iron powder (133.1 mg, 2380.0 μmol), ammonium chloride (63.7 mg, 1190.0 μmol), and water (5.0 mL). The mixture was heated to 90°C and reacted for 6 hours. After completion of the reaction, the solid was removed by filtration using celite. The filter cake was washed with ethyl acetate, and the filtrate was concentrated and purified by silica gel column chromatography (PE / EA = 1 / 1) to yield compound 34d (100.0 mg). MS m / z (ESI): 317.1 [M+H] + .

[0587] Step 4: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(6-methyl-1-(4-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 34e)

[0588] The preparation method of compound 18d in step 3 of Example 27 was followed except that compound 18c was replaced by compound 34d to obtain compound 34e (148.0 mg). MS m / z (ESI): 644.3 [M+H] + .

[0589] Step 5: Preparation of 4-amino-N-(6-methyl-1-(4-(trifluoromethyl)benzyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 4)

[0590] The crude product was isolated and purified by reverse-phase column chromatography on a C18 column (acetonitrile / 0.05% aqueous formic acid = 60 / 40) to obtain compound 34 (85.0 mg). MS m / z (ESI): 494.1 [M+H]+.

[0591] 1 HNMR (400MHz, DMSO-d6) δ11.63(s,1H),8.94(s,1H),8.57(s,1H),8.44(d,J=6.0Hz,1H),8.26(d,J=8.7Hz,1H ),7.96(s,2H),7.69(d,J=6.0Hz,1H),7.64(d,J=8.7Hz,3H),7.52(d,J=8.1Hz,2H),4.78(s,2H),2.42(s,3H).

[0592] Example 30: 4-amino-N-(1-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 33) and 4-amino-N-(6-methyl-1-(4-(trifluoromethyl)benzoyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 32)

[0593]

[0594] Compound 34 (80.0 mg, 162.1 μmol) and NIS (40.1 mg, 178.3 μmol) were dissolved in DMSO (3.0 mL) and reacted at 100°C for 3 hours. After the reaction, the reaction solution was cooled to room temperature and directly purified by C18 reverse-phase column chromatography (acetonitrile / 0.05% formic acid aqueous solution = 40 / 60) to obtain compound 33 (32.0 mg). MS m / z (ESI): 510.1 [M+H] + ; and compound 32 (12.0 mg), MS m / z (ESI): 508.1 [M+H] +

[0595] Compound 33: 1HNMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.47(d,J=5.9Hz,1H),8.36(d,J=8.8Hz,1H),7.96(s,2H) ,7.75(d,J=6.1Hz,1H),7.69-7.63(m,4H),7.57(d,J=8.9Hz,1H),6.68(d,J=5.5Hz,1H),6.52(d,J=5.1Hz,1H),2.40(s,3H).

[0596] Compound 32: 1 HNMR (400MHz, DMSO-d6) δ11.76(s,1H),8.98(s,1H),8.62(d,J=5.9Hz,2H),8.14(d,J=8.7Hz,1H),8.07(d,J =8.1Hz,2H),8.04(d,J=5.9Hz,1H),7.99(s,2H),7.94(d,J=8.3Hz,2H),7.75(d,J=8.8Hz,1H),2.49(s,3H).

[0597] Example 31: 4-amino-N-(6-methyl-1-(1-phenoxyethyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 35)

[0598]

[0599] Step 1: Preparation of 1-(6-methyl-5-nitroisoquinolin-1-yl)ethanone (Compound 35b)

[0600] Compound 1h (300 mg, 1.35 mmol) and 35a (632.66 mg, 1.75 mmol) were dissolved in toluene (40 mL). Bistriphenylphosphine palladium dichloride (94.58 mg, 134.75 μmol) was then added. The mixture was heated to 120°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the toluene. The remaining reaction mixture was diluted with ethyl acetate and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Tetrahydrofuran (40 mL) was then added to dissolve the residue. 6N hydrochloric acid (6 mL) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 2 hours and then heated to 40°C for 1 hour. The reaction mixture was diluted with 40 mL of water. Sodium carbonate was added under ice to adjust the pH to a weak base. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to yield compound 35b (310 mg). MS m / z(ESI):231.0[M+H]+ .

[0601] Step 2: Preparation of 1-(6-methyl-5-nitroisoquinolin-1-yl)ethanol (Compound 35c)

[0602] Compound 35b (150 mg, 651.55 μmol) was dissolved in methanol (10 mL). Sodium borohydride (24.65 mg, 651.55 μmol) was added portionwise at 0°C and stirred for 5 minutes. The reaction was quenched with 10 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 19 / 1) to obtain compound 35c (120 mg). MS m / z (ESI): 233.1 [M+H] + .

[0603] Step 3: Preparation of 6-methyl-5-nitro-1-(1-phenoxyethyl)isoquinoline (Compound 35e)

[0604] Compounds 35c (120 mg, 516.72 μmol) and 35d (58.35 mg, 620.06 μmol) were dissolved in anhydrous tetrahydrofuran (10 mL) and stirred at room temperature for 10 minutes. Triphenylphosphine (176.19 mg, 671.73 μmol) was then added and the mixture was allowed to react under nitrogen for 10 minutes. Finally, diisopropyl azodicarboxylate (135.83 mg, 671.73 μmol, 131.87 μL) was added dropwise. The mixture was heated to 55°C and stirred for 16 hours under nitrogen. The reaction was quenched with 10 mL of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound 35e (76 mg). MS m / z (ESI): 309.2 [M+H] + .

[0605] Step 4: Preparation of 6-methyl-1-(1-phenoxyethyl)isoquinolin-5-amine (Compound 35f)

[0606] Compound 35e (76 mg, 0.25 μmol) was dissolved in ethanol (10 mL), followed by the addition of zinc powder (80.59 mg, 1.23 μmol), ammonium chloride (32.96 mg, 0.62 μmol), and water (2 mL). The mixture was reacted at 25°C under nitrogen for 16 hours. After completion of the reaction, the mixture was filtered and concentrated. The crude product was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 9 / 1) to obtain compound 35f (32 mg). MS m / z (ESI): 279.0 [M+H] + .

[0607] Step 5: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(6-methyl-1-(1-phenoxyethyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 35g)

[0608] Compound 2d (20 mg, 57.91 μmol), cyanuric chloride (21.36 mg, 115.82 μmol), and N-methylmorpholine (17.57 mg, 173.73 μmol) were dissolved in anhydrous DMF (10 mL). The mixture was heated to 50°C and stirred for 30 minutes. Compound 35f (20 mg, 57.91 μmol) was then added and the mixture was allowed to react at 50°C under nitrogen for 16 hours. The reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on a preparative silica gel plate (dichloromethane / methanol = 15 / 1) to obtain compound 35g (10 mg). MS m / z (ESI): 606.0 [M+H] + .

[0609] Step 6: Preparation of 4-amino-N-(6-methyl-1-(1-phenoxyethyl)isoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 35)

[0610] The crude product was prepared by the same method as in Step 8 of Example 1, except that compound 1k was replaced with compound 35g. The crude product was separated and purified by reverse-phase column chromatography on a C18 column (acetonitrile / 0.05% aqueous ammonium bicarbonate solution = 56 / 44) to give compound 35 (7.5 mg). MS m / z (ESI): 455.9 [M+H] + .

[0611] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.94(s,1H),8.56(s,1H),8.51(d,J=8.8Hz,1H),8.46(d,J=5.9Hz,1H),7.97(s,2H),7.72(d,J=5.9Hz,1H),7 .67(d,J=8.9Hz,1H),7.18(t,J=8.0Hz,2H),6.92(d,J=8.0Hz,2H),6.83(t ,J=7.3Hz,1H),6.20(q,J=6.5Hz,1H),2.42(s,3H),1.80(d,J=6.5Hz,3H).

[0612] Example 32: 4-amino-N-(1-((3-chlorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 38)

[0613]

[0614] Step 1: Preparation of N-(3-chlorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 38b)

[0615] Compound 38b (280 mg) was obtained by the same method as in the fifth step of Example 1, except that compound 1g was replaced by compound 38a. MS m / z (ESI): 314.1 [M+H] + .

[0616] Step 2: N 1 Preparation of -(3-chlorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 38c)

[0617] Compound 38c (108 mg) was obtained by the same method as in the third step of Example 29, except that compound 34c was replaced by compound 38b and methanol was replaced by ethanol. MS m / z (ESI): 284.0 [M+H] + .

[0618] Step 3: Preparation of N-(1-((3-chlorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 38d)

[0619] Compound 38d (18 mg) was obtained by the same method as in step 7 of Example 1, except that compound 1j was replaced by compound 38c. MS m / z (ESI): 605.2 [M+H] + .

[0620] Step 4: Preparation of 4-amino-N-(1-((3-chlorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 38)

[0621] The crude product was prepared by the same method as in Step 8 of Example 1, except that compound 1k was replaced with compound 38d. The crude product was separated and purified by reverse-phase column chromatography on a C18 column (acetonitrile / 0.05% aqueous ammonium bicarbonate solution = 65 / 35) to obtain compound 38 (5 mg). MS m / z (ESI): 455.1 [M+H] + .

[0622] 1H NMR (400MHz, DMSO-d6) δ13.21 (s, 1H), 9.37 (s, 1H), 8.66 (dd, J = 7.4, 1.4Hz, 1H), 8.63 (s, 1H), 8. 53(dd,J=8.3,1.4Hz,1H),8.45(d,J=8.7Hz,1H),8.38(brs,1H),8.23(brs,1H),8.17(t,J=2.0H z,1H),8.05(d,J=6.0Hz,1H),7.85(dd,J=8.3,1.2Hz,1H),7.70(t,J=8.0Hz,1H),7.64(d,J=8.7 Hz,1H),7.35(t,J=8.1Hz,1H),7.31(d,J=6.0Hz,1H),7.02(dd,J=8.0,1.2Hz,1H),2.45(s,3H).

[0623] Example 33: 4-amino-N-(1-((3-chlorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 12)

[0624]

[0625] The crude product was prepared by the same method as in the third step of Example 13, except that compound 1j was replaced with compound 38c. The crude product was separated and purified by reverse-phase column chromatography on a C18 column (acetonitrile / 0.05% aqueous ammonium bicarbonate solution = 62 / 38) to obtain compound 12 (10 mg). MS m / z (ESI): 445.0 [M+H] + .

[0626] 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.38(s,1H),8.70(s,1H),8.62(s,1H), 8.48(d,J=8.7Hz,1H),8.38(s,1H),8.25(s,1H),8.16(t,J=2.0Hz,1H),8.06( d,J=6.0Hz,1H),7.85(dd,J=8.3,1.2Hz,1H),7.64(d,J=8.8Hz,1H),7.35(t,J =8.1Hz,1H),7.25(d,J=6.0Hz,1H),7.02(dd,J=7.9,1.3Hz,1H),2.44(s,3H).

[0627] Example 34: 4-amino-N-(1-((2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 39)

[0628]

[0629] Step 1: Preparation of N-(2-fluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 39b)

[0630] Compound 39a (89.8 mg, 808.5 μmol), 1h (150.0 mg, 673.8 μmol), and TFA (76.8 mg, 673.8 μmol) were added to isopropanol (5.0 mL) and the temperature was raised to 100°C for 16 hours. After completion of the reaction, the pH of the reaction solution was adjusted to alkaline with triethylamine and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain compound 39b (195.0 mg). MS m / z (ESI): 298.1 [M+H] + .

[0631] Step 2: N 1 Preparation of -(2-fluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 39c)

[0632] Compound 39b (100.0 mg, 336.4 μmol) was added to ethanol (3.0 mL) and water (1.0 mL). Iron powder (93.9 mg, 1680.0 μmol) and ammonium chloride (18.0 mg, 336.4 μmol) were then added sequentially. The temperature was raised to 80°C and the mixture was reacted for 2 hours. After the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain compound 39c (85.0 mg). MS m / z (ESI): 268.1 [M+H] + .

[0633] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 39d)

[0634] Compound 39c (20.0 mg, 74.8 μmol) and 1f (38.1 mg, 112.2 μmol) were dissolved in pyridine (2.0 mL). T3P (1 mL, 50% DMF solution) was added dropwise and allowed to react at 25°C for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The reaction solution was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (PE / EA = 3 / 2) to obtain compound 39d (35.0 mg). MS m / z (ESI): 589.2 [M+H] + .

[0635] Step 4: Preparation of 4-amino-N-(1-((2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 39)

[0636] Compound 39d (35.0 mg, 59.5 μmol) was added to trifluoroacetic acid (2.0 mL) and reacted at 80°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, alkalized by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and concentrated to obtain a crude product. The crude product was separated and purified by Prep-HPLC to obtain compound 39 (5.3 mg). MS m / z (ESI): 439.1 [M+H] + .

[0637] 1 H NMR (400MHz, DMSO-d6+D2O) δ8.67 (dd, J=7.5Hz, J=1.6Hz, 1H), 8.62 (s, 1H), 8.50 (dd, J=8.3Hz, J=1.5Hz, 1H), 8.32 (d,J=8.6Hz,1H),7.87(d,J=6.0Hz,1H),7.74(t,J=7.8Hz,1H),7.67–7.51(m,2H),7.32–7.17(m,4H),2.45(s,3H).

[0638] Example 35: 4-amino-N-(1-((4-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 41)

[0639]

[0640] Step 1: Preparation of 4-chloro-2-fluoroaniline (Compound 41b)

[0641] Compound 41a (1000.0 mg, 5700.0 μmol) was dissolved in ethanol (12.0 mL) and water (4.0 mL). Iron powder (1590.0 mg, 28480.0 μmol) and ammonium chloride (304.7 mg, 5700.0 μmol) were added sequentially. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 hours. After the reaction, the mixture was filtered through celite and the filtrate was concentrated to obtain compound 41b (800.0 mg). MS m / z (ESI): 146.1 [M+H] + .

[0642] Step 2: Preparation of N-(4-chloro-2-fluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 41c)

[0643] Compound 1h (200.0 mg, 898.4 μmol), 41b (156.9 mg, 1080.0 μmol), and TFA (102.4 mg, 898.4 μmol) were added to isopropanol (5.0 mL) and heated to 100°C for 16 hours. After completion of the reaction, the pH of the reaction solution was adjusted to alkaline with triethylamine and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain compound 41c (240.0 mg). MS m / z (ESI): 332.0 [M+H] + .

[0644] Step 3: N 1 Preparation of -(4-chloro-2-fluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 41d)

[0645] Compound 41c (100.0 mg, 301.5 μmol) was added to ethanol (3.0 mL) and water (1.0 mL). Iron powder (84.2 mg, 1510.0 μmol) and ammonium chloride (16.1 mg, 301.5 μmol) were then added sequentially. The mixture was heated to 80°C and reacted for 2 hours. After the reaction, the mixture was filtered through celite and the filtrate was concentrated to dryness to obtain compound 41d (85.0 mg). MS m / z (ESI): 302.1 [M+H] + .

[0646] Step 4: Preparation of N-(1-((4-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 41e)

[0647] Compound 41d (20.0 mg, 66.3 μmol) and 1f (33.7 mg, 99.4 μmol) were dissolved in pyridine (2.0 mL). T3P (1 mL, 50% DMF solution) was added dropwise and allowed to react at 25°C for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The reaction solution was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated and purified by silica gel column chromatography (PE / EA = 3 / 2) to obtain compound 41e (20.0 mg). MS m / z (ESI): 623.2 [M+H] + .

[0648] Step 5: Preparation of 4-amino-N-(1-((4-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 41)

[0649] Compound 41e (20.0 mg, 32.1 μmol) was added to trifluoroacetic acid (2.0 mL) and reacted at 80°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness and alkalized by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was concentrated to obtain a crude product. The crude product was separated and purified by Prep-HPLC to obtain compound 41 (4.4 mg). MS m / z (ESI): 473.0 [M+H] + .

[0650] 1 H NMR (400MHz, DMSO-d6) δ13.19(s,1H),9.13(s,1H),8.65(dd,J=7.4,1.3Hz,1H),8.62(s,1H),8.52(dd,J=8.2,1.2Hz,1H),8.44–8.14(m,3H ),7.88(d,J=6.0Hz,1H),7.74–7.57(m,3H),7.47(dd,J=10.5,2.3Hz,1H),7.29(dd,J=8.6,1.4Hz,1H),7.23(d,J=5.9Hz,1H),2.44(s,3H).

[0651] Example 36: 4-amino-N-(1-((2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 44)

[0652]

[0653] Compounds 30c (20 mg, 111.65 μmol) and 39c (29.84 mg, 111.65 μmol) were dissolved in pyridine (3 mL), and T3P (2 mL, 50% in DMF) was added. The mixture was stirred at 25°C for 16 hours. After the reaction, the pyridine was removed by rotary evaporation, and the pH of the reaction solution was adjusted to approximately 8 by dropwise addition of saturated sodium bicarbonate solution. The mixture was extracted with EA, washed with water, then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was first separated and purified by Prep-TLC (MeOH / DCM = 1 / 15), and then separated and purified by Prep-HPLC to obtain compound 44 (3 mg). MS m / z (ESI): 429.1 [M+H] + .

[0654] 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.07(s,1H),8.70(s,1H),8.62(s,1H),8.38(d,J=10.0Hz,1H),8.37(s,1H ),8.24(s,1H),7.87(d,J=6.0Hz,1H),7.62–7.56(m,2H),7.28–7.18(m,3H),7.15(d,J=6.0Hz,1H),2.43(s,3H).

[0655] Example 37: 4-amino-N-(6-methyl-1-((3-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 43)

[0656]

[0657] Step 1: Preparation of 6-methyl-5-nitro-N-(3-(trifluoromethyl)phenyl)isoquinolin-1-amine (Compound 43b)

[0658] Compound 43a (731.1 mg, 4.45 mmol) and 1h (200.0 mg, 889.4 μmol) were reacted at 130°C without solvent for 5 hours. After the reaction, the product was directly separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 43b (120.0 mg). MS m / z (ESI): 348.1 [M+H] + .

[0659] Step 2: 6-Methyl-N 1 Preparation of -(3-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (Compound 43c)

[0660] Compound 43b (120.0 mg, 345.5 μmol), reduced iron powder (59.1 mg, 1.04 mmol), and ammonium chloride (37.7 mg, 691.1 μmol) were added to a mixed solution of ethanol (24.0 mL) and water (8.0 mL). The nitrogen atmosphere was replaced three times, and the reaction temperature was raised to 80°C for 3 hours. After the reaction, the solid was removed by filtration, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 43c (90.0 mg). MS m / z (ESI): 318.1 [M+H] + .

[0661] Step 3: Preparation of 4-amino-N-(6-methyl-1-((3-(trifluoromethyl)phenyl)amino)isoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 43)

[0662] Compounds 43c (26.6 mg, 83.7 μmol) and 30c (15.0 mg, 83.7 μmol) were dissolved in pyridine (5.0 mL), followed by the addition of T3P (159.9 mg, 251.2 μmol). The mixture was reacted at 25°C for 16 hours. After the reaction, the mixture was concentrated to remove the pyridine and dissolved in ethyl acetate. Saturated sodium bicarbonate was added to alkalize the mixture, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by Prep-HPLC to obtain compound 43 (3.0 mg). MS m / z (ESI): 479.1 [M+H] + .

[0663] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),9.67(br,1H),8.70(s,1H),8.62(s,1H),8.52(d,J=8.8Hz,1H),8.38(s,1H),8.35(s,1H),8.25(s,1H),8.2 2(d,J=8.8Hz,1H),8.02(d,J=6.0Hz,1H),7.68(d,J=8.8Hz,1H),7.58(t, J=7.6Hz,1H),7.36(d,J=6.8Hz,1H),7.28(d,J=6.0Hz,1H),2.45(s,3H).

[0664] Example 38: 4-amino-N-(1-((6-(dimethylamino)pyridin-3-yl)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 36)

[0665]

[0666] Step 1: Preparation of 5-bromo-N,N-dimethylpyridin-2-amine (Compound 36b)

[0667] Compound 36a (650 mg, 3.38 mmol), dimethylamine hydrochloride (550.86 mg, 6.76 mmol), and potassium carbonate (1.4 g, 10.13 mmol) were added to DMF (10.0 mL) and reacted at 90°C for 12 hours. After the reaction, 200 mL of water was added and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 36b (512 mg). MS m / z (ESI): 201.0 [M+H] + .

[0668] Step 2: Preparation of 1-((6-(dimethylamino)pyridin-3-yl)methyl)-6-methylisoquinolin-5-amine (Compound 36c)

[0669] Compound 36b (280.8 mg, 1.40 mmol), 31e (200 mg, 698.30 mmol), palladium trifluoroacetate (23.21 mg, 69.83 μmol), tricyclohexylphosphine (39.16 mg, 139.66 μmol), and cesium carbonate (455.04 mg, 1.40 mmol) were added to toluene (10.0 mL). The atmosphere was purged with nitrogen three times and the mixture was reacted at 120°C for 3 hours. After completion of the reaction, the mixture was filtered through celite, 200 mL of water was added, and the mixture was extracted with EA. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (PE / EA = 1 / 1) to obtain compound 36c (121 mg). MS m / z (ESI): 293.2 [M+H] + .

[0670] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((6-(dimethylamino)pyridin-3-yl)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 36d)

[0671] Compound 36c (150 mg, 513.04 μmol) and 2d (212.63 mg, 615.54 μmol) were added to pyridine (10.0 mL), followed by T3P (489.71 mg, 1.54 mmol), and the mixture was allowed to react at 25°C for 3 hours. After the reaction, 50 mL of water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then separated and purified by silica gel flash column chromatography (DCM / MeOH = 20 / 1) to yield compound 36d (180 mg). MS m / z (ESI): 620.1 [M+H] + .

[0672] Step 4: Preparation of 4-amino-N-(1-((6-(dimethylamino)pyridin-3-yl)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 36)

[0673] Compound 36d (180 mg, 290.45 μmol) was added to trifluoroacetic acid (5.0 mL) and reacted at 80°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 36 (120 mg). MS m / z (ESI): 470.1 [M+H] + .

[0674] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.40(d,J=6.0Hz,1H),8.28(d,J=0.8Hz,1H),8.11(d,J=2.8Hz,1 H),7.97(s,2H),7.63(t,J=7.8Hz,2H),7.36(dd,J=8.8,2.4Hz,1H),6.52(d,J=8.4Hz,1H),4.50(s,2H),2.94(s,6H),2.42(s,3H).

[0675] Example 39: 4-amino-N-(1-((6-(dimethylamino)pyridin-3-yl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 37)

[0676]

[0677] Step 1: Preparation of 4-amino-N-(1-(6-(dimethylamino)nicotinoyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 37a)

[0678] Compound 36 (50 mg, 106.48 μmol) and NBS (3.79 mg, 21.30 μmol) were dissolved in DMSO (3.0 mL) and reacted at 80°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature and directly separated and purified by Prep-HPLC to obtain compound 37a (26 mg). MS m / z (ESI): 484.1 [M+H] + .

[0679] Step 2: Preparation of 4-amino-N-(1-((6-(dimethylamino)pyridin-3-yl)(hydroxy)methyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 37)

[0680] Compound 37a (50 mg, 106.48 μmol) was dissolved in methanol (3.0 mL). Sodium borohydride (7.82 mg, 206.81 μmol) was then added at 0°C and allowed to react at 25°C for 12 hours. After completion of the reaction, saturated ammonium chloride was added to quench the reaction, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to afford compound 37 (26 mg). MS m / z (ESI): 486.1 [M+H] + .

[0681] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.47(d,J=6. 0Hz,1H),8.32(d,J=8.8Hz,1H),8.16(d,J=2.0Hz,1H),7.97(s,2H),7.72(d,J= 6.0Hz,1H),7.57(d,J=8.8Hz,1H),7.38(dd,J=8.8,2.4Hz,1H),6.53(d,J=8.4H z,1H),6.36(d,J=5.2Hz,1H),6.21(d,J=5.6Hz,1H),2.95(s,6H),2.40(s,3H).

[0682] Example 40: 4-amino-N-(1-(4-chloro-3-((dimethylamino)methyl)benzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 42)

[0683]

[0684] Step 1: Preparation of 2-(5-bromo-2-chlorophenyl)-1,3-dioxolane (Compound 42b)

[0685] Compound 42a (2 g, 9.11 mmol) and ethylene glycol (2.83 g, 45.57 mmol) were added to toluene (22 mL), followed by p-toluenesulfonic acid (156.93 mg, 911.32 mmol). After the addition, the mixture was heated to 128°C and refluxed for 16 hours. After the reaction, 200 mL of water was added, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 42b (1.5 g).

[0686] Step 2: Preparation of 1-(4-chloro-3-(1,3-dioxolane-2-yl)benzyl)-6-methylisoquinolin-5-amine (Compound 42c)

[0687] Compound 42b (607.74 mg, 2.30 mmol), 31e (300 mg, 1.15 mmol), palladium trifluoroacetate (38.3 mg, 115.22 μmol), tricyclohexylphosphine (64.62 mg, 230.44 μmol), and cesium carbonate (750.51 mg, 2.30 mmol) were added to toluene (10.0 mL). The atmosphere was purged with nitrogen three times and the mixture was reacted at 120°C for 3 hours. After completion of the reaction, the mixture was filtered through celite, 200 mL of water was added, and the mixture was extracted with EA. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (PE / EA = 1 / 1) to obtain compound 42c (245 mg). MS m / z (ESI): 355.1 [M+H] + .

[0688] Step 3: Preparation of 4-amino-N-(1-(4-chloro-3-(1,3-dioxolane-2-yl)benzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 42e)

[0689] Compounds 42c (100 mg, 281.83 μmol) and 42d (95.86 mg, 310.01 μmol) were added to pyridine (2.0 mL), followed by T3P (269.01 mg, 845.48 μmol), and the mixture was allowed to react at 25°C for 3 hours. After the reaction, 100 mL of water was added to precipitate a solid, which was collected by filtration to yield compound 42e (125 mg). MS m / z (ESI): 533.1 [M+H] + .

[0690] Step 4: Preparation of 4-amino-N-(1-(4-chloro-3-formylbenzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 42f)

[0691] Compound 42e (180 mg, 290.45 μmol) was added to THF (3.0 mL) and water (1.00 mL), followed by concentrated hydrochloric acid (12 M, 0.5 mL). The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated to dryness, basified by adding saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 42f (30 mg). MS m / z (ESI): 488.2 [M+H] + .

[0692] Step 5: Preparation of 4-amino-N-(1-(4-chloro-3-((dimethylamino)methyl)benzyl)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide (Compound 42)

[0693] DIPEA (16.42 mg, 127.06 μmol) was added to a 3.00 mL solution of dimethylamine hydrochloride (10.36 mg, 127.06 μmol) and tetraisopropyl titanate (36.11 mg, 127.06 μmol). Compound 42f (31 mg, 63.53 μmol) was then added and allowed to react at room temperature for 12 hours. NaBH4 (3.61 mg, 95.29 μmol) was then slowly added and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated and crudely purified by silica gel column chromatography (DCM / MeOH = 10 / 1) followed by Prep-HPLC separation and purification to afford compound 42 (3.75 mg). MS m / z (ESI): 517.0 [M+H] + .

[0694] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.94(s,1H),8.57(s,1H),8.43(d,J=6.8Hz,1H),8.24(d,J=8.8Hz,1H),7.97(s,2H),7.67(d,J=6.0Hz ,1H),7.61(d,J=8.4Hz,1H),7.46(s,1H),7.30(d,J=9.2Hz,1H),7.17(d,J=8.0Hz,1H),4.66(s,2H),3.40(s,2H),2.41(s,3H),2.14(s,6H).

[0695] Example 41: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-methylquinazoline-8-carboxamide (Compound 45)

[0696]

[0697] Step 1: Preparation of 8-bromo-6-methylquinazolin-4(3H)-one (Compound 45b)

[0698] Compound 45a (1 g, 4.35 mmol) and formamidine acetate (1.41 g, 13.56 mmol) were dissolved in anhydrous ethanol (10 mL) and stirred at 85°C for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered, washed with ethanol, and the filter cake was dried to obtain compound 45b (800 mg). MS m / z (ESI): 238.1 [M+H] + .

[0699] Step 2: Preparation of methyl 6-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxylate (Compound 45c)

[0700] To the reaction vessel were added 45b (900 mg, 3.76 mmol), Pd(dppf)Cl2·DCM (153.72 mg, 188.23 μmol), methanol (15 mL), and TEA (1.90 g, 18.82 mmol, 2.62 mL). After nitrogen displacement, the atmosphere was filled with CO to 1.5 MPa and heated to 120°C for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated, filtered, and the filter cake dried to afford compound 45c (800 mg). MS m / z (ESI): 218.9 [M+H] + .

[0701] Step 3: Preparation of 6-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (Compound 45d)

[0702] Compound 45c (800 mg, 3.67 mmol) was dissolved in THF (10 mL) and methanol (5 mL). A solution of NaOH (439.95 mg, 11.00 mmol) in water (5 mL) was added and stirred at 25°C for 16 hours. After the reaction, the organic solvent was removed under reduced pressure, the mixture was diluted with water, and the pH of the solution was adjusted to approximately 5 with 2M dilute hydrochloric acid. A solid precipitated, which was filtered and dried to obtain compound 45d (710 mg). MS m / z (ESI): 205.0 [M+H] + .

[0703] Step 4: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-methyl-4-oxo-3,4-dihydroquinazoline-8-carboxamide (Compound 45e)

[0704] Compound 45d (67.67 mg, 331.41 μmol) and 1j (100 mg, 331.41 μmol) were dissolved in pyridine (4 mL), and T3P (2 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted with EA. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (DCM:MeOH = 90:10) to obtain compound 45e (80 mg). MS m / z (ESI): 487.9 [M+H] + .

[0705] Step 5: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)-6-methylquinazoline-8-carboxamide (Compound 45f)

[0706] Compound 45e (40 mg, 81.98 μmol) and PyBOP (46.93 mg, 90.18 μmol) were dissolved in DMF (4 mL). DBU (30.97 mg, 122.97 μmol) was added at 25°C. After stirring for 10 min, compound 1d (41.12 mg, 245.95 μmol) was added and the reaction was stirred at 25°C for 3 hr. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 45f (36 mg). MS m / z (ESI): 637.0 [M+H] + .

[0707] Step 6: Preparation of 4-amino-N-(1-(((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-methylquinazoline-8-carboxamide (Compound 45)

[0708] Compound 45f (36 mg, 56.51 μmol) was dissolved in TFA (3 mL) and stirred at 85°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness and saturated sodium bicarbonate solution was added dropwise to adjust the pH to approximately 8. The mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 45 (7.58 mg). MS m / z (ESI): 486.9 [M+H] + .

[0709] 1H NMR (400MHz, DMSO-d6) δ13.22(s,1H),9.28(s,1H),8.57(s,1H),8.51(s,1H),8.36(s,1H),8.34(s,1H),8.21-7.95(m,2H),7.89( d,J=5.6Hz,1H),7.62(d,J=8.8Hz,1H),7.55(t,J=7.2Hz,1H),7.37(t,J=6.8Hz,1H),7.28-7.18(m,2H),2.55(s,3H),2.44(s,3H).

[0710] Example 42: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-fluoroquinazoline-8-carboxamide (Compound 46)

[0711]

[0712] Step 1: Preparation of 8-bromo-6-fluoroquinazolin-4(3H)-one (Compound 46b)

[0713] Compound 46a (2 g, 8.55 mmol) and formamidine acetate (3.56 g, 34.18 mmol) were dissolved in anhydrous ethanol (15 mL), heated to 110°C and stirred for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Solid precipitated and was filtered, rinsed with ethanol, and the filter cake was dried to obtain compound 46b (1.82 g). MS m / z (ESI): 242.9 [M+H] + .

[0714] Step 2: Preparation of methyl 6-fluoro-4-oxo-3,4-dihydroquinazoline-8-carboxylate (Compound 46c)

[0715] Compound 46b (1.82 g, 7.49 mmol), Pd(dppf)Cl2·DCM (611.56 mg, 748.87 μmol), methanol (25 mL), and triethylamine (3.79 g, 37.44 mmol, 5.20 mL) were added sequentially to a reaction vessel. After nitrogen displacement, the atmosphere was filled with CO to 1.5 MPa and heated to 120°C for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated, filtered, and the filter cake dried to afford compound 46c (800 mg). MS m / z (ESI): 222.9 [M+H] + .

[0716] Step 3: Preparation of methyl 4-((2,4-dimethoxybenzyl)amino)-6-fluoroquinazoline-8-carboxylate (Compound 46d)

[0717] Compound 46c (472 mg, 2.12 mmol), 1d (372.98 mg, 2.23 mmol, 335.12 μL), and DBU (642.09 mg, 2.55 mmol) were added to DMF (10 mL), followed by the addition of PyBOP (1.22 g, 2.34 mmol). The mixture was stirred at 25°C for 16 h. After completion of the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse-phase C18 column chromatography (acetonitrile: 0.05% aqueous formic acid = 45:55) to afford compound 46d (340 mg). MS m / z (ESI): 372.1 [M+H] + .

[0718] Step 4: Preparation of 4-((2,4-dimethoxybenzyl)amino)-6-fluoroquinazoline-8-carboxylic acid (Compound 46e)

[0719] Compound 46d (111 mg, 298.90 μmol) was added to water (5 mL) and methanol (5 mL), followed by sodium hydroxide (35.87 mg, 896.70 μmol). The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the organic solvent was removed under reduced pressure, the mixture was diluted with water, and the pH was adjusted to approximately 5 with 2M dilute hydrochloric acid. The precipitated solid was filtered and dried under vacuum to yield compound 46e (90 mg). MS m / z (ESI): 358.0 [M+H] + .

[0720] Step 5: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)-6-fluoroquinazoline-8-carboxamide (Compound 46f)

[0721] Compound 46e (93 mg, 260.26 μmol) and 1j (78.53 mg, 260.26 μmol) were dissolved in pyridine (4 mL), and T3P (2 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After the reaction, the solvent was concentrated to dryness, and the mixture was quenched by dropwise addition of saturated sodium bicarbonate solution. The mixture was extracted with EA, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 46f (100 mg). MS m / z (ESI): 640.9 [M+H] + .

[0722] Step 6: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-fluoroquinazoline-8-carboxamide (Compound 46)

[0723] Compound 46f (100 mg, 155.99 μmol) was dissolved in TFA (4 mL) and stirred at 90°C for 3 hours. After the reaction, the reaction solution was concentrated to dryness, adjusted to pH 8 with saturated sodium bicarbonate solution, and extracted twice with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then separated and purified by Prep-HPLC to obtain compound 46 (2.09 mg). MS m / z (ESI): 490.9 [M+H] + .

[0724] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),9.25(s,1H),8.61(s,1H),8.45-8.37(m,2H),8.37–8.29(m,3H),7.91( d,J=6.0Hz,1H),7.62(d,J=8.8Hz,1H),7.58–7.52(m,1H),7.39–7.33(m,1H),7.27–7.20(m,2H),2.45(s,3H).

[0725] Example 43: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-morpholinoquinazoline-8-carboxamide (Compound 53)

[0726]

[0727] Step 1: Preparation of 2-amino-5-iodoisophthalic acid (Compound 53b)

[0728] Compound 53a (5000.00 mg, 27.33 mmol) was dissolved in N,N-dimethylformamide (50 mL), and N-iodosuccinimide (6900.00 mg, 30.06 mmol) was added. The mixture was heated to 100°C and reacted for 16 hours. After the reaction, the reaction solution was cooled to room temperature and poured into ice water. A yellow solid precipitated and was filtered. The filter cake was washed twice with ice water and dried under vacuum to obtain compound 53b (8300 mg). MS m / z (ESI): 307.9 [M+H] + .

[0729] Step 2: Preparation of 6-iodo-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (Compound 53c)

[0730] Compound 53b (9000.00 mg, 29.31 mmol) and formamidine acetate (9340.00 mg, 87.94 mmol) were added to a single-necked flask and stirred vigorously for 10 minutes. Formamide (1600.00 mg, 35.17 mmol) was then added and heated to 170°C for 1.5 hours. After the reaction, the reaction solution was cooled to room temperature, ice water was added, and stirring was continued. The solid was filtered, the filter cake was rinsed with water, and then vacuum dried to obtain compound 53c (8800 mg). MS m / z (ESI): 317.0 [M+H] + .

[0731] Step 3: Preparation of methyl 6-iodo-4-oxo-3,4-dihydroquinazoline-8-carboxylate (Compound 53d)

[0732] Compound 53c (8800.00 mg, 27.84 mmol) was added to methanol (100 mL). Concentrated sulfuric acid (5570 mg, 55.69 μmol, 3.03 mL) was added dropwise under an ice bath. After the addition was complete, the reaction solution was heated to 80°C and reacted for 20 hours. After the reaction, the reaction solution was cooled to 0°C and basified with aqueous sodium bicarbonate. The solution was diluted with water to precipitate a solid. The solid was filtered, the filter cake was rinsed with water, and then dried under vacuum to obtain compound 53d (9300 mg, 85% purity). MS m / z (ESI): 331.1 [M+H] + .

[0733] Step 4: Preparation of methyl 4-((2,4-dimethoxybenzyl)amino)-6-iodoquinazoline-8-carboxylate (Compound 53e)

[0734] Compound 53d (9300.00 mg, 23.95 mmol, 85% purity) and PyBOP (13990 mg, 26.34 mmol) were dissolved in N,N-dimethylformamide (100 mL). DBU (6700 mg, 26.34 mmol) was added at room temperature and stirred for 10 minutes. 2,4-Dimethoxybenzylamine (6130 mg, 35.92 mmol) was then added and allowed to react at 25°C for 1 hour. After the reaction, ice water was added to the reaction solution. Solid precipitated and was filtered. The filter cake was rinsed with water and then dried under vacuum to yield compound 53e (11000 mg). MS m / z (ESI): 480.0 [M+H] + .

[0735] Step 5: Preparation of methyl 4-((2,4-dimethoxybenzyl)amino)-6-morpholinoquinazoline-8-carboxylate (Compound 53f)

[0736] Compound 53e (220 mg, 459.03 μmol), morpholine (47.99 mg, 550.84 μmol), Pd2(dba)3 (42.03 mg, 45.90 μmol), RuPhos (42.84 mg, 91.81 μmol), and Cs2CO3 (448.69 mg, 1.38 mmol) were dissolved in DMF (3 mL). The atmosphere was purged with nitrogen three times and the mixture was reacted at 100°C for 5 hours. After completion of the reaction, the reaction solution was cooled in an ice-water bath, filtered through celite, diluted with 100 mL of water, and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified on a C18 reverse-phase column (acetonitrile:0.05% aqueous formic acid = 32:68) to afford compound 53f (180 mg). MS m / z (ESI): 439.1 [M+H] + .

[0737] Step 6: Preparation of 4-((2,4-dimethoxybenzyl)amino)-6-morpholinoquinazoline-8-carboxylic acid (Compound 53g)

[0738] Compound 53f (60 mg, 136.84 μmol) was dissolved in THF (3 mL) and H₂O (1 mL), and sodium hydroxide (16.42 mg, 410.51 μmol) was added. The mixture was allowed to react at 25°C for 3 hours. After completion of the reaction, the mixture was purified on a C18 reverse-phase column (acetonitrile:0.05% formic acid aqueous solution = 31:69) to obtain compound 53g (35 mg). MS m / z (ESI): 425.0 [M+H] + .

[0739] Step 7: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)-6-morpholinoquinazoline-8-carboxamide (Compound 53h)

[0740] Compound 53g (30 mg, 70.68 μmol) and 1j (21.33 mg, 70.68 μmol) were dissolved in pyridine (2 mL), and 1-propylphosphonic anhydride (0.14 mL, 50% EA solution) was added dropwise. The mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, 5 mL of saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM / MeOH = 20 / 1) to yield compound 53h (30.00 mg). MS m / z (ESI): 707.9 [M+H] + .

[0741] Step 8: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-morpholinoquinazoline-8-carboxamide (Compound 53)

[0742] Compound 53h (30.00 mg, 42.36 μmol) was dissolved in trifluoroacetic acid (2 mL) and heated to 90°C for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure and purified by C18 reverse-phase column chromatography (acetonitrile:0.05% formic acid aqueous solution = 35:65) to obtain compound 53 (18.00 mg). MS m / z (ESI): 558.1 [M+H] + .

[0743] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),9.23(s,1H),8.45(s,1H),8.41(d,J=2 .8Hz,1H),8.33(d,J=8.8Hz,1H),8.22-7.93(m,2H),7.90(d,J=6.0Hz,1H),7 .78(d,J=2.8Hz,1H),7.62(d,J=8.8Hz,1H),7.58-7.52(m,1H),7.38-7.33(m ,1H),7.28–7.19(m,2H),3.84-3.80(m,4H),3.33-3.28(m,4H),2.44(s,3H).

[0744] Example 44: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-(4-methylpiperazin-1-yl)quinazoline-8-carboxamide (Compound 54)

[0745]

[0746] Step 1: Preparation of methyl 4-((2,4-dimethoxybenzyl)amino)-6-(4-methylpiperazin-1-yl)quinazoline-8-carboxylate (Compound 54a)

[0747] Compound 53e (250.00 mg, 521.63 μmol) and N-methylpiperazine (156.74 mg, 1.56 mmol) were dissolved in N,N-dimethylformamide (15 mL). Tris(dibenzylideneacetone)dipalladium (23.89 mg, 26.09 μmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (24.34 mg, 52.16 μmol), and cesium carbonate (339.91 mg, 1.04 mmol) were added. The mixture was heated to 140°C under nitrogen for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed three times with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (dichloromethane / methanol = 19 / 1) to obtain compound 54a (43 mg). MS m / z(ESI):452.0[M+H] + .

[0748] Step 2: Preparation of 4-((2,4-dimethoxybenzyl)amino)-6-(4-methylpiperazin-1-yl)quinazoline-8-carboxylic acid (Compound 54b)

[0749] Compound 54a (43 mg, 95.23 μmol) was dissolved in a mixture of THF (3 mL), MeOH (1 mL), and water (1 mL). Lithium hydroxide monohydrate (5.99 mg, 142.85 μmol) was added and the mixture was allowed to react at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain compound 54b (41 mg). MS m / z (ESI): 438.0 [M+H] + .

[0750] Step 3: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)-6-(4-methylpiperazin-1-yl)quinazoline-8-carboxamide (Compound 54c)

[0751] The preparation method of compound 1k in step 7 of Example 1 was followed except that compound 1f was replaced by compound 54b to obtain compound 54c (25 mg). MS m / z (ESI): 721.0 [M+H] + .

[0752] Step 4: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-(4-methylpiperazin-1-yl)quinazoline-8-carboxamide (Compound 54)

[0753] The preparation method of compound 1 in step 8 of Example 1 was followed except that compound 1k was replaced by compound 54c to obtain compound 54 (17 mg). MS m / z (ESI): 571.0 [M+H] + .

[0754] 1 H NMR(400MHz,DMSO-d6)δ13.36(s,1H),9.23(s,1H),8.43(s,1H),8.40(d,J= 2.4Hz,1H),8.33(d,J=8.4Hz,1H),8.04(brs,2H),7.90(d,J=6.0Hz,1H),7.7 6(d,J=2.4Hz,1H),7.62(d,J=8.8Hz,1H),7.55(t,J=7.2Hz,1H),7.36(t,J= 6.4Hz,1H),7.24-7.20(m,2H),2.55-2.50(m,8H),2.44(s,3H),2.26(s,3H).

[0755] Example 45: 4-amino-N-(1-((4-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 55)

[0756]

[0757] Compound 41d (32.9 mg, 108.9 μmol) and 30c (15 mg, 83.7 μmol) were dissolved in pyridine (2.0 mL). T3P (3 mL, 50% DMF solution) was added dropwise and allowed to react at 25°C for 14 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The reaction solution was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 55 (3.3 mg). MS m / z (ESI): 463.1 [M+H] + .

[0758] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.70(s,1H),8.63(s,1H),8.47(d,J=8.7Hz,1H),8.37(s, 1H),8.24(s,1H),7.80–7.59(m,4H),7.39(d,J=8.6Hz,1H),7.26(d,J=6.4Hz,1H),2.46(s,3H).

[0759] Example 46: 4-amino-N-(1-((3-chloro-4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 56)

[0760]

[0761] Step 1: Preparation of N-(3-chloro-4-methoxyphenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 56b)

[0762] Compound 56a (128.7 mg, 800.4 μmol) and 1h (150.0 mg, 667.0 μmol) were dissolved in isopropanol (5 mL), and TFA (93.1 mg, 800.4 μmol) was added. The temperature was raised to 99°C and the reaction was allowed to proceed for 18 hours. After the reaction, the mixture was concentrated to obtain compound 56b (200.0 mg). MS m / z (ESI): 344.1 [M+H] + .

[0763] Step 2: N 1 Preparation of -(3-chloro-4-methoxyphenyl)-6-methylisoquinoline-1,5-diamine (Compound 56c)

[0764] Compound 56b (200.0 mg, 581.8 μmol), reduced iron powder (82.1 mg, 1.45 mmol), and ammonium chloride (157.2 mg, 2.91 mmol) were added to a mixture of ethanol (20.0 mL) and water (5.0 mL). The atmosphere was purged with nitrogen three times, and the reaction temperature was raised to 80°C for 2 hours. After the reaction, the solid was removed by filtration, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH = 19 / 1) to obtain compound 56c (150.0 mg). MS m / z (ESI): 314.0 [M+H] + .

[0765] Step 3: Preparation of 4-amino-N-(1-((3-chloro-4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 56)

[0766] Compounds 56c (26.3 mg, 83.7 μmol) and 30c (15.0 mg, 83.7 μmol) were dissolved in pyridine (5.0 mL), followed by the addition of T3P (159.9 mg, 251.2 μmol). The reaction was allowed to proceed at 25°C for 16 hours. After the reaction, the pyridine was removed by concentration, and the product was purified by Prep-HPLC to yield compound 56 (15.0 mg). MS m / z (ESI): 475.1 [M+H] + .

[0767] 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),9.20(s,1H),8.70(s,1H),8.62(s,1H),8.45(d,J=8.4Hz,1H),8.38(s,1H),8.24(s,1H),8.08(d ,J=2.4Hz,1H),7.98(d,J=6.0Hz,1H),7.77(dd,J=9.2,2.8Hz,1H),7.61(d,J=8.8Hz,1H),7.18–7.12(m,2H),3.84(s,3H),2.43(s,3H).

[0768] Example 47: 4-amino-N-(1-((4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 57)

[0769]

[0770] Step 1: Preparation of N-(4-methoxyphenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 57b)

[0771] Compound 57a (132.76 mg, 1.08 mmol) and 1h (200 mg, 898.36 μmol) were dissolved in isopropanol (5 mL). TFA (122.92 mg, 1.08 mmol, 80.08 μL) was added, and the mixture was heated at 100°C with stirring for 18 hours. After the reaction, the reaction solution was cooled to room temperature, and the solid was filtered, washed with isopropanol, and dried under reduced pressure to obtain compound 57b (270 mg). MS m / z (ESI): 310.1 [M+H] + .

[0772] Step 2: N 1 Preparation of -(4-methoxyphenyl)-6-methylisoquinoline-1,5-diamine (Compound 57c)

[0773] 57b (220 mg, 711.24 μmol), iron powder (198.61 mg, 3.56 mmol), and NH4Cl (114.13 mg, 2.13 mmol) were added to methanol (12 mL) and water (3 mL) and stirred at 90°C for 6 hours. After the reaction, the reaction solution was concentrated to dryness and purified by silica gel flash column chromatography (DCM / MeOH = 85 / 15) to obtain compound 57c (150 mg). MS m / z (ESI): 280.1 [M+H] + .

[0774] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 57d)

[0775] Compound 57c (24.69 mg, 88.41 μmol) and 1f (30 mg, 88.41 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% DMF solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, pyridine was removed under reduced pressure, and saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 57d (30 mg). MS m / z (ESI): 601.0 [M+H] + .

[0776] Step 4: Preparation of 4-amino-N-(1-((4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 57)

[0777] Compound 57d (30 mg, 49.94 μmol) was dissolved in TFA (4 mL) and stirred at 80°C for 3 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the pH was adjusted to approximately 8 by adding saturated sodium bicarbonate. The mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then separated and purified by Prep-HPLC to obtain compound 57 (6 mg). MS m / z (ESI): 451.1 [M+H] + .

[0778] 1H NMR(400MHz,DMSO-d6)δ13.17(s,1H),9.07(s,1H),8.66(dd,J=7.6,1.2Hz,1H),8 .62(s,1H),8.52(dd,J=8.4,1.2Hz,1H),8.40(d,J=8.8Hz,1H),8.38(br,1H),8.23 (br,1H),7.91(d,J=6.0Hz,1H),7.77–7.72(m,2H),7.70(t,J=7.6Hz,1H),7.57(d, J=8.8Hz,1H),7.16(d,J=6.0Hz,1H),6.94–6.90(m,2H),3.75(s,3H),2.42(s,3H).

[0779] Example 48: 4-amino-N-(1-((3-chloro-4-fluorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 58)

[0780]

[0781] Step 1: Preparation of N-(3-chloro-4-fluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 58b)

[0782] Compound 1h (400.00 mg, 1.80 mmol), 58a (313.84 mg, 2.16 mmol), and p-toluenesulfonic acid (30.94 mg, 179.67 μmol) were dissolved in isopropanol (20 mL) and heated to 90°C for 18 hours. After the reaction, the reaction solution was cooled to room temperature. A solid precipitated and was filtered. The filter cake was rinsed with methyl tert-butyl ether and dried to obtain compound 58b (550 mg). MS m / z (ESI): 332.0 [M+H] + .

[0783] Step 2: N 1 Preparation of -(3-chloro-4-fluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 58c)

[0784] The preparation method of compound 57c in step 2 of Example 47 was followed except that compound 57b was replaced by compound 58b to obtain compound 58c (300 mg). MS m / z (ESI): 301.9 [M+H] + .

[0785] Step 3: Preparation of 4-amino-N-(1-((3-chloro-4-fluorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 58)

[0786] The preparation method of compound 56 in step 3 of Example 46 was followed except that compound 56c was replaced by compound 58c to obtain compound 58 (104 mg). MS m / z (ESI): 462.9 [M+H] + .

[0787] 1 H NMR (400MHz, DMSO-d6) δ11.58(s,1H),10.51(s,1H),8.82(d,J=8.8Hz,1H),8.74(s,1H),8.67(s,1H),8.37(s,1H),8.27(s,1 H),7.98(d,J=5.6Hz,1H),7.88(d,J=8.4Hz,1H),7.65(d,J=6.8,2H),7.61(d,J=7.2,1H),7.33(d,J=6.8Hz,1H),2.51(s,3H).

[0788] Example 49: 4-amino-N-(1-((6-(dimethylamino)pyridin-3-yl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 59)

[0789]

[0790] Step 1: Preparation of N,N-dimethyl-5-nitropyridin-2-amine (Compound 59b)

[0791] Compound 59a (720 mg, 4.54 mmol) and dimethylamine (555.49 mg, 6.81 mmol) were dissolved in DMF (3 mL). Potassium carbonate (2.51 g, 18.17 mmol) was added and the mixture was allowed to react at 100°C for 12 hours. After the reaction, water was added to the reaction mixture to precipitate a solid, which was collected by filtration to obtain compound 59b (530 mg). MS m / z (ESI): 168.1 [M+H] + .

[0792] Step 2: N 2 ,N 2 Preparation of dimethylpyridine-2,5-diamine (Compound 59c)

[0793] Compound 59b (600 mg, 3.59 mmol) was dissolved in MeOH (5 mL), and palladium on carbon (60 mg, 10% by weight) was added. The nitrogen atmosphere was replaced three times, and then the hydrogen atmosphere was replaced three times. The reaction was allowed to proceed at room temperature under a hydrogen atmosphere for 3 hours. After the reaction, the mixture was filtered through celite and the filtrate was concentrated to dryness to obtain compound 59c (466 mg). MS m / z (ESI): 138.2 [M+H] + .

[0794] Step 3: N 2 ,N 2 -dimethyl-N 5 Preparation of -(6-methyl-5-nitroisoquinolin-1-yl)pyridine-2,5-diamine (Compound 59d)

[0795] Compound 59c (400 mg, 2.92 mmol) and 1h (540.95 mg, 2.43 mmol) were dissolved in isopropanol (15 mL). TFA (332.46 mg, 2.92 mmol) was added and the mixture was allowed to react at 100°C for 12 hours. After the reaction, the solvent was concentrated to dryness, and the crude product was dissolved in DMF. 100 mL of water was then added dropwise to precipitate a solid, which was collected by filtration to obtain compound 59d (732 mg). MS m / z (ESI): 324.2 [M+H] + .

[0796] Step 4: N 1 Preparation of -(6-(dimethylamino)pyridin-3-yl)-6-methylisoquinoline-1,5-diamine (Compound 59e)

[0797] Compound 59d (600 mg, 1.86 mmol) was dissolved in MeOH (5 mL), and palladium on carbon (60 mg, 10% by weight) was added. The nitrogen atmosphere was replaced three times, and then the hydrogen atmosphere was replaced three times. The mixture was allowed to react at room temperature under a hydrogen atmosphere for 12 hours. After the reaction, the mixture was filtered through celite and the filtrate was concentrated to dryness to obtain compound 59e (365.00 mg). MS m / z (ESI): 294.1 [M+H] + .

[0798] Step 5: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((6-(dimethylamino)pyridin-3-yl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 59f)

[0799] Compound 59e (31.12 mg, 106.09 μmol) and 1f (30 mg, 88.41 μmol) were dissolved in pyridine (3 mL), and 1-propylphosphonic anhydride (0.17 mL, 50% EA solution) was added dropwise. The reaction was allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to afford compound 59f (25.00 mg). MS m / z (ESI): 615.2 [M+H] + .

[0800] Step 6: Preparation of 4-amino-N-(1-((6-(dimethylamino)pyridin-3-yl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 59)

[0801] Compound 59f (24.00 mg, 39.04 μmol) was dissolved in trifluoroacetic acid (3 mL) and heated to 80°C for 2 hours. After the reaction, the solvent was removed under reduced pressure and purified by Prep-HPLC to obtain compound 59 (13.00 mg). MS m / z (ESI): 465.2 [M+H] + .

[0802] 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),9.01(s,1H),8.66(dd,J=7.6,1.6Hz,1H), 8.62(s,1H),8.52(dd,J=8.4,1.6Hz,1H),8.46-8.34(m,3H),8.23(s,1H),7.89( dd,J=8.8,2.4Hz,1H),7.86(d,J=6.0Hz,1H),7.69(t,J=8Hz,1H),7.57(d,J=8.8 Hz,1H),7.13(d,J=6.0Hz,1H),6.68(d,J=8.8Hz,1H),3.02(s,6H),2.42(s,3H).

[0803] Example 50: 4-amino-N-(1-((2-fluoro-4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 60)

[0804]

[0805] Step 1: Preparation of N-(2-fluoro-4-methoxyphenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 60b)

[0806] Compound 1h (150 mg, 673.77 μmol) and 60a (114 mg, 808.53 μmol) were added to isopropanol (6 mL), and TFA (92 mg, 808.53 μmol) was added dropwise. After the addition was complete, the temperature was raised to 90°C and the reaction was allowed to proceed for 18 hours. After the reaction, the reaction solution was cooled to room temperature. A solid precipitated and was filtered. The filter cake was rinsed with isopropanol and dried under reduced pressure to obtain compound 60b (200 mg). ESI-MS (m / z): 328.1 [M+H] + .

[0807] Step 2: N 1 Preparation of -(2-fluoro-4-methoxyphenyl)-6-methylisoquinoline-1,5-diamine (Compound 60c)

[0808] Compound 60b (200 mg, 611.04 μmol), ethanol (8 mL), and water (1 mL) were added to a reaction flask. Iron powder (170 mg, 3.06 mmol) and concentrated hydrochloric acid (12 M, 763.80 μL) were then added, and the mixture was stirred at 90°C for 2 hours. After completion of the reaction, the reaction solution was concentrated, diluted with water, and extracted three times with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 60c (190 mg). ESI-MS (m / z): 298.1 [M+H] + .

[0809] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((2-fluoro-4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 60d)

[0810] Compound 1f (25 mg, 73.67 μmol), 60c (22 mg, 73.67 μmol), and pyridine (3 mL) were added to a reaction flask. After stirring to dissolve, T3P (2 mL, 50% EA solution) was added and the mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was spin-dried, diluted with water, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. The mixture was then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (DCM:MeOH = 97:3) to obtain compound 60c (30 mg). MS m / z (ESI): 619.3 [M+H] + .

[0811] Step 4: Preparation of 4-amino-N-(1-((2-fluoro-4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 60)

[0812] Compound 60d (30 mg, 48.49 μmol) was dissolved in TFA (3 mL) and reacted at 70°C under nitrogen for 2 hours. After the reaction, the TFA was evaporated and diluted with water. The pH was adjusted to 7-8 with saturated NaHCO₃ solution, followed by extraction with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by Prep-HPLC to yield compound 60 (6 mg). MS m / z (ESI): 469.1 [M+H] + .

[0813] 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),8.91(s,1H),8.65(dd,J=7.6,1.6Hz,1H),8.62( s,1H),8.52(dd,J=8.0,1.6Hz,1H),8.45–8.30(m,2H),8.23(br,1H),7.80(d,J=6.0Hz ,1H),7.69(t,J=8.0Hz,1H),7.57(d,J=8.8Hz,1H),7.39(t,J=8.8Hz,1H),7.12(d,J=6 .0Hz,1H),6.91(dd,J=12.4,2.8Hz,1H),6.83–6.78(m,1H),3.79(s,3H),2.43(s,3H).

[0814] Example 51: 4-amino-N-(1-((2-fluoro-4-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 61)

[0815]

[0816] Compound 30c (25 mg, 111.65 μmol), 60c (33 mg, 111.65 μmol), and pyridine (2 mL) were added to a reaction flask. After stirring to dissolve, T3P (1.5 mL, 50% EA solution) was added and the mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was concentrated to dryness, diluted with water, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. The solution was then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Prep-HPLC to yield compound 61 (20 mg). MS m / z (ESI): 459.1 [M+H] + .

[0817] 1H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.93(s,1H),8.64(d,J=32.8Hz,2H),8.39–8.34(m,2H),8.24(s,1H),7.81(d,J=6.0Hz,1H),7.57 (d,J=8.4Hz,1H),7.38(t,J=9.2Hz,1H),7.09–7.05(m,1H),6.91(dd,J=12.4,2.8Hz,1H),6.83–6.78(m,1H),3.79(s,3H),2.42(s,3H).

[0818] Example 52: 4-amino-N-(1-((4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 62)

[0819]

[0820] Step 1: Preparation of 1-(4-bromo-2-(trifluoromethyl)phenyl)-N,N-dimethylmethanamine (Compound 62b)

[0821] DIPEA (521.2 mg, 3.95 mmol), dimethylamine hydrochloride (322.3 mg, 3.95 mmol), and tetraisopropyl titanate (1.13 g, 3.95 mmol) were added to ethanol (10.0 mL) and stirred thoroughly. Compound 62a (500 mg, 1.98 mmol) was then added. The reaction was stirred at 25°C for 16 hours, followed by the addition of NaBH4 (114.4 mg, 1.96 mmol) and continued stirring for 1 hour. After completion of the reaction, 2 mL of water was added to quench the reaction, which was then concentrated and purified by silica gel column chromatography (DCM / MeOH = 19 / 1) to afford compound 62b (420.0 mg). MS m / z (ESI): 282.0 [M+H] + .

[0822] Step 2: Preparation of 1-(4-((diphenylmethylene)amino)-2-(trifluoromethyl)phenyl-N,N-dimethylmethanamine (Compound 62c)

[0823] Compound 62b (320.0 mg, 2.30 mmol), benzophenone imine (1.05 g, 5.67 mmol), Pd2(dba)3 (106.0 mg, 113.4 μmol), BINAP (142.7 mg, 226.9 μmol) and KO tBu (642.9 mg, 5.67 mmol) was added to toluene (15.0 mL), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 130°C for 5 hours. After the reaction, the mixture was directly concentrated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 62c (182 mg). MS m / z (ESI): 383.2 [M+H] + .

[0824] Step 3: Preparation of 4-((dimethylamino)methyl)-3-(trifluoromethyl)aniline (Compound 62d)

[0825] Compound 62c (227.0 mg, 593.6 μmol) was dissolved in THF (5.0 mL), and HCl (1 mL, 2.0 mol / L aqueous solution) was added. The mixture was allowed to react at 25°C for 2 hours. After completion of the reaction, the mixture was directly concentrated and purified by silica gel column chromatography (DCM / MeOH = 19 / 1) to obtain compound 62d (93 mg). MS m / z (ESI): 219.1 [M+H] + .

[0826] Step 4: Preparation of N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 62e)

[0827] Compound 62d (93.0 mg, 426.2 μmol) and 1h (96.8 mg, 426.2 μmol) were dissolved in isopropanol (5.0 mL), and TFA (49.6 mg, 426.2 μmol) was added. The temperature was raised to 100°C and the mixture was reacted for 18 hours. After the reaction, the mixture was concentrated directly, and the crude product was separated and purified by silica gel column chromatography (DCM / MeOH = 19 / 1) to obtain compound 62e (20.0 mg). MS m / z (ESI): 405.1 [M+H] + .

[0828] Step 5: N 1 Preparation of -(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-6-methylisoquinoline-1,5-diamine (Compound 62f)

[0829] Compound 62e (20.0 mg, 49.5 μmol), reduced iron powder (8.5 mg, 148.4 μmol), and ammonium chloride (13.5 mg, 247.3 μmol) were added to a mixture of ethanol (6.0 mL) and water (2.0 mL). The nitrogen atmosphere was replaced three times, and the reaction temperature was raised to 80°C for 3 hours. After the reaction, the solid was removed by filtration, and the filtrate was concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain compound 62f (16.0 mg). MS m / z (ESI): 375.2 [M+H] + .

[0830] Step 6: Preparation of 4-amino-N-(1-((4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 62)

[0831] Compound 62f (16.0 mg, 42.7 μmol) and 30c (7.7 mg, 42.7 μmol) were dissolved in pyridine (5.0 mL), followed by the addition of T3P (0.16 mL, 50% EA solution). The reaction was incubated at 25°C for 16 hours. After completion of the reaction, the solvent was removed by concentration, and the product was purified by Prep-HPLC to yield compound 62 (5.0 mg). MS m / z (ESI): 536.3 [M+H] + .

[0832] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.49(s,1H),8.71(s,1H),8.63(s,1H),8.49(d,J=8.4Hz,1H),8.38(s,1H),8.32(d,J=2.0Hz,1H ),8.27–8.20(m,2H),8.04(d,J=6.0Hz,1H),7.65(dd,J=8.4,2.0Hz,2H),7.25(d,J=6.0Hz,1H),3.49(s,2H),2.44(s,3H),2.19(s,6H).

[0833] Example 53: N-(1-((4-acetylphenyl)amino)-6-methylisoquinolin-5-yl)-4-aminoquinazoline-8-carboxamide (Compound 63)

[0834]

[0835] Step 1: Preparation of 1-(4-((6-methyl-5-nitroisoquinolin-1-yl)amino)phenyl)ethan-1-one (Compound 63b)

[0836] Compound 63a (145.71 mg, 1.08 mmol) and 1h (200 mg, 898.36 μmol) were dissolved in isopropanol (5 mL). TFA (122.92 mg, 1.08 mmol, 80.08 μL) was added and the mixture was stirred at 100°C for 18 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered, rinsed with isopropanol, and the filter cake was collected and dried under reduced pressure to obtain compound 63b (200 mg). MS m / z (ESI): 322.2 [M+H] + .

[0837] Step 2: Preparation of 1-(4-((5-amino-6-methylisoquinolin-1-yl)amino)phenyl)ethanone-1-(Compound 63c)

[0838] Compound 63b (200 mg, 622.41 μmol), iron powder (173.81 mg, 3.11 mmol), and NH4Cl (99.88 mg, 1.87 mmol) were added to water (4 mL) and methanol (16 mL) and stirred at 90°C for 6 hours. After completion of the reaction, the mixture was directly purified by silica gel flash column chromatography (DCM:MeOH = 92:8) to obtain compound 63c (150 mg). MS m / z (ESI): 292.1 [M+H] + .

[0839] Step 3: Preparation of N-(1-((4-acetylphenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 63d)

[0840] Compound 1f (30 mg, 88.41 μmol) and 63c (25.76 mg, 88.41 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated and removed, quenched by dropwise addition of saturated sodium bicarbonate solution, extracted with EA, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 63d (50 mg). MS m / z (ESI): 613.0 [M+H] + .

[0841] Step 4: Preparation of N-(1-((4-acetylphenyl)amino)-6-methylisoquinolin-5-yl)-4-aminoquinazoline-8-carboxamide (Compound 63)

[0842] Compound 63d (24.78 mg, 40.45 μmol) was dissolved in TFA (4 mL) and stirred at 80°C for 3 hours. After the reaction, the solvent was concentrated and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then separated and purified by Prep-HPLC to obtain compound 63 (10 mg). MS m / z (ESI): 463.2 [M+H] + .

[0843] 1 H NMR (400MHz, DMSO-d6) δ13.23(s,1H),9.62(s,1H),8.66(dd,J=7.6,1.6Hz,1H),8.63(s,1H),8.53(dd,J=8.0,1.2Hz,1H),8.48(d,J=8.8Hz, 1H),8.36(br,1H),8.24(br,1H),8.14-8.02(m,3H),7.98-7.90(m,2H),7.74–7.62(m,2H),7.38(d,J=6.0Hz,1H),2.54(s,3H),2.46(s,3H).

[0844] Example 54: 4-amino-N-(1-((4-chloro-3-((dimethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 64)

[0845]

[0846] Step 1: Preparation of 1-(2-chloro-5-nitrophenyl)-N,N-dimethylmethanamine (Compound 64b)

[0847] Dimethylamine hydrochloride (1.32 g, 16.17 mmol) and triethylamine (1.64 g, 16.17 mmol, 2.25 mL) were added to THF (20 mL), followed by compound 64a (2 g, 10.78 mmol). NaBH(OAc)3 (3.43 g, 16.17 mmol) was then added portionwise in an ice-water bath. After addition, the mixture was allowed to warm to room temperature and react for 16 hours. After completion of the reaction, the mixture was quenched with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 64b (1.47 g). MS m / z (ESI): 215.0 [M+H] + .

[0848] Step 2: Preparation of 4-chloro-3-((dimethylamino)methyl)aniline (Compound 64c)

[0849] Compound 64b (470 mg, 2.19 mmol), iron powder (611.45 mg, 10.95 mmol), and concentrated HCl (0.1 mL, 12N) were added to ethanol (10 mL) and water (10 mL) and stirred at 90°C for 6 hours. After the reaction, the solvent was concentrated and purified by silica gel flash column chromatography (DCM:MeOH = 88:12) to obtain compound 64c (150 mg). MS m / z (ESI): 185.1 [M+H] + .

[0850] Step 3: Preparation of N-(4-chloro-3-((dimethylamino)methyl)phenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 64d)

[0851] Compound 64c (150 mg, 812.28 μmol) and 1h (180.84 mg, 812.28 μmol) were dissolved in isopropanol (8 mL), and TFA (111.14 mg, 974.74 μmol, 72.40 μL) was added. After addition, the mixture was stirred in a sealed container at 100°C for 18 hours. After completion of the reaction, the reaction solution was concentrated to dryness to obtain compound 64d (301 mg). MS m / z (ESI): 371.1 [M+H] + .

[0852] Step 4: N 1 Preparation of -(4-chloro-3-((dimethylamino)methyl)phenyl)-6-methylisoquinoline-1,5-diamine (Compound 64e)

[0853] Compound 64d (150 mg, 404.50 μmol), iron powder (112.96 mg, 2.02 mmol), and NH4Cl (64.91 mg, 1.21 mmol) were added to water (2 mL) and methanol (8 mL) and stirred at 90°C for 4 hours. After the reaction, the reaction solution was concentrated to dryness and purified by silica gel flash column chromatography (DCM:MeOH = 85:15) to obtain compound 64e (60 mg). MS m / z (ESI): 341.1 [M+H] + .

[0854] Step 5: Preparation of N-(1-((4-chloro-3-((dimethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 64f)

[0855] Compound 64e (30.13 mg, 88.41 μmol) and 1f (30 mg, 88.41 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted with EA, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 64f (60 mg). MS m / z (ESI): 662.1 [M+H] + .

[0856] Step 6: Preparation of 4-amino-N-(1-((4-chloro-3-((dimethylamino)methyl)phenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 64)

[0857] Compound 64f (60 mg, 90.61 μmol) was dissolved in TFA (4 mL) and stirred at 85°C for 3 hours. After the reaction, the TFA was concentrated to dryness, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was then separated and purified by Prep-HPLC to yield compound 64 (7 mg). MS m / z (ESI): 512.2 [M+H]+.

[0858] 1 H NMR (400MHz, DMSO-d6) δ13.20 (s, 1H), 9.33 (s, 1H), 8.66 (dd, J = 7.2, 1.2Hz, 1H), 8.63 ( s,1H),8.53(dd,J=8.4,1.2Hz,1H),8.47(d,J=8.8Hz,1H),8.37(br,1H),8.23(br,1H) ,8.05–7.97(m,2H),7.92(d,J=2.4Hz,1H),7.70(t,J=7.8Hz,1H),7.61(d,J=8.8Hz,1H ),7.35(d,J=8.8Hz,1H),7.26(d,J=6.0Hz,1H),3.48(s,2H),2.44(s,3H),2.24(s,6H).

[0859] Example 55: 4-amino-N-(6-methyl-1-(p-tolylamino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 65)

[0860]

[0861] Step 1: Preparation of 6-methyl-5-nitro-N-(p-tolyl)isoquinolin-1-amine (Compound 65b)

[0862] Compound 65a (86.6 mg, 808.5 μmol), 1h (150.0 mg, 673.8 μmol), and TFA (76.8 mg, 673.8 μmol) were added to isopropanol (5.0 mL) and the temperature was raised to 100°C for 16 hours. After the reaction, the pH of the reaction solution was adjusted to alkaline with triethylamine and concentrated. The crude product was purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 65b (140.0 mg). MS m / z (ESI): 294.1 [M+H] + .

[0863] Step 2: 6-Methyl-N 1- Preparation of (p-tolyl)isoquinoline-1,5-diamine (Compound 65c)

[0864] Compound 65b (140.0 mg, 477.3 μmol) was dissolved in ethanol (6.0 mL) and water (2.0 mL). Iron powder (133.3 mg, 2.4 mmol) and ammonium chloride (25.5 mg, 477.3 μmol) were added sequentially. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 hours. After the reaction, the mixture was filtered through Celite and the filtrate was concentrated to obtain compound 65c (113.6 mg). MS m / z (ESI): 264.1 [M+H] + .

[0865] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(6-methyl-1-(p-tolylamino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 65d)

[0866] Compound 65c (38.8 mg, 147.3 μmol) and 1f (50.0 mg, 147.3 μmol) were dissolved in pyridine (3.0 mL). T3P (1 mL, 50% DMF solution) was added dropwise and allowed to react at 25°C for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The reaction solution was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 65d (50.0 mg). MS m / z (ESI): 585.3 [M+H] + .

[0867] Step 4: Preparation of 4-amino-N-(6-methyl-1-(p-tolylamino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 65)

[0868] Compound 65d (50.0 mg, 85.5 μmol) was added to trifluoroacetic acid (3.0 mL) and reacted at 80°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 65 (2.0 mg). MS m / z (ESI): 435.0 [M+H] + .

[0869] 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),9.11(s,1H),8.66(dd,J=7.6,1.6Hz,1H), 8.63(s,1H),8.53(dd,J=8.0,1.6Hz,1H),8.44(d,J=8.4Hz,1H),8.41–8.14(m,2H ),7.95(d,J=6.0Hz,1H),7.80–7.73(m,2H),7.69(d,J=8.0Hz,1H),7.58(d,J=8. 8Hz,1H),7.20(d,J=6.0Hz,1H),7.13(d,J=8.4Hz,2H),2.43(s,3H),2.29(s,3H).

[0870] Example 56: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)pyrido[3,4-d]pyrimidine-8-carboxamide (Compound 66)

[0871]

[0872] Step 1: Preparation of methyl 4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-8-carboxylate (Compound 66b)

[0873] Compound 66a (1.7 g, 9.4 mmol), TEA (9.5 g, 93.6 mmol, 13.0 mL), Pd(dppf)Cl2·DCM (764.6 mg, 936.2 μmol), and MeOH (20 mL) were added to an autoclave. The mixture was sealed and then bubbled with carbon monoxide to a pressure of 1.0-1.2 MPa. The mixture was then heated to 120°C for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and directly purified by silica gel flash column chromatography (DCM / MeOH = 10 / 1) to obtain compound 66b (1.82 g). MS m / z (ESI): 206.1 [M+H] + .

[0874] Step 2: Preparation of 4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-8-carboxylic acid (Compound 66c)

[0875] Compound 66b (300 mg, 1.5 mmol) was dissolved in MeOH (2 mL) and THF (2 mL). Water (2 mL) and NaOH (175.5 mg, 4.4 mmol) were added and the mixture was allowed to react at 25°C for 3 h. After completion of the reaction, the pH of the reaction solution was adjusted to 5-6 with 2N hydrochloric acid. The organic solvent was removed under reduced pressure to precipitate a solid. The solid was filtered, the filter cake was rinsed with water, and dried under vacuum to yield compound 66c (220.0 mg). MS m / z (ESI): 192.1 [M+H] + .

[0876] Step 3: Preparation of N-(1-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-8-carboxamide (Compound 66d)

[0877] Compound 66c (220.0 mg, 1.2 mmol) and 1j (347.3 mg, 1.2 mmol) were dissolved in pyridine (5.0 mL). T3P (2 mL, 50% DMF solution) was added dropwise and allowed to react at 25°C for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The reaction solution was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 66d (462.0 mg). MS m / z (ESI): 475.1 [M+H] + .

[0878] Step 4: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)pyrido[3,4-d]pyrimidine-8-carboxamide (Compound 66e)

[0879] Compound 66d (200.0 mg, 421.6 μmol) and 1d (140.8 mg, 842.3 μmol, 126.5 μL) were dissolved in DMF (5 mL), and DBU (159.1 mg, 631.8 μmol, 156.2 μL) was added dropwise. After stirring for 10 min, PyBOP (263.0 mg, 505.4 μmol) was added, and the mixture was stirred at 25°C for 3 hours. After completion of the reaction, the reaction was quenched with water and extracted three times with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 66e (120.0 mg). MS m / z (ESI): 624.0 [M+H] + .

[0880] Step 5: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)pyrido[3,4-d]pyrimidine-8-carboxamide (Compound 66)

[0881] Compound 66e (50.0 mg, 80.1 μmol) was added to trifluoroacetic acid (3.0 mL) and reacted at 80°C for 6 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 66 (9.0 mg). MS m / z (ESI): 474.1 [M+H] + .

[0882] 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),9.22(s,1H),8.71(d,J=5.2Hz,1H),8.67(s,1H),8.48–8.29(m,3H),8.27(d,J=5.2 Hz,1H),7.97(d,J=6.0Hz,1H),7.65–7.59(m,2H),7.59–7.53(m,1H),7.41–7.31(m,1H),7.30–7.17(m,1H),2.54(s,3H).

[0883] Example 57: 4-amino-N-(1-((2,4-difluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 67)

[0884]

[0885] Step 1: Preparation of N-(2,4-difluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 67b)

[0886] The preparation method of compound 59d in step 3 of Example 49 was followed except that compound 59c was replaced by compound 67a to obtain compound 67b (420.00 mg). MS m / z (ESI): 316.1 [M+H] + .

[0887] Step 2: N 1 Preparation of -(2,4-difluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 67c)

[0888] The preparation method of compound 59e in step 4 of Example 49 was followed except that compound 59d was replaced by compound 67b to obtain compound 67c (450.00 mg). MS m / z (ESI): 286.1 [M+H] + .

[0889] Step 3: Preparation of N-(1-((2,4-difluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 67d)

[0890] The preparation method of compound 59f in step 5 of Example 49 was followed except that compound 59e was replaced by compound 67c to obtain compound 67d (41.00 mg). MS m / z (ESI): 607.1 [M+H] + .

[0891] Step 4: Preparation of 4-amino-N-(1-((2,4-difluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 67)

[0892] Compound 67d (20.00 mg, 32.97 μmol) was dissolved in trifluoroacetic acid (3 mL) and heated to 80°C for 2 hours. After the reaction, the solvent was removed under reduced pressure and purified by Prep-HPLC to obtain compound 67 (13.00 mg). MS m / z (ESI): 457.0 [M+H] + .

[0893] 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),9.06(s,1H),8.65(d,J=7.6Hz,1H),8.62(s,1H),8.53(d,J=8.4Hz,1H),8.45-8.14(m,3H),7.84 (d,J=5.6Hz,1H),7.69(t,J=8.0Hz,1H),7.64-7.52(m,2H),7.36-7.26(m,1H),7.19(d,J=6.0Hz,1H),7.15-7.05(m,1H),2.44(s,3H).

[0894] Example 58: 4-amino-N-(1-((3,4-dimethoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 68)

[0895]

[0896] Step 1: Preparation of N-(3,4-dimethoxyphenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 68b)

[0897] Compound 68a (125.0 mg, 816.0 μmol), 1h (181.7 mg, 816.0 μmol), and TFA (93.1 mg, 816.0 μmol) were added to isopropanol (5.0 mL) and the temperature was raised to 100°C for 16 hours. After the reaction, the pH of the reaction solution was adjusted to alkaline with triethylamine and concentrated. The crude product was separated and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 68b (120.0 mg). MS m / z (ESI): 340.0 [M+H] + .

[0898] Step 2: N 1 Preparation of -(3,4-dimethoxyphenyl)-6-methylisoquinoline-1,5-diamine (Compound 68c)

[0899] Compound 68b (120.0 mg, 353.6 μmol) was dissolved in ethanol (6.0 mL) and water (2.0 mL). Iron powder (98.8 mg, 1.8 mmol) and ammonium chloride (18.9 mg, 353.6 μmol) were added sequentially. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 hours. After the reaction, the mixture was filtered through celite and concentrated to yield compound 68c (100.0 mg). MS m / z (ESI): 310.0 [M+H] + .

[0900] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((3,4-dimethoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 68d)

[0901] Compound 68c (50.0 mg, 161.6 μmol) and 1f (54.9 mg, 161.6 μmol) were dissolved in pyridine (3.0 mL). T3P (1 mL, 50% DMF solution) was added dropwise and allowed to react at 25°C for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The reaction solution was diluted with ethyl acetate and washed three times with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 68d (53.6 mg). MS m / z (ESI): 632.0 [M+H] + .

[0902] Step 4: Preparation of 4-amino-N-(1-((3,4-dimethoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 68)

[0903] Compound 68d (53.6 mg, 85.0 μmol) was added to trifluoroacetic acid (3.0 mL) and reacted at 80°C for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness and basified by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by Prep-HPLC to obtain compound 68 (7.3 mg). MS m / z (ESI): 481.0 [M+H] + .

[0904] 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),9.05(s,1H),8.71–8.60(m,2H),8.53(dd,J=8.4,1.6Hz,1H),8.48–8.10(m,3H),7.95(d,J=6.0Hz,1H),7. 69(d,J=8.0Hz,1H),7.58(d,J=8.4Hz,1H),7.56–7.45(m,2H),7.17(d,J =6.0Hz, 1H), 6.92 (d, J = 8.8Hz, 1H), 3.76 (d, J = 12.0Hz, 6H), 2.43 (s, 3H).

[0905] Example 59: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)pyrido[4,3-d]pyrimidine-8-carboxamide (Compound 69)

[0906]

[0907] Step 1: Preparation of 8-bromopyrido[4,3-d]pyrimidin-4(3H)-one (Compound 69b)

[0908] Compound 69a (3000.00 mg, 13.82 mmol) and formamidine acetate (4320.00 mg, 41.47 mmol) were added to a single-necked flask and heated to 170°C. Formamide (1.10 mL) was added dropwise and the reaction was continued at 170°C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, poured into ice water, and stirred at room temperature for 1 hour. The mixture was filtered, the filter cake was rinsed with water, and dried to obtain compound 69b (800 mg). MS m / z (ESI): 225.9 [M+H] + .

[0909] Step 2: Preparation of methyl 4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (Compound 69c)

[0910] The preparation method of compound 2c in step 2 of Example 2 was followed except that compound 2b was replaced by compound 69b to obtain compound 69c (613 mg). MS m / z (ESI): 205.9 [M+H] + .

[0911] Step 3: Preparation of 4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine-8-carboxylic acid (Compound 69d)

[0912] The preparation method of compound 54b in step 2 of Example 44 was followed except that compound 54a was replaced by compound 69c to obtain compound 69d (390 mg). MS m / z (ESI): 191.9 [M+H] + .

[0913] Step 4: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidine-8-carboxamide (Compound 69e)

[0914] The preparation method of compound 1k in step 7 of Example 1 was followed, except that compound 1f was replaced by compound 69d and the reaction temperature was changed to 80°C, to obtain compound 69e (320 mg). MS m / z (ESI): 474.9 [M+H] + .

[0915] Step 5: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)pyrido[4,3-d]pyrimidine-8-carboxamide (Compound 69f)

[0916] The preparation method of compound 45f was followed by reference to the fifth step of Example 41 except that compound 45e was replaced by compound 69e to obtain compound 69f (17 mg). MS m / z (ESI): 623.9 [M+H] + .

[0917] Step 6: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)pyrido[4,3-d]pyrimidine-8-carboxamide (Compound 69)

[0918] The preparation method of compound 60 was followed by reference to the fourth step of Example 50 except that compound 60d was replaced by compound 69f to obtain compound 69 (4 mg). MS m / z (ESI): 474.0 [M+H] + .

[0919] 1H NMR(400MHz,DMSO-d6)δ12.53(s,1H),9.76(s,1H),9.42(s,1H),9.04-8.90(m,1H),8.75(s,1H),8.74(brs,1H),8.4 3(d,J=7.2Hz,1H),7.84(d,J=6.0Hz,1H),7.71(d,J=8.0Hz,1H),7.60-7.37(m,3H),7.35-7.25(m,2H),2.48(s,3H).

[0920] Example 60: 4-amino-N-(1-((4-chloro-2,3-difluorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 70)

[0921]

[0922] Step 1: Preparation of N-(4-chloro-2,3-difluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 70b)

[0923] Compound 1h (220.39 mg, 1.35 mmol) and 70a (200 mg, 898.36 μmol) were dissolved in isopropanol (10 mL). p-Toluenesulfonic acid monohydrate (68.35 mg, 359.34 μmol) was added and stirred at 100°C for 18 hours. After the reaction, the reaction solution was concentrated to dryness to obtain compound 70b (314 mg). MS m / z (ESI): 349.9 [M+H] + .

[0924] Step 2: N 1 Preparation of -(4-chloro-2,3-difluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 70c)

[0925] Compound 70b (314 mg, 897.86 μmol), iron powder (250.56 mg, 4.49 mmol), and NH4Cl (143.98 mg, 2.69 mmol) were added to water (4 mL) and methanol (15 mL) and stirred at 90°C for 4 hours. After completion of the reaction, the mixture was directly purified by silica gel flash column chromatography (DCM:MeOH = 88:12) to obtain compound 70c (210 mg). MS m / z (ESI): 319.9 [M+H] + .

[0926] Step 3: Preparation of 4-amino-N-(1-((4-chloro-2,3-difluorophenyl)amino)-6-methylisoquinolin-5-yl)imidazo[2,1-f][1,2,4]triazine-7-carboxamide (Compound 70)

[0927] Compound 70c (35.70 mg, 111.65 μmol) and 30c (20 mg, 111.65 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the solvent was removed by concentration, and saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM:MeOH = 96:4) to obtain compound 70 (6.88 mg). MS m / z (ESI): 480.9 [M+H] + .

[0928] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.38(s,1H),8.66(d,J=32.4Hz,2H),8.41–8.32(m,2H),8.24(s,1 H),7.92(d,J=6.0Hz,1H),7.64(d,J=8.8Hz,1H),7.47–7.40(m,2H),7.24(d,J=6.0Hz,1H),2.44(s,3H).

[0929] Example 61: 4-amino-N-(6-methyl-1-((2-(trifluoromethyl)pyridin-4-yl)amino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 71)

[0930]

[0931] Step 1: Preparation of 6-methyl-5-nitro-N-(2-(trifluoromethyl)pyridin-4-yl)isoquinolin-1-amine (Compound 71b)

[0932] Compound 70a (150 mg, 925.28 μmol), 1h (205.99 mg, 925.29 μmol), BINAP (115.23 mg, 185.06 μmol), Pd2(dba)3 (84.73 mg, 92.53 μmol), and Cs2CO3 (904.43 mg, 2.78 mmol) were added to 1,4-dioxane (10 mL) and reacted in a microwave oven at 110°C for 3 hours under nitrogen protection. After completion of the reaction, the mixture was diluted with water and extracted with EA. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 71b (300 mg). MS m / z (ESI): 349.0 [M+H] + .

[0933] Step 2: 6-Methyl-N 1 Preparation of -(2-(trifluoromethyl)pyridin-4-yl)isoquinoline-1,5-diamine (Compound 71c)

[0934] Compound 71b (300 mg, 861.38 μmol), iron powder (240.54 mg, 4.31 mmol), and NH4Cl (138.23 mg, 2.58 mmol) were added to methanol (15 mL) and water (4 mL) and stirred at 90°C for 4 hours. After completion of the reaction, the mixture was directly purified by silica gel flash column chromatography (DCM:MeOH = 88:12) to obtain compound 71c (150 mg). MS m / z (ESI): 319.0 [M+H] + .

[0935] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(6-methyl-1-((2-(trifluoromethyl)pyridin-4-yl)amino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 71d)

[0936] Compound 1f (40.00 mg, 117.87 μmol) and 71c (37.52 mg, 117.87 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 71d (40 mg). MS m / z (ESI): 640.1 [M+H] + .

[0937] Step 4: Preparation of 4-amino-N-(6-methyl-1-((2-(trifluoromethyl)pyridin-4-yl)amino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 71)

[0938] Compound 71d (40 mg, 62.54 μmol) was dissolved in TFA (3 mL) and stirred at 85°C for 3 hours. After the reaction, the TFA was concentrated to dryness, and saturated sodium bicarbonate solution was added to adjust the pH to approximately 8. The mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 71 (18 mg). MS m / z (ESI): 490.1 [M+H] + .

[0939] 1 H NMR(400MHz,DMSO-d6)δ10.04(s,1H),9.78–9.03(m,2H),8.78(d,J=5.2Hz,1 H),8.68(s,1H),8.64(d,J=8.0Hz,1H),8.56(d,J=5.6Hz,1H),8.52(d,J=8.4 Hz,1H),8.46(d,J=2.0Hz,1H),8.24(dd,J=5.6,1.6Hz,1H),8.20(d,J=6.0Hz ,1H),7.89(s,1H),7.74(d,J=8.8Hz,1H),7.49(d,J=6.0Hz,1H),2.48(s,3H).

[0940] Example 62: 4-amino-N-(1-((2,5-difluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 72)

[0941]

[0942] Step 1: Preparation of N-(2,5-difluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 72b)

[0943] The preparation method of compound 70b in the first step of Example 60 was followed, except that compound 70a was replaced by compound 72a and the reaction temperature was changed to 90°C, to obtain compound 72b (200 mg). MS m / z (ESI): 316.0 [M+H] + .

[0944] Step 2: N 1 Preparation of -(2,5-difluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 72c)

[0945] The preparation method of compound 70c in step 2 of Example 60 was followed except that compound 70b was replaced by compound 72b to obtain compound 72c (150 mg). MS m / z (ESI): 286.1 [M+H] + .

[0946] Step 3: Preparation of N-(1-((2,5-difluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 72d)

[0947] The preparation method of compound 1k in step 7 of Example 1 was followed except that compound 1j was replaced by compound 72c to obtain compound 72d (50 mg). MS m / z (ESI): 607.2 [M+H] + .

[0948] Step 4: Preparation of 4-amino-N-(1-((2,5-difluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 72)

[0949] The preparation method of compound 1 in step 8 of Example 1 was followed except that compound 1k was replaced by compound 72d to obtain compound 72 (5 mg). MS m / z (ESI): 457.1 [M+H] + .

[0950] 1 HNMR(400MHz,DMSO-d6)δ13.21(s,1H),9.13(s,1H),8.67(dd,J=7.2,1.6Hz,1H ),8.64(s,1H),8.54(dd,J=8.4,1.2Hz,1H),8.41(brs,1H),8.35(d,J=8.8Hz,1 H),8.25(brs,1H),7.96(d,J=6.0Hz,1H),7.71(t,J=8.0Hz,1H),7.68-7.62(m, 2H),7.35-7.31(m,1H),7.30(d,J=6.0Hz,1H),7.03-6.96(m,1H),2.46(s,3H).

[0951] Example 63: 4-amino-N-(1-((5-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 73)

[0952]

[0953] Step 1: Preparation of N-(5-chloro-2-fluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 73b)

[0954] Compound 73a (156.92 mg, 1.08 mmol) and 1h (200 mg, 898.36 μmol) were dissolved in isopropanol (10 mL). p-Toluenesulfonic acid monohydrate (68.35 mg, 359.34 μmol) was added and stirred at 100°C for 18 hours. After the reaction, the solvent was concentrated to obtain compound 73b (298 mg). MS m / z (ESI): 332.0 [M+H] + .

[0955] Step 2: N 1 Preparation of -(5-chloro-2-fluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 73c)

[0956] Compound 73b (298 mg, 898.33 μmol), iron powder (250.86 mg, 4.49 mmol), and NH4Cl (144.15 mg, 2.69 mmol) were added to water (4 mL) and methanol (10 mL) and stirred at 90°C for 4 hours. After completion of the reaction, the mixture was directly purified by silica gel flash column chromatography (DCM:MeOH = 90:10) to obtain compound 73c (230 mg). MS m / z (ESI): 302.1 [M+H] + .

[0957] Step 3: Preparation of N-(1-((5-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 73d)

[0958] Compound 73c (44.46 mg, 147.34 μmol) and 1f (50 mg, 147.34 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (DCM:MeOH = 92:8) to obtain compound 73d (80 mg). MS m / z (ESI): 623.1 [M+H] + .

[0959] Step 4: Preparation of 4-amino-N-(1-((5-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 325)

[0960] Compound 73d (80 mg, 128.40 μmol) was dissolved in TFA (4 mL) and stirred at 90°C for 3 hours. After the reaction, TFA was removed under reduced pressure and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 73 (23.16 mg). MS m / z (ESI): 473.1 [M+H] + .

[0961] 1 H NMR (400MHz, DMSO-d6) δ11.99(br,1H),10.17(br,1H),9.34(br,2H),8.77(d,J=7.2Hz,1H),8.70(s, 1H),8.65(d,J=8.4Hz,1H),8.51(d,J=8.4Hz,1H),7.96–7.71(m,4H),7.52–7.33(m,3H),2.51(s,3H).

[0962] Example 64: 4-amino-N-(1-((4-ethoxy-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 74)

[0963]

[0964] Step 1: Preparation of N-(4-ethoxy-2-fluorophenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 74b)

[0965] Compound 74a (125.46 mg, 808.53 μmol) and 1h (150 mg, 673.77 μmol) were dissolved in isopropanol (10 mL), and p-toluenesulfonic acid monohydrate (51.27 mg, 269.51 μmol) was added. The mixture was stirred at 100°C for 18 hours. After the reaction, the reaction solution was concentrated to dryness to obtain compound 74b (229 mg). MS m / z (ESI): 342.1 [M+H] + .

[0966] Step 2: N 1 Preparation of -(4-ethoxy-2-fluorophenyl)-6-methylisoquinoline-1,5-diamine (Compound 74c)

[0967] Compound 74b (229 mg, 670.89 μmol), iron powder (187.35 mg, 3.35 mmol), and NH4Cl (107.66 mg, 2.01 mmol) were added to methanol (10 mL) and water (3 mL). The mixture was stirred at 90°C for 4 hours and then purified by silica gel flash column chromatography (DCM:MeOH = 90:10) to obtain compound 74c (180 mg). MS m / z (ESI): 312.1 [M+H] + .

[0968] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((4-ethoxy-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 74d)

[0969] Compound 74c (45.88 mg, 147.34 μmol) and 1f (50 mg, 147.34 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM:MeOH = 92:8) to obtain compound 74d (80 mg). MS m / z (ESI): 633.3 [M+H] + .

[0970] Step 4: Preparation of 4-amino-N-(1-((4-ethoxy-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 74)

[0971] Compound 74d (80 mg, 126.45 μmol) was dissolved in TFA (4 mL) and stirred at 90°C for 3 hours. After the reaction, TFA was removed under reduced pressure, and the pH was adjusted to approximately 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (DCM:MeOH = 95:5) to obtain compound 74 (11.29 mg). MS m / z (ESI): 483.0 [M+H] + .

[0972] 1H NMR (400MHz, DMSO-d6) δ13.18(s,1H),8.92(s,1H),8.67(dd,J=7.6,1.2Hz,1H),8.63(s,1H),8.54(dd ,J=8.4Hz,1.2Hz,1H),8.41(br,1H),8.35(d,J=8.4Hz,1H),8.24(br,1H),7.81(d,J=6.0Hz,1H),7.70 (t,J=8.0Hz,1H),7.58(d,J=8.8Hz,1H),7.39(t,J=8.8Hz,1H),7.14(d,J=6.0Hz,1H),6.91(dd,J=12. 4,2.8Hz,1H),6.80(dd,J=8.4,2.4Hz,1H),4.07(q,J=6.8Hz,2H),2.44(s,3H),1.36(t,J=7.0Hz,3H).

[0973] Example 65: 4-amino-N-(1-((6-methoxypyridin-3-yl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 75)

[0974]

[0975] Step 1: Preparation of N-(6-methoxypyridin-3-yl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 75b)

[0976] Compound 75a (134.5 mg, 1.08 mmol), 1h (201 mg, 902.85 μmol), Pd2(dba)3 (82.68 mg, 90.29 μmol), BINAP (112.44 mg, 180.57 μmol), and Cs2CO3 (882.50 mg, 2.71 mmol) were added to 1,4-dioxane (5 mL). The nitrogen atmosphere was replaced three times and the mixture was microwaved at 110°C for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, filtered through celite, diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (DCM:MeOH = 30:1) to afford compound 75b (115 mg). MS m / z (ESI): 311.0 [M+H] + .

[0977] Step 2: N 1 Preparation of -(6-methoxypyridin-3-yl)-6-methylisoquinoline-1,5-diamine (Compound 75c)

[0978] Compound 75b (100 mg, 1.86 mmol), iron powder (89.99 mg, 1.61 mmol), and ammonium chloride (43.09 mg, 805.65 μmol) were added to MeOH (8 mL) and H₂O (2 mL) and reacted at 90°C for 12 hours. After completion of the reaction, the mixture was directly purified by silica gel flash column chromatography (DCM / MeOH = 10 / 1) to obtain compound 75c (50.00 mg). MS m / z (ESI): 281.1 [M+H] + .

[0979] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((6-methoxypyridin-3-yl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 75d)

[0980] Compound 75c (31 mg, 110.59 μmol) and 1f (37.53 mg, 110.59 μmol) were dissolved in pyridine (3 mL), and 1-propylphosphonic anhydride (0.2 mL, 50% EA solution) was added dropwise. The mixture was allowed to react at 25°C for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel thin-layer chromatography (DCM:MeOH = 20:1) to afford compound 75d (35.00 mg). MS m / z (ESI): 602.3 [M+H] + .

[0981] Step 4: Preparation of 4-amino-N-(1-((6-methoxypyridin-3-yl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 75)

[0982] Compound 75d (31.00 mg, 51.52 μmol) was dissolved in trifluoroacetic acid (5 mL) and heated to 90°C for 12 hours. After the reaction, the solvent was removed under reduced pressure and purified by Prep-HPLC to obtain compound 75 (15.00 mg). MS m / z (ESI): 452.1 [M+H] + .

[0983] 1H NMR (400MHz, DMSO-d6) δ13.20 (s, 1H), 9.23 (s, 1H), 8.67 (dd, J = 7.6, 1.2Hz, 1H), 8.6 4(s,1H),8.55(d,J=2.4,1H),8.54(d,J=8.4,1H)8.42(d,J=12.4Hz,2H),8.28(s,1H) ,8.15(dd,J=8.8,2.8Hz,1H),7.93(d,J=6.0Hz,1H),7.71(t,J=8.0Hz,1H),7.62(d,J =8.8Hz,1H),7.22(d,J=5.6Hz,1H),6.85(d,J=9.2Hz,1H),3.86(s,3H),2.45(s,3H).

[0984] Example 66: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-hydroxyquinazoline-8-carboxamide (Compound 76)

[0985]

[0986] Step 1: Preparation of 2-amino-5-methoxyisophthalonitrile (Compound 76b)

[0987] Compound 76a (500 mg, 1.78 mmol) and CuCN (666 mg, 7.12 mmol) were added to NMP (5 mL) and microwaved at 150°C for 3 hours. After completion of the reaction, the reaction solution was diluted with EA and poured into 50 mL of a 10% aqueous ethylenediamine solution. The mixture was stirred vigorously for 10 minutes, filtered through a pad of Celite, and the filtrate was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (mobile phase: 100% DCM) to obtain compound 76b (210 mg). MS m / z (ESI): 174.0 [M+H] + .

[0988] Step 2: Preparation of 2-amino-5-methoxyisophthalic acid (Compound 76c)

[0989] Compound 76b (210 mg, 1.21 mmol) was added to ethylene glycol ethyl ether (3 mL), followed by a solution of KOH (408 mg, 7.28 mmol) in water (8 mL). The mixture was reacted at 100°C under nitrogen for 16 hours. After completion of the reaction, the pH was adjusted to 5-6 with 3M dilute hydrochloric acid. A solid precipitated and was filtered. The filter cake was rinsed with water and then MTBE, and dried under reduced pressure to yield compound 76c (210 mg). MS m / z (ESI): 211.9 [M+H] + .

[0990] Step 3: Preparation of 6-methoxy-4-oxo-3,4-dihydroquinazoline-8-carboxylic acid (Compound 76d)

[0991] Compound 76c (210 mg, 994.45 μmol) and formamide (5 mL) were added to the reaction flask and reacted at 140°C under nitrogen for 5 hours. After the reaction, the mixture was diluted with water and the pH was adjusted to 5-6 with 3M dilute hydrochloric acid. The mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 76d (150 mg). MS m / z (ESI): 221.0 [M+H] + .

[0992] Step 4: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-methoxy-4-oxo-3,4-dihydroquinazoline-8-carboxamide (Compound 76e)

[0993] Compound 1j (205 mg, 681.26 μmol) and 76d (150 mg, 681.26 μmol) were dissolved in pyridine (9 mL), and T3P (6 mL, 50% EA solution) was added. The mixture was allowed to react overnight at room temperature under nitrogen. After completion of the reaction, the reaction solution was concentrated to dryness, diluted with water, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. The mixture was then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 76e (320 mg). MS m / z (ESI): 504.1 [M+H] + .

[0994] Step 5: Preparation of N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)-6-methoxyquinazoline-8-carboxamide (Compound 76f)

[0995] Compound 76e (300 mg, 595.34 μmol) and BOP (395 mg, 893.01 μmol) were dissolved in DMF (15 mL). DBU (450 mg, 1.79 mmol) was added dropwise at room temperature and stirred for 10 min. Compound 1d (149 mg, 893.01 μmol) was then added and stirred at room temperature for 14 hr. After the reaction, the mixture was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (mobile phase: 100% DCM) to obtain compound 76f (350 mg). MS m / z (ESI): 653.3 [M+H] + .

[0996] Step 6: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-methoxyquinazoline-8-carboxamide (Compound 76g)

[0997] Compound 76f (350 mg, 535.91 μmol) and TFA (10 mL) were added to the reaction flask and reacted at 80°C under nitrogen for 3 hours. After the reaction, the reaction solution was concentrated to dryness, diluted with water, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. The solution was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 76g (250 mg). MS m / z (ESI): 503.2 [M+H] + .

[0998] Step 7: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-hydroxyquinazoline-8-carboxamide (Compound 76)

[0999] Compound 76g (250 mg, 497.09 μmol) was dissolved in DCM (6.5 mL) and BBr3 (2 M, 2.49 mL) was added. The reaction was allowed to react at 50°C under nitrogen for 120 hours. After completion, the reaction was quenched with methanol and the pH was adjusted to 6-7 by adding saturated NaHCO3 solution. A large amount of solid precipitated, which was filtered. The filter cake was washed with water and MTBE and dried under vacuum to obtain 270 mg of crude product. 20 mg of the crude product was purified by Pre-HPLC to yield Compound 76 (4.78 mg). MS m / z (ESI): 489.0 [M+H] + .

[1000] 1 H NMR (400MHz, DMSO-d6) δ13.36(s,1H),10.28(s,1H),9.26(s,1H),8.47(s,1H),8.35(d,J=8.8Hz,1H),8.29(d,J=2.8Hz,1H),8.02(br,2H), 7.91(d,J=6.0Hz,1H),7.79(d,J=2.8Hz,1H),7.63(d,J=8.8Hz,1H),7.59–7.54(m,1H),7.40–7.34(m,1H),7.28–7.21(m,2H),2.45(s,3H).

[1001] Example 67: 4-amino-N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 77)

[1002]

[1003] Step 1: Preparation of N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 77b)

[1004] Compound 77a (162.96 mg, 1.08 mmol) and 1h (200 mg, 898.36 μmol) were dissolved in isopropanol (10 mL), and p-toluenesulfonic acid monohydrate (15.47 mg, 89.84 μmol) was added. The mixture was reacted at 99°C for 12 hours. After the reaction, the solid was collected by filtration to obtain compound 77b (285.00 mg). MS m / z (ESI): 338.0 [M+H] + .

[1005] Step 2: N 1 Preparation of -(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-methylisoquinoline-1,5-diamine (Compound 77c)

[1006] Compound 77b (205.00 mg, 607.72 μmol), iron powder (169.70 mg, 3.04 mmol), and ammonium chloride (81.27 mg, 1.52 mmol) were added to MeOH (10 mL) and H₂O (2 mL) and reacted at 90°C for 12 hours. After completion of the reaction, the reaction solution was concentrated to dryness and purified by silica gel flash column chromatography (DCM:MeOH = 10:1) to obtain compound 77c (132.00 mg). MS m / z (ESI): 308.1 [M+H] + .

[1007] Step 3: Preparation of N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 77d)

[1008] Compound 77c (45.29 mg, 147.34 μmol) and 1f (50 mg, 147.34 μmol) were dissolved in pyridine (3 mL), and 1-propylphosphonic anhydride (0.28 mL, 50% EA solution) was added dropwise. The mixture was allowed to react at 25°C for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel thin-layer chromatography (DCM:MeOH = 15:1) to yield compound 77d (20.00 mg). MS m / z (ESI): 629.3 [M+H]+ .

[1009] Step 4: Preparation of 4-amino-N-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 77)

[1010] Compound 77d (20.00 mg, 31.81 μmol) was dissolved in trifluoroacetic acid (2 mL) and heated to 80°C for 3 hours. After the reaction, the solvent was removed under reduced pressure and purified by Prep-HPLC to obtain compound 77 (12.00 mg). MS m / z (ESI): 479.1 [M+H] + .

[1011] 1 H NMR (400MHz, DMSO-d6) δ13.19 (s, 1H), 9.04 (s, 1H), 8.67 (dd, J = 7.2, 1.2Hz, 1H), 8.6 4(s,1H),8.54(dd,J=8.4,1.6Hz,1H),8.48-8.15(m,3H),7.95(d,J=6.0Hz,1H),7.71 (t,J=7.8Hz,1H),7.59(d,J=8.8Hz,1H),7.55(d,J=2.4Hz,1H),7.29(dd,J=8.8,2.4H z,1H),7.19(d,J=6.0Hz,1H),6.82(d,J=8.8Hz,1H),4.29-4.21(m,4H),2.44(s,3H).

[1012] Example 68: 4-amino-N-(1-((4-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 78)

[1013]

[1014] Step 1: Preparation of 3-fluoro-4-((6-methyl-5-nitroisoquinolin-1-yl)amino)benzonitrile (Compound 78b)

[1015] Compound 1h (100.00 mg, 449.18 μmol), 78a (64.20 mg, 471.64 μmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (7.07 mg, 17.97 μmol), tris(dibenzylideneacetone)dipalladium (8.23 mg, 8.98 μmol), and LiHMDS (898.36 μL) were added to dry 1,4-dioxane (4 mL) and reacted in a microwave oven at 150°C for 1.5 hours under nitrogen protection. After completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (PE / EA = 3 / 1) to obtain compound 78b (153 mg). MS m / z (ESI): 323.0 [M+H] + .

[1016] Step 2: Preparation of 4-((5-amino-6-methylisoquinolin-1-yl)amino)-3-fluorobenzonitrile (Compound 78c)

[1017] The preparation method of compound 73c in step 2 of Example 63 was followed except that compound 73b was replaced by compound 78b to obtain compound 78c (46 mg). MS m / z (ESI): 293.0 [M+H] + .

[1018] Step 3: Preparation of N-(1-((4-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 78d)

[1019] The preparation method of compound 73d in step 3 of Example 63 was followed except that compound 73c was replaced by compound 78c to obtain compound 78d (33 mg). MS m / z (ESI): 614.0 [M+H] + .

[1020] Step 4: Preparation of 4-amino-N-(1-((4-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 78)

[1021] The preparation method of compound 1 in step 8 of Example 1 was followed except that compound 1k was replaced by compound 78d to obtain compound 78 (2 mg). MS m / z (ESI): 464.2 [M+H] + .

[1022] 1HNMR (400MHz, DMSO-d6) δ13.24(s,1H),9.46(s,1H),8.66(d,J=6.8Hz,1H),8.64(s,1H),8.54(d,J=6.8Hz,1H),8.41(brs,1H),8.34(d,J=8.4Hz,1H ),8.24(brs,1H),8.03(d,J=6.0Hz,1H),7.97(t,J=8.0Hz,1H),7.88(dd,J =11.2,1.6Hz,1H),7.74-7.65(m,3H),7.41(d,J=6.0Hz,1H),2.47(s,3H).

[1023] Example 69: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-(2-morpholinoethoxy)quinazoline-8-carboxamide (Compound 79)

[1024]

[1025] Compound 76 (10 mg, 20.45 μmol), the hydrochloride salt of 79a (4 mg, 22.50 μmol), K2CO3 (7 mg, 51.14 μmol), and DMSO (2 mL) were added to a reaction flask and reacted at 90°C for 3 hours under nitrogen. After completion of the reaction, the mixture was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Pre-HPLC to yield compound 79 (3.5 mg). MS m / z (ESI): 602.0 [M+H] + .

[1026] 1 H NMR (400MHz, DMSO-d6) δ13.24(s,1H),9.23(s,1H),8.51(s,1H),8.34(d,J=8.4Hz,1H) ,8.22(d,J=2.8Hz,1H),8.11(br,2H),7.99(d,J=3.2Hz,1H),7.90(d,J=6.0Hz,1H),7.6 2(d,J=8.8Hz,1H),7.59–7.53(m,1H),7.39–7.32(m,1H),7.26–7.20(m,2H),4.28(t,J =6.0Hz,2H),3.62–3.57(m,4H),2.80(t,J=6.0Hz,2H),2.55–2.52(m,4H),2.44(s,3H).

[1027] Example 70: 4-amino-N-(1-((5-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 80)

[1028]

[1029] Step 1: Preparation of 4-fluoro-3-((6-methyl-5-nitroisoquinolin-1-yl)amino)benzonitrile (Compound 80b)

[1030] The preparation method of compound 73b was followed by reference to the first step of Example 63, except that compound 73a was replaced by compound 80a and the reaction temperature was changed to 90°C to obtain compound 80b (33 mg). MS m / z (ESI): 323.0 [M+H] + .

[1031] Step 2: Preparation of 3-((5-amino-6-methylisoquinolin-1-yl)amino)-4-fluorobenzonitrile (Compound 80c)

[1032] The preparation method of compound 73c in step 2 of Example 63 was followed except that compound 73b was replaced by compound 80b to obtain compound 80c (26 mg). MS m / z (ESI): 293.1 [M+H] + .

[1033] Step 3: Preparation of N-(1-((5-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 80d)

[1034] The preparation method of compound 73d in step 3 of Example 63 was followed except that compound 73c was replaced by compound 80c to obtain compound 80d (22 mg). MS m / z (ESI): 614.1 [M+H] + .

[1035] Step 4: Preparation of 4-amino-N-(1-((5-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 80)

[1036] The preparation method of compound 1 in step 8 of Example 1 was followed except that compound 1k was replaced by compound 80d to obtain compound 80 (12 mg). MS m / z (ESI): 464.1 [M+H] + .

[1037] 1H NMR (400MHz, DMSO-d6) δ13.22(s,1H),9.31(s,1H),8.67(dd,J=7.2,1.2Hz,1H),8.64(s,1H),8.39(brs,1H),8.35(d,J=8.8Hz,1H),8.25(brs,1H), 8.19(dd,J=7.2,2.0Hz,2H),7.96(d,J=6.0Hz,1H),7.73-7.68(m,2H),7.6 6(d,J=8.8Hz,1H),7.56-7.51(m,1H),7.32(d,J=6.0Hz,1H),2.47(s,3H).

[1038] Example 71: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)pyrido[3,2-d]pyrimidine-8-carboxamide (Compound 81)

[1039]

[1040] Step 1: Preparation of 8-iodopyrido[3,2-d]pyrimidin-4-amine (Compound 81b)

[1041] Compound 81a (250 mg, 1.01 mmol) and formamidine acetate (524.76 mg, 5.04 mmol) were dissolved in NMP (5 mL), the atmosphere was purged with nitrogen three times, and the mixture was microwaved at 160°C for 0.5 h. After the reaction, 100 mL of water was added to the reaction solution, and the mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 81b (220 mg). MS m / z (ESI): 272.8 [M+H] + .

[1042] Step 2: Preparation of methyl 4-aminopyrido[3,2-d]pyrimidine-8-carboxylate (Compound 81c)

[1043] Compound 81b (215 mg, 790.31 μmol), TEA (239.91 mg, 2.37 mmol), and Pd(dppf)Cl2 DCM (64.49 mg, 79.03 μmol) were dissolved in methanol (3 mL) and reacted at 120°C under a carbon monoxide atmosphere for 5 hours. After the reaction, the temperature was cooled to room temperature, the reaction solution was concentrated to dryness, and purified by silica gel flash column chromatography (DCM:MeOH = 20:1) to obtain compound 81c (60 mg). MS m / z (ESI): 205.2 [M+H] + .

[1044] Step 3: Preparation of 4-aminopyrido[3,2-d]pyrimidine-8-carboxylic acid (Compound 81d)

[1045] Compound 81c (40 mg, 195.90 μmol) was dissolved in THF (4 mL) and H₂O (1 mL), and sodium hydroxide (23.51 mg, 587.70 μmol) was added. The mixture was allowed to react at 25°C for 3 hours. After the reaction, the pH was adjusted to approximately 4 with dilute hydrochloric acid, and the solvent was concentrated to dryness to obtain compound 81d (30.00 mg). MS m / z (ESI): 191.1 [M+H] + .

[1046] Step 4: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)pyrido[3,2-d]pyrimidine-8-carboxamide (Compound 81)

[1047] Compounds 81d (30 mg, 157.76 μmol) and 1j (47.60 mg, 157.76 μmol) were dissolved in pyridine (3 mL), and 1-propylphosphoric anhydride (0.5 mL, 50% EA solution) was added dropwise. The mixture was allowed to react at 25°C for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by Prep-HPLC to yield compound 81 (20 mg). MS m / z (ESI): 474.0 [M+H] + .

[1048] 1 H NMR (400MHz, DMSO-d6) δ12.68 (s, 1H), 9.28 (s, 1H), 9.02 (d, J = 4.4Hz, 1H), 8.64(s,1H),8.51(s,1H),8.46(d,J=4.4Hz,1H),8.44(s,1H),8.38(d,J=8 .4Hz,1H),7.93(d,J=6.0Hz,1H),7.65(d,J=8.4Hz,1H),7.60-7.54(m,1H) ,7.42–7.35(m,1H),7.31(d,J=6.0Hz,1H),7.27-7.21(m,1H),2.48(s,3H).

[1049] Example 72: 4-amino-N-(6-methyl-1-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 82)

[1050]

[1051] Step 1: Preparation of 6-methyl-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-nitroisoquinolin-1-amine (Compound 82b)

[1052] Compound 82a (115 mg, 707.46 μmol), 1h (150 mg, 673.77 μmol), and p-toluenesulfonic acid (29 mg, 336.88 μmol) were added to isopropanol (5 mL) and heated in a microwave oven at 90°C for 2.5 hours under nitrogen. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 82b (230 mg). MS m / z (ESI): 349.2 [M+H] + .

[1053] Step 2: 6-Methyl-N 1 Preparation of -(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)isoquinoline-1,5-diamine (Compound 82c)

[1054] Compound 82b (230 mg, 660.17 μmol) was dissolved in EtOH (10 mL), and iron powder (368 mg, 6.60 mmol) and a solution of NH4Cl (88 mg, 1.65 mmol) in water (2.5 mL) were added. The mixture was refluxed at 90°C for 3 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 82c (81 mg). MS m / z (ESI): 319.2 [M+H] + .

[1055] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(6-methyl-1-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 82d)

[1056] Compound 1f (70 mg, 206.28 μmol) and 82c (66 mg, 206.28 μmol) were added to pyridine (3 mL), followed by the addition of T3P (2 mL, 50% EA solution), and the mixture was allowed to react at room temperature for 14 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and saturated aqueous sodium bicarbonate (5 mL) was added. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel flash column chromatography (mobile phase: DCM:MeOH = 96:4) to afford compound 82d (25 mg). MS m / z (ESI): 640.4 [M+H] + .

[1057] Step 4: Preparation of 4-amino-N-(6-methyl-1-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)isoquinolin-5-yl)quinazoline-8-carboxamide (Compound 82)

[1058] Compound 82d (25 mg, 39.08 μmol) was added to TFA (3 mL) and reacted at 80°C under nitrogen for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure, diluted with water, and the pH was adjusted to 7-8 with saturated NaHCO₃ solution. The mixture was extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Pre-HPLC to yield Compound 82 (5 mg). MS m / z (ESI): 490.0 [M+H] + .

[1059] 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),9.12(s,1H),8.66(dd,J=7.6,1.6Hz,1H),8.6 2(s,1H),8.53(dd,J=8.0,1.6Hz,1H),8.46–8.21(m,3H),7.96(d,J=6.0Hz,1H),7.69 (t,J=8.0Hz,1H),7.66–7.61(m,2H),7.59(d,J=8.4Hz,1H),7.20(d,J=6.0Hz,1H),7. 08(d,J=8.4Hz,1H),3.78–3.57(m,2H),3.32(s,3H),2.90–2.72(m,4H),2.43(s,3H).

[1060] Example 73: 4-amino-N-(1-((3-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 83)

[1061]

[1062] Step 1: Preparation of 2-fluoro-3-((6-methyl-5-nitroisoquinolin-1-yl)amino)benzonitrile (Compound 83b)

[1063] Compound 1h (130 mg, 583.94 μmol), 83a (87 mg, 642.33 μmol), and p-toluenesulfonic acid (50 mg, 291.97 μmol) were added to isopropanol (5 mL) and reacted at 90°C for 18 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the solid was filtered, and the filter cake was washed with MTBE and dried under reduced pressure to obtain compound 83b (120 mg). MS m / z (ESI): 323.1 [M+H]+ .

[1064] Step 2: Preparation of 3-((5-amino-6-methylisoquinolin-1-yl)amino)-2-fluorobenzonitrile (Compound 83c)

[1065] Compound 83b (120 mg, 372.33 μmol) was dissolved in EtOH (8 mL), and iron powder (208 mg, 3.72 mmol) and a solution of NH4Cl (50 mg, 930.83 μmol) in water (2.5 mL) were added. The mixture was stirred at 90°C for 3 hours. After the reaction, the reaction mixture was filtered, the filtrate was diluted with water, and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield compound 83c (100 mg). MS m / z (ESI): 293.1 [M+H] + .

[1066] Step 3: Preparation of N-(1-((3-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)quinazoline-8-carboxamide (Compound 83d)

[1067] Compound 1f (35 mg, 103.14 μmol) was added to pyridine (3 mL), followed by compound 83c (30 mg, 103.14 μmol) and T3P (2 mL, 50% EA solution). The mixture was allowed to react at room temperature for 14 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and saturated aqueous sodium bicarbonate (5 mL) was added, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel flash column chromatography (mobile phase: DCM / MeOH = 96 / 4) to yield compound 83d (40 mg). MS m / z (ESI): 614.4 [M+H] + .

[1068] Step 4: Preparation of 4-amino-N-(1-((3-cyano-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 83)

[1069] Compound 83d (40 mg, 65.18 μmol) was added to TFA (3 mL) and reacted at 80°C under nitrogen for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, the mixture was diluted with water, and the pH was adjusted to 7-8 with saturated NaHCO₃ solution. The mixture was then extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Pre-HPLC to yield Compound 83 (8 mg). MS m / z (ESI): 464.2 [M+H] + .

[1070] 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),9.38(s,1H),8.65(dd,J=7.6,1.6Hz,1H),8.62(s,1H),8.53(dd,J=8.0,1.6Hz,1 H),8.41–8.18(m,3H),7.97–7.91(m,2H),7.72–7.62(m,3H),7.42(t,J=8.0Hz,1H),7.30(d,J=6.0Hz,1H),2.45(s,3H).

[1071] Example 74: 4-amino-N-(1-((5-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-fluoroquinazoline-8-carboxamide (Compound 84)

[1072]

[1073] Step 1: Preparation of N-(1-((5-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)-6-fluoroquinazoline-8-carboxamide (Compound 84a)

[1074] Compound 46e (30 mg, 83.95 μmol) and 73c (24.33 mg, 80.62 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the mixture was quenched by dropwise addition of saturated sodium bicarbonate solution. The mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 84a (50 mg). MS m / z (ESI): 641.2 [M+H] + .

[1075] Step 2: Preparation of 4-amino-N-(1-((5-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-fluoroquinazoline-8-carboxamide (Compound 84)

[1076] Compound 84a (50 mg, 78.00 μmol) was dissolved in TFA (3 mL) and stirred at 85°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the crude product was separated and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 84 (22 mg). MS m / z (ESI): 491.2 [M+H] + .

[1077] 1H NMR(400MHz,DMSO-d6)δ12.70(s,1H),10.14(s,1H),8.74(br,1H),8.65(s, 1H),8.55–8.42(m,3H),7.87–7.76(m,3H),7.54–7.39(m,3H),2.51(s,3H).

[1078] Example 75: 4-amino-N-(1-((2,4-difluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-fluoroquinazoline-8-carboxamide (Compound 85)

[1079]

[1080] Step 1: Preparation of N-(1-((2,4-difluorophenyl)amino)-6-methylisoquinolin-5-yl)-4-((2,4-dimethoxybenzyl)amino)-6-fluoroquinazoline-8-carboxamide (Compound 85a)

[1081] Compound 46e (28.81 mg, 80.62 μmol) and 67c (23 mg, 80.62 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) was added. The mixture was stirred at 25°C for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 85a (50 mg). MS m / z (ESI): 625.3 [M+H] + .

[1082] Step 2: Preparation of 4-amino-N-(1-((2,4-difluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-fluoroquinazoline-8-carboxamide (Compound 85)

[1083] Compound 85a (50 mg, 80.05 μmol) was dissolved in TFA (3 mL) and stirred at 85°C for 16 hours. After the reaction, the solvent was removed under reduced pressure, and the crude product was separated and purified by Prep-HPLC to obtain the trifluoroacetic acid salt of compound 85 (27 mg). MS m / z (ESI): 475.2 [M+H] + .

[1084] 1H NMR (400MHz, DMSO-d6) δ12.85(s,1H),10.70(s,1H),8.65(s,1H),8.63(br,2H),8.58(d,J=8.8Hz,1H),8.45(d,J=9.2Hz,2H) ,7.87(d,J=8.4Hz,1H),7.79-7.66(m,2H),7.59(t,J=8.4Hz,1H),7.44(d,J=6.8Hz,1H),7.33(t,J=7.8Hz,1H),2.54(s,3H).

[1085] Example 76: 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-(2-hydroxyethoxy)quinazoline-8-carboxamide (Compound 86)

[1086]

[1087] Step 1: Preparation of 4-amino-6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 86b)

[1088] Compound 76 (40 mg, 81.82 μmol), 86a (39 mg, 163.63 μmol), and K2CO3 (28 mg, 204.57 μmol) were added to DMSO (3 mL) and reacted at 90°C under nitrogen for 3 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 86b (50 mg). MS m / z (ESI): 647.3 [M+H] + .

[1089] Step 2: Preparation of 4-amino-N-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)-6-(2-hydroxyethoxy)quinazoline-8-carboxamide (Compound 86)

[1090] Compound 86b (50 mg, 77.25 μmol) was dissolved in THF (3 mL), followed by the addition of acetic acid (2.32 mg, 38.63 μmol) and TBAF (115.88 μL, 1 M THF solution). The mixture was reacted at room temperature under nitrogen for 16 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Pre-HPLC to yield compound 86 (8 mg). MS m / z (ESI): 532.9 [M+H]+ .

[1091] 1 H NMR (400MHz, DMSO-d6) δ13.25(s,1H),9.24(s,1H),8.51(s,1H),8.34(d,J= 8.8Hz,1H),8.26–8.01(m,3H),7.98(d,J=3.2Hz,1H),7.90(d,J=6.0Hz,1H), 7.62(d,J=8.8Hz,1H),7.58–7.53(m,1H),7.39–7.33(m,1H),7.27–7.19(m,2 H), 4.98 (br, 1H), 4.19 (t, J = 4.8Hz, 2H), 3.81 (t, J = 4.8Hz, 2H), 2.44 (s, 3H).

[1092] Example 77: 4-amino-N-(1-((2-fluoro-5-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 87)

[1093]

[1094] Step 1: Preparation of N-(2-fluoro-5-methoxyphenyl)-6-methyl-5-nitroisoquinolin-1-amine (Compound 87b)

[1095] Compound 87a (114.12 mg, 808.53 μmol) and 1h (150 mg, 673.77 μmol) were dissolved in isopropanol (5 mL), and p-toluenesulfonic acid monohydrate (51.27 mg, 269.51 μmol) was added. The mixture was stirred at 100°C for 18 hours. After the reaction, the reaction solution was concentrated to dryness to obtain compound 87b (220 mg). MS m / z (ESI): 328.1 [M+H] + .

[1096] Step 2: N 1 Preparation of -(2-fluoro-5-methoxyphenyl)-6-methylisoquinoline-1,5-diamine (Compound 87c)

[1097] Compound 87b (220 mg, 672.15 μmol), iron powder (187.78 mg, 3.36 mmol), and ammonium chloride (107.90 mg, 2.02 mmol) were added to methanol (10 mL) and water (3 mL) and stirred at 90°C for 4 hours. After the reaction, the reaction solution was concentrated to dryness and purified by silica gel flash column chromatography (DCM / MeOH = 96 / 4) to obtain compound 87c (150 mg). MS m / z (ESI): 298.0 [M+H]+ .

[1098] Step 3: Preparation of 4-((2,4-dimethoxybenzyl)amino)-N-(1-((2-fluoro-5-methoxyphenyl)amino)-6-methylisoquinolin-5-yl)quinazoline-8-carboxamide (Compound 87d)

[1099] Compound 87c (26.29 mg, 88.41 μmol) and 1f (30 mg, 88.41 μmol) were dissolved in pyridine (2 mL), and T3P (0.5 mL, 50% EA solution) w...

Claims

1. A compound of formula I' or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof: in: Ring A is a benzene ring, a pyrrole ring, an imidazole ring or a pyridine ring; Ring B is a benzene ring or a pyridine ring; X 1 C, X 2 selected from C and N; X 3 Selected from CH and N, X 4 is N; Y is selected from -O-, -NH-, -C(=O)-, -CR 5 R 6 -、-CR 5 R 6 O-and-CR 5 R 6 NH-; R 1 Selected from H, C 1-6 Alkyl and C 3-6 cycloalkyl, said alkyl and cycloalkyl are each optionally substituted with one or more halogens; R 2 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, said alkyl and alkoxy are each optionally substituted with one or more halogens; R 3 For LR 3 '; L is independently a direct bond or -(CH2) n -; R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl, cycloalkyl, and cycloalkoxy groups is optionally substituted by one or more substituents independently selected from the following: hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclic group; or when L is a direct bond and m is greater than 1, two R 3 'Together with the group to which it is connected, it forms a 4-10 membered heterocyclic ring; R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic group, -NR 20a R 20b , wherein the alkyl, heteroalkyl, cycloalkyl, cycloalkoxy, and heterocyclyl groups are each optionally substituted by one or more substituents independently selected from the following: hydroxy, halogen, CN, NH2, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups; R 5 and R 6 Each independently selected from H, hydroxy, halogen, -NH2, -NHCH3, -N(CH3)2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, wherein each of said alkyl and heteroalkyl groups is optionally substituted with one or more halogens; R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each independently selected from H, OH, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; said alkyl, alkoxy, cycloalkyl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and 4-10 membered heterocyclic group; R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl groups are each optionally substituted with one or more halogens; m is 0, 1, 2, 3, 4 or 5; n is 1 or 2; and p is 0, 1, 2 or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, -NR 20a R 20b , wherein the alkyl, heteroalkyl, cycloalkyl, cycloalkoxy, and heterocyclyl groups are each optionally substituted by one or more substituents independently selected from the following: hydroxy, halogen, CN, NH2, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclic groups.

3. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 4 Each occurrence is independently selected from H, hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclic group, -NR 20a R 20b , wherein the alkyl, heteroalkyl, cycloalkyl, cycloalkoxy, and heterocyclyl groups are each optionally substituted by one or more substituents independently selected from the following: hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy and 4-6 membered heterocyclic groups.

4. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 4 Each occurrence is independently selected from H, hydroxy, halogen, C 1-4 Alkyl, C 1-4 Heteroalkyl, 4-6 membered heterocyclyl and -NR 20a R 20b , wherein the alkyl, heteroalkyl, and heterocyclyl groups are each optionally substituted by one or more substituents independently selected from the following: hydroxy, halogen, NH2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 haloalkoxy and 4-6 membered heterocyclyl; and p is 0 or 1.

5. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 4 Each occurrence is independently selected from hydroxy, F, methyl, -CH2CH2NH2, 6. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, which has a structure of Formula I: in: Ring A is a benzene ring, a pyrrole ring, an imidazole ring or a pyridine ring; Ring B is selected from a benzene ring or a pyridine ring; X 1 C, X 2 selected from C and N; X 3 and X 4 Selected from CH and N, X 4 is N; Y is selected from -O-, -NH-, -C(=O)-, -CR 5 R 6 -、-CR 5 R 6 O-and-CR 5 R 6 NH-; R 1 Selected from H, C 1-6 Alkyl and C 3-6 cycloalkyl, said alkyl and cycloalkyl are each optionally substituted with one or more halogens; R 2 Selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, said alkyl and alkoxy are each optionally substituted with one or more halogens; R 3 For LR 3 '; L is independently a direct bond or -(CH2) n -; R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl, cycloalkyl, and cycloalkoxy groups is optionally substituted by one or more substituents independently selected from the following: hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclic group; or when L is a direct bond and m is greater than 1, two R 3 'Together with the group to which it is connected, it forms a 4-10 membered heterocyclic ring; R 5 and R 6 Each independently selected from H, hydroxy, halogen, -NH2, -NHCH3, -N(CH3)2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, wherein each of said alkyl and heteroalkyl groups is optionally substituted with one or more halogens; R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R 25b Each independently selected from H, OH, -NHCH3, -N(CH3)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; said alkyl, alkoxy, cycloalkyl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and 4-10 membered heterocyclic group; R 21 and R 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl groups are each optionally substituted with one or more halogens; m is 0, 1, 2, 3, 4 or 5; and n is 1 or 2.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein Ring A is a benzene ring, a pyrrole ring or an imidazole ring.

8. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein X 3 is CH and X 4 is N.

9. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein Y is selected from -NH-, -C(=O)-, -CR 5 R 6 -、-CR 5 R 6 O-and-CR 5 R 6 NH-.

10. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: Y is selected from -NH-, -C(=O)-, -CH2-, -CHOH- and -CH(CH3)O-.

11. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: Y is selected from -NH-, -C(=O)-, -CH2- and -CHOH-.

12. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 1 H or C 1-3 alkyl.

13. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 1 For H.

14. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 2 Selected from H, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, the alkyl and alkoxy groups are each optionally substituted with one or more halogens.

15. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 2 is F or -CH3.

16. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein L is independently at each occurrence a direct bond or -CH2-.

17. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, -NR 20a R 20b 、-SR 21 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b 、-NR 23a C(=O)R 23b and -NR 24a C(=O)NR 25a R 25b , wherein each of the alkyl, heteroalkyl, cycloalkyl, and cycloalkoxy groups is optionally substituted by one or more substituents independently selected from the following: hydroxy, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy, C 1-4 Heteroalkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclic groups.

18. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, -NR 20a R 20b 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl, cycloalkyl, and cycloalkoxy groups is optionally substituted by one or more substituents independently selected from the following: hydroxy, halogen, CN, NO2, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkoxy, C 1-3 Heteroalkyl, C 3-6 cycloalkyl and 4-6 membered heterocyclic groups.

19. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 3 ' is independently selected at each occurrence from H, hydroxyl, halogen, CN, NO2, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, -NR 20a R 20b 、-S(=O)2R 22 、-S(=O)2NR 20a R 20b 、-NR 20a S(=O)2R 20b 、-C(=O)R 21 、-C(=O)NR 23a R 23b and -NR 23a C(=O)R 23b , wherein each of the alkyl, heteroalkyl, cycloalkyl, and cycloalkoxy groups is optionally substituted by one or more substituents independently selected from the group consisting of hydroxy, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Halogenated alkoxy, C 1-3 heteroalkyl and 4-6 membered heterocyclyl.

20. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 3 ' is independently selected at each occurrence from H, halogen, CN, C 1-4 Alkyl, C 1-4 Heteroalkyl, -NR 20a R 20b 、-S(=O)2R 22 and C(=O)R 21 , said alkyl and heteroalkyl are each optionally substituted by one or more independently selected from halogen, C 1-3 The substituents of the heteroalkyl and 4-6 membered heterocyclic groups are substituted.

21. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: When L is a direct bond and m is greater than 1, any two R 3 'Together with the groups to which they are connected, they form a 4-6 membered heterocyclic ring.

22. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein: R 3 'is independently F, Cl, Br, CN, methyl, trifluoromethyl, methoxy, ethoxy, -C(=O)CH3, -N(CH3)2, -S(=O)2CH3, Or when L is a direct bond and m is greater than 1, any two R 3 'Together with the groups to which they are connected, 23. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound has the following structure: wherein each group is as defined in any one of claims 1 to 5.

24. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the compound has the following structure: or wherein each group is as defined in any one of claims 1 to 6.

25. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein the heteroalkyl group is an alkoxy group.

26. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein the compound is selected from:

27. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof and one or more pharmaceutically acceptable carriers.

28. Use of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a pharmaceutical composition according to claim 27, in the preparation of a medicament for preventing or treating a disease or condition associated with RAF and / or RAS kinase activity.

29. The use of claim 28, wherein the disease or condition associated with RAF and / or RAS kinase activity is cancer or a tumor.

30. The use of claim 29, wherein the cancer or tumor is lung cancer, breast cancer, ovarian cancer, gastric cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, intestinal cancer, pancreatic cancer, head and neck cancer, uterine cancer, esophageal cancer, thyroid cancer, bladder cancer, blood cancer, lymphoma, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.

31. The use of claim 29, wherein the cancer or tumor is non-small cell lung cancer.

32. Preparation method, The method is a method for preparing a compound of formula IA, which comprises the following steps: Route A in: PG is an amino protecting group; The remaining groups are as defined in any one of claims 1 to 26; The reaction conditions of each step are as follows: Step 1: Compounds IA-1 and IA-2 undergo substitution reaction or coupling reaction to generate compound IA-3; Step 2: Compound IA-3 is reduced to generate compound IA-4; Step 3: Compound IA-4 and IA-5 undergo condensation reaction to produce compound IA-6; Step 4: Compound IA-6 is deprotected under acidic conditions to generate a compound of formula IA; Alternatively, the method is a method for preparing a compound of formula IA, comprising the following steps: Route A-1 in: PG is an amino protecting group; The remaining groups are as defined in any one of claims 1 to 26; The reaction conditions of each step are as follows: Step 1: Compound IA-5 and IA-7 are condensed to form compound IA-8; Step 2: Compound IA-1 and IA-8 undergo substitution reaction or coupling reaction to generate compound IA-6; Step 3: Compound IA-6 is deprotected under acidic conditions to generate a compound of formula IA; Alternatively, the method is a method for preparing a compound of formula IB, comprising the following steps: Route B-1 in: PG is an amino protecting group; The remaining groups are as defined in any one of claims 1 to 26; The reaction conditions of each step are as follows: Step 1: Compound IB-1 reacts with a boron-containing reagent to produce compound IB-2; Step 2: Compound IB-2 and IA-2 undergo coupling reaction to generate compound IB-3; Step 3: Compound IB-3 is reduced to generate compound IB-4; Step 4: Compound IB-4 and IA-5 are condensed to form compound IB-5; Step 5: Compound IB-5 is deprotected under acidic conditions to generate a compound of formula IB; Alternatively, the method is a method for preparing a compound of formula IB, comprising the following steps: Route B-2 in: PG is an amino protecting group; The remaining groups are as defined in any one of claims 1 to 26; The reaction conditions of each step are as follows: Step 1: Compound IB-6 and IB-7 undergo coupling reaction to generate compound IB-8; Step 2: Compound IB-8 and IA-5 are condensed to form compound IB-5; Step 3: Compound IB-5 is deprotected under acidic conditions to generate a compound of formula IB; Alternatively, the method is a method for preparing a compound of formula IC, comprising the following steps: Route C in: Each group is as defined in any one of claims 1 to 26; The method comprises subjecting compound IB to a catalytic oxidation reaction to produce a compound of formula IC; Alternatively, the method is a method for preparing a compound of formula ID, comprising the following steps: Route D-1 in: Each group is as defined in any one of claims 1 to 26; The method comprises subjecting compound IB to a catalytic oxidation reaction to produce a compound of formula ID; Alternatively, the method is a method for preparing a compound of formula ID, comprising the following steps: Route D-2 in: Each group is as defined in any one of claims 1 to 26; The method comprises subjecting compound IC to a reduction reaction to produce a compound of formula ID. The preparation method according to claim 32 , wherein the amino protecting group is 2,4-dimethoxybenzyl.

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