Bcl-2 inhibitors

Abstract

This invention generally relates to a BCL-2 protein inhibitor, which can be used to treat diseases and conditions regulated by this enzyme and has formula (I):

Description

Technical Field

[0001] This invention relates to inhibitors of the B-cell lymphoma 2 (BCL-2) protein. The inhibitors described herein can be used to treat diseases or conditions associated with BCL-2. Specifically, this invention relates to compounds and pharmaceutical compositions that inhibit BCL-2, methods for treating diseases or conditions associated with BCL-2, and methods for synthesizing such compounds. Prior Technology

[0002] Apoptosis, or planned cell death, is a physiological process that is crucial for embryonic development and maintaining tissue homeostasis (US Patent No. 9,120,791).

[0003] Dysregulation of apoptosis is associated with certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, as well as ischemia. See above. Conversely, defects in apoptosis play a significant role in the development of cancer and its chemoresistant forms, autoimmune diseases, inflammatory diseases, and viral infections. Therefore, the absence of apoptosis is not considered a phenotypic marker of cancer (Hanahan, D. et al., Cell, [2000,] 100, 57-70).

[0004] The BCL-2 protein family plays a crucial role in tumorigenesis (WO 2018 / 102,766). BCL-2 proteins are characterized by the presence of Bcl-2 homology (BH) domains. Anti-apoptotic proteins contain all BH1-4 domains; pro-apoptotic proteins contain only the BH3 domain or multiple BH domains. The BH3 domain is essential for the pro-apoptotic function of these proteins. In anti-apoptotic proteins, the BH3 domain remains hidden or embedded within other BH domains, and thus acts specifically as a protector of cell survival. BCL-2 proteins interact with each other using their BH domains. Anti-apoptotic BCL-2 proteins interact with and inhibit the function of pro-apoptotic members to maintain cellular homeostasis. It is the shift in the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins that determines the fate of cancer cells.

[0005] Cancer therapies targeting the BCL-2 family primarily focus on neutralizing one or more anti-apoptotic members by inhibiting their function using small molecule inhibitors or by suppressing their expression using antisense oligonucleotides (WO 2018 / 102,766). The concept involves inhibiting the function of anti-apoptotic Bcl-2 members, thereby allowing pro-apoptotic members to induce cell death in cancer cells. See above. However, it has been found that cancer cells treated with Bcl-2 inhibitors upregulate other anti-apoptotic BCL-2 or non-BCL-2 family proteins involved in cell survival, thereby developing treatment resistance.

[0006] There is a need for therapeutic agents that can induce cell death in tumors or cancers with increased Bcl-2 expression. This invention aims to address these unmet needs related to current BCL-2 inhibitory therapies. Summary of the Invention

[0007] The first state of this invention relates to compounds of formula (I): Or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, or tautomer thereof, wherein: R1 is selected from halogens, -OH, -CN, and -CONH2; R1a series H; Alternatively, R1 and R1a, together with the atoms they are attached to, may form another 3 to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R2 and R3 are each independently selected from C1-C6 alkyl groups; Alternatively, R2 and R3, together with the atoms they are attached to, can form another 3- to 10-membered heterocyclic base ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; Each R4 is independently selected from halogens, -OH, -CN, -NO2, -COOH, -CH2CN, CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6 alkyl). -C(O) (C1-C6 alkyl), -OC(O)O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -NHC(O) (C1-C6 alkyl), -C(O)NH2, -C(O)NH (C1-C6 alkyl), -S(O)2 (C1-C6 alkyl), -S(O)NH (C1-C6 alkyl) and S(O)N (C1-C6 alkyl)2; R5 series selected , and ; Each R6 is independently selected from halogens, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6) -alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl; Each R7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aryl; Wherein the alkyl or aryl group is substituted by one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)(C1- -C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl; Alternatively, two R7 atoms, along with the nitrogen atom they bond to and any inserted atoms, may form a heterocycle; The heterocyclic compound is, depending on the case, substituted with one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC (O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl)2; The R8 series is selected from H, C1-6 alkyl, C3-8 cycloalkyl, aryl, and C1-6 haloalkyl; The R9 group is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)1-6OR8, C3-8 cycloalkyl, aryl, and heterocyclic compounds; Wherein the alkyl, cycloalkyl, aryl, or heterocyclic group is substituted by one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC( O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl2; in, x is selected from integers 0, 1, 2, and 3; y is selected from integers 0, 1, 2, and 3; m is an integer selected from 0, 1, and 2; Each n is independently selected from integers 1, 2, and 3; Aryl groups are cyclic aromatic hydrocarbon groups having one to three aromatic rings; Heterocyclic systems have one or more saturated or partially unsaturated 3-10 member monocyclic systems, 7-12 member bicyclic systems (fused rings, bridging rings, or spirocyclic systems) selected from O, N, S, P, Se, and B.

[0008] Another aspect of the invention relates to pharmaceutical compositions comprising compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, and pharmaceutically acceptable carriers. The pharmaceutically acceptable carrier may further comprise excipients, diluents or surfactants.

[0009] Another aspect of the present invention relates to a method for treating a disease or condition related to the regulation of BCL-2 proteins, such as isoforms 1 and 2. The method comprises administering to a patient requiring treatment for a disease or condition related to the regulation of BCL-2 proteins an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0010] Another aspect of the present invention relates to a method for inhibiting BCL-2 proteins, including but not limited to isoform 1 and isoform 2. The method involves administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0011] Another aspect of the invention relates to a method for treating or preventing the disease or ailment disclosed herein in an individual in need. This method involves administering to a patient in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0012] Another aspect of the present invention relates to compounds of formula (I) for the manufacture of pharmaceutical preparations for the inhibition of BCL-2 protein, such as isoforms 1 and 2, and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof.

[0013] Another aspect of the present invention relates to compounds of formula (I) for use in the manufacture of medicaments for the treatment or prevention of the diseases or symptoms disclosed herein, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions.

[0014] Another aspect of the present invention relates to the use of compounds of formula (I) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers or pharmaceutical compositions thereof in the treatment and inhibition of diseases associated with BCL-2 protein, such as isoform 1 and isoform 2.

[0015] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof in the treatment of the diseases or conditions disclosed herein.

[0016] The present invention further provides a method for treating diseases or conditions related to BCL-2 protein regulation, including cancer and cancer metastasis, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0017] This invention provides an inhibitor of the BCL-2 protein, which is a therapeutic agent for treating diseases such as cancer and cancer metastasis.

[0018] This invention further provides compounds and compositions with improved efficacy and safety profiles compared to known BCL-2 protein inhibitors. This disclosure also provides agents with novel mechanisms of action against the BCL-2 protein in the treatment of various types of diseases, including cancer and cancer metastases.

[0019] In some embodiments, this disclosure provides compounds that can be obtained by or by a method for preparing the compounds described herein (e.g., a method comprising one or more steps described in a general procedure).

[0020] In some embodiments, this disclosure provides intermediates as described herein, which are suitable for use in methods for preparing compounds as described herein (e.g., the intermediates are selected from...). [, Preparation 1-168 The intermediate described in , ]).

[0021] In some embodiments, this disclosure provides a method for preparing the compounds of this disclosure.

[0022] In some embodiments, this disclosure provides a method for preparing a compound, which includes one or more steps described herein.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, the singular form also includes the plural unless the context clearly indicates otherwise. Although this disclosure may be practiced or tested using methods and materials similar to or equivalent to those described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not considered prior art to the claimed invention. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be restrictive. In case of conflict between the chemical structures and names of compounds disclosed herein, the chemical structure shall prevail.

[0024] Other features and advantages of this disclosure will become apparent from the following embodiments and the scope of the claims. Implementation

[0025] This disclosure relates to compounds and compositions capable of inhibiting the activity of BCL-2 proteins, including but not limited to isoforms 1 and 2. The disclosure is characterized by a method for treating, preventing, or alleviating diseases or conditions in which BCL-2 is involved, by administering to a patient in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The method of this invention can be used to treat a variety of BCL-2-mediated diseases and conditions by inhibiting the activity of BCL-2 proteins. Inhibition of BCL-2 can be an effective method for treating, preventing, or alleviating diseases, including but not limited to cancer and cancer metastasis. Reducing BCL-2 activity can inhibit cancer mutation induction, weaken tumor evolution, and / or reduce the probability of adverse outcomes such as drug resistance and / or cancer metastasis.

[0026] In the first embodiment of this invention, the compound of formula (I) is described as follows: And its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers, wherein R1, R2, R3, R4, R5, R6, x and y are described herein.

[0027] It should be understood that, for compounds of formula (I), R1, R2, R3, R4, R5, R6, x and y may each be selected from the groups described herein when applicable, and any group described herein with respect to any one of R1, R2, R3, R4, R5, R6, x and y may, when applicable, be combined with any group described herein with respect to one or more of the remaining parts of R1, R2, R3, R4, R5, R6, x and y.

[0028] The details of this invention are set forth in the following description. Although the invention may be practiced or tested using methods and materials similar to or equivalent to those described herein, illustrative methods and materials are described here. Other features, objects, and advantages of the invention will be apparent from this specification and the claims. Unless the context clearly indicates otherwise, the singular form includes the plural in the specification and the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications referenced in this specification are incorporated herein by reference in their entirety. [definition]

[0029] In this disclosure, the article "a / an" refers to one or more (i.e., at least one) grammatical object of an article. For example, "an element" means one element or more elements.

[0030] Unless otherwise stated, the term "and / or" is used in this disclosure to mean either "and" or "or".

[0031] The term "substitutably substituted" should be understood to mean that a given chemical moiety (e.g., an alkyl group) may (but does not need to) be bonded to other substituents (e.g., heteroatoms). For example, a substitutably substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the substitutably substituted alkyl group may have substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Therefore, the term "substitutably substituted" means that a given chemical moiety may contain other functional groups, but may not necessarily have any other functional groups. Suitable substituents for the described groups, as appropriate, include, but are not limited to, halogens, oxy groups, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -OH, and -OP(O)(OH). 2. -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N((C1-C6)alkyl)2. These substituted basics may be substituted as appropriate. As used herein, "substituted as appropriate" also means substituted or unsubstituted, the meaning of which is described below.

[0032] As used herein, the term "substituted" means that a specified group or portion has one or more suitable substituents, wherein such substituents may be attached to the specified group or portion at one or more positions. For example, a cycloalkyl-substituted aryl group may indicate that the cycloalkyl group is attached to an atom of the aryl group via a bond or by fusion with the aryl group and sharing two or more common atoms.

[0033] As used herein, the term "unsubstituted" means that the specified group does not contain substituents.

[0034] Unless otherwise explicitly defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. In the case of two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single position (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be substituted with one or more substituents at any connection point, for example, with one to five substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. These substituents themselves may be substituted as appropriate. Furthermore, when containing two fused rings, the aryl group as defined herein may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracene, propenyl naphthyl, phenanthryl, dihydroindenyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoxenyl, and similar groups.

[0035] Unless otherwise explicitly defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic group having 5 to 24 ring atoms, containing one or more cyclic heteroatoms selected from N, O, S, P, Se, or B, and with the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaryl group, wherein the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl as defined herein also means a tricyclic heteroaryl group containing one or more cyclic heteroatoms selected from N, O, S, P, Se, or B. The aromatic group may be independently substituted by one or more substituents described herein. Examples include, but are not limited to, furanyl, thiophene, pyrrole, pyridinyl, pyrazolyl, pyrimidinyl, imidazole, and isopropyl alcohol. azole group, azole group, diazole group, pyridine group alkyl, indolyl, thiophene-2-yl, quinolinyl, benzopiperanyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thiophene[3,2-b]thiophene, triazolyl, tri , imidazo[1,2-b]pyrazolyl, furano[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazoleyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazololo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indoleyl, indololinyl, indololinoneyl, dihydrobenzothiaphenyl, dihydrobenzofuranyl, benzofuran, Alkyl, thio Alkyl, tetrahydroquinolinyl, dihydrobenzothia Quinolinyl, isoquinolinyl, 1,6- Pyridyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6] pyridyl, thiopheno[2,3-b]pyridine , quinazolinyl, tetrazo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ2-pyrrolo[2,1-b]pyrimidinyl, dibenzo[b,d]thiophene, pyridin-2-one, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiophene Benzyl, benzo[ azole group, benzo[a] Azolyl, furano[2,3-b]pyridyl, benzothiophene, 1,5- Pyridyl, furano[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridyl Benz[c][1,2,5]thiadiazolyl, benzo[c][1,2,5] Diazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2] The heteroaryl group, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, thiazo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl, and their derivatives, contains two or more fused rings. Furthermore, when containing two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, such as a 5-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaryl ring containing 1 to 3 nitrogen atoms, wherein the saturated or partially unsaturated ring comprises 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is substituted with one or more side oxygen groups as appropriate. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to the saturated or partially unsaturated ring described herein. Exemplary ring systems of these heteroaryl groups include, for example, indololinyl, indololinone, dihydrobenzothiophene, and dihydrobenzofuran. Alkyl, thio Alkyl, tetrahydroquinolinyl, dihydrobenzothia 3,4-Dihydro-1H-isoquinolinyl, 2,3-Dihydrobenzofuranyl, benzofuranone, indololinyl, hydroxyindolyl, indolyl, 1,6-Dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 7,8-Dihydro-6H-pyrido[3,2-b]pyridinyl 8H-pyrido[3,2-b]pyridine 1,5,6,7-Tetrahydrocyclopentano[b]pyrazolo[4,3-e]pyridyl, 7,8-dihydro-6H-pyrido[3,2-b]pyridyl pyrazolo[1,5-a]pyrimidine-7(4H)-keto, 3,4-dihydropyrimidine [1,2-a]indole-1(2H)-keto or benzo[c][1,2] Boronium-1(3H)-ol.

[0036] "Halogen" or "halogen group" refers to fluorine, chlorine, bromine or iodine.

[0037] "Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, secondary butyl, tertiary butyl, isopentyl, neopentyl, and isohexyl.

[0038] "Alkoxy" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 12 carbon atoms and a terminal "O" in the chain, i.e., -O (alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0039] "Alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An alkenyl contains at least one double bond in its chain. The double bond of an alkenyl may be non-conjugated or conjugated with another unsaturated group. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. Alkenyl groups may be unsubstituted or substituted. As defined herein, alkenyl groups may be straight-chain or branched.

[0040] "Alynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2-12 carbon atoms. An alkynyl group contains at least one non-reacting bond in the chain. Examples of alynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentyynyl, or hexynyl. Alynyl groups may be unsubstituted or substituted.

[0041] The term "alkyleue" or "alkylenyl" refers to a divalent alkyl group. Any of the monovalent alkyl groups mentioned above can become an alkylenyl group by removing a second hydrogen atom from the alkyl group. As defined herein, alkylenyl groups can also be C1-C6 alkylenyl groups. alkylenyl groups can further be C1-C4 alkylenyl groups. Typical alkylenyl groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and similar groups.

[0042] "Cycloalkyl" refers to a monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system of saturated or partially unsaturated hydrocarbons having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, bicyclo[2.2.2]octyl, bicyclo[2.2.2]octenyl, decahydronaphthyl, octahydro-1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohex-1,4-dienyl, cyclohex-1,3-dienyl, 1,2,3,4-tetrahydronaphthyl, octahydrocyclopentadienyl, 3a,4,5,6,7 7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydrocyclopentadienyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.0]pentyl, spiro[3.3]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octyl, 6-methylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, adamantyl and its derivatives. In the case of polycyclic cycloalkyl groups, only one ring in the cycloalkyl group needs to be non-aromatic.

[0043] Unless otherwise stated, "heterocyclic group," "heterocycle," or "heterocyclic alkyl group" means having one or more heteroatoms (such as O, N, S, P, Se, or B) independently selected from the groups of nitrogen, oxygen, and sulfur, for example having 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or saturated or partially unsaturated 3-10 member monocyclic, 7-12 member bicyclic (fused ring, bridged ring, or spirocyclic), or 11-14 member tricyclic system (fused ring, bridged ring, or spirocyclic). Examples of heterocyclic alkyl groups include, but are not limited to, piperidinyl, piperidinyl... base, pyrrolidinyl, di Alkyl, tetrahydrofuranyl, isoindolineyl, indolineyl, imidazolidineyl, pyrazolidineyl azole, iso Azoxyl, triazoxyl, oxetane, aziridine, oxetane, thionyl, 1,2,3,6-tetrahydropyridyl, tetrahydropiperanyl, dihydropiperanyl, piperanyl linyl, tetrahydrothiopiperanyl, 1,4-diazacycloheptyl, 1,4-oxazacycloheptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1, 4-Dioxaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furano[3,4-b]pyridyl]yl, 3'H-spiro[cyclohexane-1,1'-furano[3,4-c]pyridyl]-yl, 3-azabicyclo[ [3.1.0] Hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazololo[3,4-c]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl and similar groups.

[0044] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens as defined herein. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0045] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0046] As used herein, the term "cyano" refers to a substituent that has a carbon atom bonded to a nitrogen atom via a telomery bond, i.e., C≡N.

[0047] As used herein, the term "amine" refers to primary amines (R-NH2, R≠H), secondary amines (R2-NH, R2≠H), and tertiary amines (R3-N, R≠H). Substituted amines are intended to mean amines in which at least one hydrogen atom has been replaced by a substituent.

[0048] As used herein, the term "amino" means a substituent containing at least one nitrogen atom. Specifically, -NH2, -NH (alkyl) or alkylamino, -N (alkyl)2 or dialkylamino, acetylamine-, carbamate-, urea and sulfonylurea substituents are all included in the term "amino".

[0049] The term "solvate" refers to a complex formed by a solute and a solvent with a variable stoichiometry. For the purposes of this invention, such solvents should not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are generally referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water as well as compositions containing a variable amount of water.

[0050] The term "isomer" refers to compounds that have the same composition and molecular weight but different physical and / or chemical properties. Structural differences may lie in their configuration (geometric isomers) or ability to rotate the polarizing plane (stereoisomers). Regarding stereoisomers, compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemic mixtures, racemic mixtures, and as individual mirror-image or non-mirror-image isomers.

[0051] This invention also covers isotopically labeled compounds of formula I (e.g., compounds labeled with 2H and 14C). Tritium (i.e., 2H or D) and carbon-14 (i.e., 14C) isotopes are preferred due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium can yield certain therapeutic advantages due to greater metabolic stability (e.g., prolonged in vivo half-life or reduced dose requirement), and is therefore preferred in some cases. Isotopically labeled compounds of formula I can generally be prepared by following a procedure similar to that disclosed in the schemes and / or examples below, by replacing unlabeled reagents with appropriately isotopically labeled reagents.

[0052] This disclosure also includes pharmaceutical compositions containing effective amounts of the disclosed compounds and pharmaceutically acceptable carriers. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and non-water-soluble salts such as acetates, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium salts, calcium ethylenediaminetetraacetate, camphorsulfonates, carbonates, chlorides, citrates, clavulariate, dihydrochlorides, ethylenediaminetetraacetate, ethanedisulfonate, estolate, ethanesulfonate, fumerate, and fiunarate. ), glucohepanoate, glucuronide, glutamate, hydantoin benzoate, hexafluorophosphate, hexylresorcinate, hydrabamine salt, hydrobromide, hydrochloride, hydroxynaphthylcarboxylate, iodide, isothionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, amygdalinate, methanesulfonate, methyl bromide, methyl nitrate, methanesulfonate, galactobionate, naphthalenesulfonate, nitrate, N-methylglucosamine ammonium salt, 3-hydroxy-2-naphthylcarboxylate, oleate, oxalate, palmitate, Einbonate (1,1-methylene-bis-2-hydroxy-3-naphthylcarboxylate, einbonate), pantothenate, phosphate / bisphosphonate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, hypoacetate, succinate, sulfate, sulfosalicylate, suramate, tannic acid, tartrate, theochloroate, toluenesulfonate, triethyl iodide, and valerate.

[0053] "Patient" or "individual" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0054] When used with a compound, an "effective amount" is the amount that is effective in treating or preventing an individual's disease or condition as described herein.

[0055] As used in this disclosure, the term "carrier" encompasses carriers, excipients and diluents, and means a material, composition or medium that participates in the transport or delivery of a drug from one organ or part of an individual's body to another organ or part of the body, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials.

[0056] The term "treatment" in relation to an individual refers to the improvement of at least one symptom of an individual's condition. Treatment includes curing, improving, or at least partially alleviating the condition.

[0057] Unless otherwise indicated, the term "symptom" in this disclosure is used to mean the terms disease, condition or ailment and is used interchangeably with those terms.

[0058] As used in this disclosure, the terms “administer,” “administering,” and “administration” refer to the direct administration of the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to an individual, or the administration of the compound or a pharmaceutically acceptable salt of the compound to an individual as a prodrug derivative or analog or composition thereof, which may form an equivalent amount of the active compound in the individual’s body.

[0059] As used herein, the term "prodrug" means a compound that can be converted into the disclosed compound in vivo by metabolic means (e.g., by hydrolysis).

[0060] This invention relates to compounds, such as isoform 1 and isoform 2, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of inhibiting BCL-2 protein, which can be used to treat diseases and conditions related to BCL-2 protein regulation. This invention further relates to compounds that can be used to inhibit BCL-2, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0061] In some embodiments, the compound of formula (I) has the structure of formula (I'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0062] In some embodiments, the compound of formula (I) has the structure of formula (II): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0063] In some embodiments, the compound of formula (I) has the structure of formula (II'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0064] In some embodiments, the compound of formula (I) has the structure of formula (III-XI): Each n is independently selected from 1, 2, 3 and X is selected from NR9, O, S; and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers or tautomers.

[0065] In some embodiments, the compound of formula (I) has the structure of formula (III).

[0066] In some embodiments, the compound of formula (I) has the structure of formula (IV).

[0067] In some embodiments, the compound of formula (I) has the structure of formula (V).

[0068] In some embodiments, the compound of formula (I) has the structure of formula (VI).

[0069] In some embodiments, the compound of formula (I) has the structure of formula (VII).

[0070] In some embodiments, the compound of formula (I) has the structure of formula (VIII).

[0071] In some embodiments, the compound of formula (I) has the structure of formula (IX).

[0072] In some embodiments, the compound of formula (I) has the structure of formula (X).

[0073] In some embodiments, the compound of formula (I) has the structure of formula (XI).

[0074] In some embodiments, the compound of formula (I) has the structure of formula (III'-XI'): Each n is independently selected from 1, 2, 3, and X is selected from NR9, O, S; and its pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers or tautomers.

[0075] In some embodiments, the compound of formula (I) has the structure of formula (III').

[0076] In some embodiments, the compound of formula (I) has the structure of formula (IV').

[0077] In some embodiments, the compound of formula (I) has the structure of formula (V').

[0078] In some embodiments, the compound of formula (I) has the structure of formula (VI').

[0079] In some embodiments, the compound of formula (I) has the structure of formula (VII').

[0080] In some embodiments, the compound of formula (I) has the structure of formula (VIII').

[0081] In some embodiments, the compound of formula (I) has the structure of formula (IX').

[0082] In some embodiments, the compound of formula (I) has the structure of formula (X').

[0083] In some embodiments, the compound of formula (I) has the structure of formula (XI').

[0084] In some embodiments, the compound of formula (I) has the structure of formula (I-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0085] In some embodiments, the compound of formula (I) has the structure of formula (I-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0086] In some embodiments, the compound of formula (I) has the structure of formula (I-2): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0087] In some embodiments, the compound of formula (I) has the structure of formula (I-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0088] In some embodiments, the compound of formula (I) has the structure of formula (I-3): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0089] In some embodiments, the compound of formula (I) has the structure of formula (I-3'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0090] In some embodiments, the compound of formula (I) has the structure of formula (I-4): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0091] In some embodiments, the compound of formula (I) has the structure of formula (I-4'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0092] In some embodiments, the compound of formula (I) has the structure of formula (II-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0093] In some embodiments, the compound of formula (I) has the structure of formula (II-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0094] In some embodiments, the compound of formula (I) has the structure of formula (II-2): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0095] In some embodiments, the compound of formula (I) has the structure of formula (II-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0096] In some embodiments, the compound of formula (I) has the structure of formula (II-3): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0097] In some embodiments, the compound of formula (I) has the structure of formula (II-3'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0098] In some embodiments, the compound of formula (I) has the structure of formula (II-4): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0099] In some embodiments, the compound of formula (I) has the structure of formula (II-4'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0100] In some embodiments, the compound of formula (I) has the structure of formula (II-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0101] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0102] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0103] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0104] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0105] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0106] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0107] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0108] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0109] In some embodiments, the compound of formula (I) has the structure of formula (II-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0110] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0111] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0112] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0113] In some embodiments, the compound of formula (I) has the structure of formula (II-B-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0114] In some embodiments, the compound of formula (I) has the structure of formula (II-B-3): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0115] In some embodiments, the compound of formula (I) has the structure of formula (II-B-3'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0116] In some embodiments, the compound of formula (I) has the structure of formula (II-B-4): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0117] In some embodiments, the compound of formula (I) has the structure of formula (II-B-4'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0118] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0119] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0120] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0121] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0122] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0123] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0124] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0125] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0126] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0127] In some embodiments, the compound of formula (I) has the structure of formula (II-BA): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0128] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0129] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0130] In some embodiments, the compound of formula (I) has the structure of formula (II-B-2-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0131] In some embodiments, the compound of formula (I) has the structure of formula (II-B-2-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0132] In some embodiments, the compound of formula (I) has the structure of formula (II-B-3-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0133] In some embodiments, the compound of formula (I) has the structure of formula (II-B-3-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0134] In some embodiments, the compound of formula (I) has the structure of formula (II-B-4-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0135] In some embodiments, the compound of formula (I) has the structure of formula (II-B-4-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0136] In some embodiments, the compound of formula (I) has the structure of formula (II-AB): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0137] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0138] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-B'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0139] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0140] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-B'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0141] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0142] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3-B'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0143] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0144] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4-B'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0145] In some embodiments, the compound of formula (I) has the structure of formula (II-BB): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0146] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0147] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-B'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0148] In some embodiments, the compound of formula (I) has the structure of formula (II-B-2-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0149] In some embodiments, the compound of formula (I) has the structure of formula (II-B-2-B'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0150] In some embodiments, the compound of formula (I) has the structure of formula (II-B-3-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0151] In some embodiments, the compound of formula (I) has the structure of formula (II-B-3-B'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0152] In some embodiments, the compound of formula (I) has the structure of formula (II-B-4-B): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0153] In some embodiments, the compound of formula (I) has the structure of formula (II-B-4-B'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0154] In some embodiments, the compound of formula (I) has the structure of formula (II-AC): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0155] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-C): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0156] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-C'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0157] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-C): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0158] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-C'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0159] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3-C): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0160] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3-C'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0161] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4-C): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0162] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4-C'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0163] In some embodiments, the compound of formula (I) has the structure of formula (II-BC): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0164] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-C): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0165] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-C'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0166] In some embodiments, the compound of formula (I) has the structure of formula (II-B-2-C): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0167] In some embodiments, the compound of formula (I) has the structure of formula (II-B-2-C'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0168] In some embodiments, the compound of formula (I) has the structure of formula (II-B-3-C): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0169] In some embodiments, the compound of formula (I) has the structure of formula (II-B-3-C'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0170] In some embodiments, the compound of formula (I) has the structure of formula (II-B-4-C): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0171] In some embodiments, the compound of formula (I) has the structure of formula (II-B-4-C'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0172] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0173] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0174] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-Aa): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof, wherein the Hal is a halogen and all other variables are as defined herein.

[0175] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-a'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer or tautomer thereof, wherein the Hal is a halogen and all other variables are as defined herein.

[0176] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-2): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0177] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0178] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-3): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0179] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-3'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0180] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-4): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0181] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-4'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0182] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-5): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0183] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-5'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0184] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-6): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0185] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-6'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0186] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-7): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0187] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-7'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0188] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-8): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0189] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-8'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0190] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-9): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0191] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-A-9'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0192] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0193] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0194] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-2): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0195] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0196] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-3): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0197] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-3'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0198] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-4): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0199] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-4'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0200] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-5): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0201] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-5'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0202] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-6): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0203] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-6'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0204] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-7): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0205] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-7'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0206] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-8): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0207] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-8'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0208] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-9): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0209] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-9'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0210] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-10): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0211] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-10'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0212] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-11): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0213] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-11'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0214] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-12): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0215] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-12'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0216] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-13): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0217] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-13'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0218] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-14): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0219] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-14'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0220] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-15): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0221] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-15'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0222] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-16): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0223] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-16'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0224] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-17): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0225] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-17'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0226] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-18): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0227] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-18'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0228] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-19): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0229] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-19'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0230] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-20): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0231] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-20'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0232] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-21): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0233] In some embodiments, the compound of formula (I) has the structure of formula (II-A-2-A-21'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0234] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3-A-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0235] In some embodiments, the compound of formula (I) has the structure of formula (II-A-3-A-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0236] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4-A-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0237] In some embodiments, the compound of formula (I) has the structure of formula (II-A-4-A-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0238] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-A-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0239] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-A-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0240] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-A-2): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0241] In some embodiments, the compound of formula (I) has the structure of formula (II-B-1-A-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0242] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-B-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0243] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-B-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0244] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-B-2): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0245] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-B-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0246] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-C-1): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0247] In some embodiments, the compound of formula (I) has the structure of formula (II-A-1-C-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0248] In some embodiments, the compound of formula (I) has the structure of formula (II-AA-1') or formula (II-BA-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0249] In some embodiments, the compound of formula (I) has the structure of formula (II-AA-2') or formula (II-BA-2'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0250] In some embodiments, the compound of formula (I) has the structure of formula (II-AA-3') or formula (II-BA-3'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0251] In some embodiments, the compound of formula (I) has the structure of formula (II-AA-4') or formula (II-BA-4'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0252] In some embodiments, the compound of formula (I) has the structure of formula (II-AA-5') or formula (II-BA-5'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0253] In some embodiments, the compound of formula (I) has the structure of formula (II-AA-5-1') or formula (II-BA-5-1'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0254] In some embodiments, the compound of formula (I) has the structure of formula (II-AA-6') or formula (II-BA-6'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0255] In some embodiments, the compound of formula (I) has the structure of formula (VA), the structure of formula (VI-A), or the structure of formula (XI-A): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0256] In some embodiments, the compound of formula (I) has the structure of formula (V-A'), formula (VI-A'), or formula (XI-A'): Or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, stereoisomer, or tautomer thereof.

[0257] In some embodiments, R1 is a halogen, -OH, -CN, or -CONH2.

[0258] In some embodiments, R1-based halogens are used.

[0259] In some embodiments, R1-based fluorine is used.

[0260] In some embodiments, R1 is a chlorine series.

[0261] In some embodiments, R1-OH.

[0262] In some embodiments, R1 series - CN.

[0263] In some embodiments, R1a is H.

[0264] In some embodiments, R1 and R1a, together with the atoms to which they are attached, form an additional 3 to 10-membered heteroaryl ring comprising 1, 2 or 3 heteroatoms selected from N, O and S.

[0265] In some embodiments, R1 and R1a, together with the atoms to which they are attached, form an additional 5-membered heteroaryl ring comprising 1, 2, or 3 heteroatoms selected from N, O, and S.

[0266] In some embodiments, R1 and R1a, together with the atoms to which they are attached, form an additional 5-membered heteroaryl ring comprising two heteroatoms selected from N, O, and S.

[0267] In some embodiments, R1 and R1a, together with the atoms to which they are attached, form an additional 5-membered heteroaryl ring containing 2 nitrogen atoms.

[0268] In some embodiments, R2 is a C1-C6 alkyl group.

[0269] In some embodiments, R2-CH3.

[0270] In some embodiments, R3 is a C1-C6 alkyl group.

[0271] In some embodiments, R3 is CH3.

[0272] In some embodiments, R2 and R3, together with the atoms to which they are attached, form an additional 3 to 10-member heterocyclic base ring comprising 1, 2 or 3 heteroatoms selected from N, O and S.

[0273] In some embodiments, R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic base ring containing one nitrogen atom.

[0274] In some embodiments, R2 and R3, together with the atoms to which they are attached, form a 6-membered heterocyclic base ring containing one nitrogen atom.

[0275] In some embodiments, R2 and R3, together with the atoms to which they are attached, form a 7-membered heterocyclic base ring containing one nitrogen atom.

[0276] In some embodiments, each R4 is independently selected from halogens, -OH, -CN, -NO2, -COOH, -CH2CN, CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 Haloalkoxy, -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6 alkyl), -C(O)(C1-C6 alkyl), -OC(O)O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -C(O)NH2, -C(O)NH(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), -S(O)NH(C1-C6 alkyl) and S(O)N(C1-C6 alkyl)2.

[0277] In some embodiments, R4-based halogens are used.

[0278] In some embodiments, R4 series F.

[0279] In some embodiments, R4-based Cl.

[0280] In some embodiments, R4 series-CN.

[0281] In some embodiments, R4-NO2.

[0282] In some embodiments, R4-C(O)NH2.

[0283] In some embodiments, R4-C1-C6 alkyl groups.

[0284] In some embodiments, R4-CH3.

[0285] In some embodiments, R4 is a C1-C6 haloalkyl group.

[0286] In some embodiments, R4-CHF2.

[0287] In some embodiments, R4-based C1-C6 alkoxy groups are used.

[0288] In some embodiments, R4-OCH3.

[0289] In some embodiments, R4-based C1-C6 haloalkoxy groups are used.

[0290] In some embodiments, R4 series - OCHF2.

[0291] In some embodiments, R4-NHC(O) (C1-C6 alkyl).

[0292] In some embodiments, R4-NHC(O)CH3.

[0293] In some embodiments, R4-based S(O)2 (C1-C6 alkyl).

[0294] In some embodiments, R4 is S(O)2CH3.

[0295] In some embodiments, x is an integer selected from 0, 1, 2, and 3.

[0296] In some embodiments, x is 0.

[0297] In some embodiments, x is 1.

[0298] In some embodiments, x is 2.

[0299] In some embodiments, x is 3.

[0300] In some embodiments, R5 is selected from , and ;

[0301] In some embodiments, the R5 series .

[0302] In some embodiments, the R5 series .

[0303] In some embodiments, the R5 series .

[0304] In some embodiments, R5 is selected from .

[0305] In some embodiments, R5 is selected from .

[0306] In some embodiments, R5 is selected from .

[0307] In some embodiments, R5 is selected from .

[0308] In some embodiments, the R5 series is selected from the group consisting of: ,

[0309] In some embodiments, the R5 series is selected from the group consisting of: ,

[0310] In some embodiments, the R5 series is selected from the group consisting of: ,

[0311] In some embodiments, m is selected from 0, 1, and 2.

[0312] In some embodiments, m is 0.

[0313] In some embodiments, m is system 1.

[0314] In some embodiments, m is system 2.

[0315] In some embodiments, each n is independently selected from integers 1, 2, and 3.

[0316] In some embodiments, each R6 is independently selected from halogens, -OH, -CN, -COOH, -CH2CN, -CON(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1 -C6 alkyl), -C(O)(C1-C6 alkyl), -OC(O)O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)(C1-C6 alkyl), -C(O)NH(C1-C6 alkyl), -S(O)2(C1-C6 alkyl), -S(O)NH(C1-C6 alkyl) and S(O)N(C1-C6 alkyl)2.

[0317] In some embodiments, each R6 is independently selected from CN, CO(NR8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0318] In some embodiments, R6-CH3.

[0319] In some embodiments, R6-OCH3.

[0320] In some embodiments, R6 series-CN.

[0321] In some embodiments, R6-C(O)NH2.

[0322] In some embodiments, y is an integer selected from 0, 1, 2, and 3.

[0323] In some embodiments, y is 0.

[0324] In some embodiments, y is 1.

[0325] In some embodiments, y is 2.

[0326] In some embodiments, y is 3.

[0327] In some embodiments, each R7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aryl.

[0328] In some embodiments, the two R7s, together with the nitrogen atom they are bonded to and any inserted atoms, form a heterocycle.

[0329] In some embodiments, the two R7s, together with the nitrogen atom they bind and any inserted atoms, form a 6-membered heterocycle.

[0330] In some embodiments, the two R7s, together with the nitrogen atom they are bonded to and any inserted atoms, form a 6-membered heterocycle containing N and O.

[0331] In some embodiments, the R8 group is selected from H, C1-6 alkyl, C3-8 cycloalkyl, and C1-6 haloalkyl.

[0332] In some embodiments, R8 is selected from H and C1-6 alkyl groups.

[0333] In some embodiments, the R9 group is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)1-6OR8, C3-8 cycloalkyl, aryl, and heterocyclic.

[0334] In some embodiments, R9 is a C1-6 alkyl or a C1-6 haloalkyl.

[0335] In some embodiments, R9 is a C1-4 alkyl group. In some embodiments, R9 is a C1-4 haloalkyl group.

[0336] In some embodiments, R9-CH3. In some embodiments, R9-CH2F. In some embodiments, R9-CHF2. In some embodiments, R9-CF3.

[0337] The non-limiting exemplary compounds disclosed herein include The compounds presented in [Table 1] or their pharmaceutically acceptable salts, isomers, solvates, prodrugs or tautomers.

[0338] [Table 1.] Examples of Compound (I)

[0339] In some embodiments, the compound is a pharmaceutically acceptable salt.

[0340] In some embodiments, the compound is a hydrochloride.

[0341] It should be understood that all isomers are included within the scope of this invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in an E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may be in a cis or trans configuration. All tautomers are also intended to be included.

[0342] The compounds of this invention, and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist in tautomer forms (e.g., amides or imine ethers). All such tautomer forms are covered herein as part of this invention.

[0343] The compounds of this invention may contain asymmetric or antipodal centers and therefore exist in different stereoisomeric forms. All stereoisomers of the compounds of this invention, as well as mixtures thereof, including racemic mixtures, are intended to form part of this invention. Furthermore, this invention includes all geometrical and positional isomers. For example, if the compounds of this invention have double bonds or fused rings, then the cis and trans forms, as well as mixtures thereof, are included within the scope of this invention. The compounds disclosed herein include all mirror-image isomers conforming to the general structure of the compound. Compounds may exist in racemic or mirror-image isomeric pure forms, or any other stereochemical form. Analytical results may reflect collected information regarding the racemic form, mirror-image isomeric pure form, or any other stereochemical form.

[0344] Mixtures of non-mirror image isomers can be separated into their individual non-mirror image isomers based on their physicochemical differences using methods well known to those skilled in the art, such as chromatography and / or stepwise crystallization. Mirror image isomers can be separated by reacting the mixture with a suitable optically active compound (e.g., a para-armoring agent, such as para-armoring alcohol or Mosher's acid chloride) to convert the mixture into a mixture of non-mirror image isomers, separating the non-mirror image isomers, and converting (e.g., hydrolyzing) the individual non-mirror image isomers into their respective pure mirror image isomers. Furthermore, some compounds of the present invention may be configurational isomers (e.g., substituted biaryl groups) and are considered part of the invention. Mirror image isomers can also be separated using para-armoring HPLC columns.

[0345] The compounds of this invention may also exist in different tautomeric forms, and all such forms are included within the scope of this invention. Furthermore, for example, the keto-enol and imine-enamine forms of all compounds are included in this invention.

[0346] All stereoisomers of the compounds of the present invention (e.g., geometric isomers, optical isomers, and the like) (including salts, solvates, esters, and prodrugs of such compounds, and all stereoisomers of salts, solvates, and esters of prodrugs), such as stereoisomers that may exist due to asymmetric carbons on various substituents, including mirror-image isomers (which may even exist without asymmetric carbons), rotational isomers, configurational isomers, and non-mirror-image isomers, as well as positional isomers (such as 4-pyridyl and 3-pyridyl), are covered within the scope of the present invention. (For example, if a compound of formula (I) incorporates a double bond or a fused ring, both the cis and trans forms, as well as mixtures thereof, are included within the scope of the present invention. Furthermore, for example, all keto-enol and imine-enamine forms of such compounds are included in the present invention.) Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers, or may, for example, be in racemic form or mixed with all other or other selected stereoisomers. The pisiform centers of this invention may have an S-configuration or an R-configuration as defined in IUPAC 1974. The terms "salt," "solvent," "ester," "prodrug," and the like are intended equally to apply to the salts, solvates, esters, and prodrugs of mirror-image isomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or prodrugs of the compounds of this invention.

[0347] Compounds of Formula I can form salts, and such salts are also within the scope of this invention. Unless otherwise indicated, references to compounds of this formula herein should be understood to include references to their salts.

[0348] This invention relates to compounds that act as regulators of the BCL-2 protein. In one embodiment, the compound of this invention is an inhibitor of the BCL-2 protein. In another embodiment, the BCL-2 protein is isoform 1. In yet another embodiment, the BCL-2 protein is isoform 2.

[0349] This invention relates to compounds as described herein and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers, and pharmaceutical compositions comprising one or more of the compounds as described herein or their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers. Methods for synthesizing compounds

[0350] The compounds of this invention can be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are described in the schemes given below.

[0351] Compounds of formula (I) can be prepared by methods known in organic synthesis techniques as partially described in the following synthetic schemes. In the schemes described below, it should be fully understood that, where necessary, protecting groups with sensitive or reactive groups are used according to general principles or chemical methods. Protecting groups are operated according to standard methods of organic synthesis (TW Greene and PGM Watts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999). These groups are removed at appropriate stages of compound synthesis using methods readily apparent to those skilled in the art. The selection of methods, reaction conditions, and sequence by those skilled in the art will identify the presence of stereoisomeric centers in compounds of formula (I). Therefore, the present invention includes two possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but also individual mirror-image and / or non-mirror-image isomers. When a compound is required to be in the form of a single mirror-image or non-mirror-image isomer, it can be obtained by stereospecific synthesis or by analysis of the final product or any suitable intermediate. The analysis of the final product, intermediates, or starting materials can be achieved by any suitable method known in this technique. See, for example, "Stereochemistry of Organic Compounds", E.L.E. Liel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0352] The compounds described herein can be obtained from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic methods. [Preparation of Compounds]

[0353] The compounds of this invention can be prepared by a variety of methods well known to those skilled in organic synthesis. For example, the compounds of this invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. The compounds of this invention can be prepared by following... The steps outlined in [General Scheme 1] involve the synthesis of various assembly intermediates or sequences of compounds. The starting materials are commercially available or prepared using known procedures reported in the literature or as described below. General Scheme 1 is presented for illustrative purposes only, and it will be apparent to those skilled in the art that it can be modified for the specific compounds of formula (I). [General Solution 1]

[0354] [Table 2] Presentation Non-limiting exemplary conditions for the reaction described in [General Scheme 1].

[0355] Familiarity with this technique will make it apparent that appropriate protecting groups can be used for some transformations. A non-limiting list of protecting groups that can be used to prepare compounds of formula I includes: acetyl (Ac), benzoyl (Bz), benzyl (Bn), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), trimethylacetyl (Piv), triphenylmethyl (Tr), benzoxycarbonyl (Cbz), tributoxycarbonyl (Boc), and toluenesulfonyl (Ts).

[0356] Examples of this use of protecting groups are presented in compounds [3] is in the process of preparation: [Methods for using the disclosed compounds]

[0357] Another aspect of the present invention relates to a method for treating a disease or condition related to BCL-2 protein regulation. The method comprises administering an effective amount of the composition and compound of formula (I) to a patient requiring treatment for a disease or condition related to BCL-2 protein regulation.

[0358] In another embodiment, the present invention relates to a method for inhibiting the BCL-2 protein. This method involves administering an effective amount of the compound of formula (I) to a patient in need.

[0359] Another aspect of the present invention relates to a method for treating, preventing, inhibiting, or eliminating a disease or symptom associated with BCL-2 protein inhibition in a patient, the method comprising administering an effective amount of a compound of formula (I) to a patient in need. In one embodiment, the disease may be, but is not limited to, cancer and cancer metastasis.

[0360] This invention also relates to the use of BCL-2 protein inhibitors in the preparation of medicaments for the treatment, prevention, inhibition or elimination of diseases or conditions mediated by BCL-2 protein, wherein the medicaments comprise compounds of formula (I).

[0361] In another embodiment, the present invention relates to a method for manufacturing a medicament for treating, preventing, inhibiting or eliminating diseases or conditions mediated by the BCL-2 protein, wherein the medicament comprises a compound of formula (I).

[0362] Another aspect of the present invention relates to a compound of formula (I) for use in the manufacture of a medicament for the treatment and inhibition of diseases related to the BCL-2 protein.

[0363] In another embodiment, the present invention relates to the use of compounds of formula (I) in the treatment of diseases associated with the inhibition of BCL-2 protein.

[0364] Another aspect of the present invention relates to a method for treating cancer. The method comprises administering an effective amount of the compound of formula (I) to a patient in need.

[0365] Another aspect of the present invention relates to a method for treating or preventing cancer. The method comprises administering an effective amount of the compound of formula (I) to a patient in need.

[0366] In one embodiment, the present invention relates to the use of an inhibitor of the BCL-2 protein in the preparation of a medicament for the treatment, prevention, inhibition or elimination of cancer-related diseases or conditions.

[0367] In another embodiment, the present invention relates to compounds of formula (I) for the treatment of cancer or pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier, including but not limited to cancers selected from: bladder cancer, bone cancer, brain cancer, breast cancer, heart cancer, cervical cancer, colorectal cancer, rectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma, thymic carcinoma, lung cancer, ovarian cancer and prostate cancer.

[0368] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise excipients, diluents, or surfactants.

[0369] In one embodiment, a method is provided for treating diseases or conditions related to BCL-2 protein regulation, including cancer or cell proliferation disorders, comprising administering a compound of formula (I) to a patient suffering from at least one of such diseases or conditions.

[0370] One therapeutic use of the compounds or compositions of the present invention that inhibit BCL-2 protein is to provide treatment to patients or individuals suffering from cancer or cell proliferation disorders.

[0371] An effective amount of the disclosed compounds of the present invention may be administered to an individual to treat or prevent a disease and / or prevent its development.

[0372] The disclosed compounds can be administered via any mode of therapeutic delivery. These modes include systemic or local delivery, such as oral, nasal, non-intestinal, transdermal, subcutaneous, vaginal, buccal, rectal, or topical delivery.

[0373] Depending on the intended administration method, the disclosed components may be in solid, semi-solid, or liquid dosage forms, such as injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or similar forms, sometimes in unit dose form and consistent with known medical practice. Similarly, it may be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and all forms of administration are familiar to those skilled in medical practice.

[0374] Exemplary pharmaceutical compositions are tablets and gelatin capsules comprising the compounds of the present invention and pharmaceutically acceptable carriers, such as a) diluents, such as purified water, triglyceride oils (such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof), corn oil, olive oil, sunflower oil, safflower oil, fish oil (such as EPA or DHA or their esters or triglycerides, or mixtures thereof), ω-3 fatty acids or their derivatives, lactose, dextran, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) lubricants, such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, etc. Magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; also for tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, magnesium carbonate, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate), waxes, and / or polyvinylpyrrolidone, if necessary; d) disintegrants, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginate or its sodium salt, or foaming mixtures; e) absorbents, colorants, flavoring agents, and sweeteners; f) emulsifiers or dispersants, such as Tween 80. 80) Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, captex PG-12, captex 355, glyceryl laurate, vitamin E TGPS, or another acceptable emulsifier; and / or g) agents that enhance the absorption of the compound, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200.

[0375] Liquid compositions, especially injectable compositions, can be prepared, for example, by dissolution, dispersion, etc. For instance, the disclosed compound can be dissolved in or mixed with pharmaceutically acceptable solvents such as water, saline, aqueous dextran solution, glycerol, ethanol, and the like, thereby forming an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicrons, or serum proteins, can be used to dissolve the disclosed compound.

[0376] The disclosed compounds can also be formulated into suppository forms, which can be prepared from fat emulsions or suspensions using polyalkylene glycols such as propylene glycol as carriers.

[0377] The disclosed compounds can also be delivered via liposome delivery systems, such as monolayer microliposomes, monolayer macroliposomes, and multilayer microliposomes. Liposomes can be formed from various phospholipids containing cholesterol, stearamine, or phosphatidylcholine. In some embodiments, a membrane having a lipid component is hydrated with an aqueous drug solution to form a lipid layer encapsulating the drug, as described in U.S. Patent No. 5,262,564, which is incorporated herein by reference in its entirety.

[0378] The disclosed compounds can also be delivered using monoclonal antibodies coupled with the disclosed compounds as individual carriers. The disclosed compounds can also be coupled with soluble polymers that serve as targeted drug carriers. Such polymers may include polyvinylpyrrolidone substituted with palmitole residues, piperan copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartic acid-phenylenevinylamine, or polyethylene oxide polylysine. Furthermore, the disclosed compounds can be coupled with a class of biodegradable polymers that can be used to achieve controlled drug release, such as crosslinked or amphiphilic block copolymers of polylactic acid, polycaprolactone, polyhydroxybutyrate, polyorthoesters, polyacetals, polydihydropiperanone, polycyanoacrylates, and hydrogels. In one embodiment, the disclosed compounds are not covalently bonded to a polymer, such as a polycarboxylic acid polymer or polyacrylate.

[0379] Non-entericidal injectable preparations are generally intended for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable preparations can be prepared in known forms, such as liquid solutions or suspensions, or solid forms suitable for dissolving in a liquid prior to injection.

[0380] Another aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise excipients, diluents, or surfactants. In some embodiments, the pharmaceutical composition may further comprise additional pharmaceutically active agents.

[0381] The composition can be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical composition of the present invention may contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% of the disclosed compound by weight or volume.

[0382] Dosing regimens using the disclosed compounds are selected based on a variety of factors, including patient type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the specific disclosed compound used. Physicians or veterinarians familiar with this technique can easily determine and prescribe the effective dosage of the drug needed to prevent, counteract, or halt disease progression.

[0383] When used for the indicated effects, the effective dose of the disclosed compound is in the range of about 0.5 mg to about 5000 mg of the disclosed compound, depending on the therapeutic condition. The composition for in vivo or in vitro use may contain about 0.5 mg, 5 mg, 20 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1250 mg, 2500 mg, 3500 mg, or 5000 mg, or within one to another of the disclosed compounds in the dosage list. In one embodiment, the composition is in the form of a scoreable tablet. [Example]

[0384] The invention is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments and are not intended to limit the scope of this disclosure. Furthermore, it should be understood that various other embodiments, modifications, and equivalents may be employed, and those skilled in the art will conceive of such other embodiments, variations, and equivalents without departing from the spirit of this disclosure and / or the scope of the appended claims.

[0385] The following examples and abbreviations used elsewhere in this article are: [Example] [, Analysis and purification , ] Preparative HPLC

[0386] Neutral conditions are as follows: YMC-Pack ODS-AQ 250×20mm, S-10μm, pore size 12nm, gradient water-acetonitrile.

[0387] The standard acidic conditions are as follows: YMC-Pack ODS-AQ 250×20mm, S-10μm, pore size 12nm, gradient A solution-B solution; A: 1000ml water-226μl trifluoroacetic acid, B: 1000ml CH3CN-226μl trifluoroacetic acid. Data analysis, LCMS conditions:

[0388] C18 column 100×4.6mm, 5.0μm, pore size 100Å, water-acetonitrile + 0.1% trifluoroacetic acid, gradient 5 to 87%, hold for 10 minutes. [, Synthetic intermediates , ] N-(4-Chlorophenyl)-5,6,7,8-Tetrahydroindene -1-methylamine [(P3)]

[0389] [, Preparation 1 , ]:5,6,7,8-Tetrahydroindene ethyl 1-formate [P1](presents with 5,6,7,8-tetrahydroindene) (mixtures of ethyl 2-formate) Propionic anhydride (90 mL) was added to a stirred solution of piperidine-2-carboxylic acid (21 g, 162 mmol) in formic acid (70 mL) at a maintained temperature of 0 °C. The reaction mixture was heated to ambient temperature, stirred for 3 hours, and evaporated to dryness under reduced pressure on a rotary evaporator. The residue was dissolved in propionic anhydride (150 mL), and ethyl propionate (78 g, 800 mmol) was added in whole. The resulting mixture was stirred and heated at 100 °C for 1 hour. Volatile substances were removed under reduced pressure, and the residue was stirred with a 20% Na₂CO₃ aqueous solution for 2 hours. The product was extracted with DCM (2 × 200 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure on a rotary evaporator to give 28 g (89%) of 5,6,7,8-tetrahydroindole in a 5:1 ratio. ethyl 1-formate [(P1)] and 5,6,7,8-tetrahydroindene The crude product, in the form of a mixture of isomers of ethyl 2-carboxylate, is used in the next step without further purification and separation.

[0390] [, Preparation 2 , ]:5,6,7,8-Tetrahydroindene -1-formic acid [P2](presents with 5,6,7,8-tetrahydroindene) (2-Formic acid in mixture form) Add the KOH (31.3 g, 560 mmol) solution to 100 mL of water to... [, Preparation 1 The ester mixture (28 g, 140 mmol) obtained in [ ] was dissolved in methanol (300 mL). The resulting mixture was stirred and heated at 50 °C for 5 hours (TLC monitoring). Volatile substances were removed under reduced pressure. The residue was diluted with water (400 mL) and acidified to pH 2 with concentrated HCl. The precipitate formed was filtered off, washed with water, and dried by lyophilization to give 23 g (77%) of 5,6,7,8-tetrahydroindole. -1-formic acid [(P2)] and 5,6,7,8-tetrahydroindene The crude product, in the form of a mixture of isomers of 2-formic acid, is used in the next step without further purification and separation.

[0391] [, Preparation 3 , ]:N-(4-chlorophenyl)-5,6,7,8-tetrahydroindene -1-methylamine [(P3)] At ambient temperature, [, Preparation 2 The crude product (5.0 g, 30.3 mmol), 4-chloroaniline (3.8 g, 30.3 mmol), Et3N (6.5 mL, 45.5 mmol), and TBTU (11.6 g, 36.3 mmol) obtained were stirred overnight in a mixture of DCM (250 mL) and quenched with water (200 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. After evaporation, the residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→10%) and CCl4 to give 800 mg (10%) of the title compound. [P3] 4-Chloro-2-(1-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydroindyl) -3-yl)benzoic acid [(P5)]

[0392] [, Preparation 4 , ]:4-Chloro-2-(1-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydroindyl ethyl 3-yl)benzoate [(P4)] At 135 °C, N-(4-chlorophenyl)-5,6,7,8-tetrahydroindene -1-methylamine A mixture of [P3] (800 mg, 2.9 mmol), ethyl 6-bromo-1,3-benzodioxane-5-carboxylate (1.5 g, 5.8 mmol), K3PO4 (3.08 g, 14.5 mmol), and trimethylacetic acid (0.09 g, 0.8 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.4 g, 0.58 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (20 mL) and EtOAC (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 1.0 g (76%) of the title compound. [P4]. ESI LCMS[MH]+:457,458.

[0393] [, Preparation 5 , ]:4-Chloro-2-(1-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydroindyl -3-yl)benzoic acid [(P5)] At ambient temperature, the ester A solution of [P4] (1000 mg, 2.2 mmol) and NaOH (440 mg, 10.9 mol) in a mixture of EtOH (20 mL) and water (5 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL); the combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 900 mg (97%) of the title compound. [P5], which is pure enough to be used in the next step. ESI LCMS[MH]+:429,430. 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-5,6,7,8-tetrahydroindyl) -1-methylamine [(P6)]

[0394] [, Preparation of 6 , ]:3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-5,6,7,8-tetrahydroindyl) -1-methylamine [(P6)] At 60 °C, 4-chloro-2-(1-{[(4-chlorophenyl)amino]carbonyl}-5,6,7,8-tetrahydroindyl) -3-yl)benzoic acid A mixture of [P5] (900 mg, 2.1 mmol), (3S)-3-(morpholino-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (0.53 g, 2.3 mmol), DIPEA (0.55 mL, 3.1 mmol), TBTU (0.8 g, 2.5 mmol), and DMF (10 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 880 mg (65%) of the title compound. [P6]. ESI LCMS[MH]+:643,645,644. N-[4-(benzooxy)phenyl]-5,6,7,8-tetrahydroindene -1-methylamine [(P7)]

[0395] [, Preparation 7, ]:N-[4-(benzyloxy)phenyl]-5,6,7,8-tetrahydroindene -1-methylamine [(P7)] At ambient temperature, the crude product A mixture of [P2] (17.0 g, 100 mol), [4-(benzyloxy)phenyl]amine (18.0 g, 90 mmol), Et3N (22 mL, 150 mmol), and TBTU (36.0 g, 110 mmol) in DCM (250 mL) was stirred overnight and quenched with water (200 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. After evaporation, the residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→10%) and DCM to give 14.5 g (41%) of the title compound. [P7]. ESI LCMS[MH]+:347. 2-[1-({[4-(benzyloxy)phenyl]amino}carbonyl)-5,6,7,8-tetrahydroindyl 3-yl]-4-chlorobenzoic acid [(P9)]

[0396] [, Preparation of 8 , ]:2-[1-({[4-(benzoxy)phenyl]amino}carbonyl)-5,6,7,8-tetrahydroindyl) Ethyl 3-yl]-4-chlorobenzoate [(P8)] At 135 °C, N-[4-(benzyloxy)phenyl]-5,6,7,8-tetrahydroindene -1-methamide ( A mixture of [P7] (500 mg, 1.44 mmol), ethyl 2-bromo-4-chlorobenzoate (0.76 g, 2.9 mmol), K3PO4 (1.53 g, 7.2 mmol), and trimethylacetic acid (0.04 g, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.2 g, 0.29 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 450 mg (59%) of the title compound. [P8]. ESI LCMS[MH]+:529.

[0397] [, Preparation 9 , ]:2-[1-({[4-(benzoxy)phenyl]amino}carbonyl)-5,6,7,8-tetrahydroindyl) 3-yl]-4-chlorobenzoic acid [(P9)] At ambient temperature, the ester ( A solution of [P8] (450 mg, 0.85 mmol) and NaOH (170 mg, 4.2 mol) in a mixture of EtOH (20 mL) and water (5 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL); the combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 400 mg (94%) of the title compound. [P9], which is pure enough to be used in the next step. ESI LCMS[MH]+:501. N-[4-(benzooxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindyl -1-methylamine [(P10)]

[0398] [, Preparation 10, ]:N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindyl -1-methylamine [(P10)] At 60 °C, 2-[1-({[4-(benzoxy)phenyl]amino}carbonyl)-5,6,7,8-tetrahydroindole... -3-yl]-4-chlorobenzoic acid ( A mixture of [P9], 450 mg, 0.8 mmol), (3S)-3-(morpholino-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (0.23 g, 1.0 mmol), DIPEA (0.2 mL, 1.2 mmol), TBTU (0.3 g, 0.9 mmol), and DMF (10 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 400 mg (70%) of the title compound. [P10]. ESI LCMS[MH]+:715. N-[4-(benzooxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-5,6,7,8-tetrahydroindyl -1-methylamine [(P11)]

[0399] [, Preparation 11. ] N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-5,6,7,8-tetrahydroindyl -1-methylamine [(P11)] At 50 °C, N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindole -1-methamide ( A mixture of [P10] (200 mg, 0.28 mmol), tert-BuOK (125 mg, 1.1 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 2-(bromomethyl)benzonitrile (110 mg, 0.56 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 180 mg (78%) of the title compound. [P11]. ESI LCMS[MH]+:830. N-[4-(benzooxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-5,6,7,8-tetrahydroindyl -1-methylamine [(P12)]

[0400] [, Preparation 12. ] N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-5,6,7,8-tetrahydroindyl -1-methylamine [(P12)] At 50 °C, N-[4-(benzyloxy)phenyl]-3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindole -1-methamide ( A mixture of [P10] (200 mg, 0.28 mmol), tert-BuOK (125 mg, 1.1 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (130 mg, 0.56 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 200 mg (84%) of the title compound. [P12]. ESI LCMS[MH]+:849. N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P13)]

[0401] [, Preparation 13. , ] N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P13)]. At 0℃, towards [P14] (1.0 g, 7.2 mmol) was added dropwise to a stirred solution of pyridine (5 mL) with pure SOCl2 (0.55 mL, 7.6 mmol), and the reaction mixture was stirred at 0 °C for 3 hours. Then, 4-aminobenzonitrile (0.85 g, 7.2 mmol) was added dropwise to DIPEA (1.4 mL, 7.96 mmol) while maintaining the temperature at 0 °C. The reaction was heated to ambient temperature and then stirred at ambient temperature for 16 hours. Volatile substances were removed under reduced pressure. The residue was diluted with water and Et2O. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 850 mg (50%) of the title compound. 1H NMR (400MHz, DMSO-d 6), δ: 9.70 (br.s, 1H), 7.95 (d, 1H, J = 8.7Hz,), 7.7.73 (d, 1H, J = 8.7Hz), 6.73-6.64 (m, 1H), 3.54 (s, 3H), 2.47 (s, 3H). LCMS(ESI+)m / z 240[M+H]+. N-[4-(benzooxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-methylamine [(P15)]

[0402] [, Preparation 14. , ] 1,2-Dimethyl-1H-pyrrole-3-carboxylic acid [(P14)] Add the solution of NaOH (6.5 g, 163 mmol) in 10 mL of water to... [P1] was added to a solution of ethanol (50 mL). The resulting mixture was stirred and heated at 50 °C for 5 hours (TLC monitoring). Volatile substances were removed under reduced pressure. The residue was diluted with water (50 mL) and acidified with concentrated HCl to pH=2. The precipitate formed was filtered off, washed with water, and dried by lyophilization to give 4.0 g. [P14](88%). ESI+LCMS[MH]+:140.

[0403] [, Preparation 15. , ] N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-methylamine [(P15)] At ambient temperature, A mixture of [P14] (2.0 g, 14.4 mmol), [4-(benzyloxy)phenyl]amine (3.1 g, 15.58 mmol), Et3N (3.1 mL, 21.5 mmol), and TBTU (5.5 g, 17.2 mmol) in DCM (250 mL) was stirred overnight and quenched with water (20 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. After evaporation, the residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 2.5 g (54%). [P15]. ESI+LCMS[MH]+:321. 2-[4-({[4-(benzooxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chlorobenzoic acid [(P17)]

[0404] [, Preparation 16. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chlorobenzoate ethyl ester [(P16)] At 135℃, N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-methylamine ( A mixture of [P15] (1.0 g, 3.1 mmol), ethyl 6-bromo-1,3-benzodioxane-5-carboxylate (1.0 g, 3.1 mmol), K3PO4 (3.3 g, 15.6 mmol), and trimethylacetic acid (0.1 g, 0.9 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.44 g, 0.6 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 1.1 g (70%). [P16]. ESI+LCMS[MH]+:503.

[0405] [, Preparation 17. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chlorobenzoic acid [(P17)] At ambient temperature, A solution of [P16] (1100 mg, 2.2 mmol) and NaOH (440 mg, 10.9 mol) in a mixture of EtOH (20 mL) and water (5 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL); the combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 900 mg (90%). [P17], which is pure enough to be used in the next step. ESI+ LCMS[MH]+: 475. N-[4-(benzooxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[0406] [, Preparation 18. , ] N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P18)] At 60°C, 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-4-chlorobenzoic acid ( A mixture of [P17] (900 mg, 1.9 mmol), (3S)-3-(morpholino-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (0.48 g, 2.1 mmol), DIPEA (0.5 mL, 2.8 mmol), TBTU (0.73 g, 2.3 mmol), and DMF (10 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 700 mg (54%). [P18]. ESI LCMS[MH]+:689. N-[4-(benzomethoxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P19)]

[0407] [, Preparation 19., ] N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P19)] At 50°C, N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( A mixture of [P18] (150 mg, 0.2 mmol), tert-BuOK (92 mg, 0.8 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 2-(bromomethyl)benzonitrile (85 mg, 0.4 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 100 mg (57%). [P19]. ESI LCMS[MH]+:804. N-[4-(benzomethoxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P20)]

[0408] [, Preparation 20. , ] N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P20)]. At 50°C, N-[4-(benzyloxy)phenyl]-5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( A mixture of [P18] (150 mg, 0.2 mmol), tert-BuOK (92 mg, 0.8 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (98 mg, 0.4 mmol). The reaction mixture was stirred at 60 °C for 12 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 120 mg (67%). [P20] 4-Chloro-N-(3-methoxy-2-methylbenzyl)aniline [(P23)]

[0409] [, Preparation 21. , ] 1-(chloromethyl)-3-methoxy-2-methylbenzene [(P21)]. At 0°C, lithium aluminum hydride (72.0 mL, 72.2 mmol, 1.2 eq, 1 M in THF) was added to a solution of 10.0 g (60.2 mmol, 1 eq) of 3-methoxy-2-methylbenzoic acid in anhydrous THF (200 mL). After stirring the solution at room temperature for 16 hours, the mixture was diluted with water and NaOH (aq) (15%, 3 mL) and filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure to obtain a white solid. [P21] (9.0 g, 98% yield) was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl₃), δ: 7.18 (dd, J = 8.2, 7.8 Hz, ¹H), 6.98 (d, J = 7.8 Hz, ¹H), 6.83 (d, J = 8.2 Hz, ¹H), 4.68 (s, 2H), 3.84 (s, 3H), 2.22 (s, 3H).

[0410] [, Preparation 22., ] 3-Methoxy-2-methylbenzaldehyde [(P22)]. Add pyridinium chlorochromate (10.6 g, 49.3 mmol, 1.5 eq) to a solution of DCM (83 mL). [P21] (5.0 g, 32.9 mmol, 1.0 eq) was dissolved in DCM (83 mL). The solution was stirred at room temperature for 6 hours, then diluted with ether (80 mL), filtered through a diatomaceous earth filter, and washed with ether. The filtrate was concentrated under reduced pressure. The residue was purified by silicone column chromatography (0-100% EtOAc / n-hexane) to give a yellow solid. [P22](3.6 g, 72% yield). ¹H NMR (400 MHz, CDCl₃), δ: 10.32 (s, ¹H), 7.42 (d, J = 7.8 Hz, ¹H), 7.30 (dd, J = 8.0, 7.8 Hz, ¹H), 7.07 (d, J = 8.0 Hz, ¹H), 3.87 (s, ³H), 2.54 (s, ³H).

[0411] [, Preparation 23. , ] 4-Chloro-N-(3-methoxy-2-methylbenzyl)aniline [(P23)]. At room temperature, to [P22] (292 mg, 1.90 mmol, 1.0 eq), 4-chloroaniline (247 mg, 1.90 mmol, 1.0 eq), and AcOH (11 mg, 0.18 mmol, 0.1 eq) were added to a solution of [P22] in 13 mL of DCM. NaBH(OAc)3 (990 mg, 4.67 mmol, 2.5 eq) was added and the mixture was stirred at room temperature for 16 hours. The mixture was treated with NaHCO3 (aq) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-50% EtOAc / n-hexane) to give a yellow solid. [P23](350mg, 70% yield). ¹H NMR (400MHz, CDCl₃), δ: 7.18–7.09 (m, 3H), 6.93 (d, J = 7.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.8 Hz, 2H), 4.24 (d, J = 5.2 Hz, 2H), 3.84 (s, 4H, OMe and NH), 2.22 (s, 3H); LRMS (ESI+) m / z: 262.0 [M+H]+. (S)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(N-) (P-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carbonyl chloride [(P28)]

[0412] [, Preparation 24. , ] 2-Bromo-5-(difluoromethoxy)-4-fluorobenzoic acid [(P24)]. Sodium hydroxide (511 mg, 12.8 mmol) was added to a solution of ethyl 2-bromo-5-(difluoromethoxy)-4-fluorobenzoate (800 mg, 2.56 mmol) in EtOH / H₂O (4:1, 25 mL), and the mixture was stirred at room temperature for 3 hours. The pH of the mixture (pH=5) was adjusted with 2N HCl(aq), and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO₄, filtered, and concentrated under vacuum to obtain a white solid. [P24] (709 mg, 97%) was used directly in the next step without purification. ¹H NMR (400 MHz, CD3OD), δ: 7.81 (d, J = 8.4 Hz, ¹H), 7.69 (d, J = 9.6 Hz, ¹H), 6.93 (t, 2 J HF = 72.8 Hz, ¹H); LCMS (ESI) m / z: calculated value of C8H4BrF3O3 283.93; experimental value 282.8 [MH]-.

[0413] [, Preparation 25. , ] (S)-(2-bromo-5-(difluoromethoxy)-4-fluorophenyl)(3-(N- (Linylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl ketone [(P25)]. Towards [P24] (700 mg, 2.46 mmol) and (3S)-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (627 mg, 2.70 mmol) in N,N-dimethylacetamide (25 mL) were added to a solution of N,N-diisopropylethylamine (0.64 mL, 3.7 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl tetrafluoroborate. (946 mg, 2.95 mmol). After stirring at room temperature for 1 hour, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (0-80% EtOAc / n-hexane) to give a white solid. [P25](1.18g, 96%). ¹H NMR (400MHz, CDCl₃), δ: 7.58-7.29(m, 2H), 7.26-7.02(m, 3H), 7.02-6.30(m, 2H), 5.39-5.22(m, 1H), 4.56-4.17(m, 2H), 3.89-3.56(m, 4H), 3.34-3.09(m, 1H), 2.87-2.11(m, 7H); LCMS (ESI) m / z: Calculated value of C₂₂H₂₂BrF₃N₂O₃: 498.08; Experimental value: 499.2 [M+H]⁺.

[0414] [, Preparation 26. , ] (S)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(N- (Linylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester [(P26)]. Using argon [P25] (680 mg, 1.36 mmol), ethyl 1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrrole-3-carboxylate (600 mg, 2.04 mmol), and cesium carbonate (887 mg, 2.72 mmol) in N,N-dimethylformamide (10 mL) were degassed for 30 minutes. The mixture was then treated with bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (48 mg, 0.068 mmol) followed by argon degassed. The mixture was stirred at 130 °C for 2 hours under microwave irradiation. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (0-50% EtOAc / n-hexane) to obtain a yellow powder. [P26](818mg, 77%). ¹H NMR (400MHz, CDCl₃), δ: 7.52-7.31(m, 1H), 7.22-6.17(m, 7H), 5.29-4.81(m, 1H), 4.36-4.02(m, 3H), 3.82-3.50(m, 4H), 3.45-3.21(m, 2H), 3.06-2.42(m, 6H), 2.42-1.84(m, 8H), 1.29-1.25(m, 3H); LCMS (ESI) m / z: Calculated value of C₃¹H₃₄F₃N₃O₅ 585.25; Experimental value 586.8 [M+H]⁺.

[0415] [, Preparation 27. , ] (S)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(N- (Linylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid [(P27)]. Towards [P26] (610 mg, 1.04 mmol) was added to a solution of sodium hydroxide (208 mg, 5.21 mmol) in ethanol (4.0 mL) and water (1.0 mL), and then stirred at 80 °C for 16 hours. The pH of the mixture was adjusted to 5 with 2N HCl (aq) and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (0-10% MeOH / DCM, containing 1% NH4OH (aq)) to give a white solid. [P27](500mg, 86%). ¹H NMR (400MHz, CDCl₃), δ: 7.23-6.91(m, 5H), 6.91-6.24(m, 3H), 5.51-5.35(m, 1H), 4.36-4.16(m, 2H), 4.06-3.67(m, 4H), 3.64-3.11(m, 5H), 3.00-2.34(m, 7H), 2.26-2.06(m, 3H); LCMS (ESI) m / z: Calculated value of C₂₉H₃₀F₃N₃O₅: 557.21; Experimental value: 556.2 [MH]⁻.

[0416] [, Preparation 28. , ] (S)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(N- (P-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carbonyl chloride [(P28)]. At room temperature, to [P27] (100 mg, 0.179 mmol) was added to a solution of oxalichlor (31 μL, 0.36 mmol) in DCM (4.0 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent, yielding the crude product. [P28], it is used in the next step without purification. 2-Cyclopropyl-6-(5-isopropoxy-1H-indazol-3-yl)-4-(N-) (Linyl) Ta -3(2H)-keto [(P34)]

[0417] [, Preparation 29. , ] Methyl 2-bromo-5-hydroxybenzoate [(P29)]. Boron tribromide (48 mL, 0.50 mmol) was added to a solution of methyl 2-bromo-5-methoxybenzoate (20.0 g, 81.6 mmol) in anhydrous DCM (300 mL) at -78 °C. The mixture was stirred at -78 °C to room temperature for 6 hours, then the reaction was cooled to 0 °C and quenched with MeOH. The solution was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with an aqueous sodium bicarbonate solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a white solid. [P28] (3.20 g, 68%) was used directly in the next step without further purification. ¹H NMR (400 MHz, CD3OD), δ: 7.45 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 3.0 Hz, 1H), 6.83 (dd, J = 8.8, 3.0 Hz, 1H), 3.88 (s, 3H); LCMS (ESI) m / z: calculated value of C8H7BrO3 229.96; experimental value 230.7 [M+H]+.

[0418] [, Prepare 30. , ] Methyl 2-bromo-5-(difluoromethoxy)benzoate [(P30)]. At 95°C, potassium carbonate (14.2 g, 102 mmol) was added to a solution of anhydrous DMF (45 mL). A mixture of [P29] (15.8 g, 68.4 mmol) and sodium chlorodifluoroacetate (20.9 g, 136 mmol) in anhydrous DMF (90 mL). The mixture was stirred at 95 °C for 30 minutes, then diluted with EtOAc and washed with H2O and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc / n-hexane) to obtain a white gel. [P30](8.2g,45%). 1H NMR (400MHz, CD3OD), δ: 7.73(d,J=8.8Hz,1H), 7.54(d,J=2.8Hz,1H), 7.23(dd,J=8.8,2.8Hz,1H), 6.90(t,J HF=73.6Hz,1H), 3.92(s,3H).

[0419] [, Preparation 31. , ] 2-(4-((4-(benzooxy)phenyl)aminomethyl)-1,5-dimethyl-1H-pyrrole-2-yl)-5-(difluoromethoxy)benzoate [(P31)]. Using argon [P30] (200 mg, 0.624 mmol), N-(4-benzyloxyphenyl)-1,2-dimethylpyrrole-3-methylamine (263 mg, 0.936 mmol), trimethylacetic acid (19 mg, 0.19 mmol), and potassium phosphate (662 mg, 3.12 mmol) in N,N-dimethylacetamide (42 mL) were degassed for 15 minutes. Next, bis(triphenylphosphine)palladium(II) dichloride (88 mg, 0.13 mmol) was added to the mixture, and the reaction was degassed again with argon for 15 minutes. The mixture was stirred at 135 °C for 3 hours, diluted with EtOAc, and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (0-100% MeOH / H2O) to give a yellow solid. [P31] (219 mg, 59%). ¹H NMR (400 MHz, CDCl₃), δ: 7.74 (s, 1H), 7.50–7.27 (m, 10H), 6.94 (d, J = 8.8 Hz, 2H), 6.61 (t, J HF = 73.2 Hz, 1H), 6.22 (s, 1H), 5.05 (s, 2H), 3.77 (s, 3H), 3.26 (s, 3H), 2.64 (s, 3H); LCMS (ESI) m / z: Calculated value of C₂₉H₂₆F₂N₂O₅ 520.18; Experimental value 521.6 [M+H]⁺. Note: The degassing step is crucial for yield.

[0420] [, Preparation 32. , ] 2-(4-((4-(benzomethoxy)phenyl)aminomethoxy)-1,5-dimethyl-1H-pyrrole-2-yl)-5-(difluoromethoxy)benzoic acid [(P32)]. Towards [P31] (218 mg, 0.419 mmol) was added to a solution of EtOH (3.2 mL) and H2O (0.80 mL) with sodium hydroxide (84 mg, 2.1 mmol) and stirred at room temperature for 2 hours. The mixture was adjusted to pH 5 with 2N HCl (aq) and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (0-10% MeOH / DCM) to give a white solid. [P32](148mg, 70%). ¹H NMR (400MHz, CD3OD), δ: 7.70(s, 1H), 7.51–7.26(m, 9H), 7.17–6.74(m, 3H), 6.49(s, 1H), 5.07(s, 2H), 3.30(s, 3H, overlapping with solvent residues of d-methanol), 2.57(s, 3H); LCMS (ESI) m / z: calculated value of C28H24F2N2O5 506.17; experimental value 507.4 [M+H]+.

[0421] [, Preparation 33. , ] (S)-N-(4-(benzyloxy)phenyl)-5-(4-(difluoromethoxy)-2-(3-(N- (P-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P33)]. Towards [P32] (145 mg, 0.286 mmol) and 4-[[(3S)-1,2,3,4-tetrahydroisoquinoline-3-yl]methyl] A solution of porphyrin (72.9 mg, 0.315 mmol) in DMF (1.5 mL) was prepared by adding N,N-diisopropylethylamine (0.075 mL, 0.43 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl tetrafluoroborate. (110 mg, 0.344 mmol). After stirring overnight at 60 °C, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (30% EtOAc / DCM) to obtain a colorless gel. [P33](105mg, 51%). 1H NMR(400MHz, CDCl3), δ:7.47-7.28(m,8H),7.22-7.08(m,3H),7.00-6.86(m,4 H),6.75-6.51(m,2H),5.08-5.04(m,2H),4.36-4.16(m,2H),3.77-3.63(m,3H) ,3.59-3.54(m,1H),3.49(s,1H),3.20(s,3H),2.78-2.69(m,1H),2.68-2.60( m,2H),2.55-2.44(m,2H),2.38-2.30(m,4H),2.28-2.20(m,1H);LCMS(ESI)m / z The calculated value of C42H42F2N4O5 is 720.31; the experimental value is 721.9[M+H]+.

[0422] [, Preparation 34. , ] 2-Cyclopropyl-6-(5-isopropoxy-1H-indazol-3-yl)-4-(N- (Linyl) Ta -3(2H)-keto [(P34)]. At 50℃, A solution of [P33] (100 mg, 0.139 mmol) and t-BuOK (93 mg, 0.83 mmol) in t-BuOH (3.5 mL) was stirred for 30 minutes, followed by the addition of methyl methanesulfonate (3-methoxy-2-methyl-phenyl) (128 mg, 0.555 mmol). The mixture was stirred overnight at 60 °C, cooled, diluted with EtOAc, and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30% EtOAc / n-hexane, containing 3% TEA) to obtain a colorless gel. [P34](24mg,20%). 1H NMR(400MHz, CDCl3), δ:7.42-7.36(m,1H),7.35-7.27(m,3H),7.20-6.94(m,8H),6.89-6.62(m,5H) ,6.62-6.40(m,3H),5.23-5.00(m,2H),4.99-4.90(m,2H),4.82-4.63(m,1H),4.31-3.93(m,1H),3. 86-3.75(m,3H),3.72-3.60(m,3H),3.55-3.48(m,1H),3.27-3.19(m,1H),3.10(s,1H),2.94-2.74(m,1H),2.71-2.36(m,4H),2.35-2.20(m,4H),2.20-2.03(m,4H),2.02-1.87(m,2H).;Calculated value of LCMS(ESI) m / z C51H52F2N4O6: 854.39; Experimental value: 856.0[M+H]+. 1-(chloromethyl)-3-methoxy-2-methylbenzene [(P35)]

[0423] [, Preparation 35. , ] 1-(chloromethyl)-3-methoxy-2-methylbenzene [(P35)]. At 0 °C, methanesulfonyl chloride (56.0 μL, 0.722 mmol) and triethylamine (134 μL, 0.963 mmol) were added to a solution of (3-methoxy-2-methyl-phenyl)methanol (73.3 mg, 0.481 mmol) in DCM (1.5 mL). The reaction solution was stirred at 0 °C for 2 hours, quenched with H₂O, and extracted with EtOAc. The organic layer was dried over MgSO₄(s), filtered, and concentrated under reduced pressure to obtain… [P35] (82.2 mg), which was used in the next step without purification. ¹H NMR (400 MHz, CDCl₃), δ: 7.20 (t, J = 7.6 Hz, ¹H), 7.00–6.90 (m, 2H), 5.28 (s, 2H), 3.84 (s, 3H), 2.87 (s, 3H). (S)-N-(4-(benzooxy)phenyl)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(N-) (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P38)]

[0424] [, Preparation of 36. , ] (S)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(N- (P-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carbonyl chloride [(P36)]. At 0°C, 5-[5-chloro-4-(difluoromethoxy)-2-[(3S)-3-(N- [Phosphine]-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-pyrrole-3-carboxylic acid (100 mg, 0.174 mmol) was added dropwise to a solution in anhydrous DCM (2.0 mL). The reaction solution was stirred for 2 hours at room temperature. TLC analysis indicated the consumption of the starting material. The solution was concentrated to remove the solvent, giving the crude product. [P36], it is used in the next step without purification.

[0425] [, Preparation 37. , ] (S)-N-(4-(benzyloxy)phenyl)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(N- (P-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P37)]. At room temperature, towards coarse [P36] Pyridine (42.1 μL, 0.522 mmol) and 4-(benzyloxy)aniline (38.2 mg, 0.191 mmol) were added to a solution in 2.0 mL of 1,2-dichloroethane. The reaction solution was stirred at 110 °C for 16 hours and cooled to room temperature. The solution was then quenched with H2O and extracted with EtOAc. The organic layer was dried over MgSO4(s), filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (DCM:EtOAc = 1:1) to obtain a grayish-white solid. [P37] (91.0 mg, 69% yield). 1H NMR(400MHz, CDCl3), δ:7.82-7.28(m,7H),7.18-6.76(m,7H),6.66-6.36(m,2H),5.91-5.21(m,2H),5.06(s,2H),4.72-4.17(m,3H),3.69 -3.45(m,5H),3.24-2.98(m,4H),2.83-2.60(m,2H),2.53-2.47(m,1H),2.37(m,3H),2.26-2.21(m,1H),2.12-2.07(m,1H);LCMS(ESI)m / z The calculated value of C42H41ClF2N4O5 is 754.27; the experimental value is 755.3 [M+H]+.

[0426] [, Preparation 38. , ] (S)-N-(4-(benzyloxy)phenyl)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P38)]. At room temperature, to [P37] (91.0 mg, 0.120 mmol) was added to a solution of potassium butoxide (88.3 mg, 0.723 mmol) in 1.5 mL of tert-butanol. The reaction solution was stirred at 50 °C for 30 minutes, and then [the solution was further infused with potassium butoxide (P37)]. [P35] (82.2 mg, 0.482 mmol) was added and stirred at 60 °C for 1 hour. The reaction solution was cooled, quenched with H2O, and extracted with EtOAc. The organic layer was dried over MgSO4(s), filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (dichloromethane:EtOAc = 1:1) to obtain a grayish-white solid. [P38] (40.0 mg, 37% yield). ¹H NMR (400 MHz, CDCl₃), δ: 7.71–7.29 (m, 7H), 7.25–6.40 (m, 12H), 5.52–5.47 (m, 1H), 5.15–4.92 (m, 3H), 4.79–4.61 (m, 1H), 4.36–3.93 (m, 4H), 3.83–3.66 (m, 6H), 3.57–3.41 (m, 2H), 3.27–3.12 (m, 4H), 2.33–2.04 (m, 10H); LCMS (ESI) m / z: Calculated value of C₅¹H₅¹ClF₂N₄O₆ 888.35; Experimental value 889.4 [M+H]⁺. 5-[4-chloro-5-(difluoromethyl)-2-[(3S)-3-(N- [P-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-pyrrole-3-carbonyl chloride

[0427] [, Preparation 39. , ] 5-[4-chloro-5-(difluoromethyl)-2-[(3S)-3-(N- [P-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-pyrrole-3-carbonyl chloride [(P39)]. Under ice bath conditions, 5-[4-chloro-5-(difluoromethyl)-2-[(3S)-3-(N-] [Phenylmethyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-pyrrole-3-carboxylic acid (150 mg, 0.27 mmol, 1.0 eq) was added to a solution of DCM (3.0 mL) with xyl chloride (46 μL, 0.54 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under vacuum to obtain crude... [P39], and use it in the next step without further separation. (S)-N-(4-(benzooxy)phenyl)-5-(4-chloro-5-(difluoromethyl)-2-(3-(N-) (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[0428] [, Prepare 40. , ] (S)-N-(4-(benzyloxy)phenyl)-5-(4-chloro-5-(difluoromethyl)-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P40)]. At room temperature, to [P39](143 mg, 0.430 mmol) was added to a solution of pyridine (86 μL, 1.08 mmol) and 4-benzyloxy-N-[(3-methoxy-2-methyl-phenyl)methyl]aniline (crude product, 0.358 mmol) in a solution of dichloroethane (2.0 mL). The mixture was stirred at 90 °C for 6 hours. The reaction was quenched with NaHCO3(aq) and extracted with DCM. The organic layer was dried over MgSO4(s), filtered, and concentrated. The crude product was purified by silicone column chromatography (0-100% EtOAc / n-hexane, containing 3% triethylamine) to obtain a white solid. [P40](65.9mg,21%). 1H NMR(400MHz, CDCl3), δ:7.45-7.26(m,7H),7.20-6.97(m,5H),6.97-6.63(m,6H),6.60-6.45( m,2H),5.19-5.08(m,1H),5.07-4.89(m,3H),4.88-4.71(m,1H),4.28-3.90(m,1H),3.87-3.76 (m,3H),3.75-3.60(m,3H),3.59-3.46(m,2H),3.29-3.20(m,1H),3.10(s,2H),2.71-2.48(m,3H),2.47-2.37(m,1H),2.37-2.27(m,2H),2.26-2.12(m,3H),2.11-1.86(m,5H);Calculated value of LCMS(ESI) m / z C51H51ClF2N4O5: 872.35; Experimental value: 873.4 [M+H]+. (S)-4-((1,2,3,4-tetrahydroisoquinoline-3-yl)methyl) phyto [(43)]

[0429] [, Preparation 41. , ] (S)-3-( Tertiary butyl ester of phyll-4-carbonyl)-3,4-dihydroisoquinoline-2(1H)-formate [(P41)]. At room temperature, towards (3S)-3-( Add 10 g (36.06 mmol) of tributyl 3,4-dihydro-1H-isoquinoline-2-carboxylic acid (4-carbonyl) to a solution in 100 mL of acetonitrile. Phosphorus (3.98 mL, 46.16 mmol) and triethylamine (6.02 mL, 43.3 mmol) were added and stirred for 20 minutes. At room temperature, tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl (TBTU) was added to the reaction mixture. The mixture was stirred overnight at room temperature. The mixture was concentrated to obtain a residue. The residue was diluted with EtOAc and then treated with an aqueous solution of sodium bicarbonate. The organic layer was dried over MgSO4, filtered, and concentrated to give a product as a yellow solid. [P41](11.97g, 94%) was used directly in the next step without purification. ¹H NMR (400MHz, CDCl₃), δ: 7.18–7.09 (m, 4H), 5.27 (br s, 1H), 4.94–4.82 (br m, 1H), 4.46–4.38 (br m, 1H), 3.69–3.58 (br m, 8H), 3.13–2.94 (m, 2H), 1.48 (br m, 9H). Calculated LCMS (ESI) m / z for C₁₉H₂₆N₂O₄: 346.19; Experimental: 347.1 [M+H]⁺.

[0430] [, Preparation 42. , ] (S)-(N- (1,2,3,4-tetrahydroisoquinoline-3-yl) methyl ketone [(P42)]. Towards [P41] (9.07g, 26.18mmol) at 1,4-di Add 4M HCl to the 1,4-dialkyl solution (25 mL) A solution (50 mL) in alkane was prepared. The reaction was stirred at room temperature for 2 hours. The solution was quenched with saturated Na₂CO₃(aq) and extracted with DCM. The organic layer was dried over MgSO₄, filtered, and concentrated to obtain a white solid. [P42](5.1g, 79%). ¹H NMR (400M oz, DMSO-d⁶), δ: 7.10-7.07 (m, 3H), 7.01-6.99 (m, 1H), 3.88 (s, 2H), 3.87-3.83 (m, 1H), 3.71-3.37 (m, 9H), 2.85-2.78 (m, 1H), 2.69-2.64 (m, 1H); LCMS (ESI) m / z: Calculated value of C₁₄H₁₈N₂O₂ 246.14; Experimental value 247.3 [M+H]⁺.

[0431] [, Preparation 43. , ] (S)-4-((1,2,3,4-tetrahydroisoquinoline-3-yl)methyl) phyto [(P43)]. At 0℃, towards [P42] (1.85 g, 7.51 mmol) was added to a solution of LAH (15.02 mL, 15.02 mmol, 1 M in THF) in anhydrous THF (10 mL). The reaction was stirred overnight at room temperature and then quenched at 0 °C by water (0.60 mL) and 15% NaOH (aq) (0.60 mL). The solution was filtered through a diatomaceous earth mat and washed with THF. The filtrate was collected and concentrated to give an orange oily product. [P43](1.20g, 69%). ¹H NMR (400MHz, CDCl₃), δ: 7.15-7.08(m, 3H), 7.06-7.04(m, 1H), 4.09(s, 2H), 3.76-3.73(m, 4H), 3.10-3.03(m, 1H), 2.73-2.55(m, 4H), 2.50-2.40(m, 4H). LCMS (ESI) m / z: Calculated value of C₁₄H₂₀N₂O: 232.16; Experimental value: 233.2 [M+H]⁺. ethyl 1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrrole-3-carboxylate [(P45)]

[0432] [, Preparation 44. , ] ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate [(P44)]. At 0 °C, sodium hydride (7.2 g, 18.0 mmol) was slowly added to a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (25.0 g, 163 mmol) in anhydrous DMF (200 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was then treated with methyl iodoform (11 mL, 18.0 mmol) at 0 °C and stirred at room temperature for 16 hours. The mixture was then treated with water and extracted with EtOAc in an ice bath. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give an orange oil. [P44] (25.0 g, 91%) was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl₃), δ: 6.50 (d, J = 3.0 Hz, 1H), 6.45 (d, J = 3.0 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.52 (s, 3H), 2.50 (s, 3H), 1.33 (t J = 7.2 Hz, 3H); LCMS (ESI) m / z: Calculated value of C₉H₁₃NO₂ 167.09; Experimental value 168.1 [M + H]⁺.

[0433] [, Preparation 45. , ] ethyl 1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrrole-3-carboxylate [(P45)]. At room temperature, to [P44] (5.0 g, 30 mmol) and bis(pinacolyl)diboron (8.4 g, 33 mmol) in THF (75 mL) were reacted with 4,4'-bis-tert-butyl-2,2'-bipyridine (482 mg, 1.8 mmol) and (1,5-cyclooctadienyl)(methoxy)iridium(I) dimer (595 mg, 0.90 mmol). The mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere, and the mixture was concentrated under reduced pressure to obtain a red solid. [P45] (12.5 g, <99%) was used directly in the next step without further purification. ¹H NMR (400 MHz, CDCl₃), δ: 7.21 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.70 (s, 3H), 2.52 (s, 3H), 1.30–1.26 (m, 15H); LCMS (ESI) m / z: Calculated value of C₁₅H₂₄BNO₄ 293.18; Experimental value 294.1 [M + H]⁺. (S)-(2-bromo-4-chlorophenyl)(3-(N-) (Linylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl ketone [(P46)]

[0434] [, Preparation 46. , ] (S)-(2-bromo-4-chlorophenyl)(3-(N- (Linylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl)methyl ketone [(P46)]. To 2-bromo-4-chlorobenzoic acid (3.00 g, 12.7 mmol) and [P43] (3.30 g, 14.0 mmol) was added to a solution of N,N-diisopropylethylamine (3.3 mL, 19.1 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl tetrafluoroborate in N,N-dimethylacetamide (42 mL). (4.9 g, 15 mmol). After stirring at room temperature for 5 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (0-80% EtOAc / n-hexane) to give a yellow solid. [P46](4.9g, 85%). 1H NMR(400MHz, CDCl3), δ:7.68-7.60(m,1H),7.43-7.29(m,2H),7.24-7.11(m, 3H),6.92-6.88(m,1H),5.46-5.28(m,1H),4.49-4.34(m,1H),4.25-4.20(m, 1H),3.72-3.69(m,3H),3.64-3.54(m,2H),3.35-3.12(m,1H),2.94-2.74(m, 1H),2.68-2.40(m,2H),2.35-2.22(m,1H),2.21-2.09(m,2H);LCMS(ESI)m / z The calculated value of C21H22BrClN2O2 is 448.06; the experimental value is 449.2[M+H]+. (S)-5-(5-chloro-2-(3-(N-) (Linylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid [(P48)]

[0435] [, Preparation 47. , ] (S)-5-(5-chloro-2-(3-(N- (Linylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester [(P47)]. Using argon [P45] (559 mg, 1.3 mmol) [P46] (500 mg, 1.1 mmol) and cesium carbonate (723 mg, 2.2 mmol) in DMF (5.5 mL) were degassed for 30 minutes. The mixture was then treated with bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (39 mg, 0.06 mmol) followed by argon degassed. The mixture was stirred at 130 °C for 2 hours under microwave irradiation. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (0-80% EtOAc / n-hexane) to give a yellow solid. [P47](350mg, 58%). 1H NMR(400MHz, CDCl3), δ:7.44-7.38(m,2H),7.13-7.05(m,3H),6.98-6.96(m,1 H),6.83-6.76(m,1H),6.20(s,1H),5.28-5.22(m,1H),4.31-4.14(m,4H),3.71 -3.52(m,5H),3.38-3.31(m,1H),3.23(s,3H),3.00-2.75(m,1H),2.55-2.38( m,4H),2.24-2.16(m,4H),2.03-1.98(m,2H),1.26-1.19(m,3H);LCMS(ESI)m / z The calculated value of C30H34ClN3O4 is 535.22; the experimental value is 536.4 [M+H]+.

[0436] [, Preparation 48. , ] (S)-5-(5-chloro-2-(3-(N- (Linylmethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid [(P48)]. Towards [P47] (350 mg, 0.65 mmol) was added to a solution of sodium hydroxide (131 mg, 3.3 mmol) in ethanol (5.2 mL) and water (1.3 mL), and then stirred at 80 °C for 16 hours. The pH of the mixture was adjusted to 5 with 4N HCl (aq) and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silicone column chromatography (0-60% EtOAc / n-hexane) to give an orange solid. [P48](300mg, 90%). ¹H NMR (400MHz, CDCl₃), δ: 7.60–7.53 (m, 2H), 7.42 (s, 1H), 7.13–7.11 (m, 2H), 6.97–6.88 (m, 2H), 6.36 (s, 1H), 5.36 (br s, 1H), 4.30–4.16 (m, 2H), 3.89–3.79 (br m, 4H), 3.59–3.47 (m, 1H), 3.21–3.07 (m, 5H), 2.94–2.88 (m, 4H), 2.55–2.46 (m, 2H), 2.08 (s, 3H); LCMS (ESI) m / z: Calculated value of C₂₈H₃OClN₃O₄ 507.19; Experimental value 508.4 [M+H]⁺. N-(3-Methoxy-2-methylbenzyl)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole-5-amine [(P51)]

[0437] [, Preparation 49. , ] 5-nitro-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole [(P48)]. Add 2,3-dihydropiperanone (2.34 mL, 24.5 mmol) and 4-methylbenzenesulfonic acid (471 mg, 2.45 mmol) to a solution of 5-nitro-1H-indazole (2.00 g, 12.3 mmol) in DCM (60 mL). Stir the mixture overnight at room temperature, then concentrate the mixture to remove the solvent. Treat the residue with water and extract with EtOAc. Dry the organic layer with Na2SO4(s), filter, and concentrate. Purify the crude product by silicone column chromatography (0-80% EtOAc / n-hexane) to obtain... [P49](3.0g,99%). 1H NMR(400MHz, CDCl3), δ:8.71(d,J=2.0Hz,1H),8.27(d,J=9.2Hz,1H),8.21(s,1H),7.69(d,J=9.2Hz,1H),5.77(dd, J=8.8,2.4Hz,1H),4.04-3.99(m,1H),3.80-3.74(m,1H),2.56-2.47(m,1H),2.18-2.08(m,2H),1.83-1.67(m,3H).

[0438] [, Prepare 50. , ] 1-(tetrahydro-2H-piperan-2-yl)-1H-indazole-5-amine [(P50)]. At room temperature, to [P49] (3.00 g, 12.1 mmol) was added to a solution of EtOAc (120 mL) with palladium / carbon (300 mg). The mixture was purged with H2 (g) for 5 minutes. The mixture was stirred overnight at room temperature under an H2 atmosphere. The mixture was then filtered through a diatomaceous earth mat. The filtrate was then concentrated to obtain... [P50] (2.94 g, 100%) was used directly in the next step without purification. ¹H NMR (400 MHz, CDCl₃), δ: 7.82 (s, ¹H), 7.41 (d, J = 8.8 Hz, ¹H), 6.93 (s, ¹H), 6.89–6.87 (m, ¹H), 5.64 (dd, J = 9.2, 2.8 Hz, ¹H), 4.04–4.00 (m, ¹H), 3.76–3.69 (m, ¹H), 2.59–2.50 (m, ¹H), 2.16–2.11 (m, ¹H), 2.09–2.06 (m, ¹H), 1.81–1.68 (m, ³H).

[0439] [, Preparation 51. , ] N-(3-methoxy-2-methylbenzyl)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole-5-amine [(P51)]. Towards [P50] (600 mg, 2.77 mmol) and 3-methoxy-2-methylbenzaldehyde (347 mg, 2.31 mmol) were added to a solution of AcOH (1 drop) in DCM (15 mL). The mixture was stirred at room temperature for 16 hours and concentrated to remove the solvent. The residue was purified by silicone column chromatography (10-80% EtOAc / n-hexane) to obtain [P51](610mg,75%). 1H NMR(400MHz, CDCl3), δ:7.84(s,1H),7.42(d,J=8.8Hz,1H),7.14(t,J=8.0Hz,1H),6. 99(d,J=8.0Hz,1H),6.85-6.79(m,3H),5.64(dd,J=9.2,2.8Hz,1H),4.29(s,2H),4.0 4-3.99(m,1H),3.85(s,3H),3.75-3.68(m,1H),2.59-2.50(m,1H),2.25(s,3H),2.16 -2.12(m,1H),2.09(s,1H),2.08-2.07(m,1H),1.81-1.69(m,2H),1.67-1.60(m,1H). 5-(5-chloro-2-((S)-3-(N-) (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-methylamine) [(P53)]

[0440] [, Preparation of 52. , ] (S)-5-(5-chloro-2-(3-(N- (P-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-1,2-dimethyl-1H-pyrrole-3-carbonyl chloride [(P52)]. At room temperature, to [P48] (200 mg, 0.390 mmol) was added to a solution of oxalichlor (67 μl, 0.78 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent, yielding the crude product. [P52], and use it in the next step without purification.

[0441] [, Preparation 53. , ] 5-(5-chloro-2-((S)-3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-methylamine) [(P53)]. At room temperature, to [P51] (137 mg, 0.390 mmol) and [P52] (0.390 mmol) was added to a solution of pyridine (94 μl, 1.17 mmol) in 6.5 mL of dichloroethane. The mixture was stirred overnight at 90 °C. The reaction was quenched with NaHCO3 (aq) and extracted with DCM. The organic layer was dried over Na2SO4 (s), filtered, and concentrated. The crude product was purified by silicone column chromatography (0-10% MeOH / dichloromethane) to obtain... [P53](212mg, 65%). 1H NMR (400MHz, CDCl3), δ:7.89-7.84(m,1H),7.42-7.28(m,2H),7.23-6.90(m,8H),6.81-6.66(m,4H),5.47(br s,1H),5.15-4.88(m,4H),3.82-3.79(m,3H),3.72-3.61(m,3H),3.49-3.47(m,2H),3.30-3.23(m,2H ),3.05(s,2H),2.78-2.72(m,1H),2.64-2.57(m,1H),2.54-2.48(m,2H),2.37-2.28(m,2H),2.24(br m,2H),2.17(br m,1H),2.07(s,2H),2.04(br s,3H),1.99-1.82(m,3H),1.68(br s,3H);LCMS(ESI)m / z 841.5[M+H]+. 2-(((1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-5-yl)amino)methyl)benzonitrile [(P54)]

[0442] [, Preparation 54. , ] 2-(((1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-5-yl)amino)methyl)benzonitrile [(P54)]. Towards Potassium carbonate (261 mg, 1.87 mmol) was added to a solution of [P50] (274 mg, 1.26 mmol) and 2-(bromomethyl)benzonitrile (247 mg, 1.26 mmol) in acetonitrile (18 mL). The mixture was stirred at 90 °C for 16 hours. The mixture was concentrated to remove the solvent. The residue was purified by silicone column chromatography (10-70% EtOAc / n-hexane) to obtain... [P54](307mg,73%). 1H NMR (400MHz, DMSO-d 6 ), δ:7.79(s,1H),7.68-7.66(m,1H),7.55-7.32(m,4H),6.88-6.85(m,1H),6.69(d,J=2.4Hz,1H),5.61(dd,J=9.2,2.8Hz,1H ),4.60(s,2H),4.02-3.98(m,1H),3.74-3.68(m,1H),2.56-2.47(m,1H),2.15-2.10(m,2H),1.76-1.60(m,3H);LRMS(ESI)m / z 333.6[M+H]+. 5-(5-chloro-2-((S)-3-(N-) (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-cyanobenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-methylamine) [(P55)]

[0443] [, Prepare 55. , ] 5-(5-chloro-2-((S)-3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-cyanobenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-methylamine) [(P55)]. At room temperature, to [P54] (143 mg, 0.430 mmol) and [P52] (Crude product, 0.390 mmol) was added to a solution of pyridine (94 μL, 1.17 mmol) in dichloroethane (6.5 mL). The mixture was stirred overnight at 90 °C. The reaction was quenched with NaHCO3(aq) and extracted with DCM. The organic layer was dried over Na2SO4(s), filtered, and concentrated. The crude product was purified by silicone column chromatography (0-10% MeOH / dichloromethane) to obtain... [P55](40mg,12%). 1H NMR (400MHz, CDCl3), δ:7.88-7.81(m,1H),7.66-7.60(m,1H),7.56-7.48(m,3H),7.42-7.33(m,1H),7.31-7.27(m,2H),7.24-7.16 (m,3H),7.15-7.08(m,3H),7.00-6.87(m,2H),6.82-6.77(m,2H),5.68-5.58(m,1H), 5.37-5.27(m,1H),5.11-4.96(m,2H),4.26-4.09(m,1H),3.98-3.86(m,2H),3.72-3.6 2(m,6H),3.54-3.47(m,1H),3.26-3.22(m,2H),3.10(s,3H),2.81-2.40(m,2H),2.32 -2.25(m,4H),2.16-1.94(m,1H),1.77-1.64(m,2H),1.31-1.23(m,1H);LRMS(ESI)m / z 822.4[M+H]+. N-(2-Methoxybenzyl)-1-(Tetrahydro-2H-piperan-2-yl)-1H-indazole-5-amine [(P56)]

[0444] [, Preparation of 56. , ] N-(2-methoxybenzyl)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole-5-amine [(P56)]. Towards [P50] (600 mg, 2.77 mmol) and 2-methoxybenzaldehyde (315 mg, 2.31 mmol) were added to a solution in DCM (15 mL) with AcOH (1 drop) and sodium triethoxyborohydride (1.17 g, 5.54 mmol). The mixture was stirred overnight at room temperature and concentrated to remove the solvent. The residue was purified by silicone column chromatography (10-80% EtOAc / n-hexane) to obtain [P56](850mg,91%). 1H NMR(400MHz, CDCl3), δ:7.80(s,1H),7.38(d,J=8.8Hz,1H),7.31-7.21(m,2H),6.90-6.80(m,4H),5.61(dd,J=9.2,2.8Hz,1H),4.31 (s,2H),4.01-3.97(m,1H),3.86(s,3H),3.73-3.67(m,1H),2.53-2.49(m,1H),2.16-2.00(m,2H),1.76-1.60(m,3H);LCMS(ESI)m / z 338.2[M+H]+. 5-(5-chloro-2-((S)-3-(N-) (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-methylamine) [(P57)]

[0445] [, Preparation 57. , ] 5-(5-chloro-2-((S)-3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-N-(1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-5-yl)-1H-pyrrole-3-methylamine) [(P57)]. To N-(2-methoxybenzyl)-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole-5-amine ( [P56] (238 mg, 0.71 mmol) and pyridine (140 mg, 1.77 mmol) were added to a solution in 1,2-dichloroethane (3.0 mL). A solution of [P52] (311 mg, 0.59 mmol) in 6.0 mL of 1,2-dichloroethane was prepared. The reaction mixture was stirred at 80 °C for 16 hours. The solution was quenched with saturated NaHCO3(aq) solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4(s), filtered, and concentrated to obtain the residue. The residue was purified by silicone column chromatography (dichloromethane:methanol = 20:1) to obtain an orange solid. [P57] (315 mg, 65% yield). Calculated value of LCMS (ESI) m / z for C48H51ClN6O5: 826.36; experimental value: 827.4 [M+H]+. 5-[5-chloro-4-cyano-2-[(3S)-3-(N- [(3-methoxy-2-methyl-phenyl)methyl]-1,2-dimethyl-N-[4-(2-trimethylsilylethoxymethoxy)phenyl]pyrrole-3-methylamine [(P61)]

[0446] [, Preparation 58. , ] N 3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N 3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine [(P58)]. At 60 °C, a mixture of 1,2-dimethyl-N-3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrolo-3-methylamine (0.85 g, 2.3 mmol), tert-BuOK (1 g, 8.9 mmol), and tert-BuOH (10 mL) was stirred, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (1.1 g, 4.4 mmol). The reaction mixture was stirred at 60 °C for 3 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 0.95 g (82%) of the title compound. LCMS (ESI+) m / z 495 [M+H]+.

[0447] [, Preparation 59. , ] 4-Chloro-5-cyano-2-4-[((3-methoxy-2-methylbenzyl)-4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyaniline)carbonyl]-1,5-dimethyl-1H-pyrrole-2-ylbenzoate [(P59)]. Will [P58] (0.27 g, 0.5 mmol), methyl 2-bromo-4-chloro-5-cyanobenzoate ( A mixture of [P63] (0.3 g, 1 mmol), K3PO4 (0.58 g, 2.7 mmol), trimethylacetic acid (17 mg, 0.3 eq), and PdCl2(PPh3)2 (77 mg, 0.2 eq) in N,N-dimethylacetamide (10 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 minutes, and then the reaction mixture was cooled to ambient temperature. After the reaction was complete, the mixture was diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 70 mg (19%) of the title compound. LCMS (ESI+) m / z 689 [M+H]+.

[0448] [, Prepare 60. , ] 4-Chloro-5-cyano-2-4-[((3-methoxy-2-methylbenzyl)-4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyaniline)carbonyl]-1,5-dimethyl-1H-pyrrole-2-ylbenzoic acid [(P60)]. At ambient temperature, A solution of [P59] (70 mg, 0.1 mmol) and NaOH (20 mg, 5 eq) in a mixture of MeOH (2 mL) and water (0.2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (2 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 67 mg (99%) of the title compound, which was sufficiently pure for the next step. LCMS (ESI+) m / z 675 [M+H]+.

[0449] [, Preparation of 61. , ] 5-(5-chloro-4-cyano-2-[(3R)-3-(N- [3,4-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine] [(P61)]. At 60℃, [P60] (67 mg, 0.1 mmol) A mixture of [P43] (40 mg, 0.11 mol), DIPEA (0.04 mL, 0.15 mmol), TBTU (55 mg, 0.11 mmol), and DMF (2 mL) was stirred overnight. The reaction mixture was diluted with water (4 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 81 mg of crude compound, which was sufficiently pure for the next step. LCMS (ESI+) m / z 889 [M+H]+. Methyl 2-bromo-4-chloro-5-cyanobenzoate [(P63)]

[0450] [, Preparation of 62. , ] Methyl 2-amino-4-chloro-5-cyano-benzoate [(P62)]. Zn(CN)₂ (0.23 g, 1.97 mmol) and Pd(Ph₃P)₄ (0.19 g, 0.16 mmol) were added to a stirred solution of methyl 2-amino-4-chloro-5-(l₃-iodomethyl)benzoate (1 g, 3.2 mmol) in DMF (10 mL). The reaction mixture was then stirred at 120 °C for 2 h under microwave irradiation, followed by treatment with water (20 mL) and extraction with Et₂O + EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in DCM to give 600 mg (89%) of the compound. [P62]

[0451] [, Preparation of 63. , ] Methyl 2-bromo-4-chloro-5-cyanobenzoate [(P63)]. Towards [P62] (150 mg, 0.7 mmol) was added to a stirred solution of CH3CN (3 mL) containing (CH3)3CNO2 (0.182 g, 1.8 eq) and CuBr2 (0.15 mL, 1.8 eq). The reaction mixture was then stirred at room temperature for 3 hours under microwave irradiation, followed by treatment with water (1 mL) and extraction with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of CCl4:DCM to give 0.27 g (99%) of the title compound. 2-[4-({[4-(benzooxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chloro-5-methoxybenzoic acid [(P65)]

[0452] [, Preparation of 64. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chloro-5-methoxybenzoate ethyl ester [(P64)]. At 135℃, N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-methylamine ( A mixture of [P15] (500 mg, 1.6 mmol), methyl 2-bromo-4-chloro-5-methoxybenzoate (870 mg, 3.1 mmol), K3PO4 (1.6 g, 7.8 mmol), and trimethylacetic acid (50 mg, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.22 g, 0.3 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (20 mL) and EtOAC (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 150 mg (19%) of the title compound.

[0453] [, Prepare 65., ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chloro-5-methoxybenzoic acid [(P65)]. At ambient temperature, A solution of [P64] (150 mg, 0.29 mmol) and NaOH (58 mg, 1.4 mol) in a mixture of EtOH (10 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 130 mg (90%) of the title compound, which was pure enough for use in the next step. N-[4-(benzomethoxy)phenyl]-5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P66)]

[0454] [, Preparation of 66. , ] N-[4-(benzyloxy)phenyl]-5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P66)]. At 60℃, [P65] (130 mg, 0.26 mmol) A mixture of [P43] (72 mg, 0.3 mmol), DIPEA (0.07 mL, 0.39 mmol), TBTU (100 mg, 0.3 mmol), and DMF (5 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 80 mg (43%) of the title compound. N-[4-(benzomethoxy)phenyl]-5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P67)]

[0455] [, Preparation of 67. , ] N-[4-(benzyloxy)phenyl]-5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholino-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P67)]. At 50℃, A mixture of [P66] (80 mg, 0.1 mmol), tert-BuOK (50 mg, 0.4 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (46 mg, 0.2 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 80 mg (84%) of the title compound.

[0456] [, Preparation of 68. , ] Methyl 2-bromo-4-fluoro-5-methoxybenzoate [(P68)]. At 0 °C, CuBr2 (1.2 g, 0.0054 mol) was added to a solution of methyl 2-amino-4-fluoro-5-methoxybenzoate (0.6 g, 0.003 mol) and tributyl nitrite (0.55 g, 0.0054 mol) in acetonitrile (20 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in DCM to give 228 mg (29%) of the title compound. LCMS (ESI+) m / z 264 [M+H]+. 1H NMR (400MHz, CDCl3), δ: 7.70 (d, J = 5.4Hz, 1H), 7.54 (d, J = 4.8Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H). 2-[4-({[4-(benzooxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-fluoro-5-methoxybenzoic acid [(P70)]

[0457] [, Preparation of 69. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chloro-5-methoxybenzoate ethyl ester [(P69)]. At 135℃, A mixture of [P15] (220 mg, 0.86 mmol), methyl 2-bromo-4-fluoro-5-methoxybenzoate (228 mg, 0.86 mmol), K3PO4 (919 mg, 3.44 mmol), and trimethylacetic acid (26 mg, 0.2 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (150 mg, 0.17 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (20 mL) and EtOAC (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 180 mg (41%) of the title compound.

[0458] [, Preparation 70. , ] 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-fluoro-5-methoxybenzoic acid [(P70)]. At ambient temperature, A solution of [P69] (365 mg, 0.729 mmol) and LiOH (174 mg, 7.29 mmol) in a mixture of THF (16 mL) and water (4 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 160 mg (55%) of the title compound, which was sufficiently pure for further use in the next step. N-[4-(benzomethoxy)phenyl]-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P71)]

[0459] [, Preparation 71. , ] N-[4-(benzyloxy)phenyl]-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P71)]. At 60℃, [P70] (150 mg, 0.31 mmol) A mixture of [P43] (86 mg, 0.37 mmol), DIPEA (0.08 mL, 0.46 mmol), TBTU (118 mg, 0.37 mmol), and DMF (8 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 50 mg (23%) of the title compound. N-[4-(benzomethoxy)phenyl]-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P72)]

[0460] [, Preparation 72. , ] N-[4-(benzyloxy)phenyl]-5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P72)]. At 50℃, A mixture of [P71] (50 mg, 0.071 mmol), tert-BuOK (32 mg, 0.28 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (33 mg, 0.14 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 33 mg (55%) of the title compound. N-(4-Chlorophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P73)]

[0461] [, Preparation 73. , ] N-(4-chlorophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [(P73)]. At 0℃, towards [P14] (1.0 g, 7.2 mmol) was added dropwise to a stirred solution of pyridine (5 mL) with SOCl2 (0.55 mL, 7.6 mmol), and the reaction mixture was stirred at 0 °C for 3 hours. Then, (4-chlorophenyl)amine (0.85 g, 7.2 mmol) was added dropwise to DIPEA (1.4 mL, 7.96 mmol) while maintaining the temperature at 0 °C. The reaction was heated to ambient temperature and then stirred at ambient temperature for 16 hours. Volatile substances were removed under reduced pressure. The residue was diluted with water and Et2O. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 850 mg (50%) of the title compound. methyl 2-bromo-5-cyano-4-fluorobenzoate [(P77)]

[0462] [, Preparation 74. , ] Methyl 2-amino-4-fluorobenzoate [(P74)]. SOCl2 (15.52 mL, 0.21 mol) was added over 15 minutes to a solution of 2-amino-4-fluorobenzoic acid (30.0 g, 0.19 mol) in MeOH (0.3 L). After the addition was complete, the reaction was heated under reflux for 16 hours. The MeOH was evaporated under reduced pressure. 2 M Na2CO3 aqueous solution (300 mL) was added to the residue, and the mixture was extracted with EtOAc (400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 18.1 g (56%) of the compound. [P74]

[0463] [, Preparation 75. , ] Methyl 2-amino-4-fluoro-5-iodobenzoate [(P75)]. Potassium iodide (10.7 g, 64.5 mmol) was added dropwise to water (22.5 mL) over a 2-hour period until the solution containing the compound was reached. [P74] (10 g, 64.5 mmol), sodium periodate (13.7 g, 64.5 mmol), and sodium chloride (0.69 g, 129 mmol) were added to acetic acid (203.2 mL). The mixture was stirred overnight at room temperature, then poured into ice water (30 mL), quenched with excess sodium thiosulfate solution, and extracted with DCM (6 × 50 mL). The pH of the solution was adjusted to 5 by adding 1 N NaOH. The solution was decolorized by adding NaHSO3 and the DCM layer was evaporated to obtain a light brown solid. The solid was washed with water and dried in a vacuum oven to obtain 12.56 g (69%) of a brown solid. [P75]

[0464] [, Preparation of 76. , ] Methyl 2-amino-5-cyano-4-fluorobenzoate [(P76)]. Will [P75] (1.25 g, 4.14 mmol) was dissolved in N,N-dimethylformamide (10 mL), zinc cyanide (0.268 g, 2.4 mmol) and tetra(triphenylphosphine)palladium (0.254 g, 0.2 mmol) were added, and the reaction was carried out at room temperature for 0.5 h, followed by reaction in MW at 120 °C for 2 h. After the reaction was complete, the hot reaction mixture was filtered, the filtrate was poured into ice water, and the precipitate formed was filtered off. The precipitate was heated with a small amount of n-hexane (3 mL) and the target product was filtered off to obtain the desired product. [P76](0.6g, 74.2%).

[0465] [, Preparation 77. , ] Methyl 2-bromo-5-cyano-4-fluorobenzoate ( [P77]). At 0 °C, CuBr2 (0.69 g, 3.12 mmol) was added to a solution of methyl 2-amino-5-cyano-4-fluorobenzoate (0.4 g, 2.06 mmol) and tributyl nitrite (0.32 g, 3.12 mmol) in acetonitrile (7 ml), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the residue was subjected to rapid silica gel chromatography after evaporation under reduced pressure. The residue was dissolved in DCM to give 500 mg (94%) of the title compound. LCMS (ESI+) m / z 259 [M+H]+. 1H NMR (400 MHz, CDCl3), δ: 8.38 (d, J = 3.6 Hz, 1H), 8.15 (d, J = 4.6 Hz, 1H), 3.88 (s, 3H). 2-[4-{[(4-chlorophenyl)amino]carbonyl}-carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-5-cyano-4-methoxybenzoic acid ( [P80])

[0466] [, Preparation 78. , ] 2-[4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrolo-2-yl]-5-cyano-4-hydroxybenzoate ( [P78]). At 135℃, A mixture of [P73] (1.3 g, 5.2 mmol), methyl 2-bromo-5-cyano-4-fluorobenzoate (2.7 g, 10.4 mmol), K3PO4 (555 g, 26 mmol), and trimethylacetic acid (0.16 g, 1.5 mmol) in N,N-dimethylacetamide (125 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.92 g, 1.07 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (70 mL) and EtOAC (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 800 mg (36%) of the title compound.

[0467] [, Preparation 79., ] 2-[4-{[(4-chlorophenyl)amino]carbonyl}-carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-5-cyano-4-methoxybenzoate ( [P79]). Will A suspension of [P78] (0.8 g, 2.03 mmol) and K2CO3 (0.421 g, 3.05 mmol) in DMF (10 ml) was treated with CH3I (0.46 g, 3.1 mmol). The mixture was stirred overnight at room temperature, and the reaction mixture was poured into cold water. The resulting precipitate was filtered, washed with water and Et2O, and air-dried to give 300 mg (34%) of the title compound.

[0468] [, Preparation 80. , ] 2-[4-{[(4-chlorophenyl)amino]carbonyl}-carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-5-cyano-4-methoxybenzoic acid ( [P80]). At ambient temperature, A solution of [P79] (300 mg, 0.77 mmol) and LiOH (18 mg, 7.7 mmol) in a mixture of THF (8 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 280 mg (97%) of the title compound, which was pure enough for use in the next step. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P81])

[0469] [, Preparation of 81. , ] N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P81]). At 60℃, [P80] (320 mg, 0.75 mmol) A mixture of [P43] (210 mg, 1.0 mmol), DIPEA (0.2 mL, 0.110 mmol), TBTU (292 mg, 1.0 mmol), and DMF (15 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 300 mg (78%) of the title compound. 2-[4-({[4-(benzooxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chloro-5-fluorobenzoic acid

[0470] [, Preparation of 82. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chloro-5-fluorobenzoate ( [P82]). At 135℃, A mixture of [P15] (500 mg, 1.6 mmol), methyl 2-bromo-4-chloro-5-fluorobenzoate (835 mg, 3.1 mmol), K3PO4 (1.6 g, 7.8 mmol), and trimethylacetic acid (50 mg, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.22 g, 0.3 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (20 mL) and EtOAC (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 360 ​​mg (46%) of the title compound.

[0471] [, Preparation of 83. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-chloro-5-fluorobenzoic acid ( [P83]). At ambient temperature, A solution of [P82] (360 mg, 0.7 mmol) and LiOH (82 mg, 3.5 mmol) in a mixture of THF (10 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 350 mg (99%) of the title compound, which was pure enough for further use in the next step. N-[4-(benzooxy)phenyl]-5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P84])

[0472] [, Preparation of 84. , ] N-[4-(benzyloxy)phenyl]-5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P84]). At 60℃, [P83] (350mg, 0.7mmol) A mixture of [P43] (198 mg, 0.85 mmol), DIPEA (0.18 mL, 1.1 mmol), TBTU (100 mg, 0.3 mmol), and DMF (5 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 420 mg (84%) of the title compound. 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine) [P87])

[0473] [, Preparation of 85. , ] 5-[5-chloro-4-fluoro-2-[(3S)-3-(N- [Phosphorylmethyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(4-hydroxyphenyl)-1,2-dimethyl-pyrrole-3-methylamine [P85]). Will A solution of [P84] (420 mg, 0.6 mmol) in DCM (5 mL) was cooled to -78 °C, and BBr3 (300 mg, 1.2 mmol) in THF (1 mL) was added over 5 minutes. The reaction mixture was stirred at -78 °C for 1 hour and then diluted with a saturated aqueous solution of sodium bicarbonate (NaHCO3). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to give 270 mg (75%) of the title compound.

[0474] [, Preparation of 86. , ] 5-[5-chloro-4-fluoro-2-[(3S)-3-(N- [Phosphine]-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-1,2-dimethyl-N-[4-(2-trimethylsilylethoxymethoxy)phenyl]pyrrole-3-methylamine [P86]). Add NaH (21 mg, 0.5 mmol, 60%) to maintain a temperature of 0°C. [P85] (270 mg, 0.44 mmol) was added to a stirred solution in DMF (5 mL) and stirred for 30 minutes. Next, [2-(chloromethoxy)ethyl](trimethyl)silane (80 mg, 0.5 mmol) was added. The reaction mixture was stirred overnight at ambient temperature and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 130 mg (40%) of the title compound.

[0475] [, Preparation of 87. , ] 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P87]). At 50℃, A mixture of [P86] (130 mg, 0.17 mmol), tert-BuOK (78 mg, 0.7 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (80 mg, 0.35 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 120 mg (78%) of the title compound. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-5-cyano-4-methoxybenzoic acid ( [P90])

[0476] [, Preparation of 88. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-5-cyano-4-hydroxybenzoate ( [P88]). At 135℃, A mixture of [P15] (500 mg, 1.56 mmol), methyl 2-bromo-5-cyano-4-fluorobenzoate (806 mg, 3.12 mmol), K3PO4 (1.66 g, 7.8 mmol), and trimethylacetic acid (47.6 mg, 0.5 mmol) in N,N-dimethylacetamide (25 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.32 g, 0.3 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (70 mL) and EtOAC (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 520 mg (61%) of the title compound.

[0477] [, Preparation of 89. , ] 2-[4-({[4-(benzooxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-5-cyano-4-methoxybenzoate methyl ester ( [P89]). Will A suspension of [P88] (0.5 g, 1.18 mmol) and K2CO3 (0.245 g, 1.8 mmol) in DMF (6 ml) was treated with CH3I (0.33 g, 1.8 mmol). The mixture was stirred overnight at room temperature, and the reaction mixture was poured into cold water. The precipitate formed was filtered off, washed with water and Et2O, and air-dried to give 240 mg (44%) of the title compound.

[0478] [, Preparation 90. , ] 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-5-cyano-4-methoxybenzoic acid ( [P90]). At ambient temperature, A solution of [P89] (240 mg, 0.47 mmol) and LiOH (113 mg, 4.7 mmol) in a mixture of THF (8 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 158 mg (67%) of the title compound, which was pure enough for further use in the next step. N-[4-(benzomethoxy)phenyl]-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P92])

[0479] [, Preparation of 91. , ] N-[4-(benzyloxy)phenyl]-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P91]). At 60℃, [P90] (158 mg, 0.31 mmol) A mixture of [P43] (89 mg, 0.39 mmol), DIPEA (0.08 mL, 0.46 mmol), TBTU (123 mg, 0.39 mmol), and DMF (8 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and precipitated with a mixture of EtOAc (0→100%) and DCM to give 200 mg (88%) of the title compound.

[0480] [, Preparation of 92., ] N-[4-(benzyloxy)phenyl]-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P92]). At 50℃, A mixture of [P91] (200 mg, 0.28 mmol), tert-BuOK (127 mg, 1.12 mmol), and tert-BuOH (25 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (130 mg, 0.56 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 160 mg (65%) of the title compound. 5-(5-nitro-2-[(3R)-3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N3-(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-methylamine ( [P97])

[0481] [, Preparation of 93. , ] 1,2-Dimethyl-N 3-(1-Tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-methylamine ( [P93]). Acid (0.74g, 5mmol), amine [P50] (1.1 g, 5 mmol), DMAP (0.8 g, 6.5 mmol), and Et3N (3 mL, 5 eq) were added to a solution of DCM (40 mL) with EDCxHCl (1.2 g, 6 mmol). The reaction mixture was stirred overnight at ambient temperature and then diluted with water (40 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and CCl4 to give 1.35 g (75%). [P93]. LCMS(ESI+)m / z 339[M+H]+.

[0482] [, Prepare 94. , ] N 3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N 3-(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-methylamine ( [P94]). At 50℃, A mixture of [P93] (100 mg, 0.3 mmol), tert-BuOK (132 mg, 4 eq), and tert-BuOH (2 mL) was stirred for 5 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (146 mg, 2 eq). The reaction mixture was stirred at 80 °C for 2 hours and then partitioned between DCM and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 50 mg of the compound. [P94]. LCMS(ESI+)m / z 473[M+H]+.

[0483] [, Preparation of 95. , ] methyl 4-nitro-2-(4-[(3-methoxy-2-methylbenzyl)(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)amino]carbonyl-1,5-dimethyl-1H-pyrrole-2-yl)benzoate ( [P95]). At 130°C, the compound A mixture of [P94] (400 mg, 0.8 mmol), bromide (430 mg, 1.66 mmol), K3PO4 (896 mg, 5 eq), trimethylacetic acid (26 mg, 0.3 eq), and PdCl2(PPh3)2 (118 mg, 0.2 eq) in N,N-dimethylacetamide (15 mL) was stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (25 mL) and EtOAC (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 220 mg (45%) of the title compound. LCMS (ESI+) m / z 652 [M+H]+.

[0484] [, Preparation of 96. , ] 4-nitro-2-(4-[(3-methoxy-2-methylbenzyl)(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)amino]carbonyl-1,5-dimethyl-1H-pyrrole-2-yl)benzoic acid ( [P96]). At ambient temperature, the ester A solution of [P95] (220 mg, 0.3 mmol) and NaOH (50 mg, 4 eq) in a mixture of MeOH / H2O was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (3 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 5 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 180 mg (99%). [P96]

[0485] [, Preparation 97. , ] 5-(5-nitro-2-[(3R)-3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N3-(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-methylamine ( [P97]). At 60℃, [P96] (180mg, 0.28mmol) A mixture of [P43] (72 mg, 0.3 mmol), DIPEA (0.0744 mL, 1.5 eq), TBTU (0.10 g, 0.3 mmol), and DMF (4 mL) was stirred overnight. The reaction mixture was diluted with water (10 mL), the precipitate was filtered and dried to give 180 mg of crude product. [P97]. LCMS(ESI+)m / z 852[M+H]+. 5-(5-nitro-2-[(3R)-3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(2-cyanobenzyl)-1,2-dimethyl-N3-(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-methylamine ( [P101])

[0486] [, Preparation of 98. , ] N 3-(2-cyanophenylmethyl)-1,2-dimethyl-N 3-(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-methylamine ( [P98]). At 50℃, A mixture of [P93] (800 mg, 2.3 mmol), tert-BuOK (1.06 g, 4 eq), and tert-BuOH (10 mL) was stirred for 5 minutes, followed by the addition of 2-(bromomethyl)benzonitrile (928 mg, 2 eq). The reaction mixture was stirred at 80 °C for 2 hours and then partitioned between DCM and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 950 mg (89%). [P98]. LCMS(ESI+)m / z 454[M+H]+.

[0487] [, Preparation 99. , ] methyl 4-nitro-2-(4-[(2-cyanobenzyl)(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)amino]carbonyl-1,5-dimethyl-1H-pyrrole-2-yl)benzoate ( [P99]). At 130℃, A mixture of [P98] (950 mg, 2 mmol), bromide (1.08 g, 4 mmol), K3PO4 (2.2 g, 5 eq), trimethylacetic acid (64 mg, 0.3 eq), PdCl2 (74 mg, 0.2 eq), and PPh3 (109 mg, 0.2 eq) in N,N-dimethylacetamide (40 mL) was stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (40 mL) and EtOAC (150 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 800 mg (62%). [P99]. LCMS(ESI+)m / z 633[M+H]+.

[0488] [, Prepare 100. , ] 4-nitro-2-(4-[(2-cyanobenzyl)(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)amino]carbonyl-1,5-dimethyl-1H-pyrrole-2-yl)benzoic acid ( [P100]). At ambient temperature, the ester A solution of [P99] (800 mg, 1.3 mmol) and NaOH (300 mg, 6 eq) in a mixture of MeOH / H2O was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (3 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 700 mg (90%). [P100]

[0489] [, Preparation 101. , ] 5-(5-nitro-2-[(3R)-3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(2-cyanobenzyl)-1,2-dimethyl-N3-(1-tetrahydro-2H-piperan-2-yl-1H-indazol-5-yl)-1H-pyrrole-3-methylamine ( [P101]). At 60℃, acid [P100] (690mg, 1.1mmol) A mixture of [P43] (288 mg, 1.2 mmol), DIPEA (0.3 mL, 1.5 eq), TBTU (0.4 g, 1.2 mmol), and DMF (7 mL) was stirred overnight. The reaction mixture was diluted with water (10 mL), the precipitate was filtered and dried to give 800 mg [P101]. LCMS(ESI+)m / z 833[M+H]+. 4-Cyano-2-(4-{[(2-methoxybenzyl)(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrole-2-yl)benzoic acid ( [P105])

[0490] [, Preparation 102. , ] methyl 4-cyano-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrole-2-yl)benzoate ( [P102]). A mixture of 1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrolo-3-methylamine (0.0g, 0.83mmol), methyl 2-bromo-5-cyanobenzoate (400mg, 1.66mol), K3PO4 (880g, 4.2mmol), trimethylacetic acid (254g, 0.25mmol), and PdCl2(PPh3)2 (1.2g, 0.17mmol) in N,N-dimethylacetamide (10mL) was heated to 135°C. The resulting mixture was stirred at 135°C for 30 minutes, and then the reaction mixture was cooled to ambient temperature. After the reaction was complete, the mixture was diluted with water (30mL) and Et2O (30mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 140 mg (33%) of the title compound. LCMS (ESI+) m / z 520 [M+H]+.

[0491] [, Preparation 103., ] 4-Cyano-2-(1,5-Dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrole-2-yl)benzoic acid ( [P103]). At ambient temperature, A solution of [P102] (140 mg, 0.27 mmol) and NaOH (54 mg, 1.4 mmol) in a mixture of EtOH (10 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (10 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 120 mg (88%) of the title compound, which was sufficiently pure for the next step. LCMS (ESI+) m / z 506 [M+H]+.

[0492] [, Prepare 104. , ] 5-(5-cyano-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P104]). At 60℃, [P103] (120 mg, 0.24 mmol) A mixture of [P43] (65 mg, 0.28 mmol), DIPEA (0.06 mL, 0.35 mmol), TBTU (90 mg, 0.28 mmol), and DMF (10 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 140 mg (82%) of the title compound. LCMS (ESI+) m / z 719 [M+H]+.

[0493] [, Preparation 105. , ] 4-Cyano-2-(4-{[(2-methoxybenzyl)(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrole-2-yl)benzoic acid ( [P105]). At 50℃, A mixture of [P104] (140 mg, 0.19 mmol), tert-BuOK (87 mg, 0.8 mmol), and tert-BuOH (20 mL) was stirred for 30 minutes, followed by the addition of 1-(chloromethyl)-2-methoxybenzene (60 mg, 0.4 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 110 mg (94%) of the title compound. LCMS (ESI+) m / z 863 [M+H]+. N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(5-(methylsulfonylurea)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine) [P109])

[0494] [, Preparation 106. , ] N 3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N 3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine ( [P106]). A mixture of 1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrolo-3-methylamine (0.85 g, 2.3 mmol), tert-BuOK (1 g, 8.9 mmol), and tert-BuOH (10 mL) was stirred at 60 °C, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (1.1 g, 4.4 mmol). The reaction mixture was stirred at 60 °C for 3 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 0.95 g (82%) of the title compound. LCMS (ESI+) m / z 495 [M+H]+.

[0495] [, Preparation 107. , ] 2-(4-{[(3-methoxy-2-methylbenzyl)(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrole-2-yl)-4-(methylsulfonylurea)benzoate ( [P107]). Will A mixture of [P106] (0.3 g, 0.6 mmol), methyl 2-bromo-4-chloro-5-cyanobenzoate (0.3 g, 1.2 mmol), K3PO4 (0.58 g, 2.7 mmol), trimethylacetic acid (17 mg, 0.3 eq), and PdCl2(PPh3)2 (77 mg, 0.2 eq) in N,N-dimethylacetamide (10 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 minutes, and then the reaction mixture was cooled to ambient temperature. After the reaction was complete, the mixture was diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 200 mg (48%) of the title compound. LCMS(ESI+)m / z 706[M+H]+.

[0496] [, Preparation 108. , ] 2-(4-{[(3-methoxy-2-methylbenzyl)(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrole-2-yl)-4-(methylsulfonylurea)benzoic acid ( [P108]). At ambient temperature, A solution of [P107] (200 mg, 0.28 mmol) and LiOH (32 mg, 1.4 mmol) in a mixture of THF (2 mL) and water (0.2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (2 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 180 mg (92%) of the title compound, which was sufficiently pure for the next step. LCMS (ESI+) m / z 692 [M+H]+.

[0497] [, Preparation 109. , ] N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(5-(methylsulfonylurea)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P109]). At 60℃, [P108] (180 mg, 0.26 mmol) A mixture of [P43] (72 mg, 0.3 mol), DIPEA (0.07 mL, 0.4 mmol), TBTU (100 mg, 0.3 mmol), and DMF (2 mL) was stirred overnight. The reaction mixture was diluted with water (4 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 160 mg of crude compound, which was sufficiently pure for the next step. LCMS (ESI+) m / z 908 [M+H]+. 1-(tetrahydro-2H-piperan-2-yl)-1H-indazole-6-amine [P111])

[0498] [, Preparation of 110. , ] 6-nitro-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole ( [P110]). p-Toluenesulfonic acid (1.06 g, 6 mmol) was added to a stirred solution of 6-nitro-1H-indazole (10.0 g, 0.06 mol) and dihydropiperanone (15.5 g, 0.18 mol) in DCM (250 mL). After stirring the mixture for 8 hours at room temperature, it was diluted with DCM (100 mL), washed with saturated sodium bicarbonate solution, and purified by column chromatography (DCM:hexane = 1:2-1:1) to give 11.6 g (76%) of the title compound as a pale yellow precipitate.

[0499] [, Preparation 111. , ] 1-(tetrahydro-2H-piperan-2-yl)-1H-indazole-6-amine ( [P111]). Will [P110] (11.6 g, 0.47 mol) was dissolved in ethanol (300 mL). Pd / C (1.1 g, 10% w / w) was added and the mixture was stirred for 3 hours under 20 bar hydrogen. The catalyst was removed by filtration and the solution was evaporated under reduced pressure to give 10 g (98%) of the title compound. 1H NMR (400MHz, CDCl3), δ: 7.74 (s, 1H), 7.36 (d, 1H, J = 4Hz,) 6.61 (s, 1H), 6.53 (d, 1H, J = 4.4Hz), 5.53 (d, 1H, J = 3.8Hz), 5.34 (s, 1H), 3. 87(d,1H,J=6Hz),3.68-3.62(m,1H),2.42-2.32(m,1H),2.03-1.99(m,1H),1.92-1.88(m,1H),1.75-1.66(m,1H),1.57-1.52(m,1H). 1,2-Dimethyl-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P112])

[0500] [, Preparation of 112. , ] 1,2-Dimethyl-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P112]). Towards [P14](7.1g, 50.2mmol), [P111] (8.9 g, 40.1 mmol), DMAP (7.5 g, 60.1 mmol), and Et3N (20 g, 28.5 mL, 0.2 mol) were added to a stirred solution of DCM (50 mL) with EDC*HCl (11.7 g, 60.1 mmol). The reaction mixture was stirred overnight at ambient temperature. After the reaction was complete (monitored by LCMS), the mixture was quenched with water (100 mL), the organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 8.4 g (60%) of the title compound. N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P116])

[0501] [, Preparation of 113. , ] N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P113]). At 50℃, A mixture of [P112] (1.5 g, 4.4 mmol), tert-BuOK (1.98 g, 17.6 mmol), and tert-BuOH (12 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (1.5 g, 8.8 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 1.64 g (78%). [P113]. LCMS(ESI+)m / z 473[M+H]+.

[0502] [, Preparation of 114. , ] 2-[4-({(3-methoxy-2-methylbenzyl)[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-4-nitrobenzoate ( [P114]). At 130℃, A mixture of [P113] (800 mg, 1.7 mmol), ethyl 2-bromo-4-nitrobenzoate (0.93 mg, 3.4 mmol), K3PO4 (1.4 g, 6.8 mmol), trimethylacetic acid (52 mg, 0.51 mmol), and PdCl2(PPh3)2 (151 mg, 0.34 mmol) in N,N-dimethylacetamide (15 mL) was stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (25 mL) and EtOAC (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 300 mg (27%) of the title compound. LCMS (ESI+) m / z 652 [M+H]+.

[0503] [, Preparation 115. , ] 2-[4-({(3-methoxy-2-methylbenzyl)[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-4-nitrobenzoic acid ( [P115]). At ambient temperature, A solution of [P114] (330 mg, 0.5 mmol) and NaOH (55 mg, 1.5 mmol) in a mixture of MeOH / H2O was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 170 mg (53%) of the title compound, which was pure enough for use in the next step.

[0504] [, Preparation of 116. ] N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P116]). At 60℃, [P115] (170 mg, 0.26 mmol) A mixture of [P43] (68 mg, 0.28 mmol), DIPEA (0.07 mL, 0.39 mmol), TBTU (94 mg, 0.28 mmol), and DMF (5 mL) was stirred overnight. The reaction mixture was diluted with water (10 mL), the precipitate was filtered and dried to give 230 mg of crude product. LCMS (ESI+) m / z 853 [M+H]+. N-(2-methoxybenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine

[0505] [, Preparation 117. , ] N-(2-methoxybenzyl)-1,2-dimethyl-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P117]). At 50℃, A mixture of [P112] (1.2 g, 3.5 mmol), tert-BuOK (1.6 g, 14.0 mmol), and tert-BuOH (12 mL) was stirred for 30 minutes, followed by the addition of 2-methoxybenzyl chloride (1.1 g, 7.0 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 0.6 g (37%). [P117]. LCMS(ESI+)m / z 459[M+H]+.

[0506] [, Preparation of 118. , ] 2-[4-({(2-methoxybenzyl)[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-nitrobenzoate ( [P118]). At 130℃, A mixture of [P117] (600 mg, 1.3 mmol), ethyl 2-bromo-4-nitrobenzoate (0.71 mg, 2.6 mmol), K3PO4 (1.1 g, 5.2 mmol), trimethylacetic acid (40 mg, 0.39 mmol), and PdCl2(PPh3)2 (174 mg, 0.26 mmol) in N,N-dimethylacetamide (15 mL) was stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (25 mL) and EtOAC (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 700 mg (83%) of the title compound. LCMS (ESI+) m / z 638 [M+H]+.

[0507] [, Preparation of 119. , ] 2-[4-({(2-methoxybenzyl)[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-4-nitrobenzoic acid ( [P119]). At ambient temperature, a solution of ethyl 2-[4-({(2-methoxybenzyl)[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-nitrobenzoate (700 mg, 1.1 mmol) and NaOH (440 mg, 11.0 mmol) in a mixture of MeOH / H₂O was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na₂SO₄ and evaporated to dryness under reduced pressure to give 300 mg (44%) of the title compound, which was sufficiently pure for further use in the next step.

[0508] [, Preparation 120. ] N-(2-methoxybenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P120]). At 60℃, [P119] (300mg, 0.48mmol) A mixture of [P43] (123 mg, 0.96 mmol), DIPEA (0.125 mL, 1.43 mmol), TBTU (174 mg, 0.72 mmol), and DMF (15 mL) was stirred overnight. The reaction mixture was diluted with water (100 mL), the precipitate was filtered and dried to give 350 mg of crude product. LCMS (ESI+) m / z 838 [M+H]+. N-(2-cyanophenylmethyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P124])

[0509] [, Preparation of 121. , ] N-(2-cyanophenylmethyl)-1,2-dimethyl-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P121]). At 50℃, A mixture of [P112] (1.5 g, 4.4 mmol), tert-BuOK (1.9 g, 17.6 mmol), and tert-BuOH (12 mL) was stirred for 30 minutes, followed by the addition of 2-(bromomethyl)benzonitrile (1.7 g, 8.8 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 1.0 g (49%). [P121]. LCMS(ESI+)m / z 454[M+H]+.

[0510] [, Preparation of 122. , ] 2-[4-({(2-cyanophenylmethyl)[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-nitrobenzoate ( [P122]). At 130℃, A mixture of [P121] (1 g, 2.2 mmol), ethyl 2-bromo-4-nitrobenzoate (1.2 g, 4.4 mmol), K3PO4 (1.8 g, 8.8 mmol), trimethylacetic acid (67 mg, 0.66 mmol), and PdCl2(PPh3)2 (250 mg, 0.44 mmol) in N,N-dimethylacetamide (25 mL) was stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (25 mL) and EtOAC (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 500 mg (36%) of the title compound. LCMS (ESI+) m / z 633 [M+H]+.

[0511] [, Preparation 123. , ]2-[4-({(2-cyanophenylmethyl)[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-4-nitrobenzoic acid ( [P123]). At ambient temperature, A solution of [P122] (500 mg, 0.8 mmol) and NaOH (340 mg, 9.0 mmol) in a mixture of MeOH / H2O was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 50 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 440 mg (94%) of the title compound, which was pure enough for further use in the next step.

[0512] [, Preparation of 124. ] N-(2-cyanophenylmethyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-[1-(tetrahydro-2H-piperan-2-yl)-1H-indazol-6-yl]-1H-pyrrole-3-methylamine ( [P124]). At 60℃, [P123] (440 mg, 0.71 mmol) A mixture of [P43] (182 mg, 0.81 mmol), DIPEA (0.186 mL, 1.13 mmol), TBTU (251 mg, 0.82 mmol), and DMF (15 mL) was stirred overnight. The reaction mixture was diluted with water (100 mL), the precipitate was filtered and dried to give 350 mg of crude product. LCMS (ESI+) m / z 833 [M+H]+. 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine) [P127])

[0513] [, Preparation at 125°C. , ] methyl 4-chloro-2-(4-{[(4-cyanophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrolo-2-yl)-5-fluorobenzoate ( [P125]). Will A mixture of [P13] (250 mg, 1.0 mmol), methyl 2-bromo-4-chloro-5-fluorobenzoate (560 mg, 2.0 mmol), K3PO4 (1.1 g, 5.2 mmol), trimethylacetic acid (32 mg, 0.3 mmol), and PdCl2(PPh3)2 (147 mg, 0.2 mmol) in N,N-dimethylacetamide (3 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 minutes, and then the reaction mixture was cooled to ambient temperature. After the reaction was complete, the mixture was diluted with water (10 mL) and Et2O (10 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 100 mg (23%) of the title compound. LCMS(ESI+)m / z 426[M+H]+.

[0514] [, Preparation of 126. , ] 4-Chloro-2-(4-{[(4-cyanophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrolo-2-yl)-5-fluorobenzoic acid ( [P126]). At ambient temperature, A solution of [P125] (100 mg, 0.2 mmol) and LiOH (28 mg, 1.2 mmol) in a mixture of THF (10 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 80 mg (82%) of the title compound, which was sufficiently pure for use in the next step. LCMS (ESI+) m / z 413 [M+H]+.

[0515] [, Preparation 127. , ] 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P127]). At 60℃, [P126] (80 mg, 0.05 mmol) A mixture of [P43] (54 mg, 0.23 mmol), DIPEA (0.050 mL, 0.3 mmol), TBTU (75 mg, 0.23 mmol), and DMF (5 mL) was stirred overnight. The reaction mixture was diluted with water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 90 mg (75%) of the title compound. LCMS (ESI+) m / z 627 [M+H]+. 2-(4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrolo-2-yl)-5-cyano-4-methoxybenzoic acid [P130])

[0516] [, Preparation 128., ] 2-(4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrolo-2-yl)-5-cyano-4-hydroxybenzoate methyl ester ( [P128]). At 135℃, [P73](1.3g, 5.2mmol), A mixture of [P77] (2.7 g, 10.4 mmol), K3PO4 (5.5 g, 26.0 mmol), and trimethylacetic acid (0.16 g, 1.5 mmol) in N,N-dimethylacetamide (50 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.9 g, 1.02 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (70 mL) and EtOAC (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 800 mg (36%) of the title compound.

[0517] [, Preparation 129. , ] 2-(4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrolo-2-yl)-5-cyano-4-methoxybenzoate methyl ester ( [P129]). methyl A suspension of [P128] (0.86 g, 2.03 mmol) and K2CO3 (0.42 g, 3.0 mmol) in DMF (6 ml) was treated with CH3I (0.46 g, 3.2 mmol). The mixture was stirred overnight at room temperature, and the reaction mixture was poured into cold water. The resulting precipitate was filtered, washed with water and Et2O, and air-dried to give 300 mg (34%) of the title compound.

[0518] [, Prepare 130. , ] 2-(4-{[(4-chlorophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrolo-2-yl)-5-cyano-4-methoxybenzoic acid ( [P130]). At ambient temperature, A solution of [P129] (100 mg, 0.223 mmol) and LiOH (55 mg, 2.23 mmol) in a mixture of THF (8 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 90 mg (93%) of the title compound, which was pure enough for further use in the next step. N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P131])

[0519] [, Preparation of 131. , ] N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P131]). At 60℃, [P130] (150 mg, 0.31 mmol) A mixture of [P43] (86 mg, 0.37 mmol), DIPEA (0.08 mL, 0.46 mmol), TBTU (118 mg, 0.37 mmol), and DMF (8 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 50 mg (23%) of the title compound. methyl 2-bromo-4-cyanobenzoate ( [P132])

[0520] [, Preparation of 132. , ] Methyl 2-bromo-4-cyanobenzoate ( [P132]). Zn(CN)₂ (0.329 g, 0.0028 mol) and Pd(Ph₃P)₄ (0.325 g, 0.1 eq) were added to a stirred solution of methyl 2-bromo-4-(iodomethyl)benzoate (1 g, 0.0028 mol) in DMF (10 mL). The reaction mixture was then stirred overnight at 100 °C and treated with water (20 mL), followed by extraction with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of DCM:CCl₄ to give 670 mg (99%) of the title compound. 1H NMR (400MHz, CDCl3), δ: 7.97 (s, 1H), 7.88 (dd, J = 2.3Hz, J = 8.0Hz, 1H), 7.68 (dd, J = 2.4Hz, J = 8.1Hz, 1H), 3.98 (s, 3H). 2-(4-[4-(benzyloxy)anilino]carbonyl-1,5-dimethyl-1H-pyrrolo-2-yl)-4-cyanobenzoic acid [P134])

[0521] [, Preparation of 133. , ] 2-(4-[4-(benzoxy)anilino]carbonyl-1,5-dimethyl-1H-pyrrolo-2-yl)-4-cyanobenzoate ( [P133]). At 130℃, [P15](300mg, 0.9mmol) A mixture of [P132] (450 mg, 1.8 mmol), K3PO4 (993 mg, 5 eq), trimethylacetic acid (29 mg, 0.3 eq), and PdCl2(PPh3)2 (131 mg, 0.2 eq) in N,N-dimethylacetamide (15 mL) was stirred for 2 hours. After the reaction was complete, the mixture was diluted with water (25 mL) and EtOAC (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 266 mg (59%). [P133]. LCMS(ESI+)m / z 480[M+H]+.

[0522] [, Preparation of 134. , ] 2-(4-[4-(benzoxy)anilino]carbonyl-1,5-dimethyl-1H-pyrrole-2-yl)-4-cyanobenzoic acid ( [P134]). At ambient temperature, the ester A solution of [P133] (290 mg, 0.6 mmol) and LiOH (150 mg, 10 eq) in a mixture of THF / H2O was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (3 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 5 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 280 mg (99%) title acid. [P134], which is pure enough to be used in the next step. LCMS(ESI+)m / z 466[M+H]+. N 3-[4-(benzyloxy)phenyl]-5-(5-cyano-2-[3-(N- (-3,4-dihydro-2(1H)-isoquinolinyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P135])

[0523] [, Prepare 135. , ] N 3-[4-(benzyloxy)phenyl]-5-(5-cyano-2-[3-(N- (-3,4-dihydro-2(1H)-isoquinolinyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P135]). At 60℃, acid [P134] (280 mg, 0.6 mmol) A mixture of [P43] (0.14 g, 0.66 mmol), DIPEA (0.14 mL, 1.5 eq), TBTU (0.199 g, 0.66 mmol), and DMF (4 mL) was stirred overnight. The reaction mixture was diluted with water (6 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 221 mg (54%) of the title compound. LCMS (ESI+) m / z 680 [M+H]+. 5-(5-cyano-2-[3-(N-) [Pyrrolylmethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl]-N-3-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P136])

[0524] [, Preparation of 136. , ] N 3-[4-(benzyloxy)phenyl]-5-(5-cyano-2-[3-(N- (-3,4-dihydro-2(1H)-isoquinolinyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P136]). compound The solution of [P135] (220 mg, 0.3 mmol) in DCM (5 mL) was cooled to -78 °C and a solution of BBr3 (0.09 mL, 0.6 mmol) was added over 5 minutes. The reaction mixture was stirred at -78 °C for 1 hour and then diluted with a saturated aqueous solution of sodium bicarbonate (NaHCO3). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in an EtOAc mixture to give 202 mg (98%) of the title compound. LCMS (ESI+) m / z 590 [M+H]+. 5-(5-cyano-2-[3-(N-) (-3,4-dihydro-2(1H)-isoquinolinyl)carbonylphenyl)-1,2-dimethyl-N3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine) [P137])

[0525] [, Preparation of 137. , ] 5-(5-cyano-2-[3-(N- (-3,4-dihydro-2(1H)-isoquinolinyl)carbonylphenyl)-1,2-dimethyl-N3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine) [P137]). Add NaH (16 mg, 60%) to maintain the temperature at 0°C. [P136] (200 mg, 0.3 mmol) was added to a stirred solution in DMF (5 mL) and stirred for 30 minutes. Then, [2-(chloromethoxy)ethyl](trimethyl)silane (0.1 mL, 0.45 mmol) was added. The reaction mixture was stirred overnight at ambient temperature and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 123 mg (50%) of the title compound. LCMS (ESI+) m / z 720 [M+H]+. 5-(5-cyano-2-[3-(N-) [[2-(1,1,1-trimethylsilyl)ethoxy]carbonylphenyl]-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine] [P138])

[0526] [, Preparation of 138. , ] 5-(5-cyano-2-[3-(N- [3,4-(1H)-isoquinolinyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine] [P138]). At 50℃, A mixture of [P137] (120 mg, 0.16 mmol), tert-BuOK (80 mg, 4 eq), and tert-BuOH (3 mL) was stirred for 5 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (80 mg, 2 eq). The reaction mixture was stirred at 80 °C for 0.5 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 50 mg [P138]. LCMS(ESI+)m / z 854[M+H]+. 5-(5-(aminocarbonyl)-2-[3-(N-) [3,4-(1H)-isoquinolinyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine] [P139])

[0527] [, Preparation of 139. , ] 5-(5-(aminocarbonyl)-2-[3-(N- [3,4-(1H)-isoquinolinyl)-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N3-(4-[2-(1,1,1-trimethylsilyl)ethoxy]methoxyphenyl)-1H-pyrrole-3-methylamine] [P139]). At 50℃, A mixture of [P138] (120 mg, 0.16 mmol), tert-BuOK (80 mg, 4 eq), and tert-BuOH (3 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (80 mg, 2 eq). The reaction mixture was stirred at 60 °C for 3 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 70 mg of the compound. [P139]. LCMS(ESI+)m / z 872[M+H]+. 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine) [P142])

[0528] [, Prepare 140. , ] N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P140]). At 0℃, towards [P13] (1.0 g, 7.2 mmol) was added dropwise to a stirred solution of pyridine (5 mL) with pure SOCl2 (0.55 mL, 7.6 mmol), and the reaction mixture was stirred at 0 °C for 3 hours. Then, aminobenzonitrile (0.85 g, 7.2 mmol) was added dropwise to DIPEA (1.4 mL, 7.96 mmol) while maintaining the temperature at 0 °C. The reaction was heated to ambient temperature and then stirred at ambient temperature for 16 hours. Volatile substances were removed under reduced pressure. The residue was diluted with water and Et2O. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 850 mg (50%) of the title compound. 1H NMR (400MHz, DMSO-d 6), δ: 9.70 (br.s, 1H), 7.95 (d, 1H, J = 8.7Hz,), 7.73 (d, 1H, J = 8.7Hz), 6.73-6.64 (m, 1H), 3.54 (s, 3H), 2.47 (s, 3H). LCMS(ESI+)m / z 240[M+H]+.

[0529] [, Preparation of 141. , ] 4-Chloro-2-(4-{[(4-cyanophenyl)amino]carbonyl}-1,5-dimethyl-1H-pyrrole-2-yl)benzoic acid ( [P141]). At ambient temperature, A solution of [P140] (200 mg, 0.47 mmol) and LiOH (54 mg, 2.4 mmol) in a mixture of EtOH (10 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 180 mg (96%) of the title compound, which was sufficiently pure for the next step. LCMS (ESI+) m / z 394 [M+H]+.

[0530] [, Preparation of 142. , ] 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine( [P142]). At 60℃, [P141] (180 mg, 0.45 mmol) A mixture of [P43] (127 mg, 0.55 mmol), DIPEA (0.12 mL, 0.69 mmol), TBTU (176 mg, 0.55 mmol), and DMF (5 mL) was stirred overnight. The reaction mixture was diluted with water (200 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 170 mg (61%) of the title compound. LCMS (ESI+) m / z 609 [M+H]+. N-(2-cyanophenylmethyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine [P146])

[0531] [, Preparation 143., ] methyl 2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrolo-2-yl)-4-nitrobenzoate ( [P143]). A mixture of 1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrolo-3-methylamine (500 g, 1.4 mmol), methyl 2-bromo-4-nitrobenzene (720 mg, 2.8 mol), K3PO4 (1.47 g, 6.9 mmol), trimethylacetic acid (42 mg, 0.4 mmol), and PdCl2(PPh3)2 (194 mg, 0.28 mmol) in N,N-dimethylacetamide (50 mL) was heated to 135 °C. The resulting mixture was stirred at 135 °C for 30 minutes, and then the reaction mixture was cooled to ambient temperature. After the reaction was complete, the mixture was diluted with water (50 mL) and Et2O (50 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 40 mg (59%) of the title compound. LCMS (ESI+) m / z 540 [M+H]+.

[0532] [, Preparation of 144. , ] 2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrolo-2-yl)-4-nitrobenzoic acid ( [P144]). At ambient temperature, A solution of [P143] (440 mg, 0.8 mmol) and NaOH (162 mg, 4.0 mmol) in a mixture of EtOH (40 mL) and water (5 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (50 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 400 mg (94%) of the title compound, which was sufficiently pure for the next step. LCMS (ESI+) m / z 525 [M+H]+.

[0533] [, Preparation 145., ] 1,2-Dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P145]). At 60℃, [P144] (400mg, 0.76mmol) A mixture of [P43] (210 mg, 0.9 mmol), DIPEA (0.2 mL, 1.15 mmol), BTU (290 mg, 0.9 mmol), and DMF (10 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 450 mg (80%) of the title compound. LCMS (ESI+) m / z 740 [M+H]+.

[0534] [, Preparation of 146. ] N-(2-cyanophenylmethyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine ( [P146]). At 50℃, A mixture of [P146] (150 mg, 0.2 mmol), tert-BuOK (87 mg, 0.8 mmol), and tert-BuOH (20 mL) was stirred for 30 minutes, followed by the addition of 2-(bromomethyl)benzonitrile (80 mg, 0.4 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 120 mg (70%) of the title compound. LCMS (ESI+) m / z 856 [M+H]+. N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine) [P147])

[0535] [, Preparation 147. , ] N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P146]). At 50℃, A mixture of [P145] (200 mg, 0.27 mmol), tert-BuOK (120 mg, 1.1 mmol), and tert-BuOH (20 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (124 mg, 0.54 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 210 mg (89%) of the title compound. LCMS (ESI+) m / z 875 [M+H]+. 5-(5-(acetylamino)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine) [P149])

[0536] [, Preparation 148., ] 5-(5-amino-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P148]). Will A stirred mixture of [P145] (200 mg, 0.2 mmol), catalyst (5 mg of 5% palladium / charcoal), and tert-butanol (2 mL) was hydrogenated at 20 atm in H2 for 56 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness to give 180 mg (93%) of the title compound.

[0537] [, Preparation 149. , ] 5-(5-(acetylamino)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P149]). At ambient temperature, A mixture of [P148] (180 mg, 0.21 mmol), Ac2O (22 mg, 0.21 mmol), and DCM (2 mL) was stirred for 3 hours and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 150 mg (80%) of the title compound. LCMS (ESI+) m / z 887 [M+H]+. 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4,5-difluorobenzoic acid ( [P151])

[0538] [, Prepare 150., ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-4,5-difluorobenzoate ( [P150]). At 135 °C, N-[4-(benzyloxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-methylamine was... A mixture of [P15] (500 mg, 1.6 mmol), methyl 2-bromo-4,5-difluorobenzoate (785 mg, 3.1 mmol), K3PO4 (1.6 g, 7.8 mmol), and trimethylacetic acid (50 mg, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.22 g, 0.3 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (20 mL) and EtOAC (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 400 mg (53%) of the title compound.

[0539] [, Preparation 151. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-4,5-difluorobenzoic acid ( [P151]). At ambient temperature, A solution of [P150] (400 mg, 0.8 mmol) and NaOH (165 mg, 4.0 mmol) in a mixture of MeOH (10 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 380 mg (98%) of the title compound, which was pure enough for further use in the next step. N-[4-(benzomethoxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P152])

[0540] [, Preparation 152. , ] N-[4-(benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P152]). At 60℃, [P151] (380 mg, 0.8 mmol) A mixture of [P43] (220 mg, 0.95 mmol), DIPEA (0.2 mL, 1.2 mmol), TBTU (300 mg, 0.95 mmol), and DMF (5 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 300 mg (55%) of the title compound. N-[4-(benzomethoxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P153])

[0541] [, Preparation 153. ] N-[4-(benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P153]). At 50℃, A mixture of [P152] (100 mg, 0.14 mmol), tert-BuOK (65 mg, 0.56 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (67 mg, 0.28 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 70 mg (58%) of the title compound. N-[4-(benzomethoxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P154])

[0542] [, Prepare 154. ] N-[4-(benzyloxy)phenyl]-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P154]). At 50℃, A mixture of [P152] (100 mg, 0.14 mmol), tert-BuOK (65 mg, 0.56 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 2-(bromomethyl)benzonitrile (57 mg, 0.28 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 100 mg (86%) of the title compound. (4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amine [P156])

[0543] [, Prepare 155. , ] Trimethyl{2-[(4-nitrophenoxy)methoxy]ethyl}silane ( [P155]). At 0°C, SemCl (100 mL, 0.40 mol, 70%) was added dropwise to a stirred solution of 4-nitrophenol (50.0 g, 0.36 mol) and Et3N (78 mL, 0.54 mol) in DCM (500 mL), and the reaction mixture was stirred at 0°C for 30 minutes. The reaction was then heated to ambient temperature and stirred at ambient temperature for 4 hours. Water was added, and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The residue was used in the next step without further purification or separation.

[0544] [, Preparation of 156. , ] 4-{[2-(trimethylsilyl)ethoxy]methoxy}aniline ( [P156]). Will [P155] (97 g, 0.36 mol) was dissolved in ethanol (1000 mL). Pd / C (5.0 g, 10% w / w) was added and the mixture was stirred at 20 bar hydrogen for 3 hours. The catalyst was removed by filtration and the solution was evaporated under reduced pressure. The residue was subjected to silica gel rapid chromatography and precipitated with a mixture of EtOAc (0→10%) and DCM to give 60 g (70%) of the title compound. ¹H NMR (400 MHz, CDCl₃), δ: 6.90–6.89 (m, 4H), 6.73–6.56 (m, 4H), 5.13 (s, 2H), 3.82–3.69 (m, 2H), 3.59–3.19 (m, 2H), 1.03–0.90 (m, 2H), 0.08–0.07 (m, 9H). 1,2-Dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine ( [P157])

[0545] [, Preparation 157., ] 1,2-Dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine ( [P157]). At 0℃, towards [P14] (45.0 g, 0.32 mol) was added dropwise to a stirred solution of pyridine (500 mL) and pure SOCl2 (28 mL, 0.39 mol) was added dropwise. The reaction mixture was stirred at 0 °C for 3 hours. Then, it was added dropwise to Et3N (117 mL, 0.8 mol). [P156] (61.8 g, 0.26 mmol), while maintaining the temperature at 0 °C. The reaction was heated to ambient temperature and then stirred at ambient temperature for 16 hours. Volatile substances were removed under reduced pressure. The residue was diluted with water and Et2O. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 48 g (42%) of the title compound. 1H NMR (400MHz, DMSO-d 6 ),δ:9.21(s,1H),7.91(d,J=9.0Hz,1H),7.76-7.65(m,3H),6.65(dd,J=13.8,3.0Hz,1H),6.96-9.62(m,2H ),6.70(s,1H),5.16(s,2H),3.75-3.61(m,5H),3.24(s,3H),2.46(s,3H),0.98-0.80(m,2H),0.00(s,9H). LCMS(ESI+)m / z 361[M+H]+. 5-Chloro-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrolo-2-yl)-3-methylbenzoic acid [P159])

[0546] [, Preparation 158. , ] methyl 5-chloro-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrolo-2-yl)-3-methylbenzoate ( [P158]). At 135℃, A mixture of [P157] (0.5 g, 1.38 mmol), methyl 2-bromo-5-chloro-3-methylbenzoate (0.7 g, 2.76 mmol), K3PO4 (1.18 g, 5.6 mmol), and trimethylacetic acid (0.04 g, 0.4 mmol) in N,N-dimethylacetamide (10 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (0.25 g, 0.1 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (70 mL) and EtOAC (120 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 200 mg (26%) of the title compound.

[0547] [, Preparation 159. , ] 5-Chloro-2-(1,5-dimethyl-4-{[(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)amino]carbonyl}-1H-pyrrolo-2-yl)-3-methylbenzoic acid ( [P159]). At ambient temperature, A solution of [P158] (200 mg, 0.136 mmol) and LiOH (88 mg, 1.36 mmol) in a mixture of THF (8 mL) and water (2 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 190 mg (97%) of the title compound, which was pure enough for further use in the next step. 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine) [P160])

[0548] [, Prepare 160., ] 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P160]). At 60℃, [P159] (190 mg, 0.378 mmol) A mixture of [P43] (105 mg, 0.42 mmol), DIPEA (0.098 mL, 0.56 mmol), TBTU (146 mg, 0.42 mmol), and DMF (15 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 200 mg (72%) of the title compound. 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine) [P161])

[0549] [, Preparation of 161. , ] 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P161]). At 50℃, A mixture of [P160] (80 mg, 0.112 mmol), tert-BuOK (51 mg, 0.448 mmol), and tert-BuOH (9 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (53 mg, 0.224 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 30 mg (21%). 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine) [P162])

[0550] [, Preparation of 162. , ] 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-N-(4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-1H-pyrrole-3-methylamine( [P162]). At 50℃, A mixture of [P160] (80 mg, 0.112 mmol), tert-BuOK (48 mg, 0.448 mmol), and tert-BuOH (9 mL) was stirred for 30 minutes, followed by the addition of 2-methoxybenzyl methanesulfonate (34 mg, 0.224 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 30 mg (21%). methyl 2-bromo-4-fluorobenzoate ( [P163])

[0551] [, Preparation 163. , ] Methyl 2-bromo-4-fluorobenzoate ( [P163]). At 0℃, towards [P74] (2.2 g, 13.92 mmol) and tributyl nitrite (2.59 g, 25.06 mmol) in acetonitrile (50 ml) were reacted with CuBr2 (5.69 g, 25.06 mmol) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the residue was subjected to rapid silica gel chromatography after evaporation under reduced pressure. The residue was dissolved in DCM to give (1.4 g, 47%) the title compound. LCMS (ESI+) m / z 234 [M+H]+. 1H NMR (400 MHz, CDCl3), δ: 7.87 (t, J = 6.8 Hz, 1H), 7.74 (d, J = 5.4 Hz, 1H), 7.39 (t, J = 8.8 Hz, 1H), 3.85 (s, 3H). 2-[4-({[4-(benzyloxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-fluorobenzoic acid [P165])

[0552] [, Prepare 164. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrolo-2-yl]-4-fluorobenzoate ethyl ester ( [P164]). At 135℃, [P15] (500mg, 1.56mmol), A mixture of [P163] (728 mg, 3.12 mmol), K3PO4 (1.32 g, 6.24 mmol), and trimethylacetic acid (47 mg, 0.38 mmol) in N,N-dimethylacetamide (30 mL) was stirred for 15 minutes, followed by the addition of PdCl2(PPh3)2 (250 mg, 0.31 mmol). The resulting mixture was stirred at 135 °C for 30 minutes. After the reaction was complete, the mixture was diluted with water (50 mL) and EtOAc (50 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 215 mg (31%) of the title compound.

[0553] [, Prepare 165. , ] 2-[4-({[4-(benzoxy)phenyl]amino}carbonyl)-1,5-dimethyl-1H-pyrrole-2-yl]-4-fluorobenzoic acid ( [P165]). At ambient temperature, A solution of [P164] (215 mg, 0.45 mmol) and LiOH (109 mg, 4.5 mmol) in a mixture of THF (16 mL) and water (4 mL) was stirred for 12 hours. Volatile substances were removed under reduced pressure, and water (20 mL) was added to the residue. The solution was acidified to pH 1 with 6 M HCl and extracted with DCM (2 × 10 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure to give 116 mg (55%) of the title compound, which was pure enough for further use in the next step. N-[4-(benzomethoxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P166])

[0554] [, Prepare 166. , ] N-[4-(benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P166]). At 60℃, [P165] (116 mg, 0.25 mmol) A mixture of [P43] (71 mg, 0.35 mmol), DIPEA (0.066 mL, 0.75 mmol), TBTU (97 mg, 0.35 mmol), and DMF (15 mL) was stirred overnight. The reaction mixture was diluted with water (20 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 100 mg (59%) of the title compound. N-[4-(benzomethoxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P167])

[0555] [, Preparation 167. , ] N-[4-(benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P167]). At 50℃, A mixture of [P166] (35 mg, 0.052 mmol), tert-BuOK (23 mg, 0.208 mmol), and tert-BuOH (9 mL) was stirred for 30 minutes, followed by the addition of 2-methoxybenzyl chloride (16 mg, 0.104 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 33 mg (81%). N-[4-(benzomethoxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [P168])

[0556] [, Preparation of 168. , ] N-[4-(benzyloxy)phenyl]-5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [P168]). At 50℃, A mixture of [P166] (100 mg, 0.149 mmol), tert-BuOK (67 mg, 0.576 mmol), and tert-BuOH (15 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (69 mg, 0.298 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 33 mg (27%) of the title compound. [, Examples of compound (I) , ]

[0557] [, Example 1 , ]:3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-N-(2-cyanobenzyl)-5,6,7,8-tetrahydroindyl) -1-methamide ( [1]) At 50 °C, 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-5,6,7,8-tetrahydroindole) -1-methamide ( A mixture of [P6] (150 mg, 0.23 mmol), tert-BuOK (104 mg, 0.9 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 2-(bromomethyl)benzonitrile (91 mg, 0.46 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 154 mg (87%) of the title compound. [1]. 1H NMR (400MHz, DMSO-d 6 ), δ:7.93-7.35(m,8H),7.31-6.85(m,8H),5.37-4.92(m,4H),4.20-3.64(m,7H),3.55-3.24(m,6H),3.18-2.72(m,4H),1.79-0.88(m,4H). ESI LCMS[MH]+:758.

[0558] [, Example 2. , ] 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-N-(3-methoxy-2-methylbenzyl)-5,6,7,8-tetrahydroindyl) -1-methamide ( [2]) At 50 °C, 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-5,6,7,8-tetrahydroindole) -1-methamide ( A mixture of [P6] (150 mg, 0.23 mmol), tert-BuOK (104 mg, 0.9 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (107 mg, 0.46 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 60 mg (34%) of the title compound. [2]. 1H NMR (400MHz, DMSO-d 6 ), δ:7.61-7.26(m,3H),7.24-6.93(m,8H),6.89-6.73(m,2H),6.71-6.51(m,2H),5.43-4.98(m,2H),4.98-4.65(m,2H),4.28-3.88(m,2H ),3.84-3.68(m,4H),3.65-3.38(m,6H),3.04-2.78(m,2H),2.72-2.57(m,1H),2.38-2.25(m,2H),2.21-1.78(m,6H),1.76-1.36(m,4H). ESI LCMS[MH]+:777.

[0559] [, Example 3 , ]. 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-N-(4-hydroxyphenyl)-5,6,7,8-tetrahydroindyl) -1-methamide ( [3]) compound A solution of [P11] (180 mg, 0.22 mmol) in DCM (5 mL) was cooled to -78 °C, and BBr3 (108 mg, 0.43 mmol) in THF (1 mL) was added over 5 minutes. The reaction mixture was stirred at -78 °C for 1 hour and then diluted with a saturated sodium bicarbonate (NaHCO3) aqueous solution. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to give 73 mg (46%) of the title compound. [3]. 1H NMR(400MHz,DMSO-d 6), δ:9.60-9.26(m,1H),7.83-7.25(m,7H),7.21-6.79(m,5H),6.74-6.32(m,4H),5.39-4.71(m,4H),4.34-3.82(m,2 H),3.72-3.38(m,6H),3.14-2.77(m,2H),2.75-2.56(m,1H),2.41-2.25(m,2H),2.20-1.82(m,2H),1.80-1.33(m,6H). ESI LCMS[MH]+:740.

[0560] [, Example 4. , ] 3-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-5,6,7,8-tetrahydroindyl) -1- Methionine ( [4]) and N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-3-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-5,6,7,8-tetrahydroindyl -1-methamide ( [5]) In an H2 atmosphere, the compound A mixture of [P12] (200 mg), catalyst (10 mg of 5% palladium / charcoal), and methanol (2 mL) was hydrogenated for 2 hours with stirring. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was purified by HPLC to give 40 mg (22%) of the compound. [4] and 14 mg (8%) of the compound [5]. Compounds [4]:1H NMR(400MHz,DMSO-d 6 ), δ:9.49-9.13(m,1H),7.64-7.24(m,3H),7.24-6.71(m,8H),6.71-6.47(m,2H),6.47-6.24(m,2H),5.32-4.52(m,4H),4.28-3.89(m,2H ),3.86-3.68(m,3H),3.64-3.37(m,6H),3.08-2.82(m,2H),2.75-2.64(m,1H),2.39-2.23(m,2H),2.23-1.83(m,7H),1.78-1.39(m,4H). ESI LCMS[MH]+: 759. Compound [5]:1H NMR(400MHz,DMSO-d 6 ), δ:9.45-9.12(m,1H),7.55-7.32(m,3H),7.32-6.71(m,9H),6.70-6.45(m,3H),6.44-6.22(m,2H),5.27-4.49(m,4H),4.31-3 .94(m,2H),3.86-3.68(m,3H),3.68-3.37(m,6H),3.07-2.86(m,2H),2.79-2.56(m,1H),2.37-2.23(m,2H),2.15-1.36(m,10H). ESI LCMS[MH]+:725.

[0561] [, Example 5. , ] 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-cyanobenzyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [6]) will A solution of [P19] (100 mg, 0.12 mmol) in DCM (5 mL) was cooled to -78 °C, and BBr3 (62 mg, 0.25 mmol) in THF (1 mL) was added over 5 minutes. The reaction mixture was stirred at -78 °C for 1 hour and then diluted with a saturated sodium bicarbonate (NaHCO3) aqueous solution. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to give 60 mg (67%) of the title compound. [6]. 1H NMR (400MHz, DMSO-d 6 ), δ:9.59-9.26(m,1H),7.93-7.65(m,2H),7.62-7.06(m,8H),7.04-6.68(m,3H),6.63-6.32(m,3H),5.54-4.71(m,4H) ),4.34-3.88(m,2H),3.69-3.39(m,5H),3.18-3.02(s,2H),2.98-2.65(m,2H),2.43-2.25(m,3H),2.25-1.66(m,5H). ESI LCMS[MH]+:714.

[0562] [, Example 6. , ] 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [7]) and N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-methylamine ( [8]) In an H2 atmosphere, the compound A mixture of [P20] (120 mg), catalyst (10 mg of 5% palladium / charcoal), and methanol (2 mL) was hydrogenated for 2 hours with stirring. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was purified by HPLC to give 28 mg (28%) of the compound. [7] and 18 mg (13%) of the compound [8]. Compounds [7]:1H NMR(400MHz,DMSO-d 6 ), δ:9.48-9.09(m,1H),7.65-7.38(m,2H),7.38-6.91(m,7H),6.91-6.73(m,2H),6.69-6.43(m,2H),6.41-6.26(s,2H),5.46-4.54(m,4H ),4.31-3.85(m,2H),3.86-3.69(m,3H),3.65-3.39(m,5H),3.19-3.02(s,2H),3.00-2.63(m,1H),2.43-2.23(m,3H),2.22-1.71(m,9H). ESI LCMS[MH]+: 733. Compound [8]:1H NMR(400MHz,DMSO-d 6 ), δ:9.45-9.11(m,1H),7.57-7.25(m,3H),7.26-6.73(m,9H),6.70-6.45(m,2H),6.39-6.20(s,2H),5.47-4.43(m,4H),4.32-3 .89(m,2H),3.85-3.66(m,3H),3.65-3.36(m,5H),3.19-2.99(s,2H),2.97-2.65(m,1H),2.38-2.24(m,3H),2.23-1.68(m,9H). ESI LCMS[MH]+:699.

[0563] [, Example 7. , ] (S)-N-(4-chlorophenyl)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[26] ) At room temperature, towards [P23] (56 mg, 0.21 mmol) was added to a solution of pyridine (42 μL, 0.53 mmol) in dichloroethane (1.0 mL). [P28] (crude product, 0.179 mmol) was dissolved in dichloroethane (2.0 mL). The mixture was stirred at 90 °C for 8 hours. The reaction was quenched with NaHCO3(aq) and extracted with DCM. The organic layer was dried over MgSO4(s), filtered, and concentrated. The crude product was purified by reversed-phase chromatography (0-100% CAN / H2O) to give a white powder.

[26] (23 mg, 23%). ¹H NMR (400 MHz, CDCl₃), δ: 7.19–6.44 (m, 15H), 5.62–5.00 (m, 3H), 4.95–4.67 (m, 1H), 4.26–3.98 (m, 1H), 3.84–3.78 (m, 3H), 3.68–3.50 (m, 4H), 3.32–3.11 (m, 3H), 2.76–2.03 (m, 14H); LCMS (ESI) m / z: Calculated value of C₄₄H₄₄ClF₃N₄O₅: 800.30; Experimental value: 801.4 [M+H]⁺; HPLC purity: 99.9%, t R = 27.232 min.

[0564] [, Example 8. , ] (S)-N-(4-(benzyloxy)phenyl)-5-(4-(difluoromethoxy)-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[31] ) Towards [P34] (24 mg, 0.028 mmol) was added to a solution of MeOH (4.0 mL) with 10% Pd / C (28 mg) and degassed with H2 (g) solution. The mixture was stirred at room temperature for 30 minutes under hydrogen (1 atm), then diluted with a solution of 20% MeOH in DCM and filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and purified by reversed-phase chromatography (0-100% MeOH / H2O, containing 1% NH4HCO3) to obtain a white solid compound.

[31] (13.3mg,62%). 1H NMR(400MHz,DMSO-d 6), δ:9.39-9.22(m,1H),7.54-7.25(m,2H),7.25-7.04(m,6H),7.03-6.85(m,3H ),6.80-6.48(m,1H),6.28(s,2H),5.39-4.96(m,2H),4.94-4.52(m,2H),4.30-4. 14(m,1H), 4.03-3.89(m,1H), 3.82-3.68(m,3H), 3.62-3.47(m,4H), 3.30-3.27(m,1H), 3.07(s,2H), 2.96-2.64(m,1H), 2.60-2.53(m,1H), 2.46-2.24(m,4H), 2.23 2.07(m,3H), 2.03-1.93(m,3H), 1.91-1.68(m,2H); LCMS(ESI) m / z C44H46F2N4O6 calculated value 764.34; experimental value 765.4 [M+H]+; HPLC purity: 98.9%, t R=20.23min.

[0565] [, Example 9. , ] (S)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(N- (P-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[36] ) At room temperature, to [P38] (40.0 mg, 0.0449 mmol) was added to a solution of Pd / C (4.0 mg, 10% w / w) in ethanol (4.0 mL) under H2(g) atmosphere. The reaction solution was stirred at room temperature for 24 hours, then filtered through a diatomaceous earth filter and washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by C18 rapid column chromatography (0-100% methanol / H2O) to give a white solid compound.

[36] (7.4 mg, 20% yield). ¹H NMR (400MHz, CDCl₃), δ: 7.22-6.34 (m, 14H), 5.50-5.33 (m, 1H), 5.12-4.76 (m, 4H), 4.26-3.93 (m, 2H), 3.82-3.78 (m, 3H), 3.67-3.66 (m, 3H), 3.53-3.50 (m, 1H), 3.27 (s, 1H), 3.10 (s, 1H), 2.80-2.14 (m, 10H), 2.06-1.96 (m, 4H); LCMS (ESI) m / z: Calculated value of C₄₄H₄₅ClF₂N₄O₆: 798.30; Experimental value: 799.4 [M+H]⁺; HPLC purity: 97.8%, t R = 21.662 min.

[0566] [, Example 10. , ] (S)-5-(4-chloro-5-(difluoromethyl)-2-(3-(N- (P-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(4-chlorophenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[39] ) Towards [P39] (0.27 mmol) was added to a solution in dichloroethane (3.0 mL). [P23] (85 mg, 0.32 mmol, 1.2 eq) and pyridine (65 μL, 0.81 mmol, 3.0 eq). The reaction mixture was stirred at 90 °C for 16 hours. The reaction mixture was treated with water and extracted with DCM. The organic layer was dried over MgSO4(s), filtered, and concentrated under vacuum to obtain the residue. The residue was purified by rapid column chromatography (0-2% MeOH / DCM, containing 1% NH4OH(aq)) to obtain a brown gel-like substance.

[39] (43.7mg, 21%). 1H NMR(400MHz, CDCl3), δ:7.41(d,J=8.8Hz,2H),7.16-6.71(m,11H),6.53(d,J=8.8Hz,2H),5.15-4.76(m,4H),4.23-4.19(m,1H),3.99-3 .95(m,1H),3.83-3.79(m,5H),3.70-3.55(m,4H),3.28-3.26(m,2H),3.11(s,3H),2.85-2.30(m,5H),2.22-1.95(m,6H);LRMS(ESI)m / z 801.4[M+H]+; HPLC purity: 97.7%, t R=28.195min.

[0567] [, Example 11. , ] (S)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(4-cyanophenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[40] ) Towards [P36] (0.35 mmol) was added to a solution of pyridine (2.0 mL) with 4-[(3-methoxy-2-methyl-phenyl)methylamino]benzonitrile (97 mg, 0.39 mmol, 1.1 eq). The reaction mixture was stirred at 120 °C for 2 days. The reaction mixture was treated with water and extracted with DCM. The organic layer was dried over MgSO4(s), filtered, and concentrated under vacuum to obtain the residue. The residue was purified by rapid column chromatography (0-2% MeOH / DCM, containing 1% NH4OH(aq)) and subsequently by reversed-phase HPLC (10-90% acetonitrile / H2O) to obtain a brown gel-like substance.

[40] (3.2mg,1%). 1H NMR(400MHz, CDCl3), δ:7.25-6.67(m,15H),5.13-4.79(m,4H),4.22(m,1H),3.99(m,1H ),3.84-3.81(m,5H),3.67-3.55(m,7H),3.17(s,3H),2.84-2.00(m,14H);LRMS(ESI)m / z 808.3[M+H]+; HPLC purity: 99.3%, t R=25.188min.

[0568] [, Example 12. , ] (S)-5-(5-chloro-4-(difluoromethoxy)-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(4-cyanophenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[43] ) Towards [P40] (65 mg, 0.074 mmol) was added to a solution of EtOH (4.0 mL), and 10% Pd / C (74 mg) was added. The solution was then degassed with H2 (g). The mixture was stirred at room temperature for 6 hours under hydrogen (1 atm). The solution was then diluted with 20% MeOH in DCM and filtered through a diatomaceous earth filter. The filtrate was concentrated under reduced pressure and purified by reversed-phase chromatography (0-100% ACN / H2O) to give a white solid compound.

[43] (5.4 mg, 9%). 1H NMR(400MHz,DMSO-d 6), δ:7.63-7.28(m,2H),7.25-6.88(m,6H),6.85-6.63(m,4H),6.55-6.3 2(m,3H),5.56-4.77(m,3H),4.29-3.88(m,1H),3.84-3.78(m,3H),3.75-3 .61(m,3H),3.58-3.47(m,2H),3.27(s,1H),3.08(s,2H),2.83-2.45(m,3H ),2.43-2.29(m,2H),2.27-2.14(m,3H),2.11-1.87(m,5H);LCMS(ESI)m / z The calculated value of C44H45ClF2N4O5 was 782.30; the experimental value was 783.4 [M+H]+; the HPLC purity was 98.6%, and the t-R ratio was 21.193 min.

[0569] [, Example 13. , ] (S)-N-(4-cyanophenyl)-5-(4-(difluoromethoxy)-5-fluoro-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[44] ) Towards [P28] (0.36 mmol) was added to a solution of pyridine (2.0 mL) with 4-[(3-methoxy-2-methyl-phenyl)methylamino]benzonitrile (100 mg, 0.40 mmol, 1.1 eq). The reaction mixture was stirred at 120 °C for 2 days. The reaction mixture was treated with water and extracted with DCM. The organic layer was dried over MgSO4(s), filtered, and concentrated under vacuum to obtain the residue. The residue was purified by rapid column chromatography (0-2% MeOH / DCM, containing 1% NH4OH(aq)) and subsequently by reversed-phase HPLC (10-90% acetonitrile / H2O) to obtain a brown gel-like substance.

[44] (5.5mg,4%). 1H NMR (400 MHz, CDCl3), δ: 7.28-6.62(m,15H),5.15-4.80(m,4H),4.24-4.22(m,1H),4.01-3.97(m 1H), 3.84-3.81(m,3H), 3.70-3.55(m,4H), 3.25-3.17(m,3H), 2.81-2.00(m,14H); LRMS(ESI) m / z 792.4[M+H]+; HPLC purity: 98.8%, t R=23.896min.

[0570] [, Example 14. , ] (S)-5-(5-chloro-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(1H-indazol-5-yl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[70] ) Towards [P53] (100 mg, 0.119 mmol) was added to a solution of TFA (0.20 mL) in DCM (1.0 mL). The reaction was stirred at room temperature for 2 hours. The mixture was concentrated to remove the solvent. The crude product was purified by preparative thin-layer chromatography (5% MeOH / DCM) to obtain the compound.

[70] (29mg,37%). 1H NMR (400MHz, CDCl3), δ:7.89-7.84(m,1H),7.42-7.28(m,2H),7.22-6.90(m,8H),6.81-6.67(m,4H),5.47(br s,1H),5.25-4.68(m,3H),4.21-4.08(m,1H),3.92-3.60(m,7H),3.53-3.45(m,1H),3.30-3.20(m,1H),3.05(br s,2H),2.78-2.72(m,1H),2.66-2.50(m,2H),2.40-2.32(m,1H),2.24(br m,2H), 2.07-2.05(m,3H), 1.98-1.82(m,1H), 1.67(br s,3H); LCMS(ESI) m / z 757.4 [M+H]+.; HPLC purity: 95.1%, t R=19.5min.

[0571] [, Example 15. , ] (S)-5-(5-chloro-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(2-cyanobenzyl)-N-(1H-indazol-5-yl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[68] ) Towards [P55] (40 mg, 0.049 mmol) was added to a solution of TFA (0.10 mL) in DCM (1.0 mL). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated to remove the solvent. The crude product was purified by preparative thin-layer chromatography (5% MeOH / DCM) to obtain the compound.

[68] (16mg,44%). 1H NMR(400MHz, CDCl3), δ:7.92-7.87(m,1H),7.71-7.63(m,1H),7.51-7.49(m,2H),7.41-7.01(m,9H),6.95-6.92 (m,1H),6.82-6.77(m,2H),5.45-5.27(m,2H),5.13-4.95(m,2H),4.21-4.10(m,1H),3.94-3.87(m,1H),3.65(br m,5H),3.50-3.48(m,1H),3.25(br s,2H),3.09(br s,2H), 2.75-2.53(m,3H), 2.42-2.37(m,1H), 2.29(s,3H), 2.21-1.84(m,1H), 1.28-1.24(m,1H); LCMS(ESI) m / z 738.4 [M+H]+.; HPLC purity: 93.8%, t R=17.896min.

[0572] [, Example 16. , ] (S)-5-(5-chloro-2-(3-(N- (-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-N-(1H-indazol-5-yl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[69] ) Towards [P57] (265 mg, 0.32 mmol) was added to a solution of TFA (2.0 mL) in DCM (4.0 mL). The reaction was stirred overnight at room temperature and then concentrated. The residue was purified by C18 reversed-phase column chromatography (0-100% MeOH / water) to give a white solid compound.

[69] (31 mg, 13% yield). 1H NMR(400MHz, CDCl3), δ:7.87-7.83(m,1H),7.45-7.28(m,3H),7.24-7.04(m,5H),7.01-6.82(m,4H),6.75-6.70(m,2H),5.56-4.99(m,4H),4.23 -4.09(m,1H),3.92-3.87(m,1H),3.65-3.42(m,9H),3.30-3.18(m,2H), 3.04-2.46(m,5H),2.43-2.06(m,5H),1.99-1.83(m,2H).;LCMS(ESI)m / z The calculated value of C43H43ClN6O4 was 742.30; the experimental value was 743.3 [M+H]+. HPLC purity: 93.5%, t R = 18.577 min.

[0573] [, Example 17. , ] 5-(5-chloro-4-cyano-2-[(3R)-3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(4-hydroxyphenyl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine [9]) At ambient temperature, A mixture of [P61], H2SO4 (0.1 mL), and methanol / THF (2 mL, 1:1) was stirred for 2 hours. A 20% sodium carbonate aqueous solution (pH 7) was added, and the product was extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of MeOH (0→2%) and DCM to give 17 mg (25%) of the title compound. 1H NMR(400MHz,DMSO-d 6), δ:9.32-9.24(m,1H),8.01-7.81(m,1H),7.74-7.58(m,1H),7.24-6.24(m,10H),5.63-5.25(m,1H),5.12-4.54(m,4H),4. 28-3.83(m,2H),3.83-3.65(m,3H),3.65-3.36(m,6H),3.13(s,2H),3.00-2.62(m,1H),2.44-2.25(m,5H),2.25-1.61(m,7H). LCMS(ESI+)m / z 759[M+H]+.

[0574] [, Example 18. , ] 5-(5-chloro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[11] ) In an H2 atmosphere, [P67] A mixture of catalyst (5 mg of 5% palladium / charcoal) and methanol (2 mL) was hydrogenated for 2 hours with stirring. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was purified by HPLC to give 15 mg (21%). ¹H NMR (400 MHz, DMSO-d₆), δ: 9.53–9.11 (m, 1H), 7.51–5.98 (m, 12H), 5.45–4.44 (m, 4H), 4.33–3.67 (m, 12H), 3.57 (s, 6H), 3.16–2.64 (m, 3H), 2.38–1.73 (m, 9H). LCMS (ESI+) m / z 764 [M+H]+.

[0575] [, Example 19. , ] 5-(5-fluoro-4-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine ( [twenty one]). In an H2 atmosphere, [P72] A mixture of catalyst (5 mg of 5% palladium / charcoal) and methanol (2 mL) was hydrogenated for 2 hours with stirring. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was purified by HPLC to give 18 mg (64%) of the compound. [twenty one]. 1H NMR(400MHz,DMSO-d 6), δ:9.48-9.14(m,1H),7.30-6.71(m,9H),6.71-6.44(m,2H),6.31(s,2H),5.42-4.46(m,4H), 4.32-3.68(m,10H),3.66-3.36(m,6H),3.18-2.67(m,4H),2.48-2.27(m,3H),2.22-1.72(m,6H). MS(ESI+)m / z 747[M+H]+.

[0576] [, Example 20. ] N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[56] ), 5-(4-(aminocarbonyl)-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-chlorophenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[63] ). At 50℃, A mixture of [P81] (100 mg, 0.157 mmol), tert-BuOK (88 mg, 0.8 mmol), and tert-BuOH (25 mL) was stirred for 30 minutes, followed by the addition of 2-methoxybenzyl methanesulfonate (60 mg, 0.314 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by HPLC to give 16.0 mg (12%) of the compound.

[56] and 6 mg (4%) of the compound

[63] . Compounds

[56] : ¹H NMR (400MHz, DMSO-d₆), δ: 7.86–7.59 (m, ¹H), 7.34–6.67 (m, ¹⁵H), 5.12–4.65 (m, ⁴H), 4.28–3.85 (m, ⁵H), 3.76–3.36 (m, ⁸H), 3.19 (s, ⁻¹H), 2.95–2.63 (m, ¹H), 2.42–2.25 (m, ⁻¹H), 2.20–1.75 (m, ⁶H). LCMS (ESI+) m / z 759 [M+H]+. Compound

[63] :LCMS(ESI+)m / z 777[M+H]+.

[0577] [, Example 21. , ] 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[27] ). At ambient temperature, A mixture of [P87], H2SO4 (0.15 mL), and methanol / THF (2 mL, 1:1) was stirred for 1 hour. Volatile substances were removed under reduced pressure, and the residue was stirred with a 20% Na2CO3 aqueous solution for 5 minutes. The product was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure on a rotary evaporator. The residue was purified by HPLC to give 40 mg (40%) of the title compound. 1H NMR (400MHz, DMSO-d 6), δ: 9.52- 9.15(m,1H),7.65-7.24(m,2H),7.24-6.42(m,8H),6.34(s,2H),5.46-4.60(m,4H),4.33-3.96(m,2 H),3.92-3.67(m,3H),3.65-3.39(m,6H),3.17-2.62(m,3H),2.42-2.23(m,4H),2.18-1.81(m,9H). LCMS(ESI+)m / z 752[M+H]+.

[0578] [, Example 22. , ] 5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[58] ). In an H2 atmosphere, [P92] A mixture of catalyst (5 mg of 5% palladium / charcoal) and methanol (10 mL) was hydrogenated for 2 hours with stirring. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was purified by HPLC to give 29 mg (25%) of the compound.

[58] . 1H NMR(400MHz,DMSO-d 6), δ:9.52-9.15(m,1H),7.87-7.46(m,1H),7.29-6.72(m,9H),6.72-6.43(m,2H),6.43-6.27(m,2H),5.25(s,1H),5.07-4.57(m,4H),4.3 7-3.99(m,2H),3.92(s,3H),3.83-3.69(m,3H),3.62-3.40(m,6H),3.18(s,2H),3.01-2.57(m,2H),2.45-2.22(m,3H),2.20-1.82(m,6H). LCMS(ESI+)m / z 754[M+H]+.

[0579] [, Example 23. , ] 5-(5-nitro-2-[(3R)-3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(1H-indazol-5-yl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[65] ). At ambient temperature, the crude compound The mixture of [P97] (180 mg) and TFA (0.4 mL) in DCM (3 mL) was stirred for 3 hours. An aqueous solution (20%, NaHCO3) (pH 7) was added, and the product was extracted with DCM (2 × 6 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by HPLC to give 40 mg of the compound.

[65] . LCMS(ESI+)m / z 768[M+H]+. 1H NMR(400MHz,DMSO-d 6), δ:13.18-12.76(m,1H),8.38-8.08(m,1H),8.00-7.80(m,3H),7.66-6.45(m,11H),5.55-4.68(m,4H),4.40-3.85 (m,2H),3.84-3.66(m,3H),3.64-3.37(m,6H),3.08(s,2H),2.81-2.56(m,1H),2.43-2.16(m,3H),2.09-1.71(m,8H).

[0580] [, Example 24. , ] 5-(5-nitro-2-[(3R)-3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(1H-indazol-5-yl)-N3-(2-cyanobenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[71] ). At ambient temperature, the crude compound The mixture of [P101] (100 mg) and TFA (0.48 mL) in DCM (2 mL) was stirred for 3 hours. NaHCO3 aqueous solution (20%) was added (until pH 7), and the product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by HPLC to give 56 mg (64%) of the compound.

[71] . LCMS(ESI+)m / z 749[M+H]+. 1H NMR(400MHz,DMSO-d 6), δ:9.48-9.09(m,1H),7.65-7.38(m,2H),7.38-6.91(m,7H),6.91-6.73(m,2H),6.69-6.43(m,2H),6.41-6.26(s,2H),5.46-4.54(m,4 H),4.31-3.85(m,2H),3.86-3.69(m,3H),3.65-3.39(m,5H),3.19-3.02(s,2H),3.00-2.63(m,1H),2.43-2.23(m,3H),2.22-1.71(m,9H).

[0581] [, Example 25. , ] 5-(5-cyano-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[55] ). At ambient temperature, A mixture of [P105], H2SO4 (1.2 mL), and methanol / THF (20 mL, 1:1) was stirred for 2 hours. A 20% aqueous sodium carbonate solution (pH 7) was added, and the product was extracted with DCM (2 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of MeOH (0→2%) and DCM to give 80 mg (86%) of the title compound. 1H NMR(400MHz,DMSO-d 6), δ:9.51-9.10(m,1H),8.10-7.33(m,3H),7.33-6.65(m,10H),6.64-6.29(m,3H),5.60-4.50(m,4H),4. 36-3.85(m,2H),3.80-3.40(m,8H),3.10(s,2H),3.00-2.61(m,1H),2.45-2.21(m,3H),2.23-1.74(m,6H). LCMS(ESI+)m / z 724[M+H]+.

[0582] [, Example 26. , ] N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(5-(methylsulfonyl)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1H-pyrrole-3-methylamine (

[49] ). At ambient temperature, A mixture of [P109], H2SO4 (1.5 mL), and methanol / THF (2 mL, 1:1) was stirred for 2 hours. A 20% aqueous sodium carbonate solution (pH 7) was added, and the product was extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of MeOH (0→2%) and DCM to give 130 mg (95%) of the title compound. 1H NMR(400MHz,DMSO-d 6), δ:9.48-9.14(m,1H),8.11-7.85(m,1H),7.82-7.43(m,2H),7.29-6.24(m,12H), 5.58-4.58(m,4H),4.33-3.90(m,2H),3.87-3.67(m,3H),3.67-3.48(m,8H),3.12(s, 2H),3.02-2.66(m,1H),2.43-2.27(m,4H),2.26-1.74(m,8H). LCMS(ESI+)m / z 777[M+H]+.

[0583] [, Example 27. , ] N-1H-indazol-6-yl-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-methylamine (

[67] ). At ambient temperature, The mixture of [P116] (230 mg, 0.27 mmol) and TFA (1 mL) in DCM (2 mL) was stirred for 3 hours. A 20% NaHCO3 aqueous solution (pH 7) was added, and the product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography, dissolved in a mixture of EtOAc (0→20%) and DCM, to give 23 mg (11%) of the title compound. LCMS (ESI+) m / z 768 [M+H]+. 1H NMR(400MHz,DMSO-d 6), δ:13.01-12.60(m,1H),8.37-8.07(m,1H),8.01-7.78(m,2H),7.72-6.35(m,12H),5.53-4.70(m,4H),4.30-3.82 (m,2H),3.84-3.68(m,3H),3.67-3.36(m,6H),3.07(s,2H),2.95-2.62(m,1H),2.43-2.16(m,3H),2.08-1.64(m,8H).

[0584] [, Example 28. , ] N-1H-indazol-6-yl-N-(2-methoxybenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-methylamine (

[72] ). At ambient temperature, the coarse The mixture of [P120] (350 mg, 0.4 mmol) and TFA (1 mL) in DCM (2 mL) was stirred for 3 hours. A 20% NaHCO3 aqueous solution (pH 7) was added, and the product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography, dissolved in a mixture of EtOAc (0→20%) and DCM, to give 6.6 mg (3%) of the title compound. LCMS (ESI+) m / z 754 [M+H]+.

[0585] [, Example 29., ] N-1H-indazol-6-yl-N-(2-cyanophenylmethyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-methylamine (

[66] ). At ambient temperature, the coarse The mixture of [P124] (350 mg, 0.4 mmol) and TFA (1 mL) in DCM (2 mL) was stirred for 3 hours. A 20% NaHCO3 aqueous solution (pH 7) was added, and the product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→20%) and DCM to give 69 mg (23%) of the title compound. LCMS (ESI+) m / z 749 [M+H]+. 1H NMR(400MHz,DMSO-d 6), δ:13.11-12.82(m,1H),8.37-8.08(m,1H),8.07-7.84(m,2H),7.83-7.33(m,6H),7.28-6.42(m,7H),5.67-4.74( m,4H),4.33-3.80(m,2H),3.74-3.46(m,6H),3.08(s,2H),2.98-2.58(m,1H),2.39-2.22(m,2H),2.21-1.66(m,6H).

[0586] [, Example 30. , ] 5-(5-chloro-4-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-cyanophenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[73] ). At 50℃, A mixture of [P127] (90 mg, 0.14 mmol), tert-BuOK (64 mg, 0.58 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (66 mg, 0.29 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 20 mg (20%) of the title compound. ¹H NMR (400MHz, DMSO-d₆), δ: 7.82–7.33 (m, 5H), 7.27–6.52 (m, 9H), 5.91–5.48 (m, 1H), 5.33–4.74 (m, 4H), 4.35–3.92 (m, 2H), 3.86–3.67 (m, 3H), 3.67–3.40 (m, 4H), 3.16–2.81 (m, 2H), 2.69 (s, 3H), 2.42–2.14 (m, 3H), 2.09–1.76 (m, 7H). Calculated LCMS (ESI) m / z for C₄₄H₄₃ClFN₅O₄: 760.32; experimental value: 760.6 [M+H]⁺.

[0587] [, Example 31. ] N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[60] ). At 50℃, A mixture of [P131] (95 mg, 0.149 mmol), tert-BuOK (67 mg, 0.57 mmol), and tert-BuOH (9 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (69 mg, 0.29 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 79 mg (68%). 1H NMR(400MHz,DMSO-d 6), δ:7.84-7.53(m,1H),7.26-6.75(m,11H),6.72-6.51(m,2H),5.86-5.26(m,1H),5.14-4.69(m,4H),3.94(s,5 H),3.84-3.69(m,3H),3.67-3.37(m,6H),3.19(s,2H),3.04-2.58(m,2H),2.44-2.22(m,3H),2.23-1.68(m,6H). LCMS(ESI+)m / z 773[M+H]+.

[0588] [, Example 32. , ] N-(4-chlorophenyl)-N-(2-cyanophenylmethyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[59] ). At 50℃, A mixture of [P131] (190 mg, 0.298 mmol), tert-BuOK (134 mg, 1.14 mmol), and tert-BuOH (18 mL) was stirred for 30 minutes, followed by the addition of 2-(bromomethyl)benzonitrile (117 mg, 0.598 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 63 mg (28%). 1H NMR(400MHz,DMSO-d 6), δ:7.98-7.34(m,4H),7.29-6.69(m,10H),5.44-4.69(m,4H),4.40-3.84(m,6H),3. 76-3.39(m,6H),3.19(s,2H),2.99-2.65(m,1H),2.46-2.26(m,3H),2.24-1.81(m,5H). LCMS(ESI+)m / z 754[M+H]+.

[0589] [, Example 33. , ] 5-(5-cyano-2-[3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(4-hydroxyphenyl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[57] ). At ambient temperature, [P139] (50 mg) and H2SO4 (0.1 mL) were stirred in methanol / THF (2 mL, 1:1) for 1 hour. A 20% NaHCO3 aqueous solution (pH 7) was added, and the product was extracted with DCM (2 × 6 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of MeOH (0→2%) and DCM to give 20 mg (50%) of the compound.

[57] . LCMS(ESI+)m / z 724[M+H]+. 1H NMR(400MHz,DMSO-d 6), δ:9.52-9.12(m,1H),8.05-7.30(m,3H),7.30-6.41(m,9H),6.41-6.24(m,3H),5.33-4.55(m,4H),4.36-3.87(m ,2H),3.87-3.66(m,3H),3.66-3.38(m,6H),3.10(s,2H),3.02-2.61(m,1H),2.45-2.12(m,3H),2.09-1.78(m,8H).

[0590] [, Example 34. , ] 5-(5-(aminocarbonyl)-2-[3-(N- [Pyroxymethyl]-3,4-dihydro-2(1H)-isoquinolinyl]carbonylphenyl)-N3-(4-hydroxyphenyl)-N3-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine

[64] ). At ambient temperature, the compound [P139] (70 mg) and H2SO4 (0.1 mL) were stirred in a methanol / THF (2 mL, 1:1) mixture for 1 hour. A 20% NaHCO3 aqueous solution (pH 7) was added, and the product was extracted with DCM (2 × 6 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was subjected to rapid silica chromatography and dissolved in a mixture of MeOH (0→2%) and DCM to give 40 mg (67%) of the compound.

[64] . LCMS(ESI+)m / z 742[M+H]+. 1H NMR (400MHz, DMSO-d 6), δ:9.45-9.14(m,1H),8.17-7.34(m,6H), 7.26-6.74(m,7H),6.73-6.40(m,2H),6.31(s,2H),5.55-4.53(m,4H),4.33-3.89(m,2H),3.87-3.6 8(m,3H),3.68-3.36(m,4H),3.09(s,2H),3.05-2.65(m,1H),2.47-2.21(m,4H),2.20-1.72(m,9H).

[0591] [, Example 35. , ] 5-[5-chloro-2-[(3S)-3-(N- [(3-methoxy-2-methyl-phenyl)-3,4-dihydro-1H-isoquinoline-2-carbonyl]phenyl]-N-(4-cyanophenyl)-N-[(3-methoxy-2-methyl-phenyl)methyl]-1,2-dimethyl-pyrrole-3-methylamine]

[33] ). At 50℃, A mixture of [P142] (170 mg, 0.28 mmol), tert-BuOK (125 mg, 1.1 mmol), and tert-BuOH (5 mL) was stirred for 30 minutes, followed by the addition of 3-methoxy-2-methylbenzyl methanesulfonate (128 mg, 0.56 mmol). The reaction mixture was stirred at 60 °C for 1 hour and then partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of EtOAc (0→100%) and DCM to give 17 mg (10%) of the title compound. ¹H NMR (400MHz, DMSO-d₆), δ: 7.83–6.47 (m, 15H), 5.87–5.52 (m, 1H), 5.41–4.68 (m, 5H), 4.31–3.91 (m, 2H), 3.87–3.69 (m, 3H), 3.69–3.40 (m, 6H), 3.19–2.62 (m, 3H), 2.41–2.21 (m, 2H), 2.21–1.71 (m, 7H). Calculated LCMS (ESI) m / z for C₄₄H₄₄ClN₅O₄: 742.32; experimental value: 742.3 [M+H]⁺. [, Example 36. , ] N-(2-cyanophenylmethyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-methylamine (

[62] ). At ambient temperature, A mixture of [P146], H2SO4 (1.4 mL), and methanol / THF (20 mL, 1:1) was stirred for 2 hours. A 20% aqueous sodium carbonate solution (pH 7) was added, and the product was extracted with DCM (2 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of MeOH (0→2%) and DCM to give 64 mg (63%) of the title compound. 1H NMR(400MHz,DMSO-d 6), δ:9.61-9.28(m,1H),8.48-7.91(m,2H),7.86-7.29(m,6H),7.29-6.81(m,5H),6.62-6.28(m,3H),5.37-4.77(m ,4H),4.31-3.88(m,2H),3.74-3.34(m,7H),3.13(s,2H),2.96-2.63(m,1H),2.43-2.17(m,3H),2.17-1.72(m,4H). LCMS(ESI+)m / z 725[M+H]+. [, Example 37. , ] N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-5-(2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-nitrophenyl)-1H-pyrrole-3-methylamine (

[61] ). At ambient temperature, A mixture of [P147], H2SO4 (1.4 mL), and methanol / THF (20 mL, 1:1) was stirred for 2 hours. A 20% aqueous sodium carbonate solution (pH 7) was added, and the product was extracted with DCM (2 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of MeOH (0→2%) and DCM to give 96 mg (54%) of the title compound. 1H NMR(400MHz,DMSO),δ:9.52-9.09(m,1H),8.38-7.40(m,Hz,1H),7.25-6.73(m,16H),6.67-6.46(m ,5H),6.33(s,5H),5.54-4.59(m,9H),4.33-4.10(m,4H),3.96(s,3H),3.77(s,3H),3.67-3.49(m, 7H),3.13(s,3H),2.96-2.63(m,1H),2.43-2.17(m,3H),2.17-1.72(m,4H). LCMS(ESI+)m / z 744[M+H]+. [, Example 38. , ] 5-(5-(acetylamino)-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[48] ). At ambient temperature, A mixture of [P149], H2SO4 (1.7 mL), and methanol / THF (20 mL, 1:1) was stirred for 2 hours. A 20% aqueous sodium carbonate solution (pH 7) was added, and the product was extracted with DCM (2 × 200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography and dissolved in a mixture of MeOH (0→2%) and DCM to give 15 mg (12%) of the title compound. 1H NMR(400MHz,DMSO-d 6), δ:10.09(s,1H),9.44-9.06(m,1H),7.66-7.31(m,2H),7.25-6.44(m,12H),6.39-6.14(m,2H),5.42-4.52(m,4H),4.34-3. 94(m,2H),3.76(d,J=22.8Hz,3H),3.70-3.38(m,6H),3.08(s,2H),2.96-2.64(m,1H),2.40-2.23(m,2H),2.22-1.71(m,11H). LCMS(ESI+)m / z 756[M+H]+. [, Example 39. , ] 5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[51] ). In an H2 atmosphere, [P153] A mixture of catalyst (5 mg of 5% palladium / charcoal) and methanol (2 mL) was hydrogenated with stirring for 2 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was purified by HPLC to give 25 mg (40%) of the title compound. ¹H NMR (400MHz, chloroform-d), δ: 9.48–9.16 (m, 1H), 7.61–7.24 (m, 2H), 7.24–6.72 (m, 7H), 6.71–6.44 (m, 3H), 6.41–6.21 (m, 2H), 5.45–4.60 (m, 4H), 4.32–3.95 (m, 2H), 3.91–3.70 (m, 3H), 3.68–3.42 (m, 8H), 3.08 (s, 2H), 2.96–2.65 (m, 1H), 2.45–2.22 (m, 3H), 2.22–1.75 (m, 6H). LCMS (ESI+) m / z 735 [M+H]+. [, Example 40. ] N-(2-cyanophenylmethyl)-5-(4,5-difluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[53] ). In an H2 atmosphere, [P154] A mixture of catalyst (5 mg of 5% palladium / charcoal) and methanol (2 mL) was hydrogenated for 2 hours with stirring. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was purified by HPLC to give 62 mg (70%) of the title compound. ¹H NMR (400 MHz, chloroform-d), δ: 9.58–9.27 (m, 1H), 7.97–7.26 (m, 7H), 7.22–6.66 (m, 6H), 6.62–6.31 (m, 3H), 5.50–4.69 (m, 4H), 4.35–3.94 (m, 2H), 3.73–3.42 (m, 6H), 3.09 (s, 2H), 2.84–2.57 (m, 1H), 2.41–2.26 (m, 2H), 2.20–1.75 (m, 5H). LCMS(ESI+)m / z 716[M+H]+. [, Example 41.] N-(4-chlorophenyl)-5-(4-cyano-5-methoxy-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[50] ). At ambient temperature, A mixture of [P161], H2SO4 (0.03 mL), and methanol / THF (10 mL, 1:1) was stirred for 2 hours. A 20% aqueous sodium carbonate solution (pH 7) was added, and the product was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure on a rotary evaporator. The residue was subjected to rapid silica gel chromatography, dissolved in a mixture of MeOH (0→2%) and DCM, to give 4 mg (16%) of the title compound. LCMS (ESI+) m / z 748 [M+H]+. [, Example 42. , ] 5-(4-chloro-2-methyl-6-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[74] ). At ambient temperature, A mixture of [P162], H2SO4 (0.03 mL), and methanol / THF (10 mL, 1:1) was stirred for 2 hours. A 20% sodium carbonate aqueous solution (pH 7) was added, and the product was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography, dissolved in a mixture of MeOH (0→2%) and DCM, to give 12 mg (8%) of the title compound. LCMS (ESI+) m / z 734 [M+H]+. [, Example 43., ] 5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(2-methoxybenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine(

[54] ). In an H2 atmosphere, [P167] A mixture of catalyst (5 mg of 5% palladium / charcoal) and methanol (2 mL) was hydrogenated for 2 hours with stirring. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was purified by HPLC to give 3 mg (18%) of the compound.

[54] . LCMS(ESI+)m / z 703[M+H]+. [, Example 44. , ] 5-(5-fluoro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(4-hydroxyphenyl)-N-(3-methoxy-2-methylbenzyl)-1,2-dimethyl-1H-pyrrole-3-methylamine (

[52] ). In an H2 atmosphere, [P168] A mixture of catalyst (5 mg of 5% palladium / charcoal) and met...

Claims

1. The use of a compound of formula (I) in the preparation of a medicament for inhibiting BCL-2 protein, 1. Among them: R1 is selected from halogens, -OH, -CN, and -CONH2; R1a is H; or R1 and R1a together with the atoms they are attached to form a 3 to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R2 and R3 are each independently selected from C1-C6 alkyl groups; or R2 and R3 together with the atoms they are attached to form a 3 to 10-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S. Each R4 is independently selected from halogens, -OH, -CN, -NO2, -COOH, -CH2CN, CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6 alkyl). -C(O) (C1-C6 alkyl), -OC(O)O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -NHC(O) (C1-C6 alkyl), -C(O)NH2, -C(O)NH (C1-C6 alkyl), -S(O)2 (C1-C6 alkyl), -S(O)NH (C1-C6 alkyl) and S(O)N (C1-C6 alkyl)2; R5 series is selected from , and ; Each R6 is independently selected from halogens, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6) -alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl; each R7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl;The alkyl or aryl group may be substituted, as appropriate, with one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -O C(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl)2; or two R7 atoms together with the nitrogen atom they are bonded to and any inserted atom to form a heterocycle; The heterocyclic compound is, depending on the case, substituted with one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC (O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl)2; R8 series is selected from H, C1-6 alkyl, C3-8 cycloalkyl, aryl, C1-6 haloalkyl; R9 series is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)1-6OR8, C3-8 cycloalkyl, aryl, heterocyclic;Wherein the alkyl, cycloalkyl, aryl, or heterocyclic group is substituted by one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC( O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl2; Where x is selected from integers 0, 1, 2, and 3; y is selected from integers 0, 1, 2, and 3; m is selected from integers 0, 1, and 2; each n is independently selected from integers 1, 2, and 3; aryl groups are cyclic aromatic hydrocarbon groups having 1 to 3 aromatic rings; heterocyclic groups are saturated or partially unsaturated 3-10 member monocyclic systems, 7-12 member bicyclic systems (fused rings, bridging rings, or spirocyclic systems) or 11-14 member tricyclic systems (fused rings, bridging rings, or spirocyclic systems) having one or more heteroatoms selected from O, N, S, P, Se, and B.

2. As claimed in claim 1, wherein the compound has the formula (I'):

2. Or a pharmaceutically acceptable salt or stereoisomer thereof.

3. As claimed in claim 1, wherein the compound is a compound of formula (II):

3. Or a pharmaceutically acceptable salt or stereoisomer thereof.

4. As claimed in claim 1, wherein the compound is a compound of formula (II'):

4. Or a pharmaceutically acceptable salt or stereoisomer thereof.

5. As claimed in claim 1, wherein the compound has the formula (II-A):

5. Or a pharmaceutically acceptable salt or stereoisomer thereof.

6. As claimed in claim 1, wherein the compound has formula (II'):

6. Or a pharmaceutically acceptable salt or stereoisomer thereof.

7. As claimed in claim 1, wherein the compound has the formula (II-AA), (II-AB), or (II-AC):

7. Or a pharmaceutically acceptable salt or stereoisomer thereof.

8. As claimed in claim 1, wherein the compound has the formula (II-BA), formula (II-BB), or formula (II-BC):

8. Or a pharmaceutically acceptable salt or stereoisomer thereof.

9. As claimed in claim 1, wherein the compound is selected from:

9. Or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

10. Use of a pharmaceutical composition in the preparation of a medicament for inhibiting BCL-2 protein, the pharmaceutical composition comprising the compound of any one of claims 1 to 9, a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

11. As claimed in claim 10, wherein the pharmaceutical composition further comprises additional pharmaceutical active agents.

12. Use of a compound of formula (I) in the preparation of a medicament for treating diseases or conditions related to the inhibition of BCL-2 protein.

12. Among them: R1 is selected from halogens, -OH, -CN, and -CONH2; R1a is H; or R1 and R1a together with the atoms they are attached to form a 3 to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R2 and R3 are each independently selected from C1-C6 alkyl groups; or R2 and R3 together with the atoms they are attached to form a 3 to 10-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S. Each R4 is independently selected from halogens, -OH, -CN, -NO2, -COOH, -CH2CN, CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6 alkyl). -C(O) (C1-C6 alkyl), -OC(O)O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -NHC(O) (C1-C6 alkyl), -C(O)NH2, -C(O)NH (C1-C6 alkyl), -S(O)2 (C1-C6 alkyl), -S(O)NH (C1-C6 alkyl) and S(O)N (C1-C6 alkyl)2; R5 series is selected from , and ; Each R6 is independently selected from halogens, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6) -alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl; each R7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl;The alkyl or aryl group may be substituted, as appropriate, with one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -O C(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl)2; or two R7 atoms together with the nitrogen atom they are bonded to and any inserted atom to form a heterocycle; The heterocyclic compound is, depending on the case, substituted with one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC (O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl)2; R8 series is selected from H, C1-6 alkyl, C3-8 cycloalkyl, aryl, C1-6 haloalkyl; R9 series is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)1-6OR8, C3-8 cycloalkyl, aryl, heterocyclic;Wherein the alkyl, cycloalkyl, aryl, or heterocyclic group is substituted by one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC( O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl2; Where x is selected from integers 0, 1, 2, and 3; y is selected from integers 0, 1, 2, and 3; m is selected from integers 0, 1, and 2; each n is independently selected from integers 1, 2, and 3; aryl groups are cyclic aromatic hydrocarbon groups having 1 to 3 aromatic rings; heterocyclic groups are saturated or partially unsaturated 3-10 member monocyclic systems, 7-12 member bicyclic systems (fused rings, bridging rings, or spirocyclic systems) or 11-14 member tricyclic systems (fused rings, bridging rings, or spirocyclic systems) having one or more heteroatoms selected from O, N, S, P, Se, and B.

13. As claimed in claim 12, wherein the compound has the formula (I'):

13. Or a pharmaceutically acceptable salt or stereoisomer thereof.

14. As claimed in claim 12, wherein the compound is a compound of formula (II):

14. Or a pharmaceutically acceptable salt or stereoisomer thereof.

15. As claimed in claim 12, wherein the compound is a compound of formula (II'):

15. Or a pharmaceutically acceptable salt or stereoisomer thereof.

16. As claimed in claim 12, wherein the compound has the formula (II-A):

16. Or a pharmaceutically acceptable salt or stereoisomer thereof.

17. As claimed in claim 12, wherein the compound has formula (II'):

17. Or a pharmaceutically acceptable salt or stereoisomer thereof.

18. As claimed in claim 12, wherein the compound has the formula (II-AA), (II-AB), or (II-AC):

18. Or a pharmaceutically acceptable salt or stereoisomer thereof.

19. As claimed in claim 12, wherein the compound has the formula (II-BA), formula (II-BB), or formula (II-BC):

19. Or a pharmaceutically acceptable salt or stereoisomer thereof.

20. As claimed in claim 12, wherein the compound is selected from:

20. Or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

21. Use of a pharmaceutical composition in the preparation of a medicament for treating and inhibiting diseases or conditions related to BCL-2 protein, the pharmaceutical composition comprising the compound of any one of claims 12 to 20, a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

22. As claimed in claim 21, wherein the pharmaceutical composition further comprises additional pharmaceutical active agents.

23. Use of a compound of formula (I) in the preparation of a medicament for treating and inhibiting cancers related to the BCL-2 protein.

23. Among them: R1 is selected from halogens, -OH, -CN, and -CONH2; R1a is H; or R1 and R1a together with the atoms they are attached to form a 3 to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R2 and R3 are each independently selected from C1-C6 alkyl groups; or R2 and R3 together with the atoms they are attached to form a 3 to 10-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S. Each R4 is independently selected from halogens, -OH, -CN, -NO2, -COOH, -CH2CN, CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6 alkenyl), -O-(C2-C6 alkynyl), C2-C6 alkenyl, C2-C6 alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6 alkyl). -C(O) (C1-C6 alkyl), -OC(O)O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl)2, -NHC(O) (C1-C6 alkyl), -C(O)NH2, -C(O)NH (C1-C6 alkyl), -S(O)2 (C1-C6 alkyl), -S(O)NH (C1-C6 alkyl) and S(O)N (C1-C6 alkyl)2; R5 series is selected from , and ; Each R6 is independently selected from halogens, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6) -alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl; each R7 is independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl;The alkyl or aryl group may be substituted, as appropriate, with one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -O C(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl)2; or two R7 atoms together with the nitrogen atom they are bonded to and any inserted atom to form a heterocycle; The heterocyclic compound is, depending on the case, substituted with one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, -CH2N(R8)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC (O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl)2; R8 series is selected from H, C1-6 alkyl, C3-8 cycloalkyl, aryl, C1-6 haloalkyl; R9 series is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)1-6OR8, C3-8 cycloalkyl, aryl, heterocyclic;Wherein the alkyl, cycloalkyl, aryl, or heterocyclic group is substituted by one or more independent substituents selected from the following: halogen, -OH, -CN, -COOH, -CH2CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, C2-C6 alkenyl, C2-C6 ynyl, -OH, -OP(O)(OH)2, -OC( O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH(C1-C6)alkyl, -N(C1-C6)alkyl2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N(C1-C6)alkyl2; Where x is selected from integers 0, 1, 2, and 3; y is selected from integers 0, 1, 2, and 3; m is selected from integers 0, 1, and 2; each n is independently selected from integers 1, 2, and 3; aryl groups are cyclic aromatic hydrocarbon groups having 1 to 3 aromatic rings; heterocyclic groups are saturated or partially unsaturated 3-10 member monocyclic systems, 7-12 member bicyclic systems (fused rings, bridging rings, or spirocyclic systems) or 11-14 member tricyclic systems (fused rings, bridging rings, or spirocyclic systems) having one or more heteroatoms selected from O, N, S, P, Se, and B.

24. As claimed in claim 23, wherein the compound has the formula (I'):

24. Or a pharmaceutically acceptable salt or stereoisomer thereof.

25. As claimed in claim 23, wherein the compound is a compound of formula (II):

25. Or a pharmaceutically acceptable salt or stereoisomer thereof.

26. As claimed in claim 23, wherein the compound is a compound of formula (II'):

26. Or a pharmaceutically acceptable salt or stereoisomer thereof.

27. As claimed in claim 23, wherein the compound has the formula (II-A):

27. Or a pharmaceutically acceptable salt or stereoisomer thereof.

28. As claimed in claim 23, wherein the compound has formula (II'):

28. Or a pharmaceutically acceptable salt or stereoisomer thereof.

29. As claimed in claim 23, wherein the compound has the formula (II-AA), (II-AB), or (II-AC):

29. Or a pharmaceutically acceptable salt or stereoisomer thereof.

30. As claimed in claim 23, wherein the compound has the formula (II-BA), formula (II-BB), or formula (II-BC):

30. Or a pharmaceutically acceptable salt or stereoisomer thereof.

31. As claimed in claim 23, wherein the compound is selected from:

31. Or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

32. For any of claims 23 to 31, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, heart cancer, cervical cancer, colorectal cancer, rectal cancer, esophageal cancer, fibrosarcoma, stomach cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma cancer, thymic cancer, lung cancer, ovarian cancer and prostate cancer.

33. Use of a pharmaceutical composition in the preparation of a medicament for treating and inhibiting cancers associated with the BCL-2 protein, the pharmaceutical composition comprising the compound of any one of claims 23 to 31, a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

34. As claimed in claim 33, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, heart cancer, cervical cancer, colorectal cancer, rectal cancer, esophageal cancer, fibrosarcoma, stomach cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma cancer, thymic cancer, lung cancer, ovarian cancer and prostate cancer.

35. As claimed in claim 33, wherein the pharmaceutical composition further comprises additional pharmaceutical active agents.

36. As claimed in claim 35, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, heart cancer, cervical cancer, colorectal cancer, rectal cancer, esophageal cancer, fibrosarcoma, stomach cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma cancer, thymic cancer, lung cancer, ovarian cancer and prostate cancer.

37. The use of any of the claims 1-9, 12-20, 23-31, wherein the system is a mammal.

38. As requested in any of items 1-9, 12-20, 23-31, where the system is human.

39. As used in any of the claims 1-9, 12-20, 23-31, wherein the BCL-2 protein is isotype 1.

40. As used in any of the claims 1-9, 12-20, 23-31, wherein the BCL-2 protein is isotype 2.