Sulfur-containing heteroaromatic ring compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a sulfur-containing heteroaromatic ring compound as well as a pharmaceutical composition and application thereof. Specifically, the invention discloses a compound as shown in a formula (I), pharmaceutically acceptable salts of the compound, solvates of the compound or solvates of the pharmaceutically acceptable salts of the compound. The sulfur-containing heteroaromatic ring compound provided by the invention has good PARG inhibitory activity. # imgabs0 #

Description

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

[0001] This application claims priority from the following Chinese patent applications:

[0002] Chinese patent application 2022108455508, filed on July 19, 2022;

[0003] Chinese patent application 2022109244222 with a filing date of August 2, 2022;

[0004] Chinese patent application 2022110438233, filed on August 29, 2022;

[0005] Chinese patent application 2022110772559, filed on September 7, 2022;

[0006] Chinese patent application 2022112391509, filed on October 13, 2022;

[0007] Chinese patent application 2022112986321, filed on October 21, 2022;

[0008] Chinese patent application 2022113653922, filed on November 2, 2022;

[0009] Chinese patent application 2023100231325, filed on January 6, 2023;

[0010] Chinese patent application 2023102534040, filed on March 16, 2023;

[0011] Chinese patent application 2023106179387, filed on May 29, 2023;

[0012] Chinese patent application 2023108003365 with an application date of July 3, 2023.

[0013] This application cites the full text of the above-mentioned Chinese patent application. Technical Field

[0014] The present invention relates to a sulfur-containing heteroaromatic ring compound, a pharmaceutical composition thereof and use thereof. Background Art

[0015] Cancer is caused by uncontrolled and unregulated cell proliferation. A consequence of this often rapid proliferation is high levels of oxidative stress within tumors, which damages DNA and leads to greatly increased DNA mutation rates. Consequently, tumor cell survival is critically dependent on DNA damage repair mechanisms.

[0016] Single-strand breaks (SSBs) in DNA are the most common type of damage in cells. PARG (poly ADP-ribose glycohydrolase) and PARP (poly ADP-ribose polymerase), along with many other proteins, are involved in single-strand break repair (SSBR) and base excision repair (BER) mechanisms. When other DNA repair mechanisms fail, cancer cells may become addicted to specific DNA repair pathways. Tumors carrying mutations in proteins involved in double-strand break repair are often more sensitive to PARP inhibitors, which target SSBRs.

[0017] PARP inhibitors are currently undergoing numerous clinical trials, exploring the concepts of synthetic lethality or chemosensitization. Clinical resistance to PARP inhibitors has been reported, necessitating the identification of alternative inhibitors that target DNA damage repair mechanisms. Because PARG knockdown reduces SSBR rates to the same extent as PARP1 knockdown, PARG inhibition may offer therapeutic advantages in PARP inhibitor-resistant cells.

[0018] Summary of the Invention

[0019] The technical problem to be solved by the present invention is to overcome the deficiency of insufficient types of PARG inhibitors in the prior art and provide a novel sulfur-containing heteroaromatic ring compound, a pharmaceutical composition thereof and its use. The sulfur-containing heteroaromatic ring compound of the present invention has good PARG inhibitory activity.

[0020] The present invention solves the above technical problems through the following technical solutions.

[0021] The present invention provides a compound as represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0022] in,

[0023] X1 and X2 are independently N or CR7;

[0024] R7 is independently hydrogen, deuterium, halogen, CN, OH, NR a R b , C1-C6 alkyl or one or more R 7-2 Substituted C1-C6 alkyl;

[0025] R a and R b are independently hydrogen or C1-C6 alkyl;

[0026] R 7-2are independently deuterium, halogen, CN, OH or NR a R b ;

[0027] R8 is hydrogen or halogen;

[0028] R1 is hydrogen, deuterium, halogen, OH, CN, NR a R b , C2-C4 alkynyl, C1-C6 alkyl or one or more R 1-2 Substituted C1-C6 alkyl;

[0029] R 1-2 are independently deuterium, halogen, OH or NR a R b ;

[0030] R2 is hydrogen, deuterium, OH, C1-C6 alkyl, C3-C6 cycloalkyl, 1 or more R 2-1 Substituted C1-C6 alkyl or one or more R 2-2 substituted C3-C6 cycloalkyl;

[0031] R 2-1 and R 2-2 are independently deuterium, OH, halogen or NR a R b ;

[0032] R3 is hydrogen, deuterium, OH, NR a R b , C1-C6 alkyl or one or more R 3-2 Substituted C1-C6 alkyl;

[0033] R 3-2 Deuterium, OH, NR a R b or halogen;

[0034] X3 is N-(C=O)-L-CR5R6-OR 11 or N-(C=O)-(C=O)-R 12 ;

[0035] L is (CR9R 10 )m;

[0036] R9 and R 10 are independently hydrogen, deuterium, OH, CN, N(R 9-1 )2, C1-C6 alkyl or one or more R 9-2 Substituted C1-C6 alkyl;

[0037] R 9-1 are independently hydrogen or C1-C6 alkyl;

[0038] R 9-2 are independently deuterium, OH, N(R 9-1 )2 or halogen;

[0039] m is 0 or 1;

[0040] R5 and R6 are independently hydrogen, deuterium, OH, CN, NR a R b , C1-C6 alkyl, C3-C6 cycloalkyl, 1 or more R 5-2 Substituted C1-C6 alkyl or one or more R 5-3 substituted C3-C6 cycloalkyl;

[0041] R 5-2 and R 5-3 Deuterium, OH, NR a R b or halogen;

[0042] Alternatively, R5 and R6 and the carbon atom to which they are attached together form a C3-C6 cycloalkyl, a 3-6 membered heterocycloalkyl, a 5-3 Substituted C3-C6 cycloalkyl or one or more R 5-4 Substituted 3-6 membered heterocycloalkyl, wherein the number of heteroatoms in each "3-6 membered heterocycloalkyl" is independently 1 or 2, and the type of heteroatoms is independently selected from one or more of N, O and S;

[0043] R 5-3 and R 5-4 are independently deuterium, hydroxyl, NR a R b or halogen;

[0044] R 11 is hydrogen, C1-C6 alkyl, or C1-C6 alkyl substituted by one or more halogens;

[0045] R 12 NR a R b , C1-C6 alkyl, C3-C6 cycloalkyl, 1 or more R 12-1 Substituted C1-C6 alkyl or one or more R 12-2 substituted C3-C6 cycloalkyl;

[0046] R 12-1 and R 12-2 are independently halogen, OH, CN or NR a R b .

[0047] In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I), its pharmaceutically acceptable salt, its solvate and the solvate of its pharmaceutically acceptable salt are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0048] In one embodiment of the present invention, each "halogen" can independently be F, Cl, Br or I, such as F.

[0049] In one embodiment of the present invention, each "C1-C6 alkyl" may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, for example, methyl, ethyl, isopropyl or tert-butyl.

[0050] In one embodiment of the present invention, each "C2-C4 alkynyl" may independently be ethynyl, propynyl or propargyl, for example, ethynyl.

[0051] In one embodiment of the present invention, each "C3-C6 cycloalkyl" may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl.

[0052] In a certain embodiment of the present invention, each "3-6 membered heterocycloalkyl group" may independently be a 3-6 membered heterocycloalkyl group having 1 or 2 heteroatoms, wherein the heteroatoms are N and / or O, such as oxirane, aziridine, oxetane, azetidine, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl.

[0053] In one embodiment of the present invention, X2 is CR7.

[0054] In one embodiment of the present invention, R7 is independently hydrogen or halogen.

[0055] In one embodiment of the present invention, R8 is hydrogen.

[0056] In one embodiment of the present invention, R1 is hydrogen, CN, C2-C4 alkynyl or C1-C6 alkyl, preferably CN, C2-C4 alkynyl or C1-C6 alkyl, more preferably CN or C1-C6 alkyl.

[0057] In one embodiment of the present invention, R2 is C1-C6 alkyl or is replaced by 1, 2 or 3 R 2-1 Substituted C1-C6 alkyl, preferably methyl or substituted by 1, 2 or 3 R 2-1 The substituted methyl group is preferably 1, 2 or 3 R 2-1 Substituted methyl.

[0058] In one embodiment of the present invention, R 2-1 It is a halogen.

[0059] In one embodiment of the present invention, R2 is C1-C6 alkyl or is replaced by 1, 2 or 3 R 2-1 Substituted C1-C6 alkyl, R 2-1 is a halogen;

[0060] Preferably, R2 is methyl or is replaced by 1, 2 or 3 R 2-1 Substituted methyl, R 2-1 is a halogen;

[0061] More preferably, R2 is replaced by 1, 2 or 3 R 2-1 Substituted methyl, R 2-1 It is a halogen.

[0062] In one embodiment of the present invention, R3 is hydrogen, C1-C6 alkyl or 1, 2 or 3 R 3-2 Substituted C1-C6 alkyl, preferably C1-C6 alkyl or substituted by 1, 2 or 3 R 3-2 Substituted C1-C6 alkyl, more preferably methyl or substituted by 1, 2 or 3 R 3- 2-substituted methyl.

[0063] In one embodiment of the present invention, R 3-2 are independently halogen.

[0064] In one embodiment of the present invention, R3 is hydrogen, C1-C6 alkyl or 1, 2 or 3 R 3-2 Substituted C1-C6 alkyl, R 3-2 are independently halogen;

[0065] Preferably, R3 is C1-C6 alkyl or is replaced by 1, 2 or 3 R 3-2 Substituted C1-C6 alkyl, R 3-2 are independently halogen;

[0066] More preferably, R3 is methyl or is replaced by 1, 2 or 3 R 3-2 Substituted methyl, R 3-2 are independently halogen.

[0067] In one embodiment of the present invention, R9 and R 10 are independently hydrogen, N(R 9-1 )2 or C1-C6 alkyl, for example N(R 9-1 )2 or C1-C6 alkyl, preferably C1-C6 alkyl.

[0068] In one embodiment of the present invention, R 9-1 are independently hydrogen.

[0069] In one embodiment of the present invention, R9 and R 10 are independently N(R9-1 )2 or C1-C6 alkyl, R 9-1 are independently hydrogen.

[0070] In one embodiment of the present invention, R 10 For hydrogen.

[0071] In one embodiment of the present invention, m is 0.

[0072] In one embodiment of the present invention, R5 and R6 are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl or 1, 2 or 3 R 5-3 Substituted C3-C6 cycloalkyl, preferably hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl, more preferably C1-C6 alkyl or substituted by 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl.

[0073] In one embodiment of the present invention, R 5-2 and R 5-3 is independently OH or halogen, preferably halogen.

[0074] In one embodiment of the present invention, R5 and R6 are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl or 1, 2 or 3 R 5-3 Substituted C3-C6 cycloalkyl, R 5-2 and R 5-3 are each independently OH or halogen;

[0075] Preferably, R5 and R6 are independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl, R 5-2 are independently OH or halogen;

[0076] More preferably, R5 and R6 are independently C1-C6 alkyl or substituted by 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl, R 5-2 are independently halogen.

[0077] In one embodiment of the present invention, R5 is hydrogen or C1-C6 alkyl, R6 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or one or more R 5-2 Substituted C1-C6 alkyl, R 5-2 is independently OH or halogen.

[0078] In one embodiment of the present invention, X1 and X2 are independently N or CR7;

[0079] R7 is independently hydrogen or halogen;

[0080] R8 is hydrogen or halogen;

[0081] R1 is CN, C2-C4 alkynyl or C1-C6 alkyl;

[0082] R2 is C1-C6 alkyl or is replaced by 1, 2 or 3 R 2-1 Substituted C1-C6 alkyl;

[0083] R 2-1 is a halogen;

[0084] R3 is hydrogen, C1-C6 alkyl or 1, 2 or 3 R 3-2 Substituted C1-C6 alkyl;

[0085] R 3-2 are independently halogen;

[0086] X3 is N-(C=O)-L-CR5R6-OR 11 or N-(C=O)-(C=O)-R 12 ;

[0087] L is (CHR9)m;

[0088] R9 is N(R 9-1 )2 or C1-C6 alkyl;

[0089] R 9-1 are independently hydrogen;

[0090] m is 0 or 1;

[0091] R5 and R6 are independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl;

[0092] R 5-2 are independently OH or halogen;

[0093] R 11 is hydrogen, C1-C6 alkyl, or C1-C6 alkyl substituted by 1, 2 or 3 halogens;

[0094] R 12 N(R 12-1 )2, C1-C6 alkyl or C3-C6 cycloalkyl;

[0095] R 12-1 are independently hydrogen.

[0096] In one embodiment of the present invention, X1 is N or CH.

[0097] In one embodiment of the present invention, X2 is N, CH or CF, preferably CH or CF.

[0098] In one embodiment of the present invention, for For example

[0099] In one embodiment of the present invention, R8 is H or F, preferably H.

[0100] In one embodiment of the present invention, R1 is hydrogen, CN, ethynyl or methyl, for example, CN, ethynyl or methyl, preferably CN or methyl, more preferably CN.

[0101] In one embodiment of the present invention, R2 is methyl or CHF2, preferably CHF2.

[0102] In one embodiment of the present invention, R3 is hydrogen, methyl or CH2F, preferably methyl or CH2F.

[0103] In one embodiment of the present invention, for For example,

[0104] In one embodiment of the present invention, R5 is hydrogen or methyl.

[0105] In one embodiment of the present invention, R6 is hydrogen, methyl, isopropyl, tert-butyl, cyclopropyl, methyl substituted by 1, 2 or 3 fluorine groups, tert-butyl substituted by 1, 2 or 3 fluorine groups or tert-butyl substituted by 1, 2 or 3 OH groups, for example, hydrogen, methyl, isopropyl, tert-butyl, cyclopropyl, CF3,

[0106] In one embodiment of the present invention, R6 is methyl, tert-butyl, methyl substituted by 1, 2 or 3 fluorine groups or tert-butyl substituted by 1, 2 or 3 fluorine groups, such as methyl, tert-butyl, CF3,

[0107] In one embodiment of the present invention, R5 is hydrogen or methyl,

[0108] R6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, methyl substituted by 1, 2 or 3 fluorine groups, tert-butyl substituted by 1, 2 or 3 fluorine groups or tert-butyl substituted by 1, 2 or 3 OH groups, for example hydrogen, methyl, isopropyl, tert-butyl, cyclopropyl, CF3,

[0109] In one embodiment of the present invention, R5 is hydrogen or methyl,

[0110] R6 is methyl, tert-butyl, methyl substituted by 1, 2 or 3 fluorine groups or tert-butyl substituted by 1, 2 or 3 fluorine groups, for example, methyl, tert-butyl, CF3,

[0111] In one embodiment of the present invention, R 11 is hydrogen, methyl, ethyl or methyl substituted by 1, 2 or 3 fluorine groups, for example hydrogen, methyl, ethyl or CHF2.

[0112] In one embodiment of the present invention, R 12 is isopropyl, amino, cyclopropyl, tert-butyl or methyl.

[0113] In one embodiment of the present invention, for

[0114] In one embodiment of the present invention, the compound represented by formula (I) is a compound represented by formula (I-1), (I-2) or (I-3):

[0115] Among them, the carbon atom marked with "*" indicates that when it is a chiral carbon atom, it is independently in R configuration, S configuration or a mixture thereof, X1, X2, R8, R1, R2, R3, R 10 , R5, R6, R 11 and R 12 The definition of is as described in the previous scheme.

[0116] In one embodiment of the present invention, 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).

[0117] Among them, the carbon atom marked with "*" indicates that when it is a chiral carbon atom, it is independently in R configuration, S configuration or a mixture thereof, R1, R2, R7, R5, R6, R 11 and R 12 The definition of is as described in the previous scheme;

[0118] Preferably, the above formulas satisfy one or both of the following conditions:

[0119] I: R2 is CHF2;

[0120] II: R1 is CN.

[0121] In one embodiment of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0122] The present invention also provides a pharmaceutical composition comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a compound as represented by formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0123] The present invention also provides a use of the substance X or the pharmaceutical composition in the preparation of a PARG inhibitor.

[0124] The present invention also provides a use of the substance X or the pharmaceutical composition in preparing a drug for a disease associated with PARG. Preferably, the disease associated with PARG is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or gastric cancer.

[0125] The present invention also provides a use of the substance X or the pharmaceutical composition in preparing a drug for preventing and / or treating cancer. Preferably, the cancer is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or gastric cancer.

[0126] Unless otherwise specified, the terms used in this invention have the following meanings:

[0127] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0128] As used herein, a substituent may be preceded by a single dash "-" to indicate that the named substituent is bonded to the parent moiety through a single bond.

[0129] The term "plurality" refers to 2, 3 or 4.

[0130] The term "halogen" refers to F, Cl, Br or I.

[0131] The term "alkyl" refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and the like.

[0132] The term "alkynyl" refers to a straight or branched hydrocarbon group having one or more triple bonds with a specified number of carbon atoms (e.g., C2-C4). The one or more carbon-carbon triple bonds can be internal or terminal.

[0133] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of ring carbon atoms (e.g., C3-C6) and the ring atoms consisting only of carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0134] The term "heterocycloalkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-6 members), a specified number of heteroatoms (e.g., 1 or 2), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S). Examples of heterocycloalkyl include, but are not limited to, oxirane, aziridine, oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, or piperazinyl.

[0135] When any variable (such as R 2-1 ) When a variable appears multiple times in the definition of a compound, the definition of the variable at each position is independent of the definition at the remaining positions, and their meanings are independent of each other and do not affect each other.

[0136] The term "pharmaceutically acceptable salt" refers to salts prepared from compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.

[0137] The term "solvate" refers to a compound of the present invention combined with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or non-ordered arrangement.

[0138] The term "pharmaceutically acceptable salt" and "solvate" in the term "pharmaceutically acceptable salt solvate" as described above refer to substances prepared by the compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids or bases; and formed in combination with stoichiometric or non-stoichiometric solvents.

[0139] The term "pharmaceutically acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances contained in pharmaceutical preparations, other than the active ingredient. For more information, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

[0140] In the present invention, the "inhibitor" can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art.

[0141] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating 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) slowing the progression of the condition or one or more biological manifestations of the condition.

[0142] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0143] The positive improvement effect of the present invention is that the compound of the present invention has good inhibitory activity on PARG. DETAILED DESCRIPTION

[0144] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0145] The reagents and raw materials used in the present invention are commercially available or can be prepared with reference to WO2021055744A1, for example, with reference to References 4-5 in WO2021055744A1 and the intermediate methods in subsequent related compounds.

[0146] Example 1

[0147] To a solution of compound EVO29284-1 (100.0 mg, 0.21 mmol) in N,N-dimethylformamide (5 mL) were added 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) at room temperature. The reaction solution was stirred at 25 degrees Celsius for 2 hours. The reaction solution was separated and purified by reverse phase column chromatography (methanol:water = 1:1) to obtain EVO29284 (50.0 mg, yield 43.00%). LCMS (ESI) m / z = 553.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ8.98(s,1H),8.51(s,1H),7.61(t,J=53.1Hz,1H),7.18(s,1H),5.07(d,J=6.8Hz,1H),4.51(p,J=6.5Hz ,1H),3.89–3.70(m,4H),3.47(d,J=13.1Hz,4H),1.45(dd,J=8.2,5.5Hz,2H),1.32(dd,J=8.3,5.5Hz,2H),1.25(d,J=6.5Hz,3H).

[0148] Example 2

[0149] Compound EVO292825-1 (120.0 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL) at room temperature. (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 allowed to react at room temperature for 2 hours. The reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to afford EVO29285 (30.0 mg, 22.00% yield). LCMS (ESI) m / z = 567.1 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ9.33(s,1H),8.87(s,1H),8.48(s,1H),7.60(t,J=53.1Hz,1H),7.15(s,1H),5.03(s,1H),4. 55(d,J=71.9Hz,2H,4.09–3.62(m,3H),3.29(s,3H),1.47–1.43(m,2H),1.32(d,J=2.6Hz,2H),1.25(d,J=6.5Hz,5H).

[0150] Example 3

[0151] To a solution of compound EVO29334-1 (150.0 mg, 0.31 mmol) in N,N-dimethylformamide (5 mL) were added 2-(7-azobenzotriazole)-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) at room temperature. 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The residue was isolated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain EVO29334 (95.0 mg, 56.0% yield). LCMS (ESI) m / z = 567.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.86(s,1H),8.48(d,J=10.2Hz,1H),7.60(t,J=53.1Hz,1H),7.15(d,J=10.1Hz,1H),4.97(d,J=7.2Hz ,1H),4.76–4.27(m,2H),4.08–3.61(m,3H),3.14(t,J=46.9Hz,2H),1.44(d,J=2.7Hz,3H),1.34–1.26(m,4H),1.22(dd,J=11.1,5.7Hz,3H).

[0152] Example 4

[0153] Step 1:

[0154] To a solution of compound EVO29335-1 (100.0 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) were added 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 (2R)-3-methyl-2-hydroxybutyric acid (29.0 mg, 0.24 mmol) at room temperature. The reaction solution was stirred at 25 degrees Celsius for 2 hours. The reaction solution was separated and purified by reverse phase column chromatography (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] + . 1 HNMR(400MHz, DMSO-d6)δ8.86(s,1H),8.48(s,1H),7.61(t,J=53.1Hz,1H),7.16(s,1H),4.98(d,J=79.1Hz,1H),4.53(t,J=59.4Hz,1H),4.15–3.98 (m,2H),3.91–3.61(m,3H),3.18(d,J=8.3Hz,1H),2.06–1.85(m,1H),1.5 1–1.40(m,3H),1.31(t,J=6.5Hz,4H),1.24(s,1H),0.89(t,J=7.4Hz,6H).

[0155] Example 5

[0156] Step 1:

[0157] To a solution of compound EVO29339-1 (100.0 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) were added 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) at room temperature. The reaction solution was stirred at 25 degrees Celsius for 2 hours. The reaction solution was separated and purified by reverse phase column chromatography (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] + . 1H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.87(s,1H),8.46(s,1H),7.61(t,J=53.1Hz,1H),7.15(s,1H),5.51(s,1H),4.75(d,J=54.5Hz,1H),3.84(d,J =12.1Hz,1H),3.73(d,J=12.3Hz,1H),3.34(s,1H),3.10(d,J=119.6Hz,3 H), 1.55–1.42 (m, 3H), 1.36 (d, J = 7.1Hz, 6H), 1.31 (dd, J = 8.0, 5.3Hz, 4H).

[0158] Example 6

[0159] Step 1:

[0160] At room temperature, compound EVO29001A3 (2.24 g, 5.49 mmol), acetic acid (20 mL), and water (5 mL) were added to a vial under nitrogen. The temperature was lowered to 0°C, and N-chlorosuccinimide (879.7 mg, 6.59 mmol) was added and stirred at 0-25°C for 12 hours. TLC analysis showed no residual starting material. Water (60 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (75 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude solid. The product was then separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain EVO29103A1 (1.70 g, 80.00% yield) as a pale yellow solid. No response was observed by LCMS.

[0161] Step 2:

[0162] 1-Amino-1-cyclopropyl cyanide hydrochloride (2.31 g, 19.48 mmol) and anhydrous pyridine (20 mL) were stirred under an ice-water bath, and compound EVO29103A1 (2.50 g, 6.49 mmol) was added to the bottle. The reaction was allowed to react at room temperature for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was concentrated to obtain a yellow oil, which was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain a yellow solid EVO29103A2 (1.55 g, yield 51.73%), LCMS (ESI) m / z = 431.0 [M+H] +.

[0163] Step 3:

[0164] 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), 1,4-dioxane (45 mL) were added to the reaction flask, and the mixture was stirred in an oil bath at 90 degrees Celsius for 3 hours under nitrogen protection. 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 oil was separated and purified by silica gel column chromatography (methanol / dichloromethane = 0-25%) to give a yellow foamy product EVO29103A3 (1.20 g, yield 71.00%), LCMS (ESI) m / z = 581.0 [M+H] + .

[0165] Step 4:

[0166] EVO29103A3 (200 mg, 0.34 mmol) and ethyl acetate (1 mL) were added to the reaction flask. With stirring in an ice-water bath, a solution of hydrogen chloride in ethyl acetate (2 mL, 4 M) was added and the mixture was warmed to room temperature and stirred for 2 hours. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain crude EVO29103A4, which was used directly in the next step. LCMS (ESI) m / z = 481.0 [M+H] + .

[0167] Step 5:

[0168] EVO29103A4 (90 mg, 0.19 mmol), glycolic acid (20 mg, 0.23 mmol), 2-(7-azobenzotriazole)-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 the reaction flask. The mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was added with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water, dried, and then purified by silica gel column chromatography (methanol / dichloromethane = 0-10%) to afford EVO29103 (8.6 mg, 9.30% yield) as a white solid. LCMS (ESI) m / z = 538.8 [M+H] + . 1H NMR (DMSO-d6, 400MHz): δ9.39 (s, 1H), 8.95 (s, 1H), 8.49 (s, 1H), 7.61 (t, J = 53.1Hz, 1H), 7.16 (s, 1H), 4.71 ( t,J=5.5Hz,1H),4.18(d,J=5.5Hz,2H),3.70(d,J=42.7Hz,4H),3.46(s,4H),2.03–1.95(m,2H),1.45(m,2H).

[0169] Example 7

[0170] Step 1:

[0171] EVO29336A1 (5.00 g, 20 mmol) was dissolved in 1,2-dioxane (60 mL), and 2-bromo-5-methyl-1,3,4-thiadiazole (11.00 g, 60.07 mmol), N,N-dimethylcyclohexanediamine (2.84 g, 20 mmol), cuprous iodide (1.90 g, 10.00 mmol), and potassium phosphate (12.90 g, 60.07 mmol) were added. The reaction was stirred at 90 degrees Celsius for 35 hours under nitrogen protection, cooled to room temperature, and ammonia water (150 mL) was added. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was extracted with ethyl acetate (100 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and slurried with methanol (50 mL) to obtain EVO29336A2 (3.00 g, yield 40.00%). LCMS (ESI) m / z = 372.7 [M+H] + .

[0172] Step 2:

[0173] EVO29336A2 (7.20 g, 19.35 mmol) was dissolved in acetonitrile (40 mL) at 0°C. Acetic acid (4.5 mL) and water (1.7 mL) were added. Dichlorohydantoin (5.34 g, 34.83 mmol) was added portionwise at 0°C. The reaction was stirred at 0°C for 1 hour. The filtrate was dried to afford EVO29336A3 (6.7 g, theoretical yield), a pale yellow solid, which was used in the next step without purification. LCMS revealed no response.

[0174] Step 3:

[0175] To EVO29336A3 (2.3 g, 6.72 mmol) dissolved in pyridine (67 mL) at 0°C, 1-cyanocyclopropylamine hydrochloride (1.60 g, 13.40 mmol) was added portionwise. The reaction was stirred at 0°C for 1 hour. Most of the pyridine was concentrated, and 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, and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was slurried with methanol (50 mL) to obtain EVO29336A4 (1.1 g, 42.30% yield) as a yellow solid. LCMS (ESI) m / z = 395.0 [M+H] + .

[0176] Step 4:

[0177] 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), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (729 mg, 0.87 mmol), and cesium carbonate (3.55 g, 10.90 mmol). Under a nitrogen balloon, the mixture was stirred at 90°C for 1 hour, cooled to room temperature, and directly purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40:1) to obtain a yellow foamy solid EVO29336A5 (1.126 g, yield 92.40%). LCMS (ESI) m / z = 559.0 [M+H] + .

[0178] Step 5:

[0179] To EVO29336A5 (1.16 g, 2.07 mmol) dissolved in methanol (1.5 mL) was added a methanolic solution of hydrogen chloride (6 mL). The reaction was stirred at room temperature for 2 hours and then concentrated to afford a yellow foamy solid, EVO29336A6 (0.9 g, 94.80% yield). LCMS (ESI) m / z = 459.0 [M+H] + .

[0180] Step 6:

[0181] To EVO29336A6 (90 mg, 0.20 mmol) dissolved in N,N-dimethylformamide (3 mL) were added D-lactic acid (36 mg, 0.39 mmol) and N,N-diisopropylethylamine (126.7 mg, 0.98 mmol). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) was added portionwise. The reaction was stirred at room temperature for 2 hours. The mixture was directly separated and purified by silica gel column chromatography (dichloromethane / methanol = 80:1) to obtain an off-white solid EVO29336 (25 g, yield 24.00%). LCMS (ESI) m / z = 531.1 [M+H] + . 1 H NMR(DMSO-d6,400MHz): δ9.29(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=126.8Hz,1H),3. 83(d,J=11.6Hz,1H),3.72(d,J=12.3Hz,1H), 3.30–3.25(m,2H),3.07(d,J=83.9 Hz, 1H), 2.76 (s, 3H), 1.44 (d, J = 2.7Hz, 1H), 1.31 (dd, J = 5.0Hz, 5H), 1.25 (s, 1H).

[0182] Example 8

[0183] Step 1:

[0184] 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) was added portionwise 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) in N,N-dimethylformamide (3 mL). The reaction was stirred at room temperature for 1.5 hours. Water (70 mL) was added and the mixture was washed with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 70:1) to afford EVO29338 (28.7 mg, 27.46% yield) as an off-white solid. LCMS (ESI) m / z = 520.2 [M+H] + . 1H NMR(DMSO-d6,400MHz): δ8.72(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),1.4 5–1.38(m,2H),1.44–1.23(m,4H),1.07(s,3H),0.67–0.61(m,2H),0.42–0.39(m,2H).

[0185] Example 9

[0186] Step 1:

[0187] To a solution of compound 29132A3 (0.20 g, 0.41 mmol) in 1,4-dioxane (8 mL) 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- The reaction mixture was stirred at 90°C for 3 hours. The solvent was removed by concentration, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to afford 29314A1 (82.21 mg, 27.00% yield) as a pale yellow solid. LCMS (ESI) m / z = 735.3 [M+H] + .

[0188] Step 2:

[0189] Trifluoroacetic acid (0.20 mL) was added to a solution of compound 29314A1 (82.21 mg, 0.11 mmol) in dichloromethane (1 mL) at room temperature, 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 solution. The layers were separated, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was then subjected to reverse phase purification to obtain EVO29314 (16.30 mg, 23.00% yield) as a pale yellow solid. LCMS (ESI) m / z = 535.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ8.72(d,J=4.5Hz,1H),8.44(d,J=5.9Hz,1H),7.12–7.05(m,1H),4.79–4.65(m, 1H),4.50(s,1H),4.33(d,J=14.2Hz,1H),4.05(d,J=13.7Hz,1H),3.89–3.61(m,4H),3.55–3.39(m,2H),3 .25(dd,J=12.5,3.6Hz,2H),3.17(d,J=10.9Hz,1H),2.95(dd,J=21.9,11.7Hz,1H),2.75(s,3H),1.70(s, 1H), 1.43 (d, J = 6.5Hz, 1H), 1.28 (d, J = 6.9Hz, 2H), 1.07 (s, 3H), 0.65 (q, J = 3.1Hz, 2H), 0.43–0.36 (m, 2H).

[0190] Example 10

[0191] Step 1:

[0192] 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 reacted at room temperature for 1.5 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), and evaporated to dryness under reduced pressure. The fractions were then prepared under medium pressure (petroleum ether / ethyl acetate = 2:1). The fractions were evaporated to dryness to obtain 100.0 mg of a yellow oil. This was separated and purified by preparative HPLC to obtain EVO29351 (6.2 mg, 11.00% yield) as a yellow-green solid. LCMS (ESI) m / z = 580.9 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ9.33(s,1H),8.86(s,1H),8.47(s,1H),7.60(t,J=53.1Hz,1H),7.13(s,1H),4.74(s,1H),4.65(s,1H),4.5 1–4.23(m,1H),4.03(d,J=13.2Hz,1H),3.85(d,J=9.1Hz,1H),3.77–3.46(m,3H),3.25–2.82(m,3H),1.49–1.21(m,7H),0.99(s,3H).

[0193] Example 11

[0194] Step 1:

[0195] To a solution of compound EVO29337-1 (100.0 mg, 0.21 mmol) in N,N-dimethylformamide (2 mL) were added 2-(7-azobenzotriazole)-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) at room temperature. The reaction mixture was stirred at 25°C for 2 hours. The solvent was removed by rotary evaporation, and an appropriate amount of water was added. The mixture was extracted with ethyl acetate (3 x 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 afford EVO29337 (29 mg, 25% yield) as a yellow solid. LCMS (ESI) m / z = 556.6 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.75 (d, J = 2.7Hz, 1H), 8.52 (d, J = 8.4Hz, 1H), 7. 13(d,J=8.7Hz,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=11.9,3.3Hz,1H),3.15–3.00(m,2H),2.76(s,3H),1.48–1.43(m ,3H), 1.39(d,J=6.7Hz,2H), 1.31(dd,J=8.1,5.1Hz,2H), 1.14(dd,J=9.9,4.2Hz,6H).

[0196] Example 12

[0197] Step 1:

[0198] At room temperature, compounds 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), and 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 mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched by adding water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL), and then washed once with saturated brine (10 mL). The residue was concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 3:1) to obtain a yellow solid. The residue was then purified by reverse-phase column chromatography (water (0.1% formic acid):acetonitrile = 1:1) and lyophilized to obtain EVO29463 (15 mg, 12% yield) as a yellow solid. LCMS (ESI) m / z = 635.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.45(s,1H),7.60(t,J=53.1Hz,1H),7.13(s,2H),5.46–5.03(m,1H),4.69( s,2H),3.78(dd,J=34.4,13.3Hz,3H),3.22–3.14(m,3H),1.58(d,J=20.3Hz,3H),1.38–1.29(m,4H),1.23(s,3H).

[0199] Example 13

[0200] Step 1:

[0201] Compound EVO29462-1 (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL). 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (130.0 mg, 0.60 mmol) were added, followed by EVO29462-2 (48.0 mg, 0.30 mmol). The mixture was stirred at room temperature for 2 hours. TLC confirmed the absence of residual starting material. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by column chromatography (petroleum ether / ethyl acetate 2:1) to obtain compound EVO29462 (15 mg, 11% yield). LCMS (ESI) m / z = 635 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.89(s,1H),8.49(d,J=17.4Hz,1H),7.60(t,J=53.1Hz,1H),7.25(s,1H),7.15( d,J=12.8Hz,1H),4.61(t,J=67.4Hz,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).

[0202] Example 14

[0203] Step 1:

[0204] Compound EVO29496-1 (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (80.0 mg, 0.60 mmol) were added. Then, EVO29496-2 (50.0 mg, 0.30 mmol) was added and the reaction was stirred 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, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give compound EVO29496 (45 mg, yield 34%), LCMS (ESI) m / z = 624.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.45(d,J=16.2Hz,1H),8.31(s,1H),7.60(t,J=53.1Hz,1H),7.21(s,1H),7.13(s,1H),5.3 9–4.19(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=1.6Hz,2H).

[0205] Example 15

[0206] Step 1:

[0207] (R)-2-Hydroxy-3,3-dimethylbutanoic 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 stirred at room temperature for 10 minutes. EVO29038M (100.0 mg, 202.21 μM) was added and allowed to react at room temperature for 17 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and preparatively treated with medium pressure (DCM:MeOH 20:1). The fraction was evaporated to dryness to obtain a yellow oil. This was then purified by preparative HPLC to afford EVO29451 (19.2 mg, 16% yield) as a yellow solid. LCMS (ESI) m / z = 609.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.21(s,1H),8.84(s,1H),8.48(s,1H),7.58(t,J=53.1Hz,1H),7.14(s,1H),4.80(d,J=7.5Hz,1H),4.71(s,1H), 4.43-4.19(m,1H),4.15-3.99(m,1H),3.84(d,J=10.9Hz,1H),3.77-3.62(m,2H),3.36(d,J=11.2Hz,1H),1.53-1.23(m,7H),0.97(s,9H).

[0208] Example 16

[0209] Compounds EVO29469-1 (100 mg, 0.207 mmol), EVO29469-2 (55.2 mg, 0.42 mmol), 2-(7-azobenzotriazole)-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 allowed to react 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 x 2) and once with saturated brine (20 ml), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain EVO29469 (25 mg, 20.8% yield) as a yellow solid. LCMS (ESI) m / z = 570.0 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.83(s,1H),8.42(s,1H),8.32(s,1H),7.60(t,J=53.0Hz,1H),7.13(s,1H),5.51(s,1H),4.76(d,J=71.4Hz,1H),3. 78(s,1H),3.73–3.55(m,2H),3.09(s,2H),1.35(d,J=7.9Hz,6H),1.27(s,2H),1.24–1.23(m,1H),1.08(s,3H),0.66(s,2H),0.40(s,2H).

[0210] Example 17

[0211] Step 1:

[0212] Compound 1 (500.00 mg, 1.01 mmol), compound 2 (173.00 mg, 1.52 mmol), 2-(7-azobenzotriazole)-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). The reaction mixture was allowed to react 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 x 2) and once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 3 (540.00 mg, 91.4% yield) as a yellow solid. LCMS (ESI) m / z = 591.1 [M+H] + .

[0213] Step 2:

[0214] 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 allowed to react at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (50 mL). The organic phase was washed once with water (20 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1-100% ethyl acetate) to afford compound 4 (430.00 mg, 82.5% yield) as a yellow solid. LCMS (ESI) m / z = 593.2 [M+H] + .

[0215] Step 3:

[0216] Compound 4 (100.00 mg, 0.17 mmol) was separated by supercritical fluid chromatography (SFC) (column: ChiralCel OX, 250×30 mm ID, 10 μm; mobile phase: phase A: CO2, phase B: 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) to afford EVO29534 (21.6 mg, retention time 1.764 minutes) and EVO29537 (46.5 mg, retention time 2.621 minutes). LCMS (ESI) m / z = 593.2 [M+H] + .

[0217] EVO29534:

[0218] 1 H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.87(s,1H),8.48(s,1H),7.63(t,J=52Hz,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).

[0219] EVO29537:

[0220] 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.86(s,1H),8.48(d,J=10.5Hz,1H),7.61(t,J=52.6Hz,1H),7.16(d,J=11.8Hz,1H),5.04–4.83(m,1H),4. 64(d,J=70.3Hz,1H), 3.98(ddd,J=97.0,68.1,55.4Hz,5H), 3.09(d,J=79.8Hz,2H), 1.36(d,J=50.6Hz,7H), 1.12(s,1H), 0.38(d,J=33.4Hz,4H).

[0221] Example 18

[0222] Step 1:

[0223] EVO29451 (50.0 mg, 82.14 μmol) was dissolved in DMAC (3 mL), and selectfluor (58.2 mg, 164.29 μmol) was added. The mixture was reacted at 60°C under argon for 14 hours. The mixture was extracted twice with water and ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was then prepared under medium pressure (PE:EA 1:1) and concentrated under reduced pressure to afford 54.0 mg of a yellow oil. Preparative HPLC separation and purification afforded EVO29757 (7.0 mg, 14% yield) as a yellow solid. LCMS (ESI) m / z = 627.2 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.66(s,1H),8.96(d,J=3.6Hz,1H),8.58(d,J=4.5Hz,1H),7.62(t,J=53.1Hz,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).

[0224] Example 19

[0225] Step 1:

[0226] To a solution of 3-fluoro-2,2-dimethylpropanoic acid hydroxy (0.7 g, 5.83 mmol) in anhydrous tetrahydrofuran (20 ml) was added methyllithium (2.5 M in diethoxymethane) (4.9 ml, 12.25 mmol) at -78°C under argon. The mixture was allowed to return to room temperature and stirred for 10 hours. 1 M HCl solution (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, yielding crude product 29751A1 (0.29 g, 42.1% yield) as a pale yellow oil.

[0227] Step 2:

[0228] To a solution of compound 29751A1 (0.29 g, 2.45 mmol) in water (10 ml) was added sodium hydroxide (0.2 g, 4.91 mmol) and potassium permanganate (0.7 g, 4.42 mmol) under ice-cooling. 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 extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, yielding 29751A2 (0.26 g, 71.6% yield) as a colorless oil. LCMS (ESI) m / z = 147.1 [M-1] - .

[0229] Step 3:

[0230] To a solution of compound 29751A2 (0.26 g, 1.75 mmol) in DMF (5 ml) was added DIPEA (0.45 g, 3.51 mmol) and PyBop (1.37 g, 2.63 mmol) under ice-cooling, and the mixture was stirred for 0.5 h. 29038M (0.79 g, 1.59 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to afford a light yellow solid, 29751A3 (0.52 g, 52.1% yield). LCMS (ESI) m / z = 625.17 [M+H] + .

[0231] Step 4:

[0232] To a solution of compound 29751A3 (0.52 g, 0.83 mmol) in tetrahydrofuran (5 mL) was added NaBH4 (37 mg, 1 mmol) under ice-cooling, 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 SFC separation (instrument: WATERS 150 preparative SFC (SFC-26), chromatographic column: ChiralPak IG, 250×30 mm ID, 10 μm, mobile phase: phase A: CO2, phase B: ethanol (0.1% NH3H2O), gradient: B 40%; flow rate: 150 mL / min; back pressure: 100 bar) to give EVO29751P1 (54 mg, yield 10.4%, retention time 2.021 minutes). LCMS (ESI) m / z = 627.17 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.86 (d, J = 4.3Hz, 1H), 8.48 (d, J = 6.8Hz, 1H), 7.60 (t ,J=53.1Hz,1H),7.14(dd,J=5.2,1.4Hz,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=4.0Hz,1H),3.11(dt,J=64. 2,10.8Hz,1H),1.44(q,J=4.6,3.8Hz,3H),1.31(dd,J=5.7,3.5Hz,4H),1.04–0.93(m,6H).

[0233] EVO29751P2 (115 mg, yield 22.1%, retention time 2.792 minutes) LCMS (ESI) m / z = 627.17 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.88(d,J=1.0Hz,1H),8.48(d,J=12.6Hz,1H),7.61(t,J= 53.1Hz,1H),7.15(d,J=13.9Hz,1H),5.02(dd,J=19.2,7.9Hz,1H),4.81(d,J=7.9Hz,1H),4.54 –4.08(m,5H),3.85(d,J=13.1Hz,1H),3.73(d,J=12.2Hz,2H),3.44–3.34(m,1H),3.29–2.99(m ,1H), 1.43(dd,J=12.7,4.8Hz,3H), 1.30(dd,J=8.5,5.2Hz,4H), 0.96(dd,J=19.5,5.9Hz,6H).

[0234] Example 20

[0235] Step 1:

[0236] Compound EVO29778A0 (2.5 g, 11.56 mol) and TEA (2.3 g, 23.12 mmol) were added to DCM (25 ml) under argon protection. CbzCl (2.1 g, 12.72 mmol) was added in an ice bath and stirred for 2 h. 1N HCl (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 ml x 3). The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, respectively. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to afford EVO29778A1 (3.5 g, 86.4%).

[0237] Step 2:

[0238] Compound EVO29778A1 (3.5 g, 9.99 mol) and DIPEA (3.2 g, 24.97 mmol) were added to DCM (30 mL) under argon protection. Methanesulfonic anhydride (2.6 g, 14.98 mmol) was added in an ice bath and stirred for 2 h. 1N HCl (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL x 3). The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, respectively, and concentrated under reduced pressure to yield crude product EVO29778A2 (4.3 g).

[0239] Step 3:

[0240] Compound EVO29778A2 (1.8 g, 4.20 mol) and TBAF (21 mL, 1 M in THF) were added to THF (22 mL) and stirred at 70°C for 3 h. Water (20 mL) was added to the mixture, and the mixture was extracted with EA (10 mL x 3). The organic phase was washed with saturated brine and concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to afford EVO29778A3 (300 mg, 20.2%).

[0241] Step 4:

[0242] Compound EVO29778A3 (300 mg, 4.20 mol) and Pd / C (90 mg) were added to methanol (10 ml), replaced with a hydrogen balloon, and stirred at room temperature overnight. The mixture was filtered through celite and the filtrate was dried to give crude product EVO29778A4 (200 mg).

[0243] Step 5:

[0244] Compounds EVO29778B0 (156 mg, 0.29 mol), 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 argon protection and stirred at 100°C for 4 hours. Water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 ml x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain EVO29778A5 (163 mg, 77.9%).

[0245] Step 6:

[0246] Compound EVO29778A5 (163 mg, 0.22 mmol) was added to DCM (1 mL), followed by TFA (2 mL) and stirred at room temperature for 4 h. Sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted with DCM (10 mL x 2), dried over anhydrous sodium sulfate, and spin-dried to afford EVO29778A6 (116 mg, 100%).

[0247] Step 7:

[0248] Compounds 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), followed by DIPEA (87.7 mg, 0.67 mmol), and stirred at room temperature overnight. Water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 ml x 2). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid chromatography to obtain EVO29778 (50 mg, 35.2%). LCMS: [M+H] + 627.15. 1 H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.85(d,J=6.2Hz,1H),8.55(d,J=15.3Hz,1H),7 .64(t,J=53.1Hz,1H),7.21(dd,J=12.4,1.3Hz,1H),5.39(dd,J=176.0,7.4Hz,1H),5 .03–4.58(m,3H),4.45(t,J=15.4Hz,1H),4.15(d,J=7.4Hz,3H),3.77–3.37(m,1H),3 .32–2.96(m,2H),1.47(t,J=4.0Hz,2H),1.35(t,J=4.0Hz,2H),1.00(d,J=9.0Hz,9H).

[0249] Example 21

[0250] Step 1:

[0251] To a reaction flask were added 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). The atmosphere was replaced with argon three times, and the mixture was heated to 90°C for 3 h. The mixture was cooled to room temperature, filtered through celite, and dried to obtain the crude product, which was then purified by flash silica gel column chromatography (DCM / PE 0-50%) to afford EVO29788A1 (2.3 g, 64.5%).

[0252] Step 2:

[0253] To a reaction flask were added 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). The atmosphere was replaced with argon, and the mixture was heated to 60°C for 2 h. The reaction was quenched with water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the organic phase was washed with saturated brine (20 mL). The crude product was then dried and purified by flash silica gel column chromatography (EA / PE 0-50%) to afford EVO29788A2 (1.7 g, 51.9%).

[0254] Step 3:

[0255] 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 addition, the mixture was allowed to react in an ice bath for 2 hours. The reaction solution was concentrated to obtain EVO29788A3 (565 mg, 100%).

[0256] Step 4:

[0257] Compound EVO29788A3 (565 mg, 1.47 mmol) and 1-amino-1-cyclopropyl cyanide hydrochloride (348.7 mg, 2.94 mmol) were added to pyridine (10 mL) and allowed to react overnight at room temperature. The reaction mixture was added to ethyl acetate (50 mL), washed with 1N hydrochloric acid solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to afford EVO29788A4 (518 mg, 81.9%).

[0258] Step 5:

[0259] 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 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 give EVO29788A5 (310 mg, 48.5%).

[0260] Step 6:

[0261] Compounds 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) under argon and stirred at 95°C for 4 h. Water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (10 ml x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to afford EVO29788A6 (180 mg, 72.3%).

[0262] Step 7:

[0263] Compound EVO29788A6 (180 mg, 0.25 mmol) was added to DCM (1 ml), followed by TFA (2 mL) and stirred at room temperature for 2 h. Sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted with DCM (10 ml x 2), dried over anhydrous sodium sulfate, and spin-dried to afford EVO29788A7 (124 mg, 96.8%).

[0264] Step 8:

[0265] Compounds 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), followed by DIPEA (194.8 mg, 1.51 mmol), and stirred at room temperature overnight. Water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 ml x 2). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative liquid chromatography to obtain EVO29788 (51 mg, 33.4%). LCMS: [M+H] + 608.45. 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.65(s,1H),8.21(d,J=3.6Hz,1H),7.67(t,J=53.1Hz,1H),7.25(d,J=1.5Hz,1H),7.07(t,J= 4.5Hz,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=4.9Hz,9H).

[0266] Example 22

[0267] Step 1:

[0268] To a 100ml single-necked flask, add EVO29451 (500.0 mg, 0.82 mmol), 20mL of DMAC, and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) (580.0 mg, 1.64 mmol). Stir at 50°C for 4 hours. After the reaction, add 60mL of water and extract twice with 80mL of ethyl acetate. The combined organic phases are washed once with saturated brine and dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and perform medium pressure preparative chromatography (PE:EA=1:1). The fraction is evaporated to dryness to obtain a yellow oil. This is then purified by preparative HPLC to afford EVO29792 (45.0 mg, 8.7% yield) as a yellow solid. LCMS (ESI) m / z=645.1 [M+H] + .

[0269] 1 H NMR(400MHz, DMSO-d6)δ9.02(s,1H),7.63(t,J=53.1Hz,1H),4.80(d,J=7.5Hz,1H),4.71(s,1H),4.43-4.19(m,1H),4.15–3.99 (m,1H),3.84(d,J=10.9Hz,1H),3.77-3.62(m,2H),3.36(d,J=11.2Hz,1H),1.57–1.46(m,3H),1.43–1.26(m,4H),0.99(s,9H).

[0270] Example 23

[0271] Step 1:

[0272] 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 mixture was reacted 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, and concentrated under reduced pressure. The fraction was then prepared under medium pressure (PE:EA=2:1). The fraction was evaporated to dryness to obtain EVO29761A1 (601.0 mg, 99% yield) as a yellow solid. LCMS (ESI) m / z=595.1 [M+H] + .

[0273] Step 2:

[0274] 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 under argon at 60°C for 6 hours. The mixture was extracted twice with water and ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The fraction was then prepared under medium pressure (PE:EA 1:1). The fraction was evaporated to dryness to obtain EVO29761A2 (168.0 mg, 54% yield) as a yellow oil. LCMS (ESI) m / z = 513.1 [M+H-Boc] + .

[0275] Step 3:

[0276] EVO29761A2 (168.0 mg, 274.22 μmol) was dissolved in DCM (1 mL), and TFA (1.5 g, 13.07 mmol) was added. The mixture was reacted at room temperature for 2 h. Saturated aqueous sodium bicarbonate solution was added to neutralize the reaction solution, 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 a yellow oil, EVO29761A3 (118.0 mg, yield 84%).

[0277] Step 4:

[0278] (S)-2-Trifluoromethyl-2-hydroxypropionic acid (36.4 mg, 230.23 μmol) and EVO29761A3 (118.0 mg, 230.23 μmol) were dissolved in DMF (5 mL). TEA (35.0 mg, 345.34 μmol) and HATU (113.8 mg, 299.30 μmol) were added and reacted at room temperature for 3 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The fractions were evaporated to dryness under medium pressure (PE:EA 1:1) to give 50.0 mg of a brown liquid. This was then separated and purified by preparative HPLC to afford EVO29761 (9.4 mg, 6% yield) as a yellow solid. LCMS (ESI) m / z = 653.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.66(s,1H),8.97(d,J=9.0Hz,1H),8.58(d,J=4.4Hz,1H),7.62(t,J=53.0Hz,1H),7.22(s,1H ),5.15–4.74(m,1H),4.74–4.24(m,1H),3.69(d,J=11.4Hz,1H),3.63–3.36(m,3H),3.26(s,1H),1.66–1.26(m,10H).

[0279] Example 24

[0280] Step 1:

[0281] (R)-2-Trifluoromethyl-2-hydroxypropionic acid (82.7 mg, 522.90 μmol) and EVO29761A3 (134.0 mg, 261.45 μmol) were dissolved in DMF (5 mL), and TEA (79.4 mg, 784.34 μmol) and HATU (218.7 mg, 575.18 μmol) were added. The mixture was reacted 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, and concentrated under reduced pressure. The fractions were evaporated to dryness under medium pressure (PE:EA 1:1) to obtain 47.0 mg of a brown liquid. This was then separated and purified by preparative HPLC to obtain EVO29762 (16.3 mg, 6% yield) as a yellow solid. LCMS (ESI) m / z = 653.3 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.04(s,1H),8.58(s,1H),7.61(t,J=53.0Hz,1H),7.21(s,1H),5.26–4.75(m,1H),4 .74–4.30(m,1H),3.69(d,J=10.9Hz,1H),3.53(s,1H),3.47–3.35(m,2H),3.19(s,1H),1.65–1.27(m,10H).

[0282] Example 25

[0283] Step 1:

[0284] To a solution of 3,3-difluoro-2,2-dimethylpropanoic acid hydroxy (0.8 g, 5.83 mmol) in anhydrous tetrahydrofuran (20 ml) was added methyllithium (2.5 M in diethoxymethane) (4.9 ml, 12.25 mmol) at -78°C under argon. The mixture was allowed to return to room temperature and stirred for 10 hours. 1 M HCl solution (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, yielding 29752A1 (0.33 g, 41.9% yield) as a pale yellow oil (crude).

[0285] Step 2:

[0286] To a solution of compound 29752A1 (0.33 g, 2.42 mmol) in water (10 ml) was added sodium hydroxide (0.19 g, 4.85 mmol) and potassium permanganate (0.69 g, 4.36 mmol) under ice-cooling. 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 extracted with ethyl acetate. The organic phase was concentrated to remove the solvent, yielding 29752A2 (0.29 g, 72.1% yield) as a colorless oil. LCMS (ESI) m / z = 165.1 [M-1] - .

[0287] Step 3:

[0288] To a solution of compound 29752A2 (0.29 g, 1.75 mmol) in DMF (5 ml) was added DIPEA (0.45 g, 3.51 mmol) and PyBop (1.37 g, 2.63 mmol) under ice-cooling, and the mixture was stirred for 0.5 h. 29038M (0.79 g, 1.59 mmol) was then added to the reaction mixture, and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to afford a light yellow solid, 29752A3 (0.32 g, 32.0% yield). LCMS (ESI) m / z = 643.17 [M+H] + .

[0289] Step 4:

[0290] To a solution of compound 29752A3 (0.32 g, 0.49 mmol) in tetrahydrofuran (5 mL) was added NaBH4 (22 mg, 0.59 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 h. Water was added to the reaction solution, extracted with ethyl acetate, and the organic phase was concentrated to remove the solvent. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether) and SFC separation (instrument: WATERS 150 preparative SFC (SFC-26), chromatographic column: ChiralPak IG, 250×30 mm ID, 10 μm, mobile phase: phase A: CO2, phase B: 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 (400MHz, DMSO-d6) δ9.33(s,1H),8.86(d,J=4.4Hz,1H),8.48(d,J=8.6Hz,1H),7.61(t ,J=53.1Hz,1H),7.21–7.09(m,1H),6.21–5.50(m,2H),4.69(d,J=9.5Hz,1H),4.35(d,J=7. 5Hz,1H),4.26–4.12(m,1H),3.85(d,J=11.0Hz,1H),3.73(t,J=12.6Hz,2H),3.39–3.33(m ,1H),3.25–3.00(m,1H),1.49–1.41(m,3H),1.32(q,J=3.4,2.6Hz,4H),1.12–0.98(m,6H).

[0291] EVO29752P2 (137 mg, yield 42.8%, RT = 1.819 min) LCMS (ESI) m / z = 645.17 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.88(d,J=0.9Hz,1H),8.48(d,J=13.1Hz,1H),7.60(t,J= 53.1Hz,1H),7.14(d,J=14.5Hz,1H),5.97(t,J=57.3Hz,1H),5.34(t,J=9.8Hz,1H),4.83–4.07( m,3H),3.87(t,J=14.7Hz,1H),3.73(d,J=12.2Hz,2H),3.44–3.33(m,1H),3.14(dt,J=77.5,11 .0Hz,1H),1.44(p,J=5.5,4.9Hz,3H),1.31(td,J=7.5,6.7,4.7Hz,4H),1.01(d,J=23.8Hz,6H).

[0292] Example 26

[0293] Step 1:

[0294] (R)-2-Hydroxy-3,3-dimethylbutanoic 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 stirred at room temperature for 10 minutes. EVO29798A1 (250.0 mg, 517.00 μM) was added and the mixture was allowed to react 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. The mixture was filtered, concentrated under reduced pressure, and subjected to medium pressure preparation (PE:EA 1:1). The fraction was evaporated to dryness to obtain a yellow solid (130.0 mg, 42% yield). LCMS (ESI) m / z = 598.1 [M+H] + .

[0295] Step 2:

[0296] EVO29798A2 (130.0 mg, 217.50 μmol) was dissolved in DMAC (4 mL), and selectfluor (123.3 mg, 348.00 μmol) was added. The mixture was reacted at 60°C under argon for 6 hours. Water was added to precipitate the solid, which was filtered to obtain 140.0 mg of a yellow solid. Preparative HPLC separation and purification yielded EVO29798 (24.4 mg, 18% yield) as a yellow solid. LCMS (ESI) m / z = 616.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.91(d,J=3.6Hz,1H),8.60(s,1H),8.53(d,J=4.6Hz,1H) ,7.60(t,J=53.1Hz,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=6.5Hz,1H),1.30( d,J=6.7Hz,2H),1.15(s,3H),0.96(s,9H),0.76–0.62(m,2H),0.51–0.39(m,2H).

[0297] Example 27

[0298] Step 1:

[0299] A solution of EVO29038M (670 mg, 1.35 mmol), EVO29790A0 (433.96 mg, 3.39 mmol), and DMAP (49.65 mg, 0.406 mmol) in DMSO (10 mL) was reacted at 110°C overnight; the temperature was 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 EVO29790A1 (300 mg, yield 35.56%); LCMS (ESI) m / z = 623.22 [M+H] + .

[0300] Step 2:

[0301] Sodium borohydride (36.45 mg, 0.964 mmol) was slowly added to a solution of compound EVO29790A1 (300.00 mg, 0.482 mmol) in methanol (10 mL) and allowed to react at room temperature for 1 hour. Saturated ammonium chloride (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (50 mL). The organic phase was washed once with water (20 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1-1:2) to obtain the product EVO29790 (180.00 mg, yield 59.81%). LCMS (ESI) m / z = 625.41 [M+H] + .

[0302] Step 3:

[0303] Compound EVO29790 (180.00 mg) was separated by supercritical fluid chromatography (SFC) (Chromatographic column: ChiralCel OX, 250×30 mm ID, 10 μm; mobile phase: phase A: CO2, phase B: 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) to afford EVO29790P1 (65.30 mg, retention time 1.712 minutes) and EVO29790P2 (35.42 mg, retention time 2.722 minutes). LCMS (ESI) m / z = 625.2 [M+H] + .

[0304] EVO29790P1 1 H NMR (400MHz, DMSO-d6) δ9.33 (s, 1H), 8.90 (s, 1H), 8.50 (d, J = 8Hz, 1H), 7.63 (t,J=52Hz,1H),7.17(d,J=8Hz,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).

[0305] EVO29790P2 1 H NMR (400MHz, DMSO-d6) δ9.36(s,1H),8.89(s,1H),8.50(s,1H),7.63(t,J=52Hz,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).

[0306] Example 28

[0307] Step 1

[0308] 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), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (157.23 mg, 0.19 mmol), and cesium carbonate (1.53 g, 4.70 mmol). Under argon, the mixture was stirred at 100°C for 12 hours, cooled to room temperature, and the filtrate was collected by filtration. The solvent was removed by rotary evaporation, and the residue was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain a yellow solid EVO29725A1 (0.52 g, yield 79.67%). LCMS (ESI) m / z = 696.2 [M+H] + .

[0309] Step 2:

[0310] Trifluoroacetic acid (6 mL) was added to a dichloromethane solution (3 mL) of compound EVO29725A1 (0.52 g, 0.75 mmol) at room temperature, and the reaction mixture was stirred at 25°C for 2 hours. After the reaction, saturated sodium bicarbonate was added to the reaction mixture until the pH reached 8. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to yield EVO29725A2 (0.37 g, 95.67% yield) as a brown solid.

[0311] Step 3:

[0312] To a solution of compound EVO29725A2 (0.10 g, 0.20 mmol) in N,N-dimethylformamide (5 mL) were added (R)-2-hydroxy-3,3-dimethylbutanoic acid (32.00 mg, 0.24 mmol), N,N-diisopropylethylamine (64.35 mg, 0.60 mmol), and 1H-benzotriazol-1-yloxytripyrrolidinoyl hexafluorophosphate (130.00 mg, 0.24 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 hours. After completion, the reaction was quenched by the addition of water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by preparative HPLC to afford EVO29725 as a bright yellow solid (84.00 mg, 64.89% yield) with a purity of 98.90%. 1H NMR(400MHz, DMSO-d6)δ8.21(dd,J=7.2,1.4Hz,1H),7.22(dd,J=11.9,1.5Hz,1H), 4.93(d,J=7.7Hz,1H),4.77(s,1H),4.47(dd,J=80.3,11.9Hz,3H),4.14(d,J=7.7Hz ,1H),3.66(dd,J=12.5,3.6Hz,1H),3.41(d,J=10.6Hz,1H),3.21(q,J=12.3Hz,1H), 1.52–1.45(m,2H),1.42–1.31(m,3H),1.25(d,J=6.6Hz,2H),0.99(d,J=4.2Hz,9H).

[0313] Example 29

[0314] Compound EVO29412A1 (100 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (3 mL). EVO29412A2 (36 mg, 0.34 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (129 mg, 0.34 mmol), and N,N-diisopropylethylamine (149 mg, 1.15 mmol) were added and allowed to react at room temperature for 2 hours. The reaction mixture was added with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:3) to obtain EVO29412 (55.1 mg, 43.08% yield). LCMS (ESI) m / z = 534.1 [M+H] + . 1 H NMR(DMSO-d6,400MHz): δ8.72(s,1H),8.44(s,1H),8.27(s,1H),7.10(s,1H ),4.69(s,1H),4.22(t,J=59.8Hz,2H),3.80(d,J=11.2Hz,1H),3.70(d,J=1 2.4Hz,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=10.6Hz,5H),1.07(s,3H),0.72–0.58(m,2H),0.46–0.33(m,2H).

[0315] Example 30

[0316] Step 1

[0317] To a solution of compound EVO29411A1 (100 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) was added 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) at room temperature. 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to afford EVO29411 (60 mg, 50.80% yield) as a pale yellow solid. LCMS (ESI) m / z = 545.1 [M+H] + . 1 H NMR(DMSO-d6,400MHz)δ9.31(s,1H),8.76(s,1H),8.48(s,1H),7.11(s,1H),4.40(dd,J=188.4,62.5Hz,3H),3.84 (d,J=11.4Hz,1H),3.73(d,J=12.5Hz,1H),3.28–2.90(m,6H),2.76(s,3H),1.49–1.36(m,3H),1.34–1.24(m,7H).

[0318] Example 31

[0319] Step 1:

[0320] Compounds EVO29409A1 (100 mg, 0.20 mmol), EVO29409A2 (31.5 mg, 0.30 mmol), 2-(7-azobenzotriazole)-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). The reaction mixture was allowed to react 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 with water (20 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and 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, 54.50% yield). LCMS (ESI) m / z = 581.1 [M+H] + .1 H NMR (DMSO-d6, 400MHz): δ9.32 (s, 1H), 8.86 (s, 1H), 8.48 (s, 1H), 7.60 (t, J = 53.1Hz, 1H), 7.15 (s, 1H), 4.63 (d, J=43.0Hz, 1H), 4.16 (d, J=83.2Hz, 2H), 3.80 (dd, J=51.6, 12.0Hz, 2H), 3.29–2.94 (m, 5H), 1.49–1.19 (m, 11H).

[0321] Example 32

[0322] Step 1:

[0323] 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 toluene (20 ml). The reaction mixture was refluxed at 115°C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford key INT-2 (2.7 g, 7.1% yield) as a colorless oil. 1 H NMR (400MHz, DMSO) δ7.54–7.20(m,5H),5.33(d,J=5.9Hz,1H),5.23–5.03(m, 2H), 3.85 (t, J=5.4Hz, 1H), 2.01–1.84 (m, 1H), 0.83 (dd, J=21.1, 6.8Hz, 6H).

[0324] Step 2:

[0325] Key INT-2 (2.7 g, 13.0 mmol) and 1,8-bis(dimethylaminonaphthalene) (5.6 g, 25.9 mmol) were dissolved in dichloromethane (100 ml) and trimethyloxonium tetrafluoroborate (3.8 g, 25.9 mmol) was added. The reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was filtered, rinsed with dichloromethane (50 ml x 2), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to afford key INT-3 (2.7 g, 93.4% yield) as a colorless oil. 1H NMR (400MHz, DMSO) δ7.48–7.23(m,5H),5.17(q,J=12.3Hz,2H),3.62(d,J=5.3Hz,1H),3.26(s,3H),2.06–1.86(m,1H),0.85(dd,J=15.1,6.9Hz,6H).

[0326] Step 3:

[0327] Palladium on carbon (2.0 g) was added to a solution of key INT-3 (2.7 g, 12.1 mmol) in methanol (50 mL). The reaction mixture was replaced with hydrogen three times and allowed to react at room temperature for 2 hours. The reaction mixture was filtered, washed twice with methanol (50 mL), and concentrated under reduced pressure to afford the crude product key INT (1.54 g, 96.3% yield), which was used directly in the next step.

[0328] Step 4:

[0329] Compound EVO29418-1 (150 mg, 0.30 mmol), key INT (60.2 mg, 0.45 mmol), 2-(7-azobenzotriazole)-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 allowed to react 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 x 2) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain EVO29418 (91.5 mg, 50.1% yield) as a yellow solid. LCMS (ESI) m / z = 609.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.32 (s, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 7.60 (t, J = 53.1H z,1H),7.15(s,1H),4.71(s,1H),4.35(dd,J=73.9,13.0Hz,1H),3.86(d,J=1 0.8Hz,1H),3.72(t,J=13.4Hz,2H),3.34–3.10(m,6H),1.96(d,J=6.5Hz,1H) ,1.44(t,J=6.6Hz,3H), 1.32(d,J=3.2Hz,4H), 0.91(dd,J=40.1,6.5Hz,6H).

[0330] Example 33

[0331] Step 1:

[0332] To a solution of compound EVO29419-1 (80 mg, 0.16 mmol) in N,N-dimethylformamide (2 ml) were added 2-(7-azobenzotriazole)-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) at room temperature. The reaction mixture was stirred at 25 degrees Celsius for 2 hours. The solvent was removed by rotary evaporation, and water (20 ml) was added. The mixture was then extracted with ethyl acetate (3 x 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 afford EVO29419 (34.7 mg, 36% yield) as a yellow solid. LCMS (ESI) m / z = 598.7 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.81(s,1H),8.44(s,1H),8.31(s,1H),7.60(t,J=53.1Hz,1 H),7.14(s,1H),4.72(s,1H),4.35(dd,J=72.3,13.1Hz,1H),3.88–3.59(m,4H),3 .29–2.95(m,5H),1.98(d,J=7.2Hz,1H),1.43(s,1H),1.32(d,J=6.1Hz,2H),1.0 8(s,3H),0.96(d,J=6.3Hz,3H),0.86(d,J=6.7Hz,3H),0.66(s,2H),0.40(s,2H).

[0333] Example 34

[0334] Step 1:

[0335] Compound EVO29410-1 (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (130.0 mg, 0.60 mmol) were added. Then, EVO29410-2 (35.0 mg, 0.20 mmol) was added and the reaction was stirred 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, and concentrated. 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 (400MHz, DMSO-d6) δ8.84(s,1H),8.45(s,1H),8.33(s,1H),7.61(t,J=53.0Hz,1H),7.15(s,1H),4.64(d,J=42.6Hz ,1H),4.17(d,J=82.9Hz,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).

[0336] Example 35

[0337] Step 1:

[0338] Compound EVO29420-1 (100.0 mg, 0.22 mmol), key INT (43.2 mg, 0.33 mmol), 2-(7-azobenzotriazole)-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). 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 x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain EVO29420 (35 mg, 28% yield) as a yellow solid. LCMS (ESI) m / z = 573.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.27(s,1H),8.75(s,1H),8.49(s,1H),7.11(s,1H),4.72(s,1H),4.36(dd,J=73.5,12.8Hz,1H),3.90–3.66 (m,3H),3.27(s,6H),2.75(s,3H),1.96(d,J=6.3Hz,1H),1.44(d,J=2.4Hz,3H),1.33(d,J=7.4Hz,4H),0.91(dd,J=39.9,6.5Hz,6H).

[0339] Example 36

[0340] Step 1:

[0341] To EVO29421A1 (100.0 mg, 0.22 mmol), (S)-2-methoxy-3-methylbutanoic acid (40.0 mg, 0.30 mmol), and diisopropylethylamine (173.4 mg, 1.34 mmol) was added portionwise 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (114.0 mg, 0.30 mmol) in N,N-dimethylformamide (3 mL). The reaction was stirred at room temperature for 1.5 hours, then water (70 mL) was added and the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 100 / 1) to afford EVO29421 (20 mg, 16% yield) as a yellow oil. LCMS (ESI) m / z = 562.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ8.71(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=11.9Hz,1H),2.75(s,3H),1 .96(dd,J=14.0,J=7.1Hz,1H),1.44(s,1H),1.31(dd,J=21.6,11.0Hz,3H),1.07(s,3H),0 .96(d,J=6.4Hz,3H), 0.86(d,J=6.7Hz,3H), 0.64(d,J=11.8Hz,2H), 0.41(d,J=5.8Hz,2H).

[0342] Example 37

[0343] Step 1:

[0344] Compound EVO29426-1 (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115.0 mg, 0.30 mmol) and N,N-diisopropylethylamine (130.0 mg, 0.60 mmol) were added. EVO29426-2 (30.0 mg, 0.20 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound EVO29426 (11 mg, 9% yield). LCMS (ESI) m / z = 595.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.87(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).

[0345] Example 38

[0346] Step 1:

[0347] 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. The mixture was purged with a hydrogen balloon three times and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was filtered through celite, and the filter cake was washed twice with methanol (10 mL). The combined filtrates were concentrated to afford EVO29592-2 (280.0 mg, 96.4% yield) as a white solid. LCMS (ESI) m / z = 153.1 [MH] - .

[0348] Step 2:

[0349] Compounds 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) at room temperature. 2-(7-Azabenzotriazole)-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 reacted at room temperature for 2 hours. The reaction mixture was quenched by adding water (60 mL) and stirred for 10 minutes. A solid precipitated and was filtered. The filter cake was washed with water (15 mL) and dried. Purification by liquid phase preparative separation afforded EVO29592 (650.0 mg, 61.7% yield) as a yellow solid. LCMS (ESI) m / z = 631.2 [M+H] + HPLC: 99.6%; 1 H NMR (400MHz, DMSO-d6): δ9.34(s,1H),8.87(s,1H),8.49(s,1H),7.61(t,J=53.0Hz,1H),7.14(s,1H),6.82(t,J=74.2Hz,1H),4.96-4.62(m,1H) ,4.44-4.30(m,1H),3.85(d,J=12.0Hz,1H),3.75(d,J=12.4Hz,2H),3.3 0-2.86(m,2H),1.63-1.51(m,6H),1.50-1.39(m,3H),1.39-1.26(m,4H).

[0350] Example 39

[0351] Compounds EVO29507-1 (50 mg, 0.10 mmol), EVO29507-2 (17 mg, 0.12 mmol), 2-(7-azobenzotriazole)-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). 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 (3 x 20 ml). The organic phase was washed once with water (20 ml x 2) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain EVO29507 (20 mg, 32.3% yield) as a yellow solid. LCMS (ESI) m / z = 598.7 [M+H] + . 1H NMR (400MHz, DMSO) δ8.84(s,1H),8.45(d,J=12.5Hz,1H),8.31(s,1H),7.60(t,J= 53.1Hz,1H),7.15(d,J=10.3Hz,1H),5.36–4.37(m,2H),3.93–3.66(m,3H),3.50–3 .34(m,2H),3.18(dd,J=40.2,30.5Hz,2H),1.48(s,1H),1.38(d,J=14.4Hz,6H),1. 30(d,J=6.5Hz,2H),1.16(t,J=6.9Hz,3H),1.08(s,3H),0.66(s,2H),0.41(s,2H).

[0352] Example 40

[0353] Compounds EVO29503-1 (100 mg, 0.21 mmol), EVO29503-2 (55.2 mg, 0.42 mmol), 2-(7-azobenzotriazole)-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 allowed to react 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 x 2) and saturated brine (20 ml), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain EVO29503 (55 mg, 45.8% yield) as a yellow solid. LCMS (ESI) m / z = 584.0 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.83(s,1H),8.43(s,1H),8.29(s,1H),7.60(t,J=53.1Hz,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=14.9Hz,4H),1.47(s,1H),1.37(d,J=12.5Hz,6H),1. 31(d,J=6.5Hz,2H),1.08(s,3H),0.71–0.60(m,2H),0.47–0.30(m,2H).

[0354] Example 41

[0355] Step 1:

[0356] To a solution of (R)-2-hydroxy-3,3-dimethylbutanoic 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) was added PyBop (0.94 g, 1.81 mmol) under ice-cooling, 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 purified by silica gel column chromatography (ethyl acetate / petroleum ether) to afford 29736A1 (0.40 g, 84.0% yield) as a white solid. LCMS (ESI) m / z = 259.4 [M+H-56] + .

[0357] Step 2:

[0358] To a solution of compound 29736A1 (0.20 g, 0.64 mmol) in DMF (2 mL) was added 60% NaH (0.03 g, 0.76 mmol) under ice-cooling, and the mixture was stirred for 0.5 hour. Iodomethane (0.11 g, 0.76 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, 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 afford 29736A2 (0.20 g, 95.7% yield) as a white solid. LCMS (ESI) m / z = 274.4 [M+H-56] + .

[0359] Step 3:

[0360] To a solution of compound 29736A2 (0.20 g, 0.64 mmol) in ethyl acetate (0.5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) at room temperature and stirred for 2 hours. The reaction mixture was concentrated to remove the solvent to afford 29246A3 as a white solid (the crude product was used directly in the next step). LCMS (ESI) m / z = 229.2 [M+H] + .

[0361] Step 4:

[0362] To a solution of compound 29001A6 (100.00 mg, 0.19 mmol) in 1,4-dioxane (3 mL) were added 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) at room temperature, and the reaction was stirred at 90 °C for 3 h. 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 light yellow solid 29736A4 (72.00 mg, yield 52.9%). LCMS (ESI) m / z = 723.1 [M+H] + .

[0363] Step 5:

[0364] Trifluoroacetic acid (0.20 mL) was added to a solution of compound 29736A4 (72.00 mg, 0.10 mmol) in dichloromethane (1 mL) at room temperature, 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). The layers were separated, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was subjected to reverse phase purification to obtain EVO29736 (23.20 mg, 37.4% yield) as a pale yellow solid. LCMS (ESI) m / z = 622.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.33(s,1H),8.95–8.79(m,1H),8.54–8.41(m,1H),7.61(t,J=53.1Hz,1H),7.19–7.08(m,1H),4.78(d,J=6.5Hz,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).

[0365] Example 42

[0366] Step 1:

[0367] (R)-1-Boc-3-methylpiperazine (4.00 g, 19.97 mmol), 2-cyclopropyl-2-oxoacetic acid (2.51 g, 21.97 mmol), 2-(7-azobenzotriazole)-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 solution was reacted at room temperature for 2 hours. Water (100 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 (50 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried 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%).

[0368] Step 2:

[0369] 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 allowed to react at room temperature for 1 hour. Saturated NH4Cl solution was added to the reaction solution, and the mixture was stirred for 10 minutes. Silica gel was then added and spin-dried. The mixture was then purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain EVO29710A2 (5.02 g, 91.49% yield).

[0370] Step 3:

[0371] 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 portionwise. The reaction was kept warm for 1 hour. EtI (3.15 g, 20.19 mmol) was added dropwise and allowed to react 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 with water (100 mL x 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain EVO29710A3 (4.86 g, 88.49% yield). LCMS (ESI) m / z = 271.23 [M+H-56] + .

[0372] Step 4:

[0373] A solution of EVO29710A3 (3.70 g, 11.33 mmol) in 4M HCl / 1,4-dioxane (40 mL) was reacted at room temperature for 5 hours; the mixture was dried under reduced pressure, and the crude EVO29710A4 was used directly in the next reaction.

[0374] Step 5:

[0375] To the crude EVO29710A4 product from the previous step, add 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), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (1.72 g, 2.06 mmol), and cesium carbonate (16.78 g, 51.51 mmol). Under argon, react at 100°C for 8 hours, cool to room temperature, filter through celite, and prepurify by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1 to 2:3). EVO29710 (2.20 g, yield 34.41%) was obtained by preparative separation and purification using high performance liquid chromatography.

[0376] EVO29710 (2.2 g) was separated by supercritical fluid chromatography (SFC) (column: ChiralCel OD, 300×50 mm ID, 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, cycle time: ~8 min, injection volume: 17.00 mL) to give EVO29710P1 (1.27 g, retention time 3.110 minutes) and EVO29710P2 (730 mg, retention time 3.473 minutes), LCMS (ESI) m / z = 621.2 [M+H] + .

[0377] EVO29710P1:

[0378] 1H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 8.90 (s, 1H), 8.54-8.50 (m, 1H), 7.64 (t, J = 52Hz ,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=8Hz,2H),0.63-0.42(m,2H),0.34-0.30(m,1H).

[0379] EVO29710P2:

[0380] 1 H NMR(400MHz, DMSO-d6)δ9.36(s,1H),8.89(s,1H),8.53(s,1H),7.64(t,J=52Hz,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).

[0381] Example 43

[0382] Step 1:

[0383] 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 portionwise. The mixture was kept warm for 1 hour. CHCl (1.86 g, 13.07 mmol) was then added dropwise and allowed to react 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 with water (500 mL x 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain EVO29715A1 (2.50 g, 91.84% yield). LCMS (ESI) m / z = 313.13 [M+H] + .

[0384] Step 2:

[0385] A solution of EVO29715A1 (1.48 g, 4.74 mmol) in 4M HCl / 1,4-dioxane (10 mL) was reacted at room temperature for 5 hours; the mixture was dried under reduced pressure, and the crude EVO29715A2 was used directly in the next reaction.

[0386] Step 3:

[0387] To the crude product of EVO29715A2 from the previous step was 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), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (706.62 mg, 0.84 mmol), and cesium carbonate (6.88 g, 21.12 mmol). Under argon protection, the reaction was carried out at 100°C for 8 hours, the temperature was cooled to room temperature, and the product was filtered through celite. The filtrate was spin-dried and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1-2:3) to obtain EVO29715 (970.00 mg, yield 37.85%).

[0388] EVO29715 (970 mg) was separated by supercritical fluid chromatography (SFC) (Chromatographic column: ChiralPak AD, 250×30 mm ID, 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) to give EVO29715P1 (501 mg, retention time 3.538 minutes) and EVO29715P2 (268 mg, retention time 3.916 minutes), LCMS (ESI) m / z = 607.2 [M+H] + .

[0389] EVO29715P1:

[0390] 11H 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).

[0391] EVO29715P2:

[0392] 1 1H 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).

[0393] Example 44

[0394] Step 1:

[0395] To a solution of compound EVO29291-1 (150.0 mg, 0.30 mmol) in N,N-dimethylformamide (5 mL) were added 2-(7-azobenzotriazole)-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) at room temperature. The reaction mixture was stirred at 25°C for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. 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] + . 1 H NMR(400MHz, DMSO-d6)δ9.30(s,1H),8.84(d,J=2.2Hz,1H),8.52(d,J=9.3Hz,1H),7.59(t,J=53.1Hz,1H),7.18(d,J=9.4Hz,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=6.0Hz, 3H), 1.37 (t, J = 7.2Hz, 2H), 1.32 (dd, J = 8.3, 5.4Hz, 2H), 1.18–1.11 (m, 6H).

[0396] Example 45

[0397] Step 1:

[0398] Compound EVO29038M (150.0 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (2 mL), and oxamic acid (41.0 mg, 0.46 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (173.0 mg, 0.46 mmol), and N,N-diisopropylethylamine (294.0 mg, 2.28 mmol) were added. The mixture was stirred at room temperature for 2 hours. LCMS showed the main peak to be the product. The reaction solution was directly separated and purified by reverse phase column chromatography (water:acetonitrile = 2:1) to obtain EVO29298 (68.5 mg, 40.0% yield). LCMS (ESI) m / z = 568.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.86(d,J=3.2Hz,1H),8.50(d,J=10.8Hz,1H),8.14(d,J=5.8Hz,1H),7.82–7.44(m,2H),7.17(d,J=10.8 Hz,1H),4.64(s,1H),4.26(d,J=13.3Hz,1H),3.97–3.65(m,3H),3.29(s,3H),3.26–2.96(m,2H),1.45(d,J=3.6Hz,2H),1.35(d,J=6.8Hz,2H).

[0399] Example 46

[0400] Step 1

[0401] To a solution of compound EVO29386-1 (100 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) were added 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-oxoacetic acid (28 mg, 0.24 mmol) at room temperature. The reaction solution was stirred at 25°C for 2 hours. The solvent was removed by rotary evaporation, and water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 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 EVO29386 (57 mg, 47.50% yield) as a pale yellow solid. LCMS (ESI) m / z = 591.0 [M+H] +. 1 H NMR(DMSO-d6,400MHz)δ9.37(s,1H),8.86(s,1H),8.51(d,J=8.4Hz,1H),7.61(t,J= 53.1Hz,1H),7.18(d,J=9.5Hz,1H),4.73–4.21(m,1H),4.02–3.86(m,1H),3.82–3.5 5(m,2H),3.40(dd,J=23.0,19.2Hz,2H),3.23–3.04(m,1H),2.40–2.27(m,1H),1.48 –1.43(m,3H),1.38(d,J=6.7Hz,2H),1.31(dd,J=8.0,5.4Hz,2H),1.21–1.10(m,4H).

[0402] Example 47

[0403] Step 1:

[0404] 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) was added portionwise 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (142.5 mg, 0.38 mmol) in N,N-dimethylformamide (3 mL). The reaction was stirred at room temperature for 1.5 hours, and water (70 mL) was added. The organic phases were washed with ethyl acetate (50 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 70:1) to give EVO29417 (110.0 mg, yield 61.00%) as an off-white solid. LCMS (ESI) m / z = 579.1 [M+H] + . 1 H NMR(DMSO-d6,400MHz): δ9.36(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=17.7Hz,4H),3.16–3.04(m,1H),1.44(d,J=4.7Hz,2H),1.33(d,J=4.8Hz,2H),1.08(s,9H),1.15(s,3H),1.13(s,3H).

[0405] Example 48

[0406] Step 1:

[0407] Compounds EVO29406A1 (100 mg, 0.21 mmol), EVO29406A2 (32.3 mg, 0.25 mmol), 2-(7-azobenzotriazole)-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). The reaction mixture was allowed to react 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 x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain EVO29406 (47.3 mg, 37.80% yield) as a yellow solid. LCMS (ESI) m / z = 596.0 [M+H] + . 1 H NMR(DMSO-d6,400MHz): δ8.81(d,J=4.4Hz,1H),8.47(d,J=8.9Hz,1H),8.33(s, 1H),7.60(t,J=53.1Hz,1H),7.17(d,J=9.0Hz,1H),4.74–4.22(m,1H),3.79(ddd ,J=39.3,27.7,10.9Hz,3H),3.38(s,1H),3.32–2.95(m,2H),1.40(dd,J=21.4, 6.6Hz, 3H), 1.23 (d, J = 4.6Hz, 9H), 1.08 (s, 3H), 0.73–0.58 (m, 2H), 0.41 (s, 2H).

[0408] Example 49

[0409] Step 1

[0410] To a solution of compound EVO29405A1 (100 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) were added 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) at room temperature. 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 x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to afford EVO29405 (65 mg, 54.20% yield) as a pale yellow solid. LCMS (ESI) m / z = 607.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz): δ9.35 (s, 1H), 8.86 (d, J = 3.7Hz, 1H), 8.52 (d, J = 9.7Hz, 1H) ,7.61(t,J=53.1Hz,1H),7.18(d,J=10.1Hz,1H),4.74–4.20(m,1H),3.97–3.67(m, 3H),3.38(dd,J=21.7,8.0Hz,1H),3.30–3.20(m,1H),3.17–2.99(m,1H),1.48–1.4 1(m,3H),1.38(d,J=6.8Hz,2H),1.32(dd,J=8.3,5.3Hz,2H),1.24(d,J=4.5Hz,9H).

[0411] Example 50

[0412] Step 1:

[0413] 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) in N,N-dimethylformamide (3 mL) was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (91.2 mg, 0.24 mmol) portionwise. The reaction was stirred at room temperature for 1.5 hours. Water (70 mL) was added and the mixture was washed with ethyl acetate (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by silica gel column chromatography (dichloromethane / methanol = 70:1) to afford EVO29388 (28.4 mg, 24.90% yield) as an off-white solid. LCMS (ESI) m / z = 554.1 [M+H]+ . 1 H NMR (DMSO-d6, 400MHz): δ8.82 (s, 1H), 8.47 (d, J = 10.1Hz, 1H), 8.34 (d, J = 4.0Hz, 1H) ,7.60(t,J=53.1Hz,1H),7.16(d,J=9.1Hz,1H),4.71–4.20(m,1H),4.12–3.85(m,1H) ,3.83–3.61(m,3H),3.42(d,J=12.2Hz,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).

[0414] Example 51

[0415] Step 1:

[0416] 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) in N,N-dimethylformamide (3 mL) was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (117.8 mg, 0.31 mmol) in portions. The reaction was stirred at room temperature for 1.5 hours. Water (70 mL) was added and the mixture was washed with ethyl acetate (50 mL*2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (dichloromethane / methanol = 70:1) to give an off-white solid EVO29387 (110 mg, yield 61.00%). LCMS (ESI) m / z = 580.1 [M+H] + . 1H NMR(DMSO-d6,400MHz): δ8.82(s,1H),8.47(d,J=8.3Hz,1H),8.33(d,J=2.8Hz,1H),7 .60(t,J=53.1Hz,1H),7.16(d,J=8.8Hz,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).

[0417] Example 52

[0418] Step 1: Compound EVO29384A1 (100 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (3 mL). EVO29384A2 (40 mg, 0.34 mmol), 2-(7-azobenzotriazole)-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. LCMS analysis indicated the product as the main peak. The reaction mixture was added with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain EVO29384 (41.6 mg, 33.28% yield). LCMS (ESI) m / z = 546.1 [M+H] + . 1 H NMR(DMSO-d6,400MHz): δ8.71(d,J=4.0Hz,1H),8.47(d,J=7.8Hz,1H),8.30(d,J=2.6 Hz,1H),7.12(d,J=7.7Hz,1H),3.97–3.64(m,3H),3.46(dd,J=36.0,12.8Hz,1H),3.3 1–3.15(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=9.5,6.8Hz,1H),0.71–0.57(m,2H),0.40(d,J=1.6Hz,2H).

[0419] Example 53

[0420] Step 1

[0421] EVO29383A1 (5 g, 12.25 mmol) was dissolved in acetonitrile (30 mL). Water (2.5 mL) and acetic acid (5 mL) were added under an ice bath. Dichlorohydantoin (3.62 g, 18.38 mmol) was then added portionwise to the reaction flask. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated, and an appropriate amount of water (100 mL) was added. Ethyl acetate (100 mL x 3) was then added for separation and extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain EVO29383A2 (4.6 g, 97.00% yield). LCMS (ESI) m / z = 386.2 [M+H] + .

[0422] Step 2

[0423] 1-Methylcyclopropylamine 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. EVO29383A2 (4.5 g, 11.72 mmol) was then added portionwise to the reaction mixture. 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 afford EVO29383A3 (2.7 g, 55.00% yield). LCMS (ESI) m / z = 420.8 [M+H] + .

[0424] Step 3

[0425] To a solution of compound EVO29383A3 (2.6 g, 6.21 mmol) in dichloromethane (20 mL) were added 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) at room temperature. 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 = 5:1) to afford EVO29383A4 (2.1 g, 66.00% yield) as a pale yellow solid. LCMS (ESI) m / z = 520.9 [M+H] + .

[0426] Step 4

[0427] 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) at room temperature, and the reaction solution was stirred at 90 degrees Celsius 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 light yellow solid EVO29383A5 (800 mg, yield 30.00%). LCMS (ESI) m / z = 684.7 [M+H] + .

[0428] Step 5

[0429] 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) at room temperature, and 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, 90.00% yield). LCMS (ESI) m / z = 484.5 [M+H] + .

[0430] Step 6

[0431] To a solution of compound EVO29383A6 (50 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol), N,N-diisopropylethylamine (40 mg, 0.31 mmol), and 3-methyl-2-oxobutanoic acid (14 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred at 25°C for 2 hours. An appropriate amount of water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was isolated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to afford EVO29383 (30 mg, 50.00% yield) as a pale yellow solid. LCMS (ESI) m / z = 582.6 [M+H] + . 1H NMR(DMSO-d6,400MHz): δ8.82(d,J=4.3Hz,1H),8.48(d,J=8.8Hz,1H),8.33(d,J=2.5Hz,1H) ,7.61(t,J=53.1Hz,1H),7.17(d,J=8.3Hz,1H),4.74–4.25(m,1H),3.89(d,J=13.5Hz,1H),3 .84–3.66(m,2H),3.58–3.37(m,1H),3.24(dd,J=12.6,3.2Hz,1H),3.17–3.00(m,2H),1.42( dd,J=25.5,6.7Hz,3H),1.18–1.11(m,6H),1.09(s,3H),0.66(d,J=5.7Hz,2H),0.41(s,2H).

[0432] Example 54

[0433] Step 1:

[0434] To a solution of compound EVO29385-1 (100.0 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL) were added 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-oxobutanoic acid (30.0 mg, 0.26 mmol) at room temperature. The reaction solution was stirred at 25°C for 2 hours. An appropriate amount of water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (3 x 20 mL). 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 afford EVO29385 (44 mg, 36% yield) as a pale yellow solid. LCMS (ESI) m / z = 557.6 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.75 (d, J = 2.7Hz, 1H), 8.52 (d, J = 8.4Hz, 1H), 7. 13(d,J=8.7Hz,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=11.9,3.3Hz,1H),3.15–3.00(m,2H),2.76(s,3H),1.48–1.43(m ,3H), 1.39(d,J=6.7Hz,2H), 1.31(dd,J=8.1,5.1Hz,2H), 1.14(dd,J=9.9,4.2Hz,6H).

[0435] Example 55

[0436] Step 1:

[0437] To a mixture of EVO29407-1 (6.0 g, 3.6 mmol) and 1,2-dioxane were added 2-bromo-5-methyl-1,3,4-thiadiazole (11.8 g, 65.7 mmol), cuprous 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 nitrogen, the temperature was raised to 110°C and the reaction was allowed to proceed for 16 hours. TLC analysis (petroleum ether:ethyl acetate = 3:1) indicated complete conversion of the starting material. The reaction solution was cooled to room temperature, 150 mL of aqueous ammonia was added and stirred for half an hour, the solid was filtered, 100 mL of water was added to the filtrate, and ethyl acetate (100 mL*3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. 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%).

[0438] Step 2:

[0439] 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 under an ice bath. Dichlorohydantoin (1.0 g, 4.8 mmol) was then added in small amounts to the reaction mixture. The reaction mixture was stirred at 25 degrees Celsius for 2 hours. The reaction mixture was concentrated, an appropriate amount of water (100 mL) was added, and ethyl acetate (50 mL*3) was added for separation and extraction. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain EVO29407-3 (2 g, yield 98%). LCMS (ESI) m / z = 348.1 [M+H] + .

[0440] Step 3:

[0441] 1-Cyanocyclopropylamine hydrochloride (870.0 mg, 7.33 mmol) was dissolved in pyridine (100 mL). EVO29407-3 (1.7 g, 4.98 mmol) was added to the reaction in small amounts over an ice bath. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain EVO29407-4 (1 g, yield 63%). LCMS (ESI) m / z = 394.0 [M+H] + .

[0442] Step 4:

[0443] To a solution of compound EVO29407-4 (1.0 g, 2.54 mmol) in dichloromethane (25 mL) were added 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) at room temperature, and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 16:9) to obtain EVO29407-5 (1.0 g, 80% yield) as a white solid. LCMS (ESI) m / z = 494.0 [M+H] + .

[0444] Step 5:

[0445] 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) at room temperature, and the reaction solution was stirred at 100 degrees Celsius for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:2) to obtain a yellow solid EVO29407-6 (1 g, yield 77%). LCMS (ESI) m / z = 658.1 [M+H] + .

[0446] Step 6:

[0447] To a solution of compound EVO29407-6 (1.0 g, 1.52 mmol) in methanol (10 mL) was added a methanolic solution of hydrogen chloride (15 mL, 6 M) at room temperature, and the reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to obtain a light yellow solid EVO29407-7 (600 mg, 86% yield). LCMS (ESI) m / z = 458.1 [M+H] + .

[0448] Step 7:

[0449] To a solution of compound EVO29407-7 (100.0 mg, 0.22 mmol) in N,N-dimethylformamide (1 mL) were added 2-(7-azobenzotriazole)-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) at room temperature. The reaction solution was stirred at 25 degrees Celsius for 2 hours. An appropriate amount of water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (3*20 mL). 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 EVO29407 (13 mg, 10% yield) as a yellow solid. LCMS (ESI) m / z = 571.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.73(t,J=5.9Hz,1H),8.49(t,J=17.4Hz,1H),7.13(d,J=9.1Hz,1H),4.67(s,1H),3.93–3.66(m,3H),3.27–3.16(m,2H),3 .03(ddd,J=33.9,11.8,8.8Hz,1H),2.75(s,3H),1.43(t,J=6.2Hz,3H),1 .38(d,J=6.8Hz,2H), 1.30(dd,J=8.1,5.1Hz,2H), 1.24(d,J=4.4Hz,10H).

[0450] Example 56

[0451] Step 1:

[0452] To a solution of compound EVO29408-1 (100.0 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) were added 2-(7-azobenzotriazole)-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) at room temperature. The reaction solution was stirred at 25 degrees Celsius for 2 hours. An appropriate amount of water (10 mL) was added to the reaction solution, followed by separation and extraction with ethyl acetate (10 mL*2). 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 EVO29408 (15 mg, 12% yield) as a pale yellow solid. LCMS (ESI) m / z = 560.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.71(d,J=4.1Hz,1H),8.48(d,J=8.0Hz,1H),8.28(d,J=2.0Hz,1 H),7.13(d,J=8.2Hz,1H),4.68(s,1H),3.89–3.62(m,3H),3.39(d,J=11.3Hz,1H),3.22(d dd,J=27.3,12.5,3.3Hz,1H),3.02(ddd,J=33.4,11.7,8.6Hz,1H),2.75(s,3H),1.41(dd ,J=21.1,6.6Hz,3H),1.24(d,J=4.5Hz,9H),1.07(s,3H),0.74–0.54(m,2H),0.40(s,2H).

[0453] Effect Example PARG in vitro assay

[0454] PARG in vitro assays were performed in standard 384-well plates in a total volume of 15 μL. 5 μL of enzyme reaction mixture (50 mM Tris-HCl pH 7.5, 50 mM KCL, Triton X-100 0.01%, BSA 0.01%, 4 pM His-GST-tagged PARG) was added to a 384-well plate containing the test compound. After incubation at room temperature for 10 minutes, 5 μL of substrate mixture (50 mM Tris-HCl pH 7.5, 50 mM KCL, Triton X-100 0.01%, BSA 0.01%, 30 nM Bio PARylated PARP1) was added to initiate the reaction. The reaction was incubated at room temperature for 20 minutes and 5 μL of detection reagent was added to terminate the reaction. The detection reagent consisted of buffer (50 mM Tris-HCl pH 7.5, 50 mM KCL, Triton X-100 0.01%, BSA 0.01%), 3 μM compound PDD00017273, and 1.5X mAb anti-6HIS. XL665 (Cisbio: 61HISXLA) and 1.5X streptavidin terbium cryptate (Cisbio: 610SATLA) were formulated. The final concentrations of compound PDD00017273, 1.5X mAb anti-6HIS XL665 (Cisbio: 61HISXLA), and 1.5X streptavidin terbium cryptate were 1 μM, 0.5X, and 0.5X, respectively. After incubation in the dark at room temperature for 120 minutes, TR-FRET signals were measured at Ex 340, Em 665, and Em 615. The ratio for each well was calculated as Em 665 / Em 615 (where the ratio corresponds to the ratio of fluorescence signals at each wavelength). Compound inhibition rates were calculated based on the obtained data. The results are shown in Table 1.

[0455] Table 1

[0456] Where A represents IC 50 <0.1μM; B means 0.1μM≤IC 50 <0.5μM; C means 0.5uM≤IC 50 <1.0μM; D means 1.0uM≤IC 50 <10.0μM.

[0457] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined 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, in, X1 and X2 are independently N or CR7; R7 is independently hydrogen, deuterium, halogen, CN, OH, NR a R b , C1-C6 alkyl or one or more R 7-2 Substituted C1-C6 alkyl; R a and R b are independently hydrogen or C1-C6 alkyl; R 7-2 are independently deuterium, halogen, CN, OH or NR a R b ; R8 is hydrogen or halogen; R1 is hydrogen, deuterium, halogen, OH, CN, NR a R b , C2-C4 alkynyl, C1-C6 alkyl or one or more R 1-2 Substituted C1-C6 alkyl; R 1-2 are independently deuterium, halogen, OH or NR a R b ; R2 is hydrogen, deuterium, OH, C1-C6 alkyl, C3-C6 cycloalkyl, 1 or more R 2-1 Substituted C1-C6 alkyl or one or more R 2-2 substituted C3-C6 cycloalkyl; R 2-1 and R 2-2 are independently deuterium, OH, halogen or NR a R b ; R3 is hydrogen, deuterium, OH, NR a R b , C1-C6 alkyl or one or more R 3-2 Substituted C1-C6 alkyl; R 3-2 Deuterium, OH, NR a R b or halogen; X3 is N-(C=O)-L-CR5R6-OR 11 or N-(C=O)-(C=O)-R 12 ; L is (CR9R 10 )m; R9 and R 10 are independently hydrogen, deuterium, OH, CN, N(R 9-1 )2, C1-C6 alkyl or one or more R 9-2 Substituted C1-C6 alkyl; R 9-1 are independently hydrogen or C1-C6 alkyl; 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 , C1-C6 alkyl, C3-C6 cycloalkyl, 1 or more R 5-2 replace C1-C6 alkyl or one or more R 5-3 substituted C3-C6 cycloalkyl; R 5-2 and R 5-3 Deuterium, OH, NR a R b or halogen; Alternatively, R5 and R6 and the carbon atom to which they are attached together form a C3-C6 cycloalkyl, a 3-6 membered heterocycloalkyl, a 5-3 Substituted C3-C6 cycloalkyl or one or more R 5-4 Substituted 3-6 membered heterocycloalkyl, wherein the number of heteroatoms in each "3-6 membered heterocycloalkyl" is independently 1 or 2, and the type of heteroatoms is independently selected from one or more of N, O and S; R 5-3 and R 5-4 are independently deuterium, hydroxyl, NR a R b or halogen; R 11 is hydrogen, C1-C6 alkyl, or C1-C6 alkyl substituted by one or more halogens; R 12 NR a R b , C1-C6 alkyl, C3-C6 cycloalkyl, 1 or more R 12-1 Substituted C1-C6 alkyl or one or more R 12-2 substituted C3-C6 cycloalkyl; R 12-1 and R 12-2 are independently halogen, OH, CN or NR a R b .

2. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) Each "halogen" is independently F, Cl, Br or I, for example F; (2) each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, for example, methyl, ethyl, isopropyl or tert-butyl; (3) each "C2-C4alkynyl" is independently ethynyl, propynyl or propargyl, for example, ethynyl; (4) Each "C3-C6 cycloalkyl" is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (5) Each "3- to 6-membered heterocycloalkyl group" is independently a 3- to 6-membered heterocycloalkyl group having 1 or 2 heteroatoms, wherein the heteroatoms are N and / or O, for example, oxirane, aziridine, oxetanyl, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl or piperazinyl.

3. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: It meets one or more of the following conditions: (1) X2 is CR7; (2) R7 is independently hydrogen or halogen; (3) R8 is hydrogen; (4) R1 is hydrogen, CN, C2-C4 alkynyl or C1-C6 alkyl, preferably CN, C2-C4 alkynyl or C1-C6 alkyl, more preferably CN or C1-C6 alkyl; (5) R2 is C1-C6 alkyl or is replaced by 1, 2 or 3 R 2-1 Substituted C1-C6 alkyl, preferably methyl or substituted by 1, 2 or 3 R 2-1 The substituted methyl group is preferably 1, 2 or 3 R 2-1 substituted methyl groups; (6)R 2-1 is a halogen; (7) R3 is hydrogen, C1-C6 alkyl or 1, 2 or 3 R 3-2 Substituted C1-C6 alkyl, preferably C1-C6 alkyl or substituted by 1, 2 or 3 R 3-2 Substituted C1-C6 alkyl, more preferably methyl or substituted by 1, 2 or 3 R 3-2 substituted methyl groups; (8)R 3-2 are independently halogen; (9)R9 and R 10 are independently hydrogen, N(R 9-1 )2 or C1-C6 alkyl, for example N(R 9-1 )2 or C1-C6 alkyl, preferably C1-C6 alkyl; (10)R 9-1 are independently hydrogen; (11) m is 0; (12) R5 and R6 are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl or 1, 2 or 3 R 5-3 Substituted C3-C6 cycloalkyl, preferably hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl, more preferably C1-C6 alkyl or substituted by 1, 2 or 3 R 5-2 Substituted C1-C6 alkyl; (13)R 5-2 and R 5-3 is independently OH or halogen, preferably halogen.

4. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, wherein: It meets one or both of the following conditions: (1)R 10 is hydrogen; (2) R5 is hydrogen or C1-C6 alkyl, R6 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or one or more R 5-2 Substituted C1-C6 alkyl, R 5-2 is independently OH or halogen.

5. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, wherein: It meets one or more of the following conditions: (1) X1 is N or CH; (2) X2 is N, CH or CF, preferably CH or CF; (3) R8 is H or F, preferably H; (4) R1 is hydrogen, CN, ethynyl or methyl, for example, CN, ethynyl or methyl, preferably CN or methyl, more preferably CN; (5) R2 is methyl or CHF2, preferably CHF2; (6) R3 is hydrogen, methyl or CH2F, preferably methyl or CH2F; (7) for (8) R5 is hydrogen or methyl; (9) R6 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, methyl substituted by 1, 2 or 3 fluorine groups, tert-butyl substituted by 1, 2 or 3 fluorine groups or tert-butyl substituted by 1, 2 or 3 OH groups, for example, hydrogen, methyl, isopropyl, tert-butyl, cyclopropyl, CF3, Preferably, R6 is methyl, tert-butyl, methyl substituted by 1, 2 or 3 fluorine groups or methyl substituted by 1, 2 or 3 fluorine groups. tert-butyl, such as methyl, tert-butyl, CF3, (10)R 11 is hydrogen, methyl, ethyl or methyl substituted by 1, 2 or 3 fluorine groups, for example hydrogen, methyl, ethyl or CHF2; (11)R 12 is isopropyl, amino, cyclopropyl, tert-butyl or methyl.

6. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, wherein: It meets one or more of the following conditions: (1) for For example (2) for For example, (3) for 7. The compound of 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: The compound represented by formula (I) is a compound represented by formula (I-1), (I-2) or (I-3): Among them, the carbon atom marked with "*" indicates that when it is a chiral carbon atom, it is independently in R configuration, S configuration or a mixture thereof, X1, X2, R8, R1, R2, R3, R 10 , R5, R6, R 11 and R 12 The definition as described in at least one of claims 1 to 6.

8. The compound of 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: 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), Among them, the carbon atom marked with "*" indicates that when it is a chiral carbon atom, it is independently in R configuration, S configuration or a mixture thereof, R1, R2, R7, R5, R6, R 11 and R 12 According to at least one of claims 1 to 6; Preferably, the above formulas satisfy one or both of the following conditions: I: R2 is CHF2; II: R1 is CN.

9. The compound of 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: The compound represented by formula (I) is any one of the following compounds:

10. A pharmaceutical composition comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a compound of 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.

11. Use of a substance X or the pharmaceutical composition according to claim 10 in the preparation of a PARG inhibitor, wherein the substance X is a compound of 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 a substance X or the pharmaceutical composition according to claim 10 in the preparation of a medicament for a disease associated with PARG, wherein the substance X is a compound of 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; preferably, the disease associated with PARG is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, or gastric cancer.

13. Use of a substance X or the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing and / or treating cancer, wherein the substance X is a compound of 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; preferably, the cancer is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, or gastric cancer.

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