Sulfur-containing heteroaromatic ring compound, pharmaceutical composition thereof, and use thereof

Abstract

The present invention discloses a sulfur-containing heteroaromatic ring compound, its pharmaceutical composition and its use. Specifically, the present invention discloses a compound represented by formula (I), its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt. The sulfur-containing heteroaromatic ring compound described in the present invention has good PARG inhibitory activity. 【Chemical 1】 TIFF2025523698000105.tif56169

Description

Technical Field

[0001] This application claims priority from Chinese Patent Application No. 2022108455508, filed on July 19, 2022, Chinese Patent Application No. 2022109244222, filed on August 2, 2022, Chinese Patent Application No. 2022110438233, filed on August 29, 2022, Chinese Patent Application No. 2022110772559, filed on September 7, 2022, Chinese Patent Application No. 2022112391509, filed on October 13, 2022, Chinese Patent Application No. 2022112986321, filed on October 21, 2022, Chinese Patent Application No. 2022113653922, filed on November 2, 2022, Chinese Patent Application No. 2023100231325, filed on January 6, 2023, Chinese Patent Application No. 2023102534040, filed on March 16, 2023, Chinese Patent Application No. 2023106179387, filed on May 29, 2023, Chinese Patent Application No. 2023108003365, filed on July 3, 2023 and claims the priority of the above Chinese patent applications. The entire text of the above Chinese patent applications is incorporated herein by reference.

[0002] The entire text of the above Chinese patent applications is incorporated herein by reference. [Technical Field] The present invention relates to sulfur-containing heteroaromatic ring compounds, pharmaceutical compositions thereof, and their uses.

Background Art

[0003] Cancer is caused by the uncontrolled and unregulated growth of cells. Usually, as a result of such rapid growth, a high level of oxidative stress occurs within the tumor, which damages DNA and leads to a significant increase in the DNA mutation rate. Therefore, the survival of tumor cells largely depends on the DNA damage repair mechanism.

[0004] Single-strand breaks (SSBs) in DNA are the most common type of damage in cells, and in the single-strand break repair (SSBR) mechanism and the base excision repair (BER) mechanism, PARG (Poly ADP-ribose Glycohydrolase) and PARP (Poly ADP-ribose Polymerase) are involved in repair together with many other proteins. When other DNA repair mechanisms do not function, cancer cells may become dependent on specific DNA repair pathways. Tumors with protein mutations involved in double-strand break repair are generally sensitive to PARP inhibitors of SSBR.

[0005] Many clinical trials are currently being conducted on PARP inhibitors to explore the concept of synthetic lethality or chemosensitization. Since clinical resistance to PARP inhibitors has been reported, it is necessary to find alternative inhibitors targeting the DNA damage repair mechanism. Since PARG knockout reduces the SSBR rate to the same extent as PARP 1 knockout, PARG inhibition may have therapeutic advantages in PARP inhibitor-resistant cells. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to solve the defect that the types of PARG inhibitors in the prior art are insufficient, and to provide a sulfur-containing heteroaromatic ring compound with a novel structure, its pharmaceutical composition and its use. The sulfur-containing heteroaromatic ring compound of the present invention has good PARG inhibitory activity.

[0007] The present invention solves the above technical problem by the following technical solutions.

[0008] The present invention provides a compound represented by formula (I), its pharmaceutically acceptable salt, its solvate or its solvate of the pharmaceutically acceptable salt,

[0009]

Chemical formula

[0010] Among them, X1 and X2 are independently N or CR7, R7 is independently hydrogen, deuterium, halogen, CN, OH, NR a R b , a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more R 7-2 and is, R a and R b are independently hydrogen or a C1-C6 alkyl group, R 7-2 is independently deuterium, halogen, CN, OH or NR a R b and is, R8 is hydrogen or halogen, R1 is hydrogen, deuterium, halogen, OH, CN, NR a R b , a C2-C4 alkynyl group, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more R 1-2 and is, R 1-2 is independently deuterium, halogen, OH or NR a R b and is, R2 is hydrogen, deuterium, OH, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkyl group substituted with one or more R 2-1 or a C3-C6 cycloalkyl group substituted with one or more R 2-2 and is, R 2-1 and R 2-2 are independently deuterium, OH, halogen or NR a R b and is, R3 is hydrogen, deuterium, OH, NR a R b , a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more R 3-2 and is, R 3-2 is independently deuterium, OH, NR aR b is hydrogen or halogen, X3 is N-(C=O)-L-CR5R6-OR 11 or N-(C=O)-(C=O)-R 12 wherein, L is (CR9R 10 )m, R9 and R 10 are independently hydrogen, deuterium, OH, CN, N(R 9-1 )2, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more R 9-2 ; R 9-1 are independently hydrogen or a C1-C6 alkyl group, R 9-2 are independently deuterium, OH, N(R 9-1 )2 or halogen, m is 0 or 1, R5 and R6 are independently hydrogen, deuterium, OH, CN, NR a R b , a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkyl group substituted with one or more R 5-2 or a C3-C6 cycloalkyl group substituted with one or more R 5-3 ; R 5-2 and R 5-3 are independently deuterium, OH, NR a R b or halogen, alternatively, R5 and R6 together with the carbon atom to which they are attached form a C3-C6 cycloalkyl group, a 3-6 membered heterocycloalkyl group, a C3-C6 cycloalkyl group substituted with one or more R 5-3 or a 3-6 membered heterocycloalkyl group substituted with one or more R 5-4 , each "3-6 membered heterocycloalkyl group" has independently 1 or 2 heteroatoms, and the types of heteroatoms are independently one or more selected from N, O and S, R 5-3 and R 5-4 are independently deuterium, hydroxy group, NR aR b is a halogen, or R 11 is hydrogen, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one or more halogens, R 12 is NR a R b , a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkyl group substituted with one or more R 12-1 or a C3-C6 cycloalkyl group substituted with one or more R 12-2 . R 12-1 and R 12-2 are independently halogen, OH, CN or NR a R b .

[0011] In some preferred embodiments of the present invention, some groups of the compounds represented by the above formula (I), their pharmaceutically acceptable salts, their solvates and solvates of their pharmaceutically acceptable salts are defined as follows, and the groups not mentioned are as described in any one form of the present invention (abbreviated as "in one form of the present invention").

[0012] In one form of the present invention, each "halogen" may independently be F, Cl, Br or I, for example F.

[0013] In one form of the present invention, each "C1-C6 alkyl group" may independently be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group, an ethyl group, an isopropyl group or a tert-butyl group.

[0014] In one form of the present invention, each "C2-C4 alkynyl group" may independently be an ethynyl group, a propynyl group or a propargyl group, for example an ethynyl group.

[0015] In one embodiment of the present invention, each "C3-C6 cycloalkyl group" may independently be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, for example, a cyclopropyl group.

[0016] In one embodiment of the present invention, each "3-6 membered heterocycloalkyl group" is independently a 3-6 membered heterocycloalkyl group having 1 or 2 heteroatoms and the heteroatom species being N and / or O, for example, an oxiranyl group, an aziridinyl group, an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group.

[0017] In one embodiment of the present invention, X2 is CR7.

[0018] In one embodiment of the present invention, R7 is independently hydrogen or halogen.

[0019] In one embodiment of the present invention, R8 is hydrogen.

[0020] In one embodiment of the present invention, R1 is hydrogen, CN, a C2-C4 alkynyl group or a C1-C6 alkyl group, preferably CN, a C2-C4 alkynyl group or a C1-C6 alkyl group, more preferably CN or a C1-C6 alkyl group.

[0021] In one embodiment of the present invention, R2 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three Rs 2-1 and is preferably a methyl group or a methyl group substituted with one, two or three Rs 2-1 and more preferably a methyl group substituted with one, two or three Rs 2-1 and is preferably a methyl group substituted with one, two or three Rs.

[0022] In one embodiment of the present invention, R 2-1 is halogen.

[0023] In one embodiment of the present invention, R2 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three R 2-1 wherein R 2-1 is halogen, preferably, R2 is a methyl group or a methyl group substituted with one, two or three R 2-1 wherein R 2-1 is halogen, more preferably, R2 is a methyl group substituted with one, two or three R 2-1 wherein R 2-1 is halogen.

[0024] In one embodiment of the present invention, R3 is hydrogen, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three R 3-2 wherein preferably it is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three R 3-2 and more preferably it is a methyl group or a methyl group substituted with one, two or three R 3-2 .

[0025] In one embodiment of the present invention, R 3-2 is independently halogen.

[0026] In one embodiment of the present invention, R3 is hydrogen, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three R 3-2 wherein R 3-2 is independently halogen, preferably, R3 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three R 3-2 wherein R 3-2 is independently halogen, more preferably, R3 is a methyl group or a methyl group substituted with one, two or three R 3-2 wherein R 3-2 is independently halogen.

[0027] In one embodiment of the present invention, R9 and R10 is independently hydrogen, N(R 9-1 )2 or a C1-C6 alkyl group, for example, N(R 9-1 )2 or a C1-C6 alkyl group, preferably a C1-C6 alkyl group.

[0028] In one embodiment of the present invention, R 9-1 is independently hydrogen.

[0029] In one embodiment of the present invention, R9 and R 10 are independently N(R 9-1 )2 or a C1-C6 alkyl group, and R 9-1 is independently hydrogen.

[0030] In one embodiment of the present invention, R 10 is hydrogen.

[0031] In one embodiment of the present invention, m is 0.

[0032] In one embodiment of the present invention, R5 and R6 are independently hydrogen, deuterium, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkyl group substituted with one, two or three R 5-2 or a C3-C6 cycloalkyl group substituted with one, two or three R 5-3 , preferably hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group or a C1-C6 alkyl group substituted with one, two or three R 5-2 , more preferably a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three R 5-2 .

[0033] In one embodiment of the present invention, R 5-2 and R 5-3 are independently OH or halogen, preferably halogen.

[0034] In one embodiment of the present invention, R5 and R6 are independently hydrogen, deuterium, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkyl group substituted with one, two or three Rs 5-2 or a C3-C6 cycloalkyl group substituted with one, two or three Rs 5-3 , and R 5-2 and R 5-3 are each independently OH or halogen, preferably, R5 and R6 are independently hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group or a C1-C6 alkyl group substituted with one, two or three Rs 5-2 , and R 5-2 is independently OH or halogen, more preferably, R5 and R6 are independently a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three Rs 5-2 , and R 5-2 is independently halogen.

[0035] In one embodiment of the present invention, R5 is hydrogen or a C1-C6 alkyl group, R6 is hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group or a C1-C6 alkyl group substituted with one or more Rs 5-2 , and R 5-2 is independently OH or halogen.

[0036] In one embodiment of the present invention, X1 and X2 are independently N or CR7, R7 is independently hydrogen or halogen, R8 is hydrogen or halogen, R1 is CN, a C2-C4 alkynyl group or a C1-C6 alkyl group, R2 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three Rs 2-1 , R 2-1 is halogen, R3 is hydrogen, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three Rs 3-2is a C1-C6 alkyl group substituted with, R 3-2 is independently halogen, X3 is N-(C=O)-L-CR5R6-OR 11 or N-(C=O)-(C=O)-R 12 and L is (CHR9)m, R9 is N(R 9-1 )2 or a C1-C6 alkyl group, R 9-1 is independently hydrogen, m is 0 or 1, R5 and R6 are independently hydrogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C1-C6 alkyl group substituted with one, two or three R 5-2 and R 5-2 is independently OH or halogen, R 11 is hydrogen, a C1-C6 alkyl group or a C1-C6 alkyl group substituted with one, two or three halogens, R 12 is N(R 12-1 )2, a C1-C6 alkyl group or a C3-C6 cycloalkyl group, R 12-1 is independently hydrogen.

[0037] In certain embodiments of the present invention, X1 is N or CH.

[0038] In certain embodiments of the present invention, X2 is N, CH or CF, preferably CH or CF.

[0039] In certain embodiments of the present invention,

[0040]

Chemical formula

[0041] is

[0042] [Chemical]

[0043] , for example

[0044] [Chemical]

[0045] is.

[0046] In one embodiment of the present invention, R8 is H or F, preferably H.

[0047] In one embodiment of the present invention, R1 is hydrogen, CN, ethynyl group or methyl group, for example, CN, ethynyl group or methyl group, preferably CN or methyl group, more preferably CN.

[0048] In one embodiment of the present invention, R2 is methyl group or CHF2, preferably CHF2.

[0049] In one embodiment of the present invention, R3 is hydrogen, methyl group or CH2F, preferably methyl group or CH2F.

[0050] In one embodiment of the present invention,

[0051] [Chemical]

[0052] is

[0053] [Chemical]

[0054] is, for example,

[0055] [Chemical]

[0056] It is.

[0057] In one aspect of the present invention, R5 is hydrogen or methyl.

[0058] In one form of the present invention, R6 is hydrogen, a methyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, a methyl group substituted with one, two or three fluorines, a tert-butyl group substituted with one, two or three fluorines or a tert-butyl group substituted with one, two or three OHs, for example, hydrogen, a methyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, CF3,

[0059]

Chemical formula

[0060] It is.

[0061] In one form of the present invention, R6 is a methyl group, a tert-butyl group, a methyl group substituted with one, two or three fluorines or a tert-butyl group substituted with one, two or three fluorines, for example, a methyl group, a tert-butyl group, CF3,

[0062]

Chemical formula

[0063] It is.

[0064] In one form of the present invention, R5 is hydrogen or a methyl group, R6 is hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a cyclopropyl group, a methyl group substituted with one, two or three fluorines, a tert-butyl group substituted with one, two or three fluorines or a tert-butyl group substituted with one, two or three OHs, for example, hydrogen, a methyl group, an isopropyl group, a tert-butyl group, a cyclopropyl group, CF3,

[0065]

Chemical formula

[0066] and so on.

[0067] In one embodiment of the present invention, R5 is hydrogen or a methyl group, R6 is a methyl group, a tert-butyl group, a methyl group substituted with one, two or three fluorines or a tert-butyl group substituted with one, two or three fluorines, for example, a methyl group, a tert-butyl group, CF3,

[0068]

Chemical formula

[0069] and so on.

[0070] In one embodiment of the present invention, R 11 is hydrogen, a methyl group, an ethyl group or a methyl group substituted with one, two or three fluorines, for example, hydrogen, a methyl group, an ethyl group or CHF2.

[0071] In one embodiment of the present invention, R 12 is an isopropyl group, an amino group, a cyclopropyl group, a tert-butyl group or a methyl group.

[0072] In one embodiment of the present invention,

[0073] [Chemistry]

[0074] is

[0075] [Chemistry]

[0076] as follows.

[0077] In certain embodiments of the present invention, the compound represented by the above formula (I) is a compound represented by formula (I-1), (I-2) or (I-3),

[0078] [Chemistry]

[0079] wherein, when the carbon atom marked with "*" is an asymmetric carbon atom, it is independently in the R configuration, S configuration or a mixture thereof, and the definitions of X1, X2, R8, R1, R2, R3, R 10 , R5, R6, R 11 and R 12 are as described in any one of the above embodiments.

[0080]

[0081] [Chemistry]

[0082] wherein, when the carbon atom marked with "*" is an asymmetric carbon atom, it is independently in the R configuration, S configuration or a mixture thereof, and R1, R2, R7, R5, R6, R 11 11 and R12 The definition is as described in any one of the above forms, Preferably, the above formulas are I: R2 is CHF2, and II: R1 is CN, satisfy one or both of the following conditions.

[0083] In one embodiment of the present invention, the compound represented by (I) above is any one of the following compounds.

[0084]

Chemical formula

[0085] The present invention further provides a pharmaceutical composition comprising a substance X which is a compound represented by formula (I) described in any one of the above aspects, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.

[0086] The present invention further provides the use of the above substance X or the above pharmaceutical composition in the preparation of a PARG inhibitor.

[0087] The present invention further provides the use of the above substance X or the above pharmaceutical composition in the preparation of a drug for a disease related to PARG, preferably, the disease related to PARG is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or gastric cancer.

[0088] The present invention further provides the use of the above-mentioned substance X or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating cancer. Preferably, the above-mentioned cancer is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or gastric cancer.

[0089] Unless otherwise specified, the terms used in the present invention have the following meanings.

[0090] Those skilled in the art can understand that, in accordance with the conventions used in this field, the

[0091]

Chemical formula

[0092] used in the structural formula of the group described in the present invention refers to that the corresponding group is linked to other fragments or groups in the compound through this site.

[0093] In the present specification, the substituents used may be attached with a single dash "-", indicating that the named substituent is attached to the parent moiety through a single bond.

[0094] The term "plural" refers to two, three or four.

[0095] The term "halogen" refers to F, Cl, Br or I.

[0096] The term "alkyl group" refers to a straight-chain or branched-chain alkyl group having a predetermined number of carbon atoms (for example, C1-C6). Examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, isobutyl group, sec-butyl group and alkyl groups such as those.

[0097] The term "alkynyl group" refers to a straight-chain or branched-chain hydrocarbon group having one or more triple bonds with a specific number of carbon atoms (for example, C2-C4). The one or more carbon-carbon triple bonds may be internal or terminal.

[0098] The term "cycloalkyl group" refers to a saturated cyclic group having a predetermined number of ring carbon atoms (e.g., C3-C6) and consisting only of carbon atoms as ring atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.

[0099] The term "heterocycloalkyl group" refers to a saturated cyclic group having a predetermined number of ring atoms (e.g., 3-6 members), a predetermined number of heteroatoms (e.g., one or two), and a predetermined type of heteroatoms (one, two, or three of N, O, and S). Examples of heterocycloalkyl groups include, but are not limited to, oxiranyl group, aziridinyl group, oxetanyl group, azetidinyl group, tetrahydropyrrolyl group, tetrahydrofuranyl group, tetrahydropyranyl group, piperidinyl group, morpholinyl group, or piperazinyl group, etc.

[0100] When any variable (e.g., R 2-1 ) appears multiple times in the definition of a compound, the definitions appearing at each position of the variable are independent of the definitions appearing at other positions, and their meanings are independent of each other and do not affect each other.

[0101] The term "pharmaceutically acceptable salt" refers to a salt obtained by preparing a compound according to the present invention with a pharmaceutically acceptable acid or base that is relatively non-toxic. When a compound according to the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of such a compound in a pure solution or a suitable inert solvent. When a compound according to the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of such a compound in a pure solution or a suitable inert solvent.

[0102] The term "solvate" refers to a substance formed by combining a compound according to the present invention with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may be present in an ordered arrangement or a disordered arrangement.

[0103] As described above, the "pharmaceutically acceptable salt" and "solvate" in the term "pharmaceutically acceptable salt solvate" refer to a substance obtained by preparing a compound according to the present invention with a pharmaceutically acceptable acid or base having relatively low toxicity and combined with a stoichiometric or non-stoichiometric solvent.

[0104] The term "pharmaceutically acceptable auxiliary materials" refers to excipients and additives used in the manufacture and formulation of pharmaceuticals, and includes all substances contained in pharmaceutical preparations except the active ingredient. Reference can be made to the fourth part of the Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0105] In the present invention, the above-mentioned "inhibitor" may be used in vivo in mammals, or mainly for experimental purposes, for example, to provide a comparison as a standard sample or a control sample, or to be used in vitro as manufactured in a reagent kit according to the usual methods in this field.

[0106] The term "treatment" refers to therapeutic treatment. When referring to a specific disease or condition, treatment means (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points of the biological cascade that causes or triggers the condition or (b) one or more biological manifestations of the condition, (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment, or (4) alleviating the progression of the condition or one or more biological manifestations of the condition.

[0107] The term "prevention" means that the risk of suffering from or developing a disease or disorder is reduced.

[0108] The positive progressive effect of the present invention is that the compound according to the present invention has good inhibitory activity against PARG.

Mode for Carrying Out the Invention

[0109] Hereinafter, the present invention will be further described by way of examples, but the present invention is not limited to the scope of the described examples. In the following examples, experimental methods for which specific conditions are not specified are selected according to ordinary methods and conditions or the product manuals.

[0110] The reagents and raw materials used in the present invention are all commercially available or prepared by referring to WO2021055744A1, for example, referring to Reference 4-5 in WO2021055744A1 and the intermediate methods of related compounds following it.

[0111] Example 1

[0112]

Chemical formula

[0113] At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (158.0 mg, 0.42 mmol), N,N-diisopropylethylamine (134.0 mg, 1.04 mmol), and (R)-2-hydroxypropionic acid (22.5 mg, 0.25 mmol) were added to a solution of compound EVO29284-1 (100.0 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL), and the reaction solution was stirred at 25 °C for 2 hours. The reaction solution was separated and purified by a reverse-phase column (methanol:water = 1:1) to obtain EVO29284 (50.0 mg, yield 43.00%). LCMS (ESI) m / z = 553.0 [M+H] + 。 1HNMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.51 (s, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.18 (s, 1H), 5.07 (d, J = 6.8 Hz, 1H), 4.51 (p, J = 6.5 Hz, 1H), 3.89 - 3.70 (m, 4H), 3.47 (d, J = 13.1 Hz, 4H), 1.45 (dd, J = 8.2, 5.5 Hz, 2H), 1.32 (dd, J = 8.3, 5.5 Hz, 2H), 1.25 (d, J = 6.5 Hz, 3H).

[0114] Example 2

[0115] [Chemical formula]

[0116] At room temperature, compound EVO292825-1 (120.0 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), (R)-2-hydroxypropionic acid (26.0 mg, 0.29 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (184.0 mg, 0.49 mmol), and N,N-diisopropylethylamine (156.0 mg, 1.21 mmol) were added, and the reaction was carried out at room temperature for 2 hours. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain EVO29285 (30.0 mg, yield 22.00%). LCMS (ESI) m / z = 567.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.87 (s, 1H), 8.48 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.15 (s, 1H), 5.03 (s, 1H), 4.55 (d, J = 71.9 Hz, 2H), 4.09 - 3.62 (m, 3H), 3.29 (s, 3H), 1.47 - 1.43 (m, 2H), 1.32 (d, J = 2.6 Hz, 2H), 1.25 (d, J = 6.5 Hz, 5H).

[0117] Example 3

[0118]

Chemical Structure

[0119] At room temperature, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (178.0 mg, 0.47 mmol), N,N-diisopropylethylamine (201.0 mg, 1.56 mmol), and L-lactic acid (77.0 mg, 0.38 mmol, 90% in water) were added to a solution of compound EVO29334-1 (150.0 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 2 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain EVO29334 (95.0 mg, yield 56.0%). LCMS (ESI) m / z = 567.1 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.86 (s, 1H), 8.48 (d, J = 10.2 Hz, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.15 (d, J = 10.1 Hz, 1H), 4.97 (d, J = 7.2 Hz, 1H), 4.76 - 4.27 (m, 2H), 4.08 - 3.61 (m, 3H), 3.14 (t, J = 46.9 Hz, 2H), 1.44 (d, J = 2.7 Hz, 3H), 1.34 - 1.26 (m, 4H), 1.22 (dd, J = 11.1, 5.7 Hz, 3H).

[0120] Example 4

[0121]

Chem.

[0122] Step 1: At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol), N,N-diisopropylethylamine (130.0 mg, 1.01 mmol), and (2R)-3-methyl-2-hydroxybutyric acid (29.0 mg, 0.24 mmol) were added to a solution of compound EVO29335-1 (100.0 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was separated and purified by reverse-phase column (methanol:water = 1:1) and silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain EVO29335 (25.0 mg, yield 20.8%). LCMS (ESI) m / z = 595.1 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.48 (s, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.16 (s, 1H), 4.98 (d, J = 79.1 Hz, 1H), 4.53 (t, J = 59.4 Hz, 1H), 4.15 - 3.98 (m, 2H), 3.91 - 3.61 (m, 3H), 3.18 (d, J = 8.3 Hz, 1H), 2.06 - 1.85 (m, 1H), 1.51 - 1.40 (m, 3H), 1.31 (t, J = 6.5 Hz, 4H), 1.24 (s, 1H), 0.89 (t, J = 7.4 Hz, 6H).

[0123] Example 5

[0124]

Chemical formula

[0125] Step 1: At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol), N,N-diisopropylethylamine (130.0 mg, 1.01 mmol), and 2-methyl-2-hydroxypropionic acid (25.0 mg, 0.24 mmol) were added to a solution of compound EVO29339-1 (100.0 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was separated and purified by reverse-phase column (methanol: water = 1:1) and silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain EVO29339 (24.4 mg, yield 20.8%). LCMS (ESI) m / z = 581.0 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.87 (s, 1H), 8.46 (s, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.15 (s, 1H), 5.51 (s, 1H), 4.75 (d, J = 54.5 Hz, 1H), 3.84 (d, J = 12.1 Hz, 1H), 3.73 (d, J = 12.3 Hz, 1H), 3.34 (s, 1H), 3.10 (d, J = 119.6 Hz, 3H), 1.55 - 1.42 (m, 3H), 1.36 (d, J = 7.1 Hz, 6H), 1.31 (dd, J = 8.0, 5.3 Hz, 4H).

[0126] Example 6

[0127]

Chem.

[0128] Step 1: At room temperature, compound EVO29001A3 (2.24 g, 5.49 mmol), acetic acid (20 mL), and water (5 mL) were added to a flask. Under nitrogen gas protection, the temperature was lowered to 0 °C, and N-chlorosuccinimide (879.7 mg, 6.59 mmol) was added. The mixture was stirred at 0 °C to 25 °C for 12 hours. It was detected by TLC that no raw material remained. Water (60 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (75 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a solid crude product. It was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 50%) to obtain pale yellow solid EVO29103A1 (1.70 g, yield 80.00%), and there was no response in LCMS.

[0129] Step 2: 1-Amino-1-cyclopropyl cyanide hydrochloride (2.31 g, 19.48 mmol) and anhydrous pyridine (20 mL) were stirred in an ice-water bath, and compound EVO29103A1 (2.50 g, 6.49 mmol) was added to the flask. The reaction was carried out at room temperature for 2 hours. It was detected by LCMS that the reaction was complete. The reaction solution was concentrated to obtain a yellow oily substance, which was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 50%) to obtain yellow solid EVO29103A2 (1.55 g, yield 51.73%). LCMS (ESI) m / z = 431.0 [M+H]+.

[0130] Step 3: EVO29103A2 (1.25 g, 2.90 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.97 g, 1.16 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (1.08 g, 2.32 mmol), cesium carbonate (8.72 g, 2.84 mmol), and 1,4-dioxane (45 mL) were added to the reaction flask. Under the protection of nitrogen gas, the mixture was stirred at 90 °C in an oil bath for 3 hours. The reaction mixture was filtered through filter paper and washed with ethyl acetate (10 mL × 3). The filtrate was concentrated under reduced pressure, and the remaining oily substance was separated and purified by silica gel column chromatography (methanol / dichloromethane = 0 - 25%) to obtain yellow foam EVO29103A3 (1.20 g, yield 71.00%). LCMS (ESI) m / z = 581.0 [M+H] + 。

[0131] Step 4: EVO29103A3 (200 mg, 0.34 mmol) was added to a reaction flask, and ethyl acetate (1 mL) was added. While stirring in an ice-water bath, a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added, and the temperature was raised to room temperature and stirred for 2 hours. The reaction was detected to have reacted completely, and the reaction solution was concentrated under reduced pressure to obtain the crude product EVO29103A4, which was used directly in the next step. LCMS (ESI) m / z = 481.0 [M+H] + 。

[0132] Step 5: EVO29103A4 (90 mg, 0.19 mmol), glycolic acid (20 mg, 0.23 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (100 mg, 0.38 mmol), N,N-diisopropylethylamine (73 mg, 0.57 mmol), and N,N-dimethylformamide (3 mL) were added to a reaction flask. Stirred at room temperature for 2 hours, and it was detected by LCMS that the reaction was complete. Water (30 mL) was added to the reaction solution, and it was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with water, dried, rotary evaporated, and purified by silica gel column chromatography (methanol / dichloromethane = 0 - 10%) to obtain the white solid EVO29103 (8.6 mg, yield 9.30%). LCMS (ESI) m / z = 538.8 [M+H] + 。 1 H NMR (DMSO-d6, 400 MHz): δ 9.39 (s, 1H), 8.95 (s, 1H), 8.49 (s, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.16 (s, 1H), 4.71 (t, J = 5.5 Hz, 1H), 4.18 (d, J = 5.5 Hz, 2H), 3.70 (d, J = 42.7 Hz, 4H), 3.46 (s, 4H), 2.03 - 1.95 (m, 2H), 1.45 (m, 2H).

[0133] Example 7

[0134] [Chemical formula]

[0135] Step 1: Dissolve EVO29336A1 (5.00 g, 20 mmol) in 1,2 - dioxane (60 mL), add 2 - bromo - 5 - methyl - 1,3,4 - thiadiazolyl (11.00 g, 60.07 mmol), N,N - dimethylcyclohexanediamine (2.84 g, 20 mmol), copper(I) iodide (1.90 g, 10.00 mmol), and potassium phosphate (12.90 g, 60.07 mmol). React with stirring at 90 °C for 35 h under nitrogen gas protection, cool to room temperature, add aqueous ammonia (150 mL), stir at room temperature for 30 min, filter, extract the filtrate with ethyl acetate (100 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and slurry with methanol (50 mL) to obtain EVO29336A2 (3.00 g, yield 40.00%). LCMS (ESI) m / z = 372.7 [M + H] + .

[0136] Step 2: Dissolve EVO29336A2 (7.20 g, 19.35 mmol) in acetonitrile (40 mL) at 0 °C, add acetic acid (4.5 mL) and water (1.7 mL), add 1,3 - dichloro - 5,5 - dimethylhydantoin (5.34 g, 34.83 mmol) in portions at 0 °C, react with stirring at 0 °C for 1 h, rotary - dry the filtrate to obtain a pale - yellow solid EVO29336A3 (6.7 g, in theoretical yield), and use it directly in the next step without purification. There was no response in LCMS.

[0137] Step 3: At 0 °C, 1-cyanocyclopropanamine hydrochloride (1.60 g, 13.40 mmol) was added portionwise to EVO29336A3 (2.3 g, 6.72 mmol) dissolved in pyridine (67 mL). The reaction was carried out with stirring at 0 °C for 1 hour, concentrated to almost remove pyridine, ethyl acetate (100 mL) was added, 0.5 M hydrochloric acid was added at 0 °C to adjust the pH to 2, the layers were separated, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was slurried with methanol (50 mL) to obtain yellow solid EVO29336A4 (1.1 g, yield 42.30%). LCMS (ESI) m / z = 395.0 [M+H] + 。

[0138] Step 4: To EVO29336A4 (0.86 g, 2.18 mmol) dissolved in 1,4-dioxane (20 mL) were added (R)-1-N-Boc-2-methylpiperidine (1.09 g, 5.46 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (814 mg, 1.74 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (729 mg, 0.87 mmol), and cesium carbonate (3.55 g, 10.90 mmol). Protected by a nitrogen balloon, the mixture was stirred at 90 °C for 1 hour, cooled to room temperature, and directly purified by silica gel column (petroleum ether / ethyl acetate = 40:1) to obtain yellow foamy solid EVO29336A5 (1.126 g, yield 92.40%). LCMS (ESI) m / z = 559.0[M+H] + 。

[0139] Step 5: To EVO29336A5 (1.16 g, 2.07 mmol) dissolved in methanol (1.5 mL), a methanol solution of hydrogen chloride (6 mL) was added, and the reaction was carried out with stirring at room temperature for 2 hours, followed by direct concentration to obtain a yellow foamy solid EVO29336A6 (0.9 g, yield 94.80%). LCMS (ESI) m / z = 459.0 [M+H] + .

[0140] Step 6: To EVO29336A6 (90 mg, 0.20 mmol) dissolved in N,N-dimethylformamide (3 mL), D-lactic acid (36 mg, 0.39 mmol) and N,N-diisopropylethylamine (126.7 mg, 0.98 mmol) were added, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) was added in several portions, and the reaction was carried out with stirring at room temperature for 2 hours, followed by direct separation and purification by silica gel column (dichloromethane / methanol = 80:1) to obtain an almost white solid EVO29336 (25 g, yield 24.00%). LCMS (ESI) m / z = 531.1 [M+H] + . 1 1H NMR (DMSO-d6, 400 MHz): δ 9.29 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 7.10 (s, 1H), 5.11 (d, J = 59.1Hz, 1H), 4.65 (s, 1H), 4.54 - 4.42 (m, 1H), 4.17 (d, J = 126.8 Hz, 1H), 3.83 (d, J = 11.6 Hz, 1H), 3.72 (d, J = 12.3 Hz, 1H), 3.30 - 3.25 (m, 2H), 3.07 (d, J = 83.9 Hz, 1H), 2.76 (s, 3H), 1.44 (d, J = 2.7 Hz, 1H), 1.31 (dd, J = 5.0Hz, 5H), 1.25 (s, 1H).

[0141] Example 8

[0142]

Chem.

[0143] Step 1: To EVO29338A1 (90 mg, 0.20 mmol), D-lactic acid (36 mg, 0.39 mmol), and N,N-diisopropylethylamine (126.7 mg, 0.98 mmol) dissolved in N,N-dimethylformamide (3 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) was added portionwise several times, and the reaction was carried out with stirring at room temperature for 1.5 h. Water (70 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column (dichloromethane / methanol = 70:1) to obtain almost white solid EVO29338 (28.7 mg, yield 27.46%). LCMS (ESI) m / z = 520.2 [M+H] + 。 1 H NMR (DMSO-d6, 400 MHz): δ 8.72 (s, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 7.10 (s, 1H), 5.03 (m,1H), 4.65 (s, 1H), 4.50 - 4.42 (m, 1H), 4.43 - 3.85 (m, 1H), 3.83 - 3.76 (m, 1H), 3.74 - 3.66 (m, 1H), 3.32 - 3.29 (m, 1H), 3.27 - 3.22 (m, 1H), 2.75 (s,1H), 1.51 - 1.46 (m, 2H), 1.45 - 1.38 (m, 2H), 1.44 - 1.23 (m, 4H), 1.07 (s, 3H), 0.67 - 0.61 (m, 2H), 0.42 - 0.39 (m, 2H).

[0144] Example 9

[0145]

Chem.

[0146] Step 1: At room temperature, to a 1,4-dioxane solution (8 mL) of compound 29132A3 (0.20 g, 0.41 mmol) were added methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.07 g, 0.08 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (0.075 g, 0.16 mmol), tert-butyl ((S)-3-hydroxy-1-((R)-2-methylpiperazin-1-yl)-1-oxopropan-2-yl)carbamate (0.24 g, 0.82 mmol) and cesium carbonate (0.67 g, 2.07 mmol), and the reaction mixture was stirred at 90 °C for 3 hours. The reaction mixture was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a pale yellow solid 29314A1 (82.21 mg, yield 27.00%). LCMS (ESI) m / z = 735.3 [M+H] + 。

[0147] Step 2: At room temperature, trifluoroacetic acid (0.20 mL) was added to a dichloromethane (1 mL) solution of compound 29314A1 (82.21 mg, 0.11 mmol), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to remove the solvent, and the residue was dissolved in ethyl acetate / sodium hydrogen carbonate solution, separated, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and the crude product was subjected to reverse phase preparative chromatography to obtain a pale yellow solid EVO29314 (16.30 mg, yield 23.00%). LCMS (ESI) m / z = 535.2 [M+H] + 。 11H NMR (DMSO-d6, 400 MHz): δ 8.72 (d, J = 4.5 Hz, 1H), 8.44 (d, J = 5.9 Hz, 1H), 7.12 - 7.05 (m, 1H), 4.79 - 4.65 (m, 1H), 4.50 (s, 1H), 4.33 (d, J = 14.2 Hz, 1H), 4.05 (d, J = 13.7 Hz, 1H), 3.89 - 3.61 (m, 4H), 3.55 - 3.39 (m, 2H), 3.25 (dd, J = 12.5, 3.6 Hz, 2H), 3.17 (d, J = 10.9 Hz, 1H), 2.95 (dd, J = 21.9, 11.7 Hz, 1H), 2.75 (s, 3H), 1.70 (s, 1H), 1.43 (d, J = 6.5 Hz, 1H), 1.28 (d, J = 6.9 Hz, 2H), 1.07 (s, 3H), 0.65 (q, J = 3.1 Hz, 2H), 0.43 - 0.36 (m, 2H).

[0148] Example 10

[0149]

Chem.

[0150] Step 1: EVO29038M (50.0 mg, 101.10 μmol) and (R)-2-hydroxymethylpropionic acid (11.6 mg, 111.21 μmol) were dissolved in 5 mL of N,N-dimethylformamide. N,N-Diisopropylethylamine (26.1 mg, 202.21 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42.5 mg, 111.21 μmol) were added, and the reaction was carried out at room temperature for 1.5 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), evaporated to dryness under reduced pressure, separated by medium pressure chromatography (petroleum ether / ethyl acetate = 2:1), and the fractions were evaporated to dryness to obtain 100.0 mg of a yellow oil. The product was separated and purified by preparative high performance liquid chromatography to obtain 6.2 mg of a yellow-green solid EVO29351 (yield 11.00%). LCMS (ESI) m / z = 580.9 [M+H] + 。 1 H NMR (DMSO-d6, 400 MHz): δ 9.33 (s, 1H), 8.86 (s, 1H), 8.47 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.13 (s, 1H), 4.74 (s, 1H), 4.65 (s, 1H), 4.51 - 4.23 (m, 1H), 4.03 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 9.1 Hz, 1H), 3.77 - 3.46 (m, 3H), 3.25 - 2.82 (m, 3H), 1.49 - 1.21 (m, 7H), 0.99 (s, 3H).

[0151] Example 11

[0152]

Chemical Structure

[0153] Step 1: At room temperature, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (87.0 mg, 0.31 mmol), N,N-diisopropylethylamine (80.0 mg, 0.62 mmol), and D-lactic acid (22.0 mg, 0.25 mmol) were added to a solution of compound EVO29337-1 (100.0 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was rotary evaporated to remove the solvent, an appropriate amount of water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain yellow solid EVO29337 (29 mg, yield 25%). LCMS (ESI) m / z = 556.6 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.75 (d, J = 2.7 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 4.74 - 4.27 (m, 1H), 3.95 - 3.83 (m, 1H), 3.82 - 3.64 (m, 2H), 3.56 - 3.37 (m, 1H), 3.22 (dd, J = 11.9, 3.3 Hz, 1H), 3.15 - 3.00 (m, 2H), 2.76 (s, 3H), 1.48 - 1.43 (m, 3H), 1.39 (d, J = 6.7 Hz, 2H), 1.31 (dd, J = 8.1, 5.1 Hz, 2H), 1.14 (dd, J = 9.9, 4.2 Hz, 6H).

[0154] Example 12

[0155]

Chemical Structure

[0156] Step 1: At room temperature, compound EVO29463-1 (100.0 mg, 0.20 mmol) and EVO29463-2 (46.9 mg, 0.30 mmol) were dissolved in N,N-dimethylformamide (3 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (153.9 mg, 0.40 mmol) and N,N-diisopropylethylamine (78.3 mg, 0.61 mmol) were added, and the reaction was carried out at room temperature for 2 hours. The reaction solution was added to water (20 mL) to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with water (10 mL), and then washed once with saturated brine (10 mL), concentrated, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain a yellow solid, which was further separated and purified by reverse phase column chromatography (water (0.1% formic acid): acetonitrile = 1:1), and freeze-dried to obtain the product, yellow solid EVO29463 (15 mg, yield 12%). LCMS (ESI) m / z = 635.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.45 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.13 (s, 2H), 5.46 - 5.03 (m, 1H), 4.69 (s, 2H), 3.78 (dd, J = 34.4, 13.3 Hz, 3H), 3.22 - 3.14 (m, 3H), 1.58 (d, J = 20.3 Hz, 3H), 1.38 - 1.29 (m, 4H), 1.23 (s, 3H).

[0157] Example 13

[0158]

Chemical Structure

[0159] Step 1: Compound EVO29462-1 (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (130.0 mg, 0.60 mmol) were added, and further EVO29462-2 (48.0 mg, 0.30 mmol) was added. The reaction was carried out with stirring at room temperature for 2 hours, and monitored by TLC for the absence of starting materials. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by column chromatography (petroleum ether / ethyl acetate 2:1) to obtain compound EVO29462 (15 mg, yield 11%). LCMS (ESI) m / z = 635 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.89 (s, 1H), 8.49 (d, J = 17.4 Hz, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.25 (s, 1H), 7.15 (d, J = 12.8 Hz, 1H), 4.61 (t, J = 67.4 Hz, 3H), 3.82 (dd, J = 32.3, 4H), 1.59 (s, 3H), 1.45 (dd, J = 8.0, 3H), 1.37 - 1.28 (m, 4H).

[0160] Example 14

[0161]

Chemical Structure

[0162] Step 1: Compound EVO29496-1 (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (80.0 mg, 0.60 mmol) were added, and further EVO29496-2 (50.0 mg, 0.30 mmol) was added. The reaction was carried out with stirring at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound EVO29496 (45 mg, yield 34%). LCMS (ESI) m / z = 624.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.45 (d, J = 16.2 Hz, 1H), 8.31 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.21 (s, 1H), 7.13 (s, 1H), 5.39 - 4.19 (m, 2H), 3.93 - 3.35 (m, 4H), 3.24 (s, 1H), 1.58 (s, 3H), 1.52 - 1.28 (m, 3H), 1.08 (s, 3H), 0.66 (s, 2H), 0.41 (d, J = 1.6 Hz, 2H).

[0163] Example 15

[0164]

Chemical Structure

[0165] Step 1: (R)-2-Hydroxy-3,3-dimethylbutyric acid (32.1 mg, 242.65 μM) was dissolved in 5 mL of DMF, PyBOP (115.7 mg, 222.43 μM) and DIPEA (40.9 mg, 404.42 μM) were added, and the mixture was stirred at room temperature for 10 minutes. EVO29038M (100.0 mg, 202.21 μM) was added and the reaction was carried out at room temperature for 17 hours. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, separated by medium pressure chromatography (DCM:MeOH 20:1), and the fractions were evaporated to dryness to obtain a yellow oil. The yellow oil was separated and purified by high performance liquid chromatography to obtain a yellow solid EVO29451 (19.2 mg, yield 16%). LCMS (ESI) m / z = 609.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.84 (s, 1H), 8.48 (s, 1H), 7.58 (t, J = 53.1 Hz, 1H), 7.14 (s, 1H), 4.80 (d, J = 7.5 Hz, 1H), 4.71 (s, 1H), 4.43-4.19 (m, 1H), 4.15 - 3.99 (m, 1H), 3.84 (d, J = 10.9 Hz, 1H), 3.77-3.62 (m, 2H), 3.36 (d, J = 11.2 Hz, 1H), 1.53 - 1.23 (m, 7H), 0.97 (s, 9H).

[0166] Example 16

[0167]

Chemical Structure

[0168] Compound EVO29469-1 (100 mg, 0.207 mmol), EVO29469-2 (55.2 mg, 0.42 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (152.9 mg, 0.42 mmol) and N,N-diisopropylethylamine (117.4 mg, 0.91 mmol) were dissolved in N,N-dimethylformamide (5 ml), and the reaction mixture was reacted at room temperature for 2 hours. Water (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed once with water (20 ml × 2) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain yellow solid EVO29469 (25 mg, yield 20.8%). LCMS (ESI) m / z = 570.0 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.60 (t, J = 53.0 Hz, 1H), 7.13 (s, 1H), 5.51 (s, 1H), 4.76 (d, J = 71.4 Hz, 1H), 3.78 (s, 1H), 3.73 - 3.55 (m, 2H), 3.09 (s, 2H), 1.35 (d, J = 7.9 Hz, 6H), 1.27 (s, 2H), 1.24 - 1.23 (m, 1H), 1.08 (s, 3H), 0.66 (s, 2H), 0.40 (s, 2H).

[0169] Example 17

[0170]

Chemical Structure

[0171] Step 1: Compound 1 (500.00 mg, 1.01 mmol), Compound 2 (173.00 mg, 1.52 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (577.60 mg, 1.52 mmol) and N,N-diisopropylethylamine (392.20 mg, 3.04 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction mixture was reacted at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed once with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain yellow solid Compound 3 (540.00 mg, yield 91.4%). LCMS (ESI) m / z = 591.1 [M+H] + 。

[0172] Step 2: Sodium borohydride (66.50 mg, 1.76 mmol) was slowly added to a solution of Compound 3 (520.00 mg, 0.88 mmol) in methanol (20 mL), and the mixture was reacted at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed once with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 100% ethyl acetate) to obtain yellow solid Compound 4 (430.00 mg, yield 82.5%). LCMS (ESI) m / z = 593.2 [M+H] + 。

[0173] Step 3: Compound 4 (100.00 mg, 0.17 mmol) was separated by supercritical fluid chromatography (SFC) (column: ChiralCel OX, 250×30 mm I.D., 10 μm, mobile phase: phase A was CO2, phase B was ethanol, gradient: B 40%, flow rate: 150 mL / min, back pressure: 100 bar, column temperature: 38 °C, wavelength: 220 nm, cycle time: ~9 min, injection volume: 1.00 mL), and EVO29534 (21.6 mg, retention time 1.764 minutes) and EVO29537 (46.5 mg, retention time 2.621 minutes) were obtained. LCMS (ESI) m / z = 593.2 [M+H] + 。

[0174] EVO29534: 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.87 (s, 1H), 8.48 (s, 1H), 7.63 (t, J = 52 Hz, 1H), 7.15 (s, 1H), 5.18 - 5.05 (m, 1H), 4.65 (s, 1H), 4.39 - 4.07 (m, 1H), 3.90 - 3.70 (m, 4H), 3.23 (s, 1H), 1.49 - 1.35 (m, 7H), 1.19 - 1.13 (m, 1H), 0.89 (s, 1H), 0.48 - 0.23 (m, 4H).

[0175] EVO29537: 11H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.86 (s, 1H), 8.48 (d, J = 10.5 Hz, 1H), 7.61 (t, J = 52.6 Hz, 1H), 7.16 (d, J = 11.8 Hz, 1H), 5.04 - 4.83 (m, 1H), 4.64 (d, J = 70.3 Hz, 1H), 3.98 (ddd, J = 97.0, 68.1, 55.4 Hz, 5H), 3.09 (d, J = 79.8 Hz, 2H), 1.36 (d, J = 50.6 Hz, 7H), 1.12 (s, 1H), 0.38 (d, J = 33.4 Hz, 4H).

[0176] Example 18

[0177]

Chem.

[0178] Step 1: EVO29451 (50.0 mg, 82.14 μmol) was dissolved in DMAC (3 mL), selectfluor (58.2 mg, 164.29 μmol) was added, and the reaction was carried out at 60 °C for 14 hours under argon gas protection. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by medium-pressure preparative chromatography (PE:EA 1:1), and concentrated under reduced pressure to obtain 54.0 mg of a yellow oil. It was separated and purified by high-performance liquid chromatography to obtain yellow solid EVO29757 (7.0 mg, yield 14%). LCMS (ESI) m / z = 627.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.96 (d, J = 3.6 Hz, 1H), 8.58 (d, J = 4.5 Hz, 1H), 7.62 (t, J = 53.1 Hz, 1H), 5.25 - 4.67 (m, 1H), 4.52 - 4.01 (m, 2H), 3.73 - 3.35 (m, 4H), 3.29 (s, 1H), 1.56 - 1.41 (m, 3H), 1.41 - 1.22 (m, 4H), 0.97 (s, 9H).

[0179] Example 19

[0180]

Chem.

[0181] Step 1: Under argon gas protection at -78 °C, methyl lithium (2.5 M in Diethoxymethane) (4.9 ml, 12.25 mmol) was added to a solution of compound 3-fluoro-2,2-dimethylpropionic acid hydroxy (0.7 g, 5.83 mmol) in anhydrous tetrahydrofuran (20 ml). After the addition was complete, the mixture was allowed to naturally return to room temperature and stirred for 10 h. 1 M HCl solution (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and a pale yellow oil 29751A1 (0.29 g, yield 42.1%) (crude) was obtained.

[0182] Step 2: In an ice bath, sodium hydroxide (0.2 g, 4.91 mmol) was added to an aqueous solution (10 ml) of compound 29751A1 (0.29 g, 2.45 mmol), and potassium permanganate (0.7 g, 4.42 mmol) was slowly added. The mixture was stirred at room temperature for 7 h. Ethanol (3 ml) was added to the reaction solution, and back extraction was performed with ethyl acetate. The aqueous phase was adjusted to pH = 2 with 1 M HCl and then extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and a colorless oily substance 29751A2 (0.26 g, yield 71.6%) was obtained. LCMS (ESI) m / z = 147.1 [M - 1] - .

[0183] Step 3: In an ice bath, DIPEA (0.45 g, 3.51 mmol) and PyBop (1.37 g, 2.63 mmol) were added to a DMF solution (5 ml) of compound 29751A2 (0.26 g, 1.75 mmol), and the mixture was stirred for 0.5 h. Then, 29038M (0.79 g, 1.59 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a pale yellow solid 29751A3 (0.52 g, yield 52.1%). LCMS (ESI) m / z = 625.17 [M + H] + .

[0184] Step 4: In an ice bath, NaBH4 (37 mg, 1 mmol) was added to a solution of compound 29751A3 (0.52 g, 0.83 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether), and further resolved by SFC (instrument: WATERS 150 preparative SFC (SFC-26), column: ChiralPak IG, 250×30 mm I.D., 10 μm, mobile phase: phase A was CO2, phase B was ethanol (0.1% NH3H2O), gradient: B 40%, flow rate: 150 mL / min, back pressure: 100 bar), to obtain EVO29751P1 (54 mg, yield 10.4%, retention time 2.021 minutes). LCMS (ESI) m / z = 627.17 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.86 (d, J = 4.3 Hz, 1H), 8.48 (d, J = 6.8 Hz, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.14 (dd, J = 5.2, 1.4 Hz, 1H), 5.66 - 5.22 (m, 1H), 4.76 - 4.62 (m, 1H), 4.45 - 4.33 (m, 1H), 4.32 - 4.14 (m, 3H), 3.91 - 3.65 (m, 3H), 3.36 (d, J = 4.0 Hz, 1H), 3.11 (dt, J = 64.2, 10.8 Hz, 1H), 1.44 (q, J = 4.6, 3.8 Hz, 3H), 1.31 (dd, J = 5.7, 3.5 Hz, 4H), 1.04 - 0.93 (m, 6H).

[0185] Also, EVO29751P2 (115 mg, yield 22.1%, retention time 2.792 minutes) was obtained. LCMS (ESI) m / z = 627.17 [M+H] + , 11H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.88 (d, J = 1.0 Hz, 1H), 8.48 (d, J = 12.6 Hz, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.15 (d, J = 13.9 Hz, 1H), 5.02 (dd, J = 19.2, 7.9 Hz, 1H), 4.81 (d, J = 7.9 Hz, 1H), 4.54 - 4.08 (m, 5H), 3.85 (d, J = 13.1 Hz, 1H), 3.73 (d, J = 12.2 Hz, 2H), 3.44 - 3.34 (m, 1H), 3.29 - 2.99 (m, 1H), 1.43 (dd, J = 12.7, 4.8 Hz, 3H), 1.30 (dd, J = 8.5, 5.2 Hz, 4H), 0.96 (dd, J = 19.5, 5.9 Hz, 6H).

[0186] Example 20

[0187]

Chemical Structure

[0188] Step 1: Compound EVO29778A0 (2.5 g, 11.56 mmol), TEA (2.3 g, 23.12 mmol) were added to DCM (25 ml). Under the protection of argon gas, CbzCl (2.1 g, 12.72 mmol) was added in an ice bath, and the mixture was stirred in the ice bath for 2 h. 1 N HCl (10 mL) was added to the system, and the mixture was extracted with DCM (10 ml × 3). The organic phase was washed with saturated sodium bicarbonate solution and saturated brine respectively, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain EVO29778A1 (3.5 g, 86.4%).

[0189] Step 2: Compound EVO29778A1 (3.5 g, 9.99 mmol), DIPEA (3.2 g, 24.97 mmol) were added to DCM (30 ml). Under the protection of argon gas, methanesulfonic anhydride (2.6 g, 14.98 mmol) was added in an ice bath, and the mixture was stirred in the ice bath for 2 h. 1 N HCl (10 mL) was added to the system, and the mixture was extracted with DCM (10 ml × 3). The organic phase was washed with saturated sodium bicarbonate solution and saturated brine respectively, and the organic phase was concentrated under reduced pressure to obtain the crude product EVO29778A2 (4.3 g).

[0190] Step 3: Compound EVO29778A2 (1.8 g, 4.20 mmol), TBAF (21 mL, 1 M in THF) were added to THF (22 ml), and the mixture was stirred at 70 o °C for 3 h. Water (20 mL) was added to the system, and the mixture was extracted with EA (10 ml × 3). The organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain EVO29778A3 (300 mg, 20.2%).

[0191] Step 4: Compound EVO29778A3 (300 mg, 4.20 mmol), Pd / C (90 mg) were added to methanol (10 ml), replaced with a hydrogen balloon, and stirred at room temperature overnight. It was filtered through diatomaceous earth, and the filtrate was rotary dried to obtain the crude product EVO29778A4 (200 mg).

[0192] Step 5: Compound EVO29778B0 (156 mg, 0.29 mmol), EVO29778A4 (64 mg, 0.29 mmol), Ruphos (109.4 mg, 0.23 mmol), RuPhos Pd G3 (98.1 mg, 0.11 mmol) and cesium carbonate (382.1 mg, 1.17 mmol) were added to 1,4-dioxane (10 ml). Under the protection of argon gas, 100 oIt was stirred in C for 4 h. Water (10 mL) was added to the system, and it was extracted with ethyl acetate (10 ml×3). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain EVO29778A5 (163 mg, 77.9%).

[0193] Step 6: Compound EVO29778A5 (163 mg, 0.22 mmol) was added to DCM (1 mL), and further TFA (2 mL) was added. It was stirred at room temperature for 4 h. A sodium bicarbonate solution was added to the system to adjust the pH to neutral, and it was extracted with DCM (10 ml×2), dried over anhydrous sodium sulfate, and rotary dried to obtain EVO29778A6 (116 mg, 100%).

[0194] Step 7: Compound EVO29778A6 (116 mg, 0.22 mmol), EVO29778B1 (44.8 mg, 0.33 mmol), and PyBOP (188.4 mg, 0.36 mmol) were added to DMF (5 mL), and further DIPEA (87.7 mg, 0.67 mmol) was added. It was stirred at room temperature overnight. Water (10 mL) was added to the system, and it was extracted with ethyl acetate (10 ml×2). The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by liquid chromatography to obtain EVO29778 (50 mg, 35.2%). LCMS: [M+H] + 627.15. 11H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.85 (d, J = 6.2 Hz, 1H), 8.55 (d, J = 15.3 Hz, 1H), 7.64 (t, J = 53.1 Hz, 1H), 7.21 (dd, J = 12.4, 1.3 Hz, 1H), 5.39 (dd, J = 176.0, 7.4 Hz, 1H), 5.03 - 4.58 (m, 3H), 4.45 (t, J = 15.4 Hz, 1H), 4.15 (d, J = 7.4 Hz, 3H), 3.77 - 3.37 (m, 1H), 3.32 - 2.96 (m, 2H), 1.47 (t, J = 4.0 Hz, 2H), 1.35 (t, J = 4.0 Hz, 2H), 1.00 (d, J = 9.0 Hz, 9H).

[0195] Example 21

[0196]

Chem.

[0197] Step 1: To the reaction flask were added compound EVO29788A0 (3.0 g, 13.02 mmol), EVO29788B0 (1.9 g, 15.62 mmol), Xantphos (1.1 g, 1.95 mmol), Pd2(dba)3 (893.9 mg, 0.97 mmol), DIPEA (5.0 g, 39.05 mmol), and 1,4-dioxane (30 mL). After replacing with argon gas three times, the mixture was heated to 90 o °C and reacted for 3 h. It was cooled to room temperature, filtered through diatomaceous earth, and rotary dried to obtain a crude product, which was purified by flash silica gel column chromatography (DCM / PE 0 - 50%) to obtain EVO29788A1 (2.3 g, 64.5%).

[0198] Step 2: Compound EVO29788A1 (2.3 g, 8.40 mmol), EVO29788B1 (2.1 g, 10.08 mmol), cesium carbonate (5.4 g, 16.8 mmol), and DMF (20 mL) were added to a reaction flask. After purging with argon gas, the mixture was heated to 60 o °C and reacted for 2 h. Water (20 ml) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (20 ml × 3). The organic phase was washed with saturated brine (20 ml), rotary evaporated to obtain a crude product, and purified by flash silica gel column chromatography (EA / PE 0 - 50%) to obtain EVO29788A2 (1.7 g, 51.9%).

[0199] Step 3: Compound EVO29788A2 (600 mg, 1.47 mmol) was added to acetonitrile / water / acetic acid (10 mL, 200:5:2.5), cooled in an ice bath, and SO2Cl2 (794.1 mg, 5.88 mmol) was slowly added. After the addition was complete, the reaction was carried out in an ice bath for 2 h. The reaction solution was concentrated to obtain EVO29788A3 (565 mg, 100%).

[0200] Step 4: Compound EVO29788A3 (565 mg, 1.47 mmol) and 1 - amino - 1 - cyclopropylcyanide hydrochloride (348.7 mg, 2.94 mmol) were added to pyridine (10 mL) and reacted overnight at room temperature. The reaction solution was washed with ethyl acetate (50 ml) with 1 N hydrochloric acid solution (10 ml × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to obtain EVO29788A4 (518 mg, 81.9%).

[0201] Step 5: Compound EVO29788A4 (518.0 mg, 1.21 mmol), Boc2O (315.6 mg, 1.45 mmol), TEA (365.8 mg, 3.62 mmol), and DMAP (14.7 mg, 0.12 mmol) were added to acetonitrile (10 mL), and the mixture was reacted at room temperature for 30 min. The reaction solution was concentrated to remove the solvent and purified by flash silica gel column chromatography (EA / PE 0 - 20%) to obtain EVO29788A5 (310 mg, 48.5%).

[0202] Step 6: Compound EVO29788A5 (190 mg, 0.35 mol), EVO29788B2 (143.6 mg, 0.71 mmol), Ruphos (133.8 mg, 0.28 mmol), RuPhos Pd G3 (119.9 mg, 0.14 mmol), and cesium carbonate (584 mg, 1.79 mmol) were added to 1,4 - dioxane (10 ml), and the mixture was stirred at 95 o °C for 4 h under argon gas protection. Water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 ml × 3). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain EVO29788A6 (180 mg, 72.3%).

[0203] Step 7: Compound EVO29788A6 (180 mg, 0.25 mmol) was added to DCM (1 ml), and then TFA (2 mL) was added. The mixture was stirred at room temperature for 2 h. A sodium bicarbonate solution was added to the system to adjust the pH to neutral, and the mixture was extracted with DCM (10 ml × 2), dried over anhydrous sodium sulfate, and rotary - dried to obtain EVO29788A7 (124 mg, 96.8%).

[0204] Step 8: Compound EVO29788A7 (124 mg, 0.25 mmol), EVO29788B3 (99.6 mg, 0.75 mmol), and PyBOP (392.2 mg, 0.75 mmol) were added to DMF (5 ml), and then DIPEA (194.8 mg, 1.51 mmol) was further added. The mixture was stirred at room temperature overnight. Water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 ml × 2). The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by preparative liquid chromatography to obtain EVO29788 (51 mg, 33.4%). LCMS: [M+H] + 608.45. 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.65 (s, 1H), 8.21 (d, J = 3.6 Hz, 1H), 7.67 (t, J = 53.1 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.07 (t, J = 4.5 Hz, 1H), 5.27 - 4.70 (m, 2H), 4.55 - 4.04 (m, 2H), 3.68 - 3.46 (m, 3H), 3.26 - 2.71 (m, 2H), 1.58 - 1.29 (m, 7H), 0.99 (d, J = 4.9 Hz, 9H).

[0205] Example 22

[0206]

Chemical Structure

[0207] Step 1: EVO29451 (500.0 mg, 0.82 mmol) and 20 mL of DMAC were added to a 100 mL single-necked flask, and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (580.0 mg, 1.64 mmol) was added. The mixture was stirred at 50 °C for 4 h. After completion of the reaction, 60 mL of water was added, and the mixture was extracted twice with 80 mL of ethyl acetate. The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and separated by medium-pressure chromatography (PE:EA = 1:1). The fraction was evaporated to dryness to obtain a yellow oil, which was separated and purified by preparative high-performance liquid chromatography to obtain yellow solid EVO29792 (45.0 mg, yield 8.7%). LCMS (ESI) m / z = 645.1 [M+H] + 。

[0208] 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 7.63 (t, J = 53.1 Hz, 1H), 4.80 (d, J = 7.5 Hz, 1H), 4.71 (s, 1H), 4.43 - 4.19 (m, 1H), 4.15 - 3.99 (m, 1H), 3.84 (d, J = 10.9 Hz, 1H), 3.77 - 3.62 (m, 2H), 3.36 (d, J = 11.2 Hz, 1H), 1.57 - 1.46 (m, 3H), 1.43 - 1.26 (m, 4H), 0.99 (s, 9H).

[0209] Example 23

[0210]

Chemical Structure

[0211] Step 1: EVO29038M (500.0 mg, 1.01 mmol) was dissolved in DCM (10 mL), and DMAP (12.4 mg, 101.10 μmol), TEA (133.0 mg, 1.31 mmol), and Boc2O (264.8 mg, 1.21 mmol) were added. The reaction was carried out at room temperature for 2 hours. Water was added, and the mixture was extracted twice with DCM. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by medium-pressure chromatography (PE:EA = 2:1), and the fractions were evaporated to dryness to obtain yellow solid EVO29761A1 (601.0 mg, yield 99%). LCMS (ESI) m / z = 595.1 [M+H] + 。

[0212] Step 2: EVO29761A1 (300.0 mg, 504.49 μmol) was dissolved in DMAC (4 mL), and selectfluor (357.4 mg, 1.01 mmol) was added. The reaction was carried out at 60 °C for 6 hours under argon gas protection. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by medium-pressure chromatography (PE:EA 1:1), and the fractions were evaporated to dryness to obtain yellow oil EVO29761A2 (168.0 mg, yield 54%). LCMS (ESI) m / z = 513.1 [M+H-Boc] + 。

[0213] Step 3: EVO29761A2 (168.0 mg, 274.22 μmol) was dissolved in DCM (1 mL), and TFA (1.5 g, 13.07 mmol) was added. The reaction was carried out at room temperature for 2 hours. Aqueous saturated sodium bicarbonate solution was added to neutralize the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow oil EVO29761A3 (118.0 mg, yield 84%).

[0214] Step 4: (S)-2-Trifluoromethyl-2-hydroxypropionic acid (36.4 mg, 230.23 μmol), EVO29761A3 (118.0 mg, 230.23 μmol) were dissolved in DMF (5 mL), TEA (35.0 mg, 345.34 μmol), HATU (113.8 mg, 299.30 μmol) were added, and the reaction was carried out at room temperature for 3 hours. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by medium pressure chromatography (PE:EA 1:1), and the fractions were evaporated to dryness to obtain 50.0 mg of a brown liquid. The liquid was separated and purified by high performance liquid chromatography to obtain yellow solid EVO29761 (9.4 mg, yield 6%). LCMS (ESI) m / z = 653.3 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.97 (d, J = 9.0 Hz, 1H), 8.58 (d, J = 4.4 Hz, 1H), 7.62 (t, J = 53.0 Hz, 1H), 7.22 (s, 1H), 5.15 - 4.74 (m, 1H), 4.74 - 4.24 (m, 1H), 3.69 (d, J = 11.4 Hz, 1H), 3.63 - 3.36 (m, 3H), 3.26 (s, 1H), 1.66 - 1.26 (m, 10H).

[0215] Example 24

[0216]

Chemical Structure

[0217] Step 1: (R)-2-Trifluoromethyl-2-hydroxypropionic acid (82.7 mg, 522.90 μmol), EVO29761A3 (134.0 mg, 261.45 μmol) were dissolved in DMF (5 mL), TEA (79.4 mg, 784.34 μmol), HATU (218.7 mg, 575.18 μmol) were added, and the reaction was carried out at room temperature for 3 hours. Water was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by medium pressure chromatography (PE:EA 1:1), and the fractions were evaporated to dryness to obtain 47.0 mg of a brown liquid. The product was separated and purified by preparative high performance liquid chromatography to obtain yellow solid EVO29762 (16.3 mg, yield 6%). LCMS (ESI) m / z = 653.3 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.58 (s, 1H), 7.61 (t, J = 53.0 Hz, 1H), 7.21 (s, 1H), 5.26 - 4.75 (m, 1H), 4.74 - 4.30 (m, 1H), 3.69 (d, J = 10.9 Hz, 1H), 3.53 (s, 1H), 3.47 - 3.35 (m, 2H), 3.19 (s, 1H), 1.65 - 1.27 (m, 10H).

[0218] Example 25

[0219]

Chemical Structure

[0220] Step 1: At -78 °C, under argon gas protection, methyl lithium (2.5 M in Diethoxymethane) (4.9 ml, 12.25 mmol) was added to a solution of hydroxy (0.8 g, 5.83 mmol) 3,3-difluoro-2,2-dimethylpropionic acid in anhydrous tetrahydrofuran (20 ml). After the addition was complete, the mixture was allowed to naturally return to room temperature and stirred for 10 h. 1 M HCl solution (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and a pale yellow oil 29752A1 (0.33 g, yield 41.9%) (crude) was obtained.

[0221] Step 2: In an ice bath, sodium hydroxide (0.19 g, 4.85 mmol) was added to a solution of compound 29752A1 (0.33 g, 2.42 mmol) in water (10 ml), and potassium permanganate (0.69 g, 4.36 mmol) was slowly added. The mixture was stirred at room temperature for 7 h. Ethanol (3 ml) was added to the reaction solution, and the mixture was back-extracted with ethyl acetate. The aqueous phase was adjusted to pH = 2 with 1 M HCl and then extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and a colorless oil 29752A2 (0.29 g, yield 72.1%) was obtained. LCMS (ESI) m / z = 165.1 [M - 1] - 。

[0222] Step 3: In an ice bath, DIPEA (0.45 g, 3.51 mmol) and PyBop (1.37 g, 2.63 mmol) were added to a solution of compound 29752A2 (0.29 g, 1.75 mmol) in DMF (5 ml), and the mixture was stirred for 0.5 h. 29038M (0.79 g, 1.59 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 4 h. The reaction solution was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain a pale yellow solid 29752A3 (0.32 g, yield 32.0%). LCMS (ESI) m / z = 643.17 [M + H] + 。

[0223] Step 4: In an ice bath, NaBH4 (22 mg, 0.59 mmol) was added to a solution of compound 29752A3 (0.32 g, 0.49 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 1 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether) and further resolved by SFC (instrument: WATERS 150 preparative SFC (SFC-26), column: ChiralPak IG, 250×30 mm I.D., 10 μm, mobile phase: phase A is CO2, phase B is ethanol (0.1% NH3H2O), gradient: B 40%, flow rate: 150 mL / min, back pressure: 100 bar) to obtain EVO29752P1 (66 mg, yield 20.6%, RT = 1.342 min). LCMS (ESI) m / z = 645.17 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.86 (d, J = 4.4 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.21 - 7.09 (m, 1H), 6.21 - 5.50 (m, 2H), 4.69 (d, J = 9.5 Hz, 1H), 4.35 (d, J = 7.5 Hz, 1H), 4.26 - 4.12 (m, 1H), 3.85 (d, J = 11.0 Hz, 1H), 3.73 (t, J = 12.6 Hz, 2H), 3.39 - 3.33 (m, 1H), 3.25 - 3.00 (m, 1H), 1.49 - 1.41 (m, 3H), 1.32 (q, J = 3.4, 2.6 Hz, 4H), 1.12 - 0.98 (m, 6H).

[0224] Also, EVO29752P2 (137 mg, yield 42.8%, RT = 1.819 min) was obtained. LCMS (ESI) m / z = 645.17 [M+H] + , 11H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.88 (d, J = 0.9 Hz, 1H), 8.48 (d, J = 13.1 Hz, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.14 (d, J = 14.5 Hz, 1H), 5.97 (t, J = 57.3 Hz, 1H), 5.34 (t, J = 9.8 Hz, 1H), 4.83 - 4.07 (m, 3H), 3.87 (t, J = 14.7 Hz, 1H), 3.73 (d, J = 12.2 Hz, 2H), 3.44 - 3.33 (m, 1H), 3.14 (dt, J = 77.5, 11.0 Hz, 1H), 1.44 (p, J = 5.5, 4.9 Hz, 3H), 1.31 (td, J = 7.5, 6.7, 4.7 Hz, 4H), 1.01 (d, J = 23.8 Hz, 6H).

[0225] Example 26

[0226]

Chem.

[0227] Step 1: (R)-2-Hydroxy-3,3-dimethylbutyric acid (82.0 mg, 620.40 μM) was dissolved in 5 mL of DMF, PyBOP (322.8 mg, 620.40 μM) and DIPEA (156.9 mg, 1.55 mM) were added, and the mixture was stirred at room temperature for 10 minutes. EVO29798A1 (250.0 mg, 517.00 μM) was added and the reaction was carried out at room temperature for 17 hours. Water was added and the mixture was extracted twice with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by medium pressure chromatography (PE:EA 1:1), and the fractions were evaporated to dryness to obtain a yellow solid (130.0 mg, yield 42%). LCMS (ESI) m / z = 598.1 [M+H] + .

[0228] Step 2: EVO29798A2 (130.0 mg, 217.50 μmol) was dissolved in DMAC (4 mL), selectfluor (123.3 mg, 348.00 μmol) was added, and the reaction was carried out at 60 °C for 6 hours under argon gas protection. Water was added to precipitate a solid, which was collected by suction filtration to obtain 140.0 mg of a yellow solid. It was separated and purified by preparative high-performance liquid chromatography to obtain yellow solid EVO29798 (24.4 mg, yield 18%). LCMS (ESI) m / z = 616.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.91 (d, J = 3.6 Hz, 1H), 8.60 (s, 1H), 8.53 (d, J = 4.6 Hz, 1H), 7.60 (t, J = 53.1 Hz, 1H), 5.18 - 4.77 (m, 1H), 4.72 (s, 1H), 4.54 - 4.18 (m, 1H), 4.16 - 3.98 (m, 1H), 3.72 - 3.35 (m, 3H), 3.29 - 3.10 (m, 1H), 1.45 (d, J = 6.5 Hz, 1H), 1.30 (d, J = 6.7 Hz, 2H), 1.15 (s, 3H), 0.96 (s, 9H), 0.76 - 0.62 (m, 2H), 0.51 - 0.39 (m, 2H).

[0229] Example 27

[0230]

Chemical formula

[0231] Step 1: A DMSO (10 mL) solution of EVO29038M (670 mg, 1.35 mmol), EVO29790A0 (433.96 mg, 3.39 mmol), and DMAP (49.65 mg, 0.406 mmol) was reacted at 110 °C overnight. The temperature was then lowered to room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the EVO29790A1 product (300 mg, yield 35.56%). LCMS (ESI) m / z = 623.22 [M+H] + 。

[0232] Step 2: Sodium borohydride (36.45 mg, 0.964 mmol) was slowly added to a methanol (10 mL) solution of compound EVO29790A1 (300.00 mg, 0.482 mmol), and the mixture was reacted at room temperature for 1 hour. Saturated ammonium chloride solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was washed once with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and rotary dried under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1 to 1:2) to obtain the product EVO29790 (180.00 mg, yield 59.81%). LCMS(ESI) m / z = 625.41 [M+H] + 。

[0233] Step 3: Compound EVO29790 (180.00 mg) was separated by supercritical fluid chromatography (SFC) (column: ChiralCel OX, 250×30 mm I.D., 10 μm, mobile phase: phase A is CO2, phase B is ethanol (0.1% NH3H2O), gradient: B 35%, flow rate: 150 mL / min, back pressure: 100 bar, column temperature: 38 °C, wavelength: 220 nm, cycle time: ~5 min, injection volume: 2.00 mL), and EVO29790P1 (65.30 mg, retention time 1.712 min) and EVO29790P2 (35.42 mg, retention time 2.722 minutes) were obtained. LCMS (ESI) m / z = 625.2 [M+H] + 。

[0234] EVO29790P1 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.90 (s, 1H), 8.50 (d, J = 8 Hz, 1H), 7.63 (t, J = 52 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 4.85 - 4.74 (m, 1H), 4.69 - 4.43 (m, 2H), 4.36 - 4.11 (m, 1H), 3.94 - 3.74 (m, 3H), 3.32 - 3.02 (m, 2H), 1.49 - 1.40 (m, 3H), 1.37 - 1.31 (m, 4H), 0.90 - 0.88 (m, 6H).

[0235] EVO29790P2 11H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.89 (s, 1H), 8.50 (s, 1H), 7.63 (t, J = 52 Hz, 1H), 7.17 (s, 1H), 4.82 (d, J = 4Hz, 1H), 4.75-4.66 (m, 2H), 4.41 - 4.23 (m, 3H), 3.89-3.86 (m, 1H), 3.80-3.63 (m, 2H), 3.25 - 3.17 (m, 2H), 1.49 - 1.46 (m, 3H), 1.35-1.30 (m, 5H), 0.91-0.89 (m, 6H).

[0236] Example 28

[0237]

Chemical formula

[0238] Step 1 To a solution of compound EVO29587A9 (500.00 mg, 0.94 mmol) in 1,4-dioxane (50 mL) were added (R)-1-N-Boc-2-methylpiperazine (282.38 mg, 0.41 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (175.44 mg, 0.38 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (157.23 mg, 0.19 mmol), and cesium carbonate (1.53 g, 4.70 mmol). Under argon gas protection, the mixture was stirred at 100 °C for 12 hours, cooled to room temperature, filtered, and the filtrate was collected. The filtrate was concentrated by distillation to remove the solvent, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain yellow solid EVO29725A1. (0.52 g, yield 79.67%). LCMS (ESI) m / z = 696.2 [M+H] + .

[0239] Step 2: At room temperature, trifluoroacetic acid (6 mL) was added to a dichloromethane solution (3 mL) of compound EVO29725A1 (0.52 g, 0.75 mmol), and the reaction solution was stirred at 25 °C for 2 hours. After completion of the reaction, saturated sodium bicarbonate was added until the pH of the reaction solution reached 8, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated by distillation to remove the solvent, and a brown solid EVO29725A2 (0.37 g, yield 95.67%) was obtained.

[0240] Step 3: At room temperature, (R)-2-hydroxy-3,3-dimethylbutyric acid (32.00 mg, 0.24 mmol), N,N-diisopropylethylamine (64.35 mg, 0.60 mmol), and 1H-benzotriazol-1-yloxytris(pyrrolidino)hexafluorophosphate (130.00 mg, 0.24 mmol) were sequentially added to an N,N-dimethylformamide solution (5 mL) of compound EVO29725A2 (0.10 g, 0.20 mmol). The reaction solution was stirred at 25 °C for 16 hours. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated by distillation to remove the solvent, and the residue was separated and purified by preparative high performance liquid chromatography to obtain a bright yellow solid EVO29725 (84.00 mg, yield 64.89%) with a purity of 98.90%. 11H NMR (400 MHz, DMSO-d6) δ 8.21 (dd, J = 7.2, 1.4 Hz, 1H), 7.22 (dd, J = 11.9, 1.5 Hz, 1H), 4.93 (d, J = 7.7 Hz, 1H), 4.77 (s, 1H), 4.47 (dd, J = 80.3, 11.9 Hz, 3H), 4.14 (d, J = 7.7 Hz, 1H), 3.66 (dd, J = 12.5, 3.6 Hz, 1H), 3.41 (d, J = 10.6 Hz, 1H), 3.21 (q, J = 12.3 Hz, 1H), 1.52 - 1.45 (m, 2H), 1.42 - 1.31 (m, 3H), 1.25 (d, J = 6.6 Hz, 2H), 0.99 (d, J = 4.2 Hz, 9H).

[0241] Example 29

[0242]

Chem.

[0243] Compound EVO29412A1 (100 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (3 mL), and EVO29412A2 (36 mg, 0.34 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (129 mg, 0.34 mmol), and N,N-diisopropylethylamine (149 mg, 1.15 mmol) were added. The mixture was reacted at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3) to obtain EVO29412 (55.1 mg, yield 43.08%). LCMS (ESI) m / z = 534.1 [M+H] + 。 11H NMR (DMSO-d6, 400 MHz): δ 8.72 (s, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 7.10 (s, 1H), 4.69 (s, 1H), 4.22 (t, J = 59.8 Hz, 2H), 3.80 (d, J = 11.2 Hz, 1H), 3.70 (d, J = 12.4 Hz, 2H), 3.30 - 3.21 (m, 4H), 3.17 - 2.87 (m, 1H), 2.75 (s, 3H), 1.45 (s, 1H), 1.28 (t, J = 10.6 Hz, 5H), 1.07 (s, 3H), 0.72 - 0.58 (m, 2H), 0.46 - 0.33 (m, 2H).

[0244] Example 30

[0245]

Chemical formula

[0246] Step 1 At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (125 mg, 0.33 mmol), N,N-diisopropylethylamine (140 mg, 1.09 mmol), and 2-methoxypropionic acid (50 mg, 0.44 mmol) were added to a solution of compound EVO29411A1 (100 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 25 °C for 1 hour. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain pale yellow solid EVO29411 (60 mg, yield 50.80%). LCMS (ESI) m / z = 545.1 [M+H] + . 11H NMR (DMSO-d6, 400 MHz) δ 9.31 (s, 1H), 8.76 (s, 1H), 8.48 (s, 1H), 7.11 (s, 1H), 4.40 (dd, J = 188.4, 62.5 Hz, 3H), 3.84 (d, J = 11.4 Hz, 1H), 3.73 (d, J = 12.5 Hz, 1H), 3.28 - 2.90 (m, 6H), 2.76 (s, 3H), 1.49 - 1.36 (m, 3H), 1.34 - 1.24 (m, 7H).

[0247] Example 31

[0248]

Chemical formula

[0249] Step 1: Compound EVO29409A1 (100 mg, 0.20 mmol), EVO29409A2 (31.5 mg, 0.30 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.3 mg, 0.30 mmol) and N,N-diisopropylethylamine (78.7 mg, 0.61 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction solution was reacted at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL × 2) and saturated brine (20 mL) respectively, dried over anhydrous sodium sulfate, and rotary dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain EVO29409 (63.3 mg, yield 54.50%). LCMS (ESI) m / z = 581.1 [M+H] + . 11H NMR (DMSO-d6, 400 MHz): δ 9.32 (s, 1H), 8.86 (s, 1H), 8.48 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.15 (s, 1H), 4.63 (d, J = 43.0 Hz, 1H), 4.16 (d, J = 83.2 Hz, 2H), 3.80 (dd, J = 51.6, 12.0 Hz, 2H), 3.29 - 2.94 (m, 5H), 1.49 - 1.19 (m, 11H).

[0250] Example 32

[0251]

Chemical Structure

[0252] Step 1: Compound key INT-1 (2.0 g, 16.9 mmol), benzyl alcohol (5 ml) and p-toluenesulfonic acid monohydrate (321.5 mg, 1.69 mmol) were dissolved in a toluene (20 ml) solution, and the reaction solution was refluxed at 115 °C for 16 hours to react. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain colorless oily key INT-2 (2.7 g, yield 7.1%). 1 1H NMR (400 MHz, DMSO) δ 7.54 - 7.20 (m, 5H), 5.33 (d, J = 5.9 Hz, 1H), 5.23 - 5.03 (m, 2H), 3.85 (t, J = 5.4 Hz, 1H), 2.01 - 1.84 (m, 1H), 0.83 (dd, J = 21.1, 6.8 Hz, 6H).

[0253] Step 2: Compound key INT-2 (2.7 g, 13.0 mmol) and 1,8-bis(dimethylamino)naphthalene (5.6 g, 25.9 mmol) were dissolved in dichloromethane (100 ml), trimethyloxonium tetrafluoroborate (3.8 g, 25.9 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, washed with dichloromethane (50 ml × 2), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give colorless oily key INT-3 (2.7 g, yield 93.4%). 1 H NMR (400 MHz, DMSO) δ 7.48 - 7.23 (m, 5H), 5.17 (q, J = 12.3 Hz, 2H), 3.62 (d, J = 5.3 Hz, 1H), 3.26 (s, 3H), 2.06 - 1.86 (m, 1H), 0.85 (dd, J = 15.1, 6.9 Hz, 6H).

[0254] Step 3: Palladium carbon (2.0 g) was added to a methanol (50 ml) solution of compound key INT-3 (2.7 g, 12.1 mmol), the reaction mixture was purged with hydrogen gas three times and stirred at room temperature for 2 h. The reaction mixture was filtered directly, washed with methanol (50 ml × 2), concentrated under reduced pressure to give crude product key INT (1.54 g, yield 96.3%), which was used directly in the next step.

[0255] Step 4: Compound EVO29418-1 (150 mg, 0.30 mmol), key INT (60.2 mg, 0.45 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (172.9 mg, 0.45 mmol) and N,N-diisopropylethylamine (117.4 mg, 0.91 mmol) were dissolved in N,N-dimethylformamide (5 ml), and the reaction mixture was reacted at room temperature for 2 hours. Water (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed once with water (20 ml × 2) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain yellow solid EVO29418 (91.5 mg, yield 50.1%). LCMS (ESI) m / z = 609.1 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 9.32 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.15 (s, 1H), 4.71 (s, 1H), 4.35 (dd, J = 73.9, 13.0 Hz, 1H), 3.86 (d, J = 10.8 Hz, 1H), 3.72 (t, J = 13.4 Hz, 2H), 3.34 - 3.10 (m, 6H), 1.96 (d, J = 6.5 Hz, 1H), 1.44 (t, J = 6.6 Hz, 3H), 1.32 (d, J = 3.2 Hz, 4H), 0.91 (dd, J = 40.1, 6.5 Hz, 6H).

[0256] Example 33

[0257]

Chemical Structure

[0258] Step 1: At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (70 mg, 0.25 mmol), N,N-diisopropylethylamine (64 mg, 0.50 mmol), and EVO29419-2 (26 mg, 0.20 mmol) were added to a solution of compound EVO29419-1 (80 mg, 0.16 mmol) in N,N-dimethylformamide (2 ml). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was rotary evaporated to remove the solvent, water (20 ml) was added, and the mixture was extracted with ethyl acetate (3 × 20 ml). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain yellow solid EVO29419 (34.7 mg, yield 36%). LCMS (ESI) m / z = 598.7 [M+H] + 。 1 H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.14 (s, 1H), 4.72 (s, 1H), 4.35 (dd, J = 72.3, 13.1 Hz, 1H), 3.88 - 3.59 (m, 4H), 3.29 - 2.95 (m, 5H), 1.98 (d, J = 7.2 Hz, 1H), 1.43 (s, 1H), 1.32 (d, J = 6.1 Hz, 2H), 1.08 (s, 3H), 0.96 (d, J = 6.3 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.66 (s, 2H), 0.40 (s, 2H).

[0259] Example 34

[0260]

Chemical formula

[0261] Step 1: Compound EVO29410-1 (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (130.0 mg, 0.60 mmol) were added, and further EVO29410-2 (35.0 mg, 0.20 mmol) was added. The reaction was carried out with stirring at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate 1:1) to obtain compound EVO29410 (5 mg, yield 4%). LCMS (ESI) m / z = 570 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 7.61 (t, J = 53.0 Hz, 1H), 7.15 (s, 1H), 4.64 (d, J = 42.6 Hz, 1H), 4.17 (d, J = 82.9 Hz, 2H), 3.78 (dd, J = 46.2, 5H), 3.26 (s, 3H), 1.45 (s, 6H), 1.09 (s, 3H), 0.67 (s, 2H), 0.42 (s, 2H).

[0262] Example 35

[0263]

Chemical Structure

[0264] Step 1: Compound EVO29420-1 (100.0 mg, 0.22 mmol), key INT (43.2 mg, 0.33 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (124.3 mg, 0.33 mmol) and N,N-diisopropylethylamine (84.4 mg, 0.65 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction mixture was reacted at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed once with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain yellow solid EVO29420 (35 mg, yield 28%). LCMS (ESI) m / z = 573.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.75 (s, 1H), 8.49 (s, 1H), 7.11 (s, 1H), 4.72 (s, 1H), 4.36 (dd, J = 73.5, 12.8 Hz, 1H), 3.90 - 3.66 (m, 3H), 3.27 (s, 6H), 2.75 (s, 3H), 1.96 (d, J = 6.3 Hz, 1H), 1.44 (d, J = 2.4 Hz, 3H), 1.33 (d, J = 7.4 Hz, 4H), 0.91 (dd, J = 39.9, 6.5 Hz, 6H).

[0265] Example 36

[0266]

Chemical Structure

[0267] Step 1: EVO29421A1 (100.0 mg, 0.22 mmol), (S)-2-methoxy-3-methylbutyric acid (40.0 mg, 0.30 mmol), and diisopropylethylamine (173.4 mg, 1.34 mmol) dissolved in N,N-dimethylformamide (3 mL) were added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114.0 mg, 0.30 mmol) in several portions, and the reaction was carried out with stirring at room temperature for 1.5 hours. Water (70 mL) was added, and the mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1) to obtain yellow oil EVO29421 (20 mg, yield 16%). LCMS (ESI) m / z = 562.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6): δ 8.71 (s, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 7.10 (s, 1H), 4.73 (s, 1H), 4.52 - 4.19 (m, 1H), 3.89 - 3.57 (m, 4H), 3.27 (s, 3H), 3.11 (d, J = 11.9 Hz, 1H), 2.75 (s, 3H), 1.96 (dd, J = 14.0, J = 7.1 Hz, 1H), 1.44 (s, 1H), 1.31 (dd, J = 21.6, 11.0 Hz, 3H), 1.07 (s, 3H), 0.96 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.64 (d, J = 11.8 Hz, 2H), 0.41 (d, J = 5.8 Hz, 2H).

[0268] Example 37

[0269]

Chemical Structure

[0270] Step 1: Compound EVO29426-1 (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (130.0 mg, 0.60 mmol) were added, and further EVO29426-2 (30.0 mg, 0.20 mmol) was added. The reaction was carried out with stirring at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound EVO29426 (11 mg, yield 9%). LCMS (ESI) m / z = 595.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.47 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.15 (s, 1H), 4.76 - 4.63 (m, 1H), 4.01 - 3.60 (m, 3H), 3.22 (s, 3H), 3.18 (s, 3H), 1.53 - 1.25 (m, 13H).

[0271] Example 38

[0272]

Chemical Structure

[0273] Step 1: At room temperature, compound EVO29592-1 (460.0 mg, 1.88 mmol) was dissolved in methanol (8 mL), palladium-carbon (10%, 30.0 mg, 281.90 μmol) and palladium hydroxide-carbon (10%, 30.0 mg, 213.62 μmol) were added, and the mixture was replaced with a hydrogen balloon three times and reacted at room temperature overnight. After completion of the reaction, the reaction solution was filtered through diatomaceous earth, the filter cake was washed twice with methanol (10 mL), the filtrates were combined and concentrated to obtain white solid EVO29592-2 (280.0 mg, yield 96.4%). LCMS (ESI) m / z = 153.1 [M-H] - .

[0274] Step 2: At room temperature, compound EVO29592-2 (280.0 mg, 1.81 mmol) and EVO29592-3 (825.0 mg, 1.67 mmol) were dissolved in N,N-dimethylformamide (10 mL), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (825.0 mg, 2.17 mmol) and N,N-diisopropylethylamine (650.0 mg, 5.02 mmol) were added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was added to water (60 mL) to quench the reaction, stirred for 10 minutes to precipitate a solid, filtered, the filter cake was washed with water (15 mL), dried, and further separated and purified by preparative liquid chromatography to obtain yellow solid EVO29592 (650.0 mg, yield 61.7%). LCMS (ESI) m / z = 631.2 [M+H] + ; HPLC: 99.6%; 11H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 8.87 (s, 1H), 8.49 (s, 1H), 7.61 (t, J = 53.0 Hz, 1H), 7.14 (s, 1H), 6.82 (t, J = 74.2 Hz, 1H), 4.96 - 4.62 (m, 1H), 4.44 - 4.30 (m, 1H), 3.85 (d, J = 12.0 Hz, 1H), 3.75 (d, J = 12.4 Hz, 2H), 3.30 - 2.86 (m, 2H), 1.63 - 1.51 (m, 6H), 1.50 - 1.39 (m, 3H), 1.39 - 1.26 (m, 4H).

[0275] Example 39

[0276] [Chemical formula]

[0277] Compound EVO29507-1 (50 mg, 0.10 mmol), EVO29507-2 (17 mg, 0.12 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (59 mg, 0.15 mmol) and N,N-diisopropylethylamine (67 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (2 ml), and the reaction solution was reacted at room temperature for 2 hours. Water (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 ml). The organic phase was washed once with water (20 ml × 2) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and rotary dried under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain yellow solid EVO29507 (20 mg, yield 32.3%). LCMS (ESI) m / z = 598.7 [M+H] + . 11H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 8.45 (d, J = 12.5 Hz, 1H), 8.31 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.15 (d, J = 10.3 Hz, 1H), 5.36 - 4.37 (m, 2H), 3.93 - 3.66 (m, 3H), 3.50 - 3.34 (m, 2H), 3.18 (dd, J = 40.2, 30.5 Hz, 2H), 1.48 (s, 1H), 1.38 (d, J = 14.4 Hz, 6H), 1.30 (d, J = 6.5 Hz, 2H), 1.16 (t, J = 6.9 Hz, 3H), 1.08 (s, 3H), 0.66 (s, 2H), 0.41 (s, 2H).

[0278] Example 40

[0279]

Chem.

[0280] Compound EVO29503-1 (100 mg, 0.21 mmol), EVO29503-2 (55.2 mg, 0.42 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (152.9 mg, 0.42 mmol) and N,N-diisopropylethylamine (117.4 mg, 0.91 mmol) were dissolved in N,N-dimethylformamide (5 ml), and the reaction mixture was reacted at room temperature for 2 hours. Water (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed once with water (20 ml × 2) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain yellow solid EVO29503 (55 mg, yield 45.8%). LCMS (ESI) m / z = 584.0 [M+H] + . 11H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.14 (s, 1H), 5.23 - 4.36 (m, 2H), 3.94 - 3.62 (m, 3H), 3.33 (s, 1H), 3.20 (d, J = 14.9 Hz, 4H), 1.47 (s, 1H), 1.37 (d, J = 12.5 Hz, 6H), 1.31 (d, J = 6.5 Hz, 2H), 1.08 (s, 3H), 0.71 - 0.60 (m, 2H), 0.47 - 0.30 (m, 2H).

[0281] Example 41

[0282]

Chem.

[0283] Step 1: In an ice bath, PyBop (0.94 g, 1.81 mmol) was added to a solution of compound (R)-2-hydroxy-3,3-dimethylbutyric acid (0.20 g, 1.51 mmol), (R)-4-Boc-2-methylpiperazine (0.33 g, 1.66 mmol), and DIPEA (0.31 mL, 1.81 mmol) in DMF (5 mL), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain white solid 29736A1 (0.40 g, yield 84.0%). LCMS (ESI) m / z = 259.4 [M+H-56] + .

[0284] Step 2: In an ice bath, 60% NaH (0.03 g, 0.76 mmol) was added to a DMF (2 mL) solution of compound 29736A1 (0.20 g, 0.64 mmol), and the mixture was stirred for 0.5 h. Iodomethane (0.11 g, 0.76 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain white solid 29736A2 (0.20 g, yield 95.7%). LCMS (ESI) m / z = 274.4 [M+H-56] + 。

[0285] Step 3: At room temperature, a 1,4-dioxane solution of hydrogen chloride (4 M, 1 mL) was added to an ethyl acetate (0.5 mL) solution of compound 29736A2 (0.20 g, 0.64 mmol), and the mixture was stirred for 2 h. The reaction solution was concentrated to remove the solvent to obtain white solid 29246A3 (the crude product was directly used in the next step). LCMS (ESI) m / z = 229.2 [M+H] + 。

[0286] Step 4: At room temperature, methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (31.50 mg, 0.04 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (35.10 mg, 0.08 mmol), 29736A3 (63.40 mg, 0.24 mmol) and cesium carbonate (183.90 mg, 0.56 mmol) were added to a 1,4-dioxane solution (3 mL) of compound 29001A6 (100.00 mg, 0.19 mmol), and the reaction solution was stirred at 90 °C for 3 h. The reaction solution was concentrated to remove the solvent, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain light yellow solid 29736A4 (72.00 mg, yield 52.9%). LCMS (ESI) m / z = 723.1 [M+H] +。

[0287] Step 5: At room temperature, trifluoroacetic acid (0.20 mL) was added to a solution of compound 29736A4 (72.00 mg, 0.10 mmol) in dichloromethane (1 mL), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to remove the solvent, and the residue was dissolved in ethyl acetate / sodium bicarbonate aqueous solution (5 mL / 5 mL), separated, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and the crude product was subjected to reverse-phase preparative chromatography to obtain a pale yellow solid EVO29736 (23.20 mg, yield 37.4%). LCMS (ESI) m / z = 622.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.95 - 8.79 (m, 1H), 8.54 - 8.41 (m, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.19 - 7.08 (m, 1H), 4.78 (d, J = 6.5 Hz, 1H), 4.59 - 4.33 (m, 1H), 4.00 - 3.68 (m, 4H), 3.30 - 3.25 (m, 3.5H), 3.22 - 2.95 (m, 1.5H), 1.49 - 1.42 (m, 2.5H), 1.36 - 1.28 (m, 4.5H), 0.96 (s, 9H).

[0288] Example 42

[0289]

Chemical Structure

[0290] Step 1: (R)-1-Boc-3-methylpiperazine (4.00 g, 19.97 mmol), 2-cyclopropyl-2-oxoacetic acid (2.51 g, 21.97 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.11 g, 23.97 mmol) and N,N-diisopropylethylamine (7.74 g, 59.92 mmol) were dissolved in N,N-dimethylformamide (20 mL), and the reaction mixture was reacted at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed once with water (50 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain EVO29710A1 (5.45 g, yield 92.08%).

[0291] Step 2: A solution of EVO29710A1 (5.45 g, 18.39 mmol) in methanol (100 mL) was cooled to 0 °C, and sodium borohydride (730.47 mg, 19.31 mmol) was slowly added. The mixture was reacted at room temperature for 1 hour. Saturated NH4Cl solution was added to the reaction mixture, and the mixture was stirred for 10 minutes. Silica gel was added and rotary evaporated, and the product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain EVO29710A2 (5.02 g, yield 91.49%).

[0292] Step 3: A solution of EVO29710A2 (5.02 g, 16.82 mmol) in N,N-dimethylformamide (50 mL) was cooled to 0 °C, and 60% NaH (1.00 g, 25.24 mmol) was added in several portions. The mixture was kept warm and reacted for 1 hour. EtI (3.15 g, 20.19 mmol) was added dropwise, and the reaction was carried out overnight. Water (250 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed once with water (100 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain EVO29710A3 (4.86 g, yield 88.49%). LCMS (ESI) m / z = 271.23 [M+H-56] + .

[0293] Step 4: A solution of EVO29710A3 (3.70 g, 11.33 mmol) in 4 M HCl / 1,4-dioxane (40 mL) was reacted at room temperature for 5 hours and rotary evaporated under reduced pressure. The crude EVO29710A4 product was used directly in the next reaction.

[0294] Step 5: To the EVO29710A4 crude product from the previous step, EVO29001A5 (4.44 g, 10.30 mmol), 1,4-dioxane (150 mL), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (1.92 g, 4.12 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (1.72 g, 2.06 mmol), and cesium carbonate (16.78 g, 51.51 mmol) were added. Under argon gas protection, the reaction was carried out at 100 °C for 8 hours, cooled to room temperature, suction filtered through diatomaceous earth, the filtrate was rotary evaporated, and preliminarily purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1 to 2:3). Further purification was carried out by preparative separation by high performance liquid chromatography to obtain EVO29710 (2.20 g, yield 34.41%).

[0295] EVO29710 (2.2 g) was separated by supercritical fluid chromatography (SFC) (column: ChiralCel OD, 300×50 mm I.D., 10 μm, mobile phase: phase A is CO2, phase B is ethanol, gradient: B 40%, flow rate: 200 mL / min, back pressure: 100 bar, column temperature: 38 °C, wavelength: 300 nm, circulation time: ~8 min, injection volume: 17.00 mL) to obtain EVO29710P1 (1.27 g, retention time 3.110 min) and EVO29710P2 (730 mg, retention time 3.473 min). LCMS (ESI) m / z = 621.2 [M+H] + 。

[0296] EVO29710P1: 11H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.90 (s, 1H), 8.54 - 8.50 (m, 1H), 7.64 (t, J = 52 Hz, 1H), 7.21 - 7.17 (m, 1H), 4.79 - 4.73 (m, 1H), 4.39 - 4.24 (m, 1H), 3.91 - 3.88 (m, 1H), 3.81 - 3.74 (m, 1H), 3.64 - 3.44 (m, 4H), 3.30 - 3.19 (m, 1H), 1.50 - 1.45 (m, 3H), 1.39 - 1.33 (m, 4H), 1.22 - 1.16 (m, 4H), 1.09 (t, J = 8 Hz, 2H), 0.63 - 0.42 (m, 2H), 0.34 - 0.30 (m, 1H).

[0297] EVO29710P2: 1 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 7.64 (t, J = 52 Hz, 1H), 7.20 (s, 1H), 4.74 - 4.71 (m, 1H), 4.35 - 4.32 (m, 1H), 3.94 - 3.90 (m, 1H), 3.81 - 3.74 (m, 1H), 3.64 - 3.45 (m, 4H), 3.23 - 3.03 (m, 1H), 1.60 - 1.30 (m, 7H), 1.28 - 1.09 (m, 4H), 0.67 - 0.31 (m, 5H).

[0298] Example 43

[0299] [Chemical Structure]

[0300] Step 1: A solution of EVO29710A2 (2.60 g, 8.71 mmol) in N,N-dimethylformamide (30 mL) was cooled to 0 °C, and 60% NaH (592.50 mg, 14.81 mmol) was added in several portions. The mixture was kept warm and reacted for 1 hour. CH3I (1.86 g, 13.07 mmol) was added dropwise, and the reaction was carried out overnight. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was washed once with water (500 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and rotary evaporated under vacuum. The crude reaction product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain EVO29715A1 (2.50 g, yield 91.84%). LCMS (ESI) m / z = 313.13 [M+H] + 。

[0301] Step 2: A solution of EVO29715A1 (1.48 g, 4.74 mmol) in 4 M HCl / 1,4-dioxane (10 mL) was reacted at room temperature for 5 hours and rotary evaporated under reduced pressure. The crude EVO29715A2 product was used directly in the next reaction.

[0302] Step 3: To the crude EVO29715A2 product from the previous step were added EVO29001A5 (1.82 g, 4.22 mmol), 1,4-dioxane (50 mL), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (788.48 mg, 1.69 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (706.62 mg, 0.84 mmol), and cesium carbonate (6.88 g, 21.12 mmol). Under argon gas protection, the reaction was carried out at 100 °C for 8 hours, cooled to room temperature, suction filtered through diatomaceous earth, and the filtrate was rotary evaporated. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1 to 2:3) to obtain EVO29715 (970.00 mg, yield 37.85%).

[0303] EVO29715 (970 mg) was separated by supercritical fluid chromatography (SFC) (column: ChiralPak AD, 250×30 mm I.D., 10 μm, mobile phase: phase A is CO2, phase B is isopropanol (0.1% NH3H2O), Gradient: B 25%, flow rate: 150 mL / min, back pressure: 100 bar, column temperature: 38 °C, wavelength: 220 nm, cycle time: ~12 min, injection volume: 3.00 mL), and EVO29715P1 (501 mg, retention time 3.538 min) and EVO29715P2 (268 mg, retention time 3.916 min) were obtained. LCMS (ESI) m / z = 607.2 [M+H] + 。

[0304] EVO29715P1: 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.90 (s, 1H), 8.54 - 8.50 (m, 1H), 7.64 (t, J = 52 Hz, 1H), 7.21 - 7.16 (m, 1H), 4.79 - 4.66 (m, 1H), 4.39 - 4.36 (m, 1H), 4.23 - 4.19 (m, 1H) 3.93 - 3.85 (m, 1H), 3.80 - 3.76 (m, 2H), 3.62 - 3.51 (m, 1H), 3.31 - 3.25 (m, 3H),1.50 - 1.46 (m, 3H), 1.36 - 1.33 (m, 4H), 1.22 - 1.13 (m, 1H), 1.11 - 1.05 (m, 2H), 0.63 - 0.42 (m, 3H).

[0305] EVO29715P2: 11H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.90 (s, 1H), 8.52 (s, 1H), 7.64 (t, J = 52 Hz, 1H), 7.19 (s, 1H), 4.71 (br s, 1H), 4.41 - 4.39 (m, 1H), 4.26 - 4.20 (m, 1H), 3.91 - 3.89 (m, 1H), 3.78 - 3.68 (m, 2H), 3.51 - 3.48 (m, 1H), 3.36 - 3.33 (m, 5H), 1.50 - 1.45 (m, 3H), 1.38 - 1.33 (m, 4H), 1.19 (br s, 1H), 0.66 - 0.59 (m, 1H), 0.56 - 0.44 (m, 1H), 0.33 - 0.27 (m, 1H).

[0306] Example 44

[0307]

Chem.

[0308] Step 1: At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (173.0 mg, 0.46 mmol), N,N-diisopropylethylamine (196.0 mg, 1.52 mmol), and 3-methyl-2-oxobutyric acid (43.0 mg, 0.36 mmol) were added to a solution of compound EVO29291-1 (150.0 mg, 0.30 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 25 °C for 2 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain EVO29291 (102.0 mg, yield 55.9%). LCMS (ESI) m / z = 593.1 [M + H] + . 11H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.84 (d, J = 2.2 Hz, 1H), 8.52 (d, J = 9.3 Hz, 1H), 7.59 (t, J = 53.1 Hz, 1H), 7.18 (d, J = 9.4 Hz, 1H), 4.75 - 4.22 (m, 1H), 3.98 - 3.67 (m, 3H), 3.59 - 3.30 (m, 2H), 3.20 - 3.03 (m, 2H), 1.44 (t, J = 6.0 Hz, 3H), 1.37 (t, J = 7.2 Hz, 2H), 1.32 (dd, J = 8.3, 5.4 Hz, 2H), 1.18 - 1.11 (m, 6H).

[0309] Example 45

[0310]

Chem.

[0311] Step 1: Compound EVO29038M (150.0 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (2 mL), oxamic acid (41.0 mg, 0.46 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (173.0 mg, 0.46 mmol), and N,N-diisopropylethylamine (294.0 mg, 2.28 mmol) were added, and the reaction was carried out with stirring at room temperature for 2 hours. LCMS indicated that the main peak was the product. The reaction solution was directly subjected to reversed-phase column chromatography (water:acetonitrile = 2:1) for separation and purification to obtain EVO29298 (68.5 mg, yield 40.0%). LCMS (ESI) m / z = 568.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.86 (d, J = 3.2 Hz, 1H), 8.50 (d, J = 10.8 Hz, 1H), 8.14 (d, J = 5.8 Hz, 1H), 7.82 - 7.44 (m, 2H), 7.17 (d, J = 10.8 Hz, 1H), 4.64 (s, 1H), 4.26 (d, J = 13.3 Hz, 1H), 3.97 - 3.65 (m, 3H), 3.29 (s, 3H), 3.26 - 2.96 (m, 2H), 1.45 (d, J = 3.6 Hz, 2H), 1.35 (d, J = 6.8 Hz, 2H).

[0312] Example 46

[0313]

Chemical formula

[0314] Step 1 At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol), N,N-diisopropylethylamine (78 mg, 0.61 mmol), and 2-cyclopropyl-2-carbonylacetic acid (28 mg, 0.24 mmol) were added to a solution of compound EVO29386-1 (100 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was rotary evaporated to remove the solvent, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a pale yellow solid EVO29386 (57 mg, yield 47.50%). LCMS (ESI) m / z = 591.0 [M+H]+. 11H NMR (DMSO-d6, 400 MHz) δ 9.37 (s, 1H), 8.86 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.18 (d, J = 9.5 Hz, 1H), 4.73 - 4.21 (m, 1H), 4.02 - 3.86 (m, 1H), 3.82 - 3.55 (m, 2H), 3.40 (dd, J = 23.0, 19.2 Hz, 2H), 3.23 - 3.04 (m, 1H), 2.40 - 2.27 (m, 1H), 1.48 - 1.43 (m, 3H), 1.38 (d, J = 6.7 Hz, 2H), 1.31 (dd, J = 8.0, 5.4 Hz, 2H), 1.21 - 1.10 (m, 4H).

[0315] Example 47

[0316]

Chem.

[0317] Step 1: To EVO29417A1 (150.0 mg, 0.31 mmol), 3-methyl-2-oxobutyric acid (43.5 mg, 0.38 mmol), and N,N-diisopropylethylamine (121.0 mg, 0.94 mmol) dissolved in N,N-dimethylformamide (3 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (142.5 mg, 0.38 mmol) was added in portions. The reaction was carried out with stirring at room temperature for 1.5 h. Water (70 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 70:1) to obtain almost white solid EVO29417 (110.0 mg, yield 61.00%). LCMS (ESI) m / z = 579.1 [M+H] + . 11H NMR (DMSO-d6, 400 MHz): δ 9.36 (s, 1H), 8.98 (s, 1H), 8.54 (s, 1H), 7.61 (s, 1H), 7.20 (s, 1H), 3.81 (s, 2H), 3.60 (s, 2H), 3.49 (d, J = 17.7 Hz, 4H), 3.16 - 3.04 (m, 1H), 1.44 (d, J = 4.7 Hz, 2H), 1.33 (d, J = 4.8 Hz, 2H), 1.08 (s, 9H), 1.15 (s, 3H), 1.13 (s, 3H).

[0318] Example 48

[0319]

Chem.

[0320] Step 1: Compound EVO29406A1 (100 mg, 0.21 mmol), EVO29406A2 (32.3 mg, 0.25 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (117.8 mg, 0.31 mmol) and N,N-diisopropylethylamine (80.0 mg, 0.62 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction solution was reacted at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed once with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and rotary dried under vacuum. The crude reaction product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain yellow solid EVO29406 (47.3 mg, yield 37.80%). LCMS (ESI) m / z = 596.0 [M+H] + . 11H NMR (DMSO-d6, 400 MHz): δ 8.81 (d, J = 4.4 Hz, 1H), 8.47 (d, J = 8.9 Hz, 1H), 8.33 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 4.74 - 4.22 (m, 1H), 3.79 (ddd, J = 39.3, 27.7, 10.9 Hz, 3H), 3.38 (s, 1H), 3.32 - 2.95 (m, 2H), 1.40 (dd, J = 21.4, 6.6 Hz, 3H), 1.23 (d, J = 4.6 Hz, 9H), 1.08 (s, 3H), 0.73 - 0.58 (m, 2H), 0.41 (s, 2H).

[0321] Example 49

[0322] [Chemical formula]

[0323] Step 1 At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol), N,N-diisopropylethylamine (130 mg, 1.01 mmol), and trimethylpyruvic acid (86 mg, 0.40 mmol) were added to a solution of compound EVO29405A1 (100 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain pale yellow solid EVO29405 (65 mg, yield 54.20%). LCMS (ESI) m / z = 607.1 [M+H] + . 11H NMR (DMSO-d6, 400 MHz): δ 9.35 (s, 1H), 8.86 (d, J = 3.7 Hz, 1H), 8.52 (d, J = 9.7 Hz, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.18 (d, J = 10.1 Hz, 1H), 4.74 - 4.20 (m, 1H), 3.97 - 3.67 (m, 3H), 3.38 (dd, J = 21.7, 8.0 Hz, 1H), 3.30 - 3.20 (m, 1H), 3.17 - 2.99 (m, 1H), 1.48 - 1.41 (m, 3H), 1.38 (d, J = 6.8 Hz, 2H), 1.32 (dd, J = 8.3, 5.3 Hz, 2H), 1.24 (d, J = 4.5 Hz, 9H).

[0324] Example 50

[0325]

Chemical formula

[0326] Step 1: To a solution of EVO29388A1 (100 mg, 0.20 mmol), pyruvic acid (27.3 mg, 0.31 mmol), and N,N-diisopropylethylamine (155 mg, 1.20 mmol) dissolved in N,N-dimethylformamide (3 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91.2 mg, 0.24 mmol) was added in portions. The reaction was carried out with stirring at room temperature for 1.5 hours. Water (70 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 70:1) to obtain almost white solid EVO29388 (28.4 mg, yield 24.90%). LCMS (ESI) m / z = 554.1 [M+H] + 。 11H NMR (DMSO-d6, 400 MHz): δ 8.82 (s, 1H), 8.47 (d, J = 10.1 Hz, 1H), 8.34 (d, J = 4.0 Hz, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.16 (d, J = 9.1 Hz, 1H), 4.71 - 4.20 (m, 1H), 4.12 - 3.85 (m, 1H), 3.83 - 3.61 (m, 3H), 3.42 (d, J = 12.2 Hz, 1H), 3.30 (s, 1H), 3.24 - 3.01 (m, 1H), 2.46 - 2.40 (m, 3H), 1.48 - 1.41 (m, 3H), 1.09 (s, 3H), 0.71 - 0.61 (m, 2H), 0.41 (d, J = 1.4Hz, 2H).

[0327] Example 51

[0328]

Chemical Structure

[0329] Step 1: To a solution of EVO29387A1 (100 mg, 0.21 mmol), 3-cyclopropyl-2-oxoacetic acid (35.4 mg, 0.31 mmol), and N,N-diisopropylethylamine (133.5 mg, 1.04 mmol) dissolved in N,N-dimethylformamide (3 mL), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (117.8 mg, 0.31 mmol) was added in several portions, and the reaction was carried out with stirring at room temperature for 1.5 h. Water (70 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 70:1) to obtain almost white solid EVO29387 (110 mg, yield 61.00%). LCMS (ESI) m / z = 580.1 [M+H] + . 11H NMR (DMSO-d6, 400 MHz): δ 8.82 (s, 1H), 8.47 (d, J = 8.3 Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 4.76 - 4.22 (m, 1H), 3.91 - 3.85 (m, 3H), 3.62 - 3.45 (m, 1H), 3.44 - 3.39 (m, 1H), 3.29 (s, 1H), 3.23 - 3.04 (m, 1H), 2.39 - 2.27 (m, 1H), 1.45 - 1.38 (m, 3H), 1.20 - 1.10 (m, 4H), 1.08 (s, 3H), 0.72 - 0.59 (m, 2H), 0.41 (s, 2H).

[0330] Example 52

[0331]

Chemical formula

[0332] Step 1: Dissolve compound EVO29384A1 (100 mg, 0.23 mmol) in N,N-dimethylformamide (3 mL), add EVO29384A2 (40 mg, 0.34 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (129 mg, 0.34 mmol), and N,N-diisopropylethylamine (149 mg, 1.15 mmol), react at room temperature for 2 hours. When detected by LCMS, the main peak was the product. Add water (50 mL) to the reaction solution, extract with ethyl acetate (30 mL × 2), combine the organic phases, wash once with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, concentrate, and separate and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain EVO29384 (41.6 mg, yield 33.28%). LCMS (ESI) m / z = 546.1 [M + H] + .1 1H NMR (DMSO-d6, 400 MHz): δ 8.71 (d, J = 4.0 Hz, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 2.6 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 3.97 - 3.64 (m, 3H), 3.46 (dd, J = 36.0, 12.8 Hz, 1H), 3.31 - 3.15 (m, 1H), 3.13 - 2.96 (m, 2H), 2.75 (s, 3H), 1.49 - 1.37 (m, 3H), 1.18 - 1.10 (m, 6H), 1.07 (s, 3H), 0.83 (dd, J = 9.5, 6.8 Hz, 1H), 0.71 - 0.57 (m, 2H), 0.40 (d, J = 1.6 Hz, 2H).

[0333] Example 53

[0334]

Chem.

[0335] Step 1 EVO29383A1 (5 g, 12.25 mmol) was dissolved in acetonitrile (30 mL), water (2.5 mL) and acetic acid (5 mL) were added in an ice bath, and 1,3-dichloro-5,5-dimethylhydantoin (3.62 g, 18.38 mmol) was added to the reaction flask in several portions. The reaction solution was stirred at 25 °C for 2 h. The reaction solution was concentrated, an appropriate amount of water (100 mL) was added, and ethyl acetate (100 mL × 3) was further added for liquid-liquid extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain EVO29383A2 (4.6 g, yield 97.00%). LCMS (ESI) m / z = 386.2 [M+H] + .

[0336] Step 2 1-Methylcyclopropanamine hydrochloride (1.88 g, 17.57 mmol) was dissolved in dichloromethane (100 mL), triethylamine (5.9 g, 58.59 mmol) was added in an ice bath, and EVO29383A2 (4.5 g, 11.72 mmol) was added to the reaction in several portions. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain EVO29383A3 (2.7 g, yield 55.00%). LCMS (ESI) m / z = 420.8 [M+H] + 。

[0337] Step 3 At room temperature, di-tert-butyl dicarbonate (2.7 g, 12.41 mmol), 4-dimethylaminopyridine (75 mg, 0.62 mmol), and triethylamine (1.25 g, 12.41 mmol) were added to a solution of compound EVO29383A3 (2.6 g, 6.21 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain a pale yellow solid EVO29383A4 (2.1 g, yield 66.00%). LCMS (ESI) m / z = 520.9 [M+H] + 。

[0338] Step 4 At room temperature, to a solution of compound EVO29383A4 (2.1 g, 5.01 mmol) in 1,4-dioxane (30 mL) were added methanesulfonic acid (2-dicyclohexylphosphino-2’,6'-diisopropoxy-1,1’-biphenyl)(2-amino-1,1’-biphenyl-2-yl)palladium(II) (1.67 g, 2.01 mmol), 2-dicyclohexylphosphino-2’,6'-diisopropoxy-1,1’-biphenyl (1.87 g, 4.01 mmol), cesium carbonate (4.88 g, 15.04 mmol), and (R)-1-N-Boc-2-methylpiperazine (2.00 g, 10.02 mmol). The reaction mixture was stirred at 90 °C for 2 hours. The reaction mixture was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain a pale yellow solid EVO29383A5 (800 mg, yield 30.00%). LCMS (ESI) m / z = 684.7 [M+H] + .

[0339] Step 5 At room temperature, to a solution of compound EVO29383A5 (800 mg, 1.17 mmol) in methanol (10 mL) was added a methanol solution of hydrogen chloride (25 mL, 6 M). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated to obtain a pale yellow solid EVO29383A6 (500 mg, yield 90.00%). LCMS (ESI) m / z = 484.5 [M+H] + .

[0340] Step 6 At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol), N,N-diisopropylethylamine (40 mg, 0.31 mmol), and 3-methyl-2-oxobutyric acid (14 mg, 0.13 mmol) were added to a solution of compound EVO29383A6 (50 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 25 °C for 2 hours. An appropriate amount of water (10 mL) was added to the reaction mixture, and then ethyl acetate (20 mL × 3) was added for liquid separation and extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain pale yellow solid EVO29383 (30 mg, yield 50.00%). LCMS (ESI) m / z = 582.6 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ 8.82 (d, J = 4.3 Hz, 1H), 8.48 (d, J = 8.8 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 7.61 (t, J = 53.1 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.74 - 4.25 (m, 1H), 3.89 (d, J = 13.5 Hz, 1H), 3.84 - 3.66 (m, 2H), 3.58 - 3.37 (m, 1H), 3.24 (dd, J = 12.6, 3.2 Hz, 1H), 3.17 - 3.00 (m, 2H), 1.42 (dd, J = 25.5, 6.7 Hz, 3H), 1.18 - 1.11 (m, 6H), 1.09 (s, 3H), 0.66 (d, J = 5.7 Hz, 2H), 0.41 (s, 2H).

[0341] Example 54

[0342]

Chemical formula

[0343] Step 1: At room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (124.0 mg, 0.33 mmol), N,N-diisopropylethylamine (85.0 mg, 0.66 mmol), and 3-methyl-2-oxobutyric acid (30.0 mg, 0.26 mmol) were added to a solution of compound EVO29385-1 (100.0 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25 °C for 2 hours. An appropriate amount of water (10 mL) was added to the reaction mixture, and ethyl acetate (3 × 20 mL) was further added for liquid-liquid extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain pale yellow solid EVO29385 (44 mg, yield 36%). LCMS (ESI) m / z = 557.6 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.75 (d, J = 2.7 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 4.74 - 4.27 (m, 1H), 3.95 - 3.83 (m, 1H), 3.82 - 3.64 (m, 2H), 3.56 - 3.37 (m, 1H), 3.22 (dd, J = 11.9, 3.3 Hz, 1H), 3.15 - 3.00 (m, 2H), 2.76 (s, 3H), 1.48 - 1.43 (m, 3H), 1.39 (d, J = 6.7 Hz, 2H), 1.31 (dd, J = 8.1, 5.1 Hz, 2H), 1.14 (dd, J = 9.9, 4.2 Hz, 6H).

[0344] Example 55

[0345]

Chemical formula

[0346] Step 1: To a mixture of EVO29407-1 (6.0 g, 3.6 mmol) in 1,2-dioxane were added 2-bromo-5-methyl-1,3,4-thiadiazolyl (11.8 g, 65.7 mmol), copper(I) iodide (2.1 mg, 10.95 mmol), N,N-dimethylcyclohexanediamine (3.2 g, 21.9 mmol) and tripotassium phosphate (13.9 g, 65.7 mmol). Under the protection of nitrogen gas, the temperature was raised to 110 °C and the reaction was carried out for 16 hours. It was detected by TLC (petroleum ether:ethyl acetate = 3:1) that the raw materials were completely converted. The reaction solution was cooled to room temperature, 150 mL of aqueous ammonia was added and stirred for 30 minutes. The solid was filtered, 100 mL of water was added to the filtrate, ethyl acetate (100 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain EVO29407-2 (3 g, yield 40%).

[0347] Step 2: EVO29407-2 (1.0 g, 2.68 mmol) was dissolved in acetonitrile (10 mL). Water (0.7 mL) and acetic acid (2 mL) were added in an ice bath, and 1,3-dichloro-5,5-dimethylhydantoin (1.0 g, 4.8 mmol) was added little by little in several portions to the reaction. The reaction solution was stirred at 25 °C for 2 hours. The reaction solution was concentrated, an appropriate amount of water was added (100 mL), and ethyl acetate (50 mL × 3) was further added for liquid separation extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by a normal-phase column (petroleum ether:ethyl acetate = 3:1) to obtain EVO29407-3 (2 g, yield 98%). LCMS (ESI) m / z = 348.1 [M+H] + 。

[0348] Step 3: 1-Cyanocyclopropanamine hydrochloride (870.0 mg, 7.33 mmol) was dissolved in pyridine (100 mL), and EVO29407-3 (1.7 g, 4.98 mmol) was added little by little in several portions to the reaction in an ice bath. The reaction solution was stirred at 0 °C for 2 hours. The reaction solution was concentrated and purified by a normal-phase column (petroleum ether:ethyl acetate = 2:1) to obtain EVO29407-4 (1 g, yield 63%). LCMS (ESI) m / z = 394.0 [M+H] + 。

[0349] Step 4: At room temperature, di-tert-butyl dicarbonate (720.0 mg, 3.3 mmol), 4-dimethylaminopyridine (75.0 mg, 0.62 mmol) and triethylamine (770.0 mg, 7.62 mmol) were added to a solution of compound EVO29407-4 (1.0 g, 2.54 mmol) in dichloromethane (25 mL). The reaction solution was stirred for 2 hours. The reaction solution was concentrated and separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 16:9) to obtain white solid EVO29407-5 (1.0 g, yield 80%). LCMS (ESI) m / z = 494.0 [M+H] + 。

[0350] Step 5: At room temperature, to a solution of compound EVO29407-5 (1.0 g, 2.03 mmol) in 1,4-dioxane (30 mL) were added methanesulfonic acid (2-dicyclohexylphosphino-2’,6'-diisopropoxy-1,1’-biphenyl)(2-amino-1,1’-biphenyl-2-yl)palladium(II) (686.0 mg, 0.82 mmol), 2-dicyclohexylphosphino-2’,6'-diisopropoxy-1,1’-biphenyl (758.0 mg, 1.63 mmol), cesium carbonate (3.3 g, 10.15 mmol), and (R)-1-N-Boc-2-methylpiperazine (609.0 mg, 3.04 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain yellow solid EVO29407-6 (1 g, yield 77%). LCMS (ESI) m / z = 658.1 [M+H] + 。

[0351] Step 6: At room temperature, to a solution of compound EVO29407-6 (1.0 g, 1.52 mmol) in methanol (10 mL) was added hydrogen chloride methanol solution (15 mL, 6 M). The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated to obtain pale yellow solid EVO29407-7 (600 mg, yield 86%). LCMS (ESI) m / z = 458.1 [M+H] + 。

[0352] Step 7: At room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (126.0 mg, 0.33 mmol), N,N-diisopropylethylamine (142.0 mg, 1.10 mmol), and EVO29407-8 (43.0 mg, 0.33 mmol) were added to a solution of compound EVO29407-7 (100.0 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 25 °C for 2 hours. An appropriate amount of water (10 mL) was added to the reaction mixture, and then ethyl acetate (3 × 20 mL) was added for liquid-liquid extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain yellow solid EVO29407 (13 mg, yield 10%). LCMS (ESI) m / z = 571.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (t, J = 5.9 Hz, 1H), 8.49 (t, J = 17.4 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 4.67 (s, 1H), 3.93 - 3.66 (m, 3H), 3.27 - 3.16 (m, 2H), 3.03 (ddd, J = 33.9, 11.8, 8.8 Hz, 1H), 2.75 (s, 3H), 1.43 (t, J = 6.2 Hz, 3H), 1.38 (d, J = 6.8 Hz, 2H), 1.30 (dd, J = 8.1, 5.1 Hz, 2H), 1.24 (d, J = 4.4 Hz, 10H).

[0353] Example 56

[0354] [Chemical formula]

[0355] Step 1: At room temperature, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (129.0 mg, 0.34 mmol), N,N-diisopropylethylamine (149.0 mg, 1.15 mmol), and EVO29408-2 (45.0 mg, 0.34 mmol) were added to a solution of compound EVO29408-1 (100.0 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 25 °C for 2 hours. An appropriate amount of water (10 mL) was added to the reaction mixture, and then ethyl acetate (10 mL × 2) was added for liquid-liquid extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain pale yellow solid EVO29408 (15 mg, yield 12%). LCMS (ESI) m / z = 560.1 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.1 Hz, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 4.68 (s, 1H), 3.89 - 3.62 (m, 3H), 3.39 (d, J = 11.3 Hz, 1H), 3.22 (ddd, J = 27.3, 12.5, 3.3 Hz, 1H), 3.02 (ddd, J = 33.4, 11.7, 8.6 Hz, 1H), 2.75 (s, 3H), 1.41 (dd, J = 21.1, 6.6 Hz, 3H), 1.24 (d, J = 4.5 Hz, 9H), 1.07 (s, 3H), 0.74 - 0.54 (m, 2H), 0.40 (s, 2H).

[0356] Effect Example PARG In Vitro Measurement Experiment The PARG in vitro measurement experiment was conducted in a standard 384-well plate with a total volume of 15 μL. 5 μL of an enzyme reaction mixture (50 mM Tris-HCL 7.5, 50 mM KCL, 0.01% Triton X-100, 0.01% BSA, 4 pM PARG with His-GST tag) was added to the 384-well plate containing the compound waiting to be measured, and after incubating at room temperature for 10 minutes, 5 μL of a substrate mixture (50 mM Tris-HCL pH7.5, 50 mM KCL, 0.01% Triton X-100, 0.01% BSA, 30 nM Bio PARylated PARP1) was added to initiate the reaction, incubated at room temperature for 20 minutes, and then 5 μL of a detection reagent was added to stop the reaction. The detection reagent was prepared from a buffer (50 mM Tris-HCL pH7.5, 50 mM KCL, 0.01% Triton X-100, 0.01% BSA), 3 μM of compound PDD00017273, 1.5X of Mab anti-6HIS XL665 (Cisbio: 61HISXLA), and 1.5X of streptavidin terbium cryptate (Cisbio: 610SATLA). The final concentrations of the three components, namely compound PDD00017273, 1.5X of Mab anti-6HIS XL665 (Cisbio: 61HISXLA), and 1.5X of streptavidin terbium cryptate, were 1 μM, 0.5X, and 0.5X respectively. After incubating at room temperature in the dark for 120 minutes, the TR-FRET signal was measured at Ex 340, Em 665, and Em 615. The ratio of each well was calculated as Em 665 / Em 615 (where the ratio here corresponds to the fluorescence signal ratio at the wavelength), and based on the obtained data, the inhibition rate of the compound was calculated, and the results are shown in Table 1.

[0357]

Table 1

[0358] Among them, A indicates IC 50 <0.1 μM, and B indicates 0.1 μM ≤ IC50 <Indicates 0.5 μM, and C is 0.5 μM ≦ IC 50 <Indicates 1.0 μM, and D is 1.0 μM ≦ IC 50 <Indicates 10.0 μM.

[0359] As described above, the specific embodiments of the present invention have been described. However, those skilled in the art should understand that these are merely illustrative descriptions, and various changes and modifications can be made to these embodiments without departing from the principles and gist of the present invention. Therefore, the scope of the present invention is limited by the appended claims.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 among them, X 1 and X 2 is independently N or CR 7 and R 7 is independently hydrogen, deuterium, halogen, CN, OH, NR a R b 、C 1 -C 6 an alkyl group or a C 7-2 substituted with one or more R 1 -C 6 alkyl group, and R a and R b each independently is hydrogen or a C 1 -C 6 alkyl group, R 7-2 is independently deuterium, halogen, CN, OH or NR a R b wherein R 8 is hydrogen or halogen, and R 1 is hydrogen, deuterium, halogen, OH, CN, NR a R b 、C 2 -C 4 an alkynyl group, C 1 -C 6 an alkyl group or a C 1-2 substituted with one or more Rs 1 -C 6 alkyl group, and R 1-2 is independently deuterium, halogen, OH or NR a R b and R 2 is hydrogen, deuterium, OH, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, one or more R 2-1 substituted C 1 -C 6 alkyl group or one or more R 2-2 substituted C 3 -C 6 cycloalkyl group, and R 2-1 and R 2-2 are, independently, deuterium, OH, halogen or NR a R b and are R 3 is hydrogen, deuterium, OH, NR a R b , C 1 -C 6 an alkyl group or a C 3-2 substituted with one or more R 1 -C 6 alkyl group, R 3-2 is independently deuterium, OH, NR a R b or halogen, and X 3 is N-(C=O)-L-CR 5 R 6 -OR 11 or N-(C=O)-(C=O)-R 12 and L is (CR 9 R 10 )m, and R 9 and R 10 are, independently, hydrogen, deuterium, OH, CN, N(R 9-1 ) 2 , C 1 -C 6 alkyl group or a C 9-2 substituted with one or more R 1 -C 6 alkyl group, and R 9-1 is independently hydrogen or a C 1 -C 6 alkyl group, R 9-2 is independently deuterium, OH, N(R 9-1 ), 2 or halogen, m is 0 or 1, R 5 and R 6 are, independently, hydrogen, deuterium, OH, CN, NR a R b , C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, one or more R 5-2 substituted C 1 -C 6 alkyl group or one or more R 5-3 substituted C 3 -C 6 cycloalkyl group, and R 5-2 and R 5-3 are independently deuterium, OH, NR a R b or halogen, and Alternatively, R 5 and R 6 together with the carbon atoms to which they are attached form a C 3 -C 6 cycloalkyl group, a 3- to 6-membered heterocycloalkyl group, a C 5-3 -C 3 cycloalkyl group substituted with one or more R 6 or a 3- to 6-membered heterocycloalkyl group substituted with one or more R 5-4 Each "3- to 6-membered heterocycloalkyl group" has independently one or two heteroatoms, and the types of heteroatoms are independently one or more selected from N, O, and S. R 5-3 and R 5-4 are independently deuterium, a hydroxy group, NR a R b or halogen, and R 11 is hydrogen, C 1 -C 6 an alkyl group or a C substituted with one or more halogens 1 -C 6 alkyl group, and R 12 is NR a R b 、 C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, one or more Rs 12-1 substituted C 1 -C 6 alkyl group or one or more Rs 12-2 substituted C 3 -C 6 cycloalkyl group, and R 12-1 and R 12-2 are, independently, halogen, OH, CN or NR a R b wherein a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

2. (1) Each "halogen" is independently F, Cl, Br or I, for example F, (2) Each "C 1 -C 6 alkyl group" is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl, sec-butyl or tert-butyl, for example, a methyl group, an ethyl group, an isopropyl group or a tert-butyl group, (3) Each "C 2 -C 4 alkynyl group" is independently an ethynyl group, a propynyl group or a propargyl group, for example, an ethynyl group, (4) Each "C 3 -C 6 cycloalkyl group" is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, for example, a cyclopropyl group, and (5) Each "3- to 6-membered heterocycloalkyl group" is independently a 3- to 6-membered heterocycloalkyl group having 1 or 2 heteroatoms and the heteroatom type being N and / or O, for example, an oxiranyl group, an aziridinyl group, an oxetanyl group, an azetidinyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group or a piperazinyl group, A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions.

3. (1) X 2 is CR 7 and (2) R 7 is independently hydrogen or halogen, (3)R 8 is hydrogen, (4)R 1 is hydrogen, CN, C 2 -C 4 -alkynyl group or C 1 -C 6 -alkyl group, preferably CN, C 2 -C 4 -alkynyl group or C 1 -C 6 -alkyl group, more preferably CN or C 1 -C 6 -alkyl group, (5) R 2 is C 1 -C 6 an alkyl group or a C 2-1 -C substituted with one, two or three Rs 1 -C 6 alkyl group, preferably a methyl group or a methyl group substituted with one, two or three Rs 2-1 and more preferably a methyl group substituted with one, two or three Rs 2-1 is a methyl group substituted with (6) R 2-1 is a halogen, (7) R 3 is hydrogen, C 1 -C 6 -alkyl group or a C 3-2 -alkyl group substituted with one, two or three Rs 1 -C 6 -alkyl group, preferably a C 1 -C 6 -alkyl group or a C 3-2 -alkyl group substituted with one, two or three Rs 1 -C 6 -alkyl group, more preferably a methyl group or a methyl group substituted with one, two or three Rs 3-2 and is that. (8) R 3-2 is independently a halogen, (9) R 9 and R 10 are independently hydrogen, N(R 9-1 ) 2 or C 1 -C 6 alkyl group, for example, N(R 9-1 ) 2 or C 1 -C 6 alkyl group, preferably C 1 -C 6 alkyl group, (10)R 9-1 is independently hydrogen, (11) m is 0, (12) R 5 and R 6 are, independently, hydrogen, deuterium, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, one, two or three Rs 5-2 substituted C 1 -C 6 alkyl group or one, two or three Rs 5-3 substituted C 3 -C 6 cycloalkyl group, preferably hydrogen, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group or one, two or three Rs 5-2 substituted C 1 -C 6 alkyl group, more preferably C 1 -C 6 alkyl group or one, two or three Rs 5-2 substituted C 1 -C 6 alkyl group, and (13) R 5-2 and R 5-3 are independently OH or halogen, preferably halogen, A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions.

4. (1) R 10 is hydrogen, and (2) R 5 is hydrogen or C 1 -C 6 is an alkyl group, and R 6 is hydrogen, C 1 -C 6 is an alkyl group, C 3 -C 6 is a cycloalkyl group or a C 5-2 alkyl group substituted with one or more R 1 -C 6 is an alkyl group, and R 5-2 is independently OH or halogen, A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or two of the following conditions.

5. (1) X 1 is N or CH, (2) X 2 is N, CH or CF, preferably CH or CF, (3)R 8 is H or F, preferably H, (4)R 1 is hydrogen, CN, an ethynyl group or a methyl group, for example, a CN, ethynyl group or methyl group, preferably a CN or methyl group, more preferably a CN, (5) R 2 is a methyl group or CHF 2 and preferably CHF 2 is (6) R 3 is hydrogen, a methyl group or CH 2 F, preferably a methyl group or CH 2 F, （7） 【Chemical 2】 is [Chemical Formula 3] being (8) R 5 is a hydrogen or methyl group, (9) R 6 is a hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, cyclopropyl group, a methyl group substituted with one, two or three fluorines, a tert-butyl group substituted with one, two or three fluorines or a tert-butyl group substituted with one, two or three OHs, for example, hydrogen, methyl group, isopropyl group, tert-butyl group, cyclopropyl group, CF 3 , 【Chemical Formula 4】 being Preferably, R 6 is a methyl group, a tert-butyl group, a methyl group substituted with one, two or three fluorines, or a tert-butyl group substituted with one, two or three fluorines, for example, a methyl group, a tert-butyl group, CF 3 , 【Chemical Formula 5】 being (10) R 11 is hydrogen, a methyl group, an ethyl group, or a methyl group substituted with one, two or three fluorines, for example, hydrogen, a methyl group, an ethyl group or CHF 2 being, and (11) R 12 is an isopropyl group, an amino group, a cyclopropyl group, a tert-butyl group or a methyl group, A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions.

6. （1） [Chemical Formula 6] is 【Chemical Formula 7】 , for example 【Chemical 8】 being （2） 【Chemical Formula 9】 is 【Chemical Formula 10】 , for example 【Chemical 11】 being （3） 【Chemical Formula 12】 is 【Chemical 13】 being A compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions.

7. The compound represented by formula (I) is a compound represented by formula (I-1), (I-2) or (I-3), 【Chemical 14】 Among them, when the carbon atom represented by "*" is an asymmetric carbon atom, it independently indicates that it is in the R configuration, S configuration, or a mixture thereof, X 1 X 2 R 8 R 1 R 2 R 3 R 10 R 5 R 6 R 11 and the definition of R 12 is as described in at least one of claims 1 to 6. A compound represented by formula (I) according to at least one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that.

8. The compound represented by formula (I) is a compound represented by formula (I-5), (I-6), (I-7), (I-8), (I-9), (I-10), (I-11), (I-12) or (I-13), 【Chemical Formula 15】 Among them, when the carbon atom represented by "*" is an asymmetric carbon atom, it independently indicates that it is in the R configuration, S configuration, or a mixture thereof, and R 1 、R 2 、R 7 、R 5 、R 6 、R 11 and R 12 are defined as described in at least one of claims 1 to 6, Preferably, each of the above formulas I: R 2 is CHF 2 and that II: R 1 is CN, Satisfies one or two of the conditions of A compound represented by formula (I) according to at least one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that.

9. The compound represented by formula (I) is 【Chemical 16】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 [Chemical] 【Chem.】 A compound represented by formula (I) according to at least one of claims 1 to 8, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it is any one of the following compounds.

10. A pharmaceutical composition comprising a substance X which is a compound represented by formula (I) according to at least one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

11. Use of substance X or the pharmaceutical composition according to claim 10 in the preparation of a PARG inhibitor, wherein the substance X is a compound represented by formula (I) according to at least one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

12. Use of substance X or the pharmaceutical composition according to claim 10 in the preparation of a drug for a disease related to PARG, wherein the substance X is a compound represented by formula (I) according to at least one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and preferably, the disease related to PARG is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or gastric cancer.

13. Use of substance X or the pharmaceutical composition according to claim 10 in the preparation of a drug for preventing and / or treating cancer, wherein the substance X is a compound represented by formula (I) according to at least one of claims 1 to 9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and preferably, the cancer is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or gastric cancer.

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