Method for preparing pyrrolidine derivative or salt thereof

Abstract

The present disclosure relates to a method for preparing a pyrrolidine derivative or a salt thereof. Specifically, the present disclosure relates to a method for preparing (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)ethyl)azanediyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propionic acid). The method exhibits a high yield.

Description

Preparation method of pyrrolidine derivatives or their salts Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology and relates to a method for preparing a pyrrolidine derivative or its salt and its uses. Background Technology

[0002] Lipoprotein(a) [Lp(a)] is a type of low-density lipoprotein (LDL) lipid particle, mainly composed of a cholesterol-rich core and a unique apolipoprotein(a) [Apo(a)]. It exhibits genetic polymorphism and long-term stability, showing a skewed distribution in the population. Studies have found that elevated Lp(a) levels are associated with an increased risk of cardiovascular events and related revascularization.

[0003] There are currently several treatment options available for elevated LDL-c, decreased HDL-c, and elevated triglycerides, but there are no approved treatments for patients with elevated Lp(a) levels.

[0004] WO2023078333A1 discloses a substituted phenylpropionic acid derivative and its preparation method, but the overall yield of the method is low and it is not suitable for industrial production. Summary of the Invention

[0005] This disclosure provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0006] The steps include the reaction of compound of formula III with chloroethylamine hydrochloride in the presence of a reducing agent. in,

[0007] R 1 Selected from hydrogen or protecting groups (PG);

[0008] R 2 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R 2A Replaced by, R 2A Each is independently selected from halogen, hydroxyl, cyano or amino groups;

[0009] R 3 Selected from OH, OR 4 or

[0010] R 4 C 1-4 alkyl;

[0011] R 5 For hydrogen, C 1-6 Alkyl group, (CH2)m R 5A R 5A Selected from phenyl, C 1-6 Alkoxy, wherein the phenyl or alkoxy group is optionally selected from one or more C 1-6 Alkyl, C 1-6 Substitution with alkoxy, halogen, or nitro groups;

[0012] R 6 R 7 Each is independently selected from hydrogen, C 1-6 Alkyl, phenyl, or benzyl, wherein the alkyl, phenyl, or benzyl group is optionally substituted with one or more R 3A Replaced by, R 3A Each is independently selected from halogen, hydroxyl, cyano or amino groups;

[0013] D and E are each independently selected from O or S;

[0014] W is 3;

[0015] L is selected from

[0016] n is an integer between 0 and 4; m is a number between 0, 1, and 2.

[0017] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Selected from hydrogen.

[0018] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 The protecting group is selected from the protecting group (PG), which is selected from tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), trichloroethoxycarbonyl (Troc), and p-toluenesulfonyl (Tos).

[0019] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 1 Selected from tert-butoxycarbonyl (Boc).

[0020] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 2 It is independently selected from hydrogen or deuterium.

[0021] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 2 It is independently selected from halogens, such as fluorine or chlorine.

[0022] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 3 Selected from OH.

[0023] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 3 Selected from OC(CH3)3.

[0024] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 3 Selected from R 5 As defined above.

[0025] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 3 Selected from R 5 Selected from CH2R 5A R 5A Selected from phenyl, wherein the phenyl is optionally mixed with one or more compounds selected from C 1-6 Alkyl, C 1-6 Substitution with alkoxy, halogen, or nitro groups.

[0026] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 3 Selected from R 5 Selected from (CH2)2R 5A R 5A Selected from phenyl.

[0027] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, R 3 Selected from

[0028] In some embodiments, the compound of formula II or a pharmaceutically acceptable salt thereof, R 1 It is selected from the protecting group (PG), which is defined as above.

[0029] In some embodiments, the compound of formula II or its pharmaceutically acceptable salt, R 2 It is independently selected from hydrogen, fluorine, or chlorine.

[0030] In some embodiments, the compound of formula II or its pharmaceutically acceptable salt, R 3 Selected from OR 4 or R 4 -R 7 As defined above.

[0031] In some embodiments, the compound of formula III or its pharmaceutically acceptable salt, R 1 It is selected from the protecting group (PG), which is defined as above.

[0032] In some embodiments, the formula III compound or its pharmaceutically acceptable salt, R 2 It is independently selected from hydrogen, fluorine, or chlorine.

[0033] In some embodiments, the formula III compound or its pharmaceutically acceptable salt, R 3 Selected from OR 4 or R 4 -R 7 As defined above.

[0034] In some embodiments, the molar ratio of chloroethylamine hydrochloride to the compound of formula III is 1:2 to 1:3, including but not limited to 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, or any value between any two numbers. In some embodiments, the molar ratio of chloroethylamine hydrochloride to the compound of formula III is 1:2 to 1:2.5. In some embodiments, the molar ratio of chloroethylamine hydrochloride to the compound of formula III is 1:2.2.

[0035] In some embodiments, the reducing agent is selected from sodium triacetoxyborohydride, sodium borohydride, sodium tripropionyloxyborohydride, and sodium cyanoborohydride.

[0036] In some embodiments, the reducing agent is selected from sodium triacetoxyborohydride.

[0037] In some embodiments, the molar ratio of the compound of formula III to the reducing agent is 1:3 to 1:4, including but not limited to 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, or any value between any two numbers. In some embodiments, the molar ratio of the compound of formula III to the reducing agent is 1:3.3 to 1:3.8. In some embodiments, the molar ratio of the compound of formula III to the reducing agent is 1:3.5.

[0038] In some embodiments, the molar ratio of compound of formula III to sodium triacetoxyborohydride is 1:3.5.

[0039] In some embodiments, the solvent used for the reaction of the compound of formula III is selected from tetrahydrofuran, methanol, ethanol, dichloromethane, and 2-methyltetrahydrofuran.

[0040] In some embodiments, the solvent used for the reaction of compound III is selected from tetrahydrofuran.

[0041] In some embodiments, the compound of formula I is the compound of formula I-1. The preparation method of compound I-1 includes the step of reacting compound III-1 with chloroethylamine hydrochloride in the presence of sodium triacetoxyborohydride.

[0042] Among them, R 1 Selected from protecting group (PG), PG, R 5 As defined above.

[0043] In some embodiments, the compound of formula I is the compound of formula I'-1. The preparation method of compound I'-1 includes the step of reacting compound III'-1 with chloroethylamine hydrochloride in the presence of sodium triacetoxyborohydride.

[0044] Among them, R 1 Selected from protecting group (PG), PG, R 5 As defined above.

[0045] In some embodiments, the compound of formula I is a compound of formula I'-1A. The preparation method of compound I'-1A includes the step of reacting compound III'-1A with chloroethylamine hydrochloride in the presence of sodium triacetoxyborohydride.

[0046] In some embodiments, the method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof further includes the step of reacting a compound of formula II with a compound of formula VI in the presence of base I. R 1 -R 3 , n as defined above.

[0047] In some implementation schemes, R 1 Selected from protecting groups, R 2 R 3 , n as defined above.

[0048] In some embodiments, the solvent used for the reaction of the compound of formula II is selected from acetonitrile, tetrahydrofuran, dichloromethane, methanol, DMF, DMSO, etc.

[0049] In some embodiments, the solvent used for the reaction of the compound of formula II is selected from acetonitrile.

[0050] In some embodiments, the base I is selected from sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate, potassium phosphate, DBU, triethylamine, diisopropylethylamine, pyridine, imidazole, dimethylaminopyridine, and N-methylmorpholine.

[0051] In some embodiments, the base I is selected from potassium carbonate.

[0052] In some embodiments, the molar ratio of compound II to base I is 1:3 to 1:4, including but not limited to 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, or any value between any two numbers. In some embodiments, the molar ratio of compound II to base I is 1:3 to 1:3. In some embodiments, the molar ratio of compound II to base I is 1:3.

[0053] In some embodiments, the molar ratio of compound II to potassium carbonate is 1:3.

[0054] In some embodiments, the molar ratio of compound II to compound VI is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, or any value between any two numbers. In some embodiments, the molar ratio of compound II to compound VI is 1:1 to 1:1.5. In some embodiments, the molar ratio of compound II to compound VI is 1:1.

[0055] In some embodiments, the method for preparing compound I-1 includes the step of reacting compound II-1 with compound VI-1 in the presence of potassium carbonate.

[0056] Among them, R 1 Selected from protecting group (PG), PG, R 5 As defined above.

[0057] In some implementation schemes, R 5 Selected from benzyl and p-methoxybenzyl.

[0058] In some embodiments, the method for preparing compound I'-1 includes the step of reacting compound II'-1 with compound VI'-1 in the presence of potassium carbonate.

[0059] Among them, R 1 Selected from protecting group (PG), PG, R 5 As defined above.

[0060] In some embodiments, the method for preparing compound I'-1A includes the step of reacting compound II'-1A with compound VI'-1A in the presence of potassium carbonate.

[0061] In some implementations, n is 0, R 3Selected from OH, compounds of formula I or their pharmaceutically acceptable salts are compounds of formula I-2. A method for preparing a compound of formula I-2 or a pharmaceutically acceptable salt thereof includes the step of reacting a compound of formula I-1 in the presence of a base II / oxidizing agent.

[0062] In some embodiments, the solvent used for the reaction of the compound of formula I-1 is selected from tetrahydrofuran or 2-methyltetrahydrofuran.

[0063] In some embodiments, the solvent used for the reaction of compound I-1 is selected from tetrahydrofuran.

[0064] In some embodiments, the base II is selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, and potassium carbonate.

[0065] In some embodiments, the base II is selected from lithium hydroxide.

[0066] In some embodiments, the molar ratio of compound I-1 to base II is 1:10 to 1:20, including but not limited to 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, or any value between any two numbers. In some embodiments, the molar ratio of compound I-1 to base II is 1:10 to 1:15. In some embodiments, the molar ratio of compound I-1 to base II is 1:15.

[0067] In some embodiments, the molar ratio of the compound of formula I-1 to lithium hydroxide is 1:15.

[0068] In some embodiments, the oxidant is selected from hydrogen peroxide.

[0069] In some embodiments, the molar ratio of the compound of formula I-1 to the oxidant is 1:10 to 1:20, including but not limited to 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, or any value between any two numbers. In some embodiments, the molar ratio of the compound of formula I-1 to the oxidant is 1:10 to 1:15. In some embodiments, the molar ratio of the compound of formula I-1 to the oxidant is 1:15.

[0070] In some embodiments, the molar ratio of compound I-1 to hydrogen peroxide is 1:15.

[0071] In some embodiments, compound I-2 is compound I'-2. The method for preparing compound I'-2 or its pharmaceutically acceptable salt includes the step of reacting compound I'-1 in the presence of lithium hydroxide / hydrogen peroxide.

[0072] In some embodiments, compound I-2 is compound I'-2A. The method for preparing compounds of formula I'-2A or pharmaceutically acceptable salts thereof includes the step of reacting compounds of formula I'-1A in the presence of lithium hydroxide / hydrogen peroxide.

[0073] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula I-3. The method for preparing compound I-3 or its pharmaceutically acceptable salt includes the step of deprotecting compound I-2 in the presence of an acid.

[0074] Among them, R 1 Selected from the protective base.

[0075] In some embodiments, the solvent used for the reaction of compound I-2 is selected from acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, etc.

[0076] In some implementations, acetonitrile is selected as the solvent for the reaction of compound I-2.

[0077] In some embodiments, the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, and p-toluenesulfonic acid.

[0078] In some embodiments, the acid is hydrochloric acid.

[0079] In some embodiments, the compound of formula I-3 is the compound of formula I'-3. A method for preparing compounds of formula I'-3 or pharmaceutically acceptable salts thereof includes the step of reacting a compound of formula I'-2A in the presence of hydrochloric acid / dioxane.

[0080] This disclosure provides compounds of formula IIA or pharmaceutically acceptable salts thereof.

[0081] in,

[0082] R 1 Selected from hydrogen or a protecting group (PG); the protecting group is selected from tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), trichloroethoxycarbonyl (Troc), p-toluenesulfonyl (Tos);

[0083] R 2 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl or C 1-6Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R 2A Replaced by, R 2A Each is independently selected from halogen, hydroxyl, cyano or amino groups;

[0084] R 3 Selected from OH, OR 4 or

[0085] R 4 C 1-6 alkyl;

[0086] R 5 For hydrogen, C 1-6 Alkyl group, (CH2) m R 5A R 5A Selected from phenyl, C 1-6 Alkoxy, wherein the phenyl or alkoxy group is optionally selected from one or more C 1-6 Alkyl, C 1-6 Substitution with alkoxy, halogen, or nitro groups;

[0087] R 6 R 7 Each is independently selected from hydrogen, C 1-6 Alkyl, phenyl, or benzyl, wherein the alkyl, phenyl, or benzyl group is optionally substituted with one or more R 3A Replaced by, R 3A Each is independently selected from halogen, hydroxyl, cyano or amino groups;

[0088] D and E are each independently selected from O or S;

[0089] L A Selected from LG is a leaving group;

[0090] n is an integer between 0 and 4; m is a number between 0, 1, and 2.

[0091] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R 1 Selected from hydrogen.

[0092] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R 1 The protecting group is selected from the protecting group (PG), which is selected from tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), trichloroethoxycarbonyl (Troc), and p-toluenesulfonyl (Tos).

[0093] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R1 Selected from tert-butoxycarbonyl (Boc).

[0094] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R 2 Each is independently selected from hydrogen, fluorine, and chlorine.

[0095] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R 3 Selected from OR 4 R 4 As defined above.

[0096] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R 3 Selected from D, E, R 5 -R 7 As defined above.

[0097] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R 3 Selected from R 5 Selected from CH2R 5A R 5A Selected from phenyl, wherein the phenyl is optionally mixed with one or more compounds selected from C 1-6 Alkyl, C 1-6 Substitution with alkoxy, halogen, or nitro groups.

[0098] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R 3 Selected from R 5 Selected from (CH2)2R 5A R 5A Selected from phenyl.

[0099] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, R 3 Selected from

[0100] In some embodiments, the compound of formula IIA or a pharmaceutically acceptable salt thereof, LG is selected from halogens or -OSO2R 8 R 8 Selected from C 1-6 Alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl group is optionally converted to one or more halogens, hydroxyl groups, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0101] In some embodiments, the compound of formula IIA or a pharmaceutically acceptable salt thereof, LG is selected from chlorine, bromine, and iodine.

[0102] In some embodiments, the compound of formula IIA or a pharmaceutically acceptable salt thereof, LG is selected from -OTs, -OTf, and -OMs.

[0103] In some embodiments, the formula IIA compound or its pharmaceutically acceptable salt, L A Selected from

[0104] In some embodiments, the compound of formula IIA is a compound of formula IIA'-1 or a pharmaceutically acceptable salt thereof. R 1 R 5 L A As defined above.

[0105] In some embodiments, the compound of formula IIA'-1 is selected from:

[0106] This disclosure also provides the use of the aforementioned compounds of formula IIA and IIA'-1 in the preparation of Lpa inhibitors.

[0107] In some embodiments, the use of compounds of formula IIA and IIA'-1 in the preparation of Lpa inhibitors, wherein the Lpa inhibitors are selected from... In some implementations, the Lpa inhibitor is

[0108] Some embodiments provide methods for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, including:

[0109] Step 1: Compound III reacts with chloroethylamine in the presence of a reducing agent to give compound II;

[0110] Step 2: Compound II reacts with compound VI in the presence of base I to give compound I. Where L is selected from R 1 -R 3 The definition is as described above.

[0111] Some embodiments provide methods for preparing a compound of formula I-1 or a pharmaceutically acceptable salt thereof, including:

[0112] Step 1: Compound III-1 reacts with chloroethylamine in the presence of a reducing agent to give compound II-1;

[0113] Step 2: Compound II-1 reacts with compound VI-1 in the presence of base I to give compound I-1;

[0114] Where L is selected from R 1 Selected from protecting group (PG), PG, R 5 As defined above.

[0115] Some embodiments provide methods for preparing compounds of formula I'-1 or pharmaceutically acceptable salts thereof, including:

[0116] Step 1: Compound III'-1 is reacted with chloroethylamine hydrochloride in the presence of sodium triacetoxyborohydride;

[0117] Step 2: The compound of formula II'-1 reacts with the compound of formula VI'-1 in the presence of potassium carbonate; Where L is selected from R 1 Selected from protecting group (PG), PG, R 5 As defined above.

[0118] Some embodiments provide methods for preparing compound I-2 or pharmaceutically acceptable salts thereof, including:

[0119] Step 1: Compound III-1 reacts with chloroethylamine in the presence of a reducing agent to give compound II-1;

[0120] Step 2: Compound II-1 reacts with compound VI-1 in the presence of base I to give compound I-1;

[0121] Step 3: Compound I-1 reacts in the presence of base II / oxidizing agent to obtain compound I-2. Where L is selected from R 1 Selected from protecting group (PG), PG, R 5 As defined above.

[0122] Some embodiments provide methods for preparing compounds of formula I'-2 or pharmaceutically acceptable salts thereof, including:

[0123] Step 1: Compound III'-1 is reacted with chloroethylamine hydrochloride in the presence of sodium triacetoxyborohydride;

[0124] Step 2: The compound of formula II'-1 reacts with the compound of formula VI'-1 in the presence of potassium carbonate;

[0125] Step 3: The compound of formula I'-1 reacts in the presence of lithium hydroxide / hydrogen peroxide;

[0126] Where L is selected from R 1 Selected from protecting group (PG), PG, R5 As defined above.

[0127] Some embodiments provide methods for preparing compounds of formula I-3 or pharmaceutically acceptable salts thereof, including:

[0128] Step 1: Compound III-1 reacts with chloroethylamine in the presence of a reducing agent to give compound II-1;

[0129] Step 2: Compound II-1 reacts with compound VI-1 in the presence of base I to give compound I-1;

[0130] Step 3: Compound I-1 reacts in the presence of base II / oxidizing agent to obtain compound I-2;

[0131] Step 4: Deprotect the compound of formula I-2 to obtain the compound of formula I-3; Where L is selected from R 1 Selected from protecting group (PG), PG, R 5 As defined above.

[0132] Some embodiments provide methods for preparing compounds of formula I'-3 or pharmaceutically acceptable salts thereof, including:

[0133] Step 1: Compound III'-1A is reacted with chloroethylamine in the presence of sodium triacetoxyborohydride to give compound II'-1A;

[0134] Step 2: Compound II'-1A reacts with compound VI'-1A in the presence of potassium carbonate to give compound I'-1A;

[0135] Step 3: Compound I'-1A is reacted in the presence of lithium hydroxide / hydrogen peroxide to give compound I'-2A.

[0136] Step 4: Compound I'-2A is reacted with hydrochloric acid to give compound I'-3;

[0137] The preparation method described in this disclosure further includes one or more steps of filtration, washing, drying, concentration or recrystallization.

[0138] Salts of the compounds / intermediates disclosed herein include, but are not limited to, addition salts of the compounds / intermediates in their free state with acids or bases, wherein the acids used to form the salts include, but are not limited to, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid.

[0139] Terminology Definition

[0140] The terms "to form" and "to transform" do not specifically refer to a single-step transformation reaction between two substrates; they can be single-step or multi-step reactions between two substrates. If the intermediate contains a protecting group, the intermediate undergoes a step of deprotection before reacting with the corresponding substrate to obtain the target product.

[0141] The values ​​in this disclosure are instrument measurements and are subject to a certain degree of error. Generally, ±10% is within the reasonable error range. Of course, the context in which the value is used must be considered. For example, in the case of particle size of the active ingredient, where the measurement error variation does not exceed ±10%, the value can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0142] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For example, formula... Compounds can be represented by the formula Or it may contain both of the aforementioned configurations.

[0143] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Non-limiting examples of alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable link, preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, C1-6 alkyl groups, C1-6 alkoxy groups, 3 to 6 membered cycloalkyl groups, or 3 to 6 membered heterocycloalkyl groups, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl group is optionally substituted by a halogen, hydroxyl, nitro, cyano, or amino group.

[0144] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxyl, oxo, cyano, amino, C1-6 alkyl, C1-6 alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl is optionally substituted by halogen, hydroxyl, nitro, cyano, or amino.

[0145] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0146] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0147] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Alkyne group, 3- to 6-membered cycloalkoxy group, 3- to 6-membered heterocycloalkoxy group, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 The alkynyl group, 3 to 6 cycloalkoxy group, 3 to 6 heterocycloalkoxy group, 3 to 8 cycloalkenyl group, 5 to 6 aryl group, or heteroaryl group may be selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0148] "Substitution" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms that are independently substituted by the corresponding number of substituents.

[0149] DMAP: 4-Dimethylaminopyridine

[0150] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0151] Li-HMDS: Lithium bis(trimethylsilylamine) Detailed Implementation

[0152] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0153] Test conditions of the instruments used in the experiment:

[0154] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0155] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0156] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0157] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0158] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0159] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0160] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0161] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the different polarities of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0162] Example 1

[0163] Step 1 (R)-3-(2-((S)-4-(4-methoxybenzyl)-2-oxooxazolidine-3-yl)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester compound 1b

[0164] (R)-2-(1-(tert-Butoxycarbonyl)pyrrolidine-3-yl)acetic acid (compound 1a, 22.27 g, 0.097 mol, 1.1 eq), (S)-4-(4-methoxybenzyl)oxazolidin-2-one (18.3 g, 0.088 mol, 1.0 eq.), DMAP (10.79 g, 0.088 mol, 1.0 eq.), EDCI (33.86 g, 0.176 mol, 2.0 eq.), and 180 mL of dichloromethane were added sequentially to the reaction flask, and the reaction was carried out at room temperature for 2 h. A 10% citric acid aqueous solution was added to the reaction solution, and the mixture was separated. The organic phase was washed once with 5% sodium bicarbonate solution, once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give compound 1b, 31.57 g, with a purity of 92.9% and a yield of 85.4%.

[0165] 1 H NMR(400M, CDCl3) δ7.11(d,J=8.2Hz,2H),6.87(d,J=8.6Hz,1H),4.63(t,1H),4.27-4.16(m,2H),3.79(s,3H),3.74-3.63(m,1H),3. 56-3.40(m,1H),3.32(m,1H),3.21(m,1H),3.13-2.91(m,3H),2.79-2.62(m,2H),2.17-2.07(m,1H),1.67-1.53(m,1H),1.47(s,9H).

[0166] Ms(ESI): m / z 319[M+1] + .

[0167] Step 2: (R)-3-((S)-3-(3-formylphenyl)-1-((S)-4-(4-methoxybenzyl)-2-oxooxazolidine-3-yl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester compound 1c

[0168] Compound 1b (17.5 g, 0.042 mol, 1.1 eq) and dichloromethane (75 mL, 8 V) were added to the reaction flask, and stirring was started. Li-HMDS (50 mL, 0.048 mol, 1.3 eq.) was added dropwise at low temperature, and the reaction was maintained at this temperature for 1 h. 1-(bromomethyl)-3-(dimethoxymethyl)benzene (9.2 g, 0.037 mol, 1.0 eq.) was added, and the reaction was maintained at this temperature for 18 h. Water was added, and the mixture was separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, ethyl acetate was added, and the mixture was stirred to disperse. 2 V hydrochloric acid / ethyl acetate solution (2.0 M) was added dropwise, and the mixture was stirred at room temperature for 1 h. Saturated sodium bicarbonate solution was added to adjust the pH to approximately 8. The aqueous phase was separated, and the organic phase was dried and concentrated. Methanol was added to the organic phase, and crystals were precipitated by stirring at room temperature. The mixture was filtered, the filter cake was washed with methanol, and the filter cake was dried under vacuum to give compound 1c, 13.46 g, with a purity of 97% and a yield of 60%.

[0169] MS(ESI): m / z 437.63 [M+1] + .

[0170] Step 3: Compound 1d of di-tert-butyl-3,3'-((2S,2'S)-((((2-chloroethyl)azonidinediyl)bis(methylene))bis(3,1-phenyl))bis(3-((S)-4-(4-methoxybenzyl)-2-oxooxazolidine-3-yl)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester)

[0171] Chloroethylamine hydrochloride (0.4 g, 0.0034 mol, 1.0 eq), compound 1c (4.07 g, 0.0076 mol, 2.2 eq), and tetrahydrofuran (20 mL, 50.0 V) were added sequentially to the reaction flask. The mixture was cooled in an ice-water bath, and sodium triacetoxyborohydride (2.6 g, 0.012 mol, 3.5 eq) was added in portions. After the addition was complete, the mixture was stirred for 6 h. The reaction was quenched with 20 mL of saturated sodium bicarbonate, separated, and the organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 1d, 3.5 g, yield 90.5%, purity 90.1%.

[0172] 1H NMR (400MHz, CDCl3): δ7.28-7.18(m,6H),7.13(t,J=6.4Hz,2H),6.86-6.79(m,4H),6.75(m,4 H),4.55-4.44(m,4H),4.07-3.96(m,2H),3.94-3.85(m,2H),3.76(s,6H),3.73-3.67(m,1H), 3.62-3.42(m,7H),3.38(t,J=7.0Hz,2H),3.28-3.16(m,2H),3.05-2.89(m,5H),2.76(m,2H), 2.68(t,J=7.1Hz,2H),2.60-2.43(m,2H),2.01-1.86(m,4H),1.80-1.64(m,3H)1.46(s,18H).

[0173] Step 4: (R)-3-((S)-3-(3-(benzyloxy)phenyl)-1-((S)-4-(4-methoxybenzyl)-2-oxooxazolidine-3-yl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester compound 1e

[0174] Compound 1b (10 g, 0.0239 mol, 1.0 eq.) and tetrahydrofuran (100 mL, 10 V) were added to a 500 mL three-necked flask, and stirring was started. Li-HMDS (28 mL, 0.0287 mol, 1.2 eq.) was added dropwise at low temperature, and the mixture was stirred for 0.5 h after the addition was complete. 3-(benzyloxy)benzyl bromide (6.95 g) was added, and the reaction was stirred for 15 h. Water and ethyl acetate were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to give compound 1e. 12 g of product was obtained, with a yield of 65% and a purity of 96.77%.

[0175] MS(ESI): m / z 515.7 [M+1-Boc] + .

[0176] Step 5: (R)-3-((S)-3-(3-hydroxyphenyl)-1-((S)-4-(4-methoxybenzyl)-2-oxooxazolidine-3-yl)-1-oxopropane-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester compound 1f

[0177] At room temperature, compound 1e (10 g), 10% palladium on carbon (1 g, 10%), and methanol (100 ml, 10 V) were added sequentially to a flask. The mixture was purged with hydrogen three times, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 12 g of crude oil. Column chromatography was used to purify compound 1f, 7.6 g, with a yield of 89% and a purity of 99.4%.

[0178] 1 H NMR (400MHz, CDCl3): δ7.11 (q, J=7.5Hz, 1H), 6.91-6.82 (m, 2H), 6.81-6.57 (m, 6H), 4.55 (q, J= 8.9Hz,1H),4.43(q,J=9.0,6.2Hz,1H),4.09-4.02(m,1H),4.01-3.94(m,1H),3.76(s,2H),3.70 -3.56(m,1H),3.52-3.41(m,1H),3.20(td,J=10.6,6.8Hz,1H),3.12-2.99(m,1H),2.98-2.80(m ,3H),2.57-2.41(m,1H),2.25-2.09(m,1H),1.95-1.84(m,1H),1.77-1.59(m,1H),1.46(s,9H).

[0179] MS(ESI): m / z 425.6 [M+1-Boc] + .

[0180] Step 6: 1 g of di-tert-butyl 3,3'-((2S,2'S)-((((2-(3-((S)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-3-((S)-4-(4-methoxybenzyl)-2-oxooxazolidine-3-yl)-3-oxopropyl)phenoxy)ethyl)azondiyl)bis(methylene))bis(3,1-phenyl))bis(3-((S)-4-(4-methoxybenzyl)-2-oxooxazolidine-3-yl)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid ester) compound

[0181] At room temperature, compound 1d (1.2 g, 0.0023 mol, 1.0 eq.), compound 1f (2.56 g, 0.0023 mol, 1.0 eq.), potassium carbonate (0.95 g, 0.0069 mol, 3.0 eq.), and acetonitrile (12 mL, 10V) were added sequentially to a flask, and the mixture was stirred overnight at 60 °C. After cooling to room temperature, the mixture was filtered, and the filtrate was evaporated to dryness. The mixture was purified by column chromatography to give compounds 1 g and 2.95 g, with a purity of 94.4% and a yield of 80.16%.

[0182] 1 H NMR (400MHz, DMSO) d6): δ7.25-7.21(m,4H),7.18-7.11(m,5H),6.85-6.77(m,1H),6.76(s,1H),6.68-6.66(m,13H),4.59 -4.54(m,3H),4.35-4.31(m,3H),4.23-4.20(m,3H),4.02(s,3H),3.94(s,2H),3.86-3.83(m,2H),3 .65(s,6H),3.64(s,2H),3.50-3.47(m,5H),3.36-3.33(m,4H),3.10-2.99(m,3H),2.96-2.89(m,9H ),2.62(s,5H),2.43-2.29(m,6H),1.91-1.89(m,3H),1.67-1.55(m,3H),1.39(s,18H),1.36(s,9H).

[0183] Step 7 (2S,2'S)-3,3'-((((2-(3-((S)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-carboxyethyl)phenoxy)ethyl)azanediyl)bis(methylene))bis(3,1-phenyl))bis(2-((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)propionic acid)compound 1h

[0184] 1 g (1.5 g, 1 eq.) of compound, 15 mL (10 V), hydrogen peroxide (1.58 g, 15 eq.), and purified water (4.5 mL, 3 V) were added to a reaction flask and stirred at room temperature. An aqueous solution of lithium hydroxide (0.335 g, 15 eq.) was added dropwise, and the mixture was stirred overnight at room temperature after the addition was complete. After the reaction was complete, water and ethyl acetate were added, and the mixture was separated. The aqueous phase was washed once with ethyl acetate. A sodium sulfite solution (2.35 g, 20 eq.) was added dropwise to the aqueous phase, and the mixture was stirred for 1 h. The pH was adjusted to acidic with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure to give 0.93 g of compound 1 h, 100% yield, 70% purity.

[0185] MS(ESI): m / z 1041.4 [M+1] + .

[0186] Step 8 (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidine-3-yl)ethyl)phenoxy)ethyl)azanediyl)bis(methylene))bis(3,1-phenyl))bis(2-((R)-pyrrolidine-3-yl)propionic acid)compound 1i

[0187] Compound 1h (2 g, 1.0 eq), 1,4-dioxane (20 mL, 10 V), and concentrated hydrochloric acid (20 mL, 10 V) were added to a reaction flask. The mixture was refluxed for 1 hour, then concentrated under reduced pressure. Water was added to the concentrate, and the pH was adjusted to neutral with saturated ammonium bicarbonate solution. Isopropanol was added dropwise, and the mixture was stirred, filtered, and dried to give compound 1i, 0.86 g, yield 60%, purity 97%.

[0188] 1 H NMR (400MHz, D2O): δ7.41-7.23(m,9H),6.92-6.90(d,1H),6.76-6.75(m,2H),4.37(s,4H),4.16-4.15(m,2H),3.54-3.48(m,5H),3. 43-3.37(m,3H),3.27-3.20(m,3H),2.99-2.94(m,3H),2.81-2.75(m,6H),2.54-2.40(m,6H),2.13-2.11(m,3H),1.80-1.68(m,3H).

[0189] Ms(ESI): m / z 741.3[M+1] + .

Claims

1. A method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof: The steps include the reaction of a compound of formula III with chloroethylamine hydrochloride in the presence of a reducing agent. in, R 1 Selected from hydrogen or protecting groups (PG); R 2 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R 2A Replaced by, R 2A Each is independently selected from halogen, hydroxyl, cyano or amino groups; R 3 Selected from OH, OR 4 or R 4 C 1-6 alkyl; R 5 For hydrogen, C 1-6 Alkyl group, (CH2) m R 5A R 5A Selected from phenyl, C 1-6 Alkoxy, wherein the phenyl or alkoxy group is optionally selected from one or more C 1-6 Alkyl, C 1-6 Substitution with alkoxy, halogen, or nitro groups; R 6 R 7 Each is independently selected from hydrogen, C 1-6 Alkyl, phenyl, or benzyl, wherein the alkyl, phenyl, or benzyl group is optionally substituted with one or more R 3A Replaced by, R 3A Each is independently selected from halogen, hydroxyl, cyano or amino groups; D and E are each independently selected from O or S; W is 3; L is selected from n is an integer between 0 and 4; m is a number between 0, 1, and 2.

2. The method according to claim 1, wherein R 3 Selected from R 5 Selected from (CH2) m R 5A R 5A Selected from phenyl, wherein the phenyl is optionally mixed with one or more of C 1-6 Alkyl, C 1-6 Substituents of alkoxy, halogen, and nitro groups, where m is selected from 0, 1, 2, and R. 5 Benzyl or p-methoxybenzyl are preferred.

3. The method according to claim 1 or 2, wherein the reducing agent is selected from sodium triacetoxyborohydride, sodium borohydride, sodium tripropionyloxyborohydride, sodium cyanoborohydride, preferably sodium triacetoxyborohydride.

4. The method according to any one of claims 1-3, further comprising the step of reacting the compound of formula II with the compound of formula VI in the presence of base I. in, R 1 Selected from protecting groups, R 2 R 3 As defined in claim 1.

5. The method according to claim 4, wherein the compound of formula I is the compound of formula I-1, and the method comprises the step of reacting the compound of formula II-1 with the compound of formula VI-1 under the presence of base I. in, R 5 As defined in claim 1.

6. The method according to claim 4 or 5, wherein the base I is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate, potassium phosphate, DBU, triethylamine, diisopropylethylamine, pyridine, imidazole, dimethylaminopyridine, N-methylmorpholine, preferably potassium carbonate.

7. The method according to any one of claims 1-6, wherein the compound of formula I is a compound of formula I-2, the method comprising the step of reacting the compound of formula I-1 in the presence of base II / oxidizing agent, in, R 1 Selected from protecting groups, R 5 As defined in claim 1.

8. The method according to claim 7, wherein the base II is selected from lithium hydroxide, potassium hydroxide, sodium hydroxide, tetrabutylammonium hydroxide, potassium carbonate, preferably lithium hydroxide or potassium hydroxide.

9. The method according to claim 7 or 8, wherein the oxidant is selected from hydrogen peroxide.

10. The method according to any one of claims 1-9, wherein the compound of formula I is a compound of formula I-3, and the method comprises the step of reacting the compound of formula I-2 in the presence of an acid. Where R 1 The acid is selected from the protecting group and is selected from hydrochloric acid.

11. The method according to any one of claims 1-10, wherein the compound of formula I is a compound of formula I'-1.

12. The method according to any one of claims 1-10, wherein the compound of formula I is a compound of formula I'-2.

13. The method according to any one of claims 1-10, wherein the compound of formula I is a compound of formula I'-3.

14. A method for preparing compounds of formula I'-3 or their pharmaceutically acceptable salts, comprising: Step 1: Compound III'-1A reacts with chloroethylamine in the presence of sodium triacetoxyborohydride to form compound II'-1A; Step 2: Compound II'-1A reacts with compound VI'-1A in the presence of potassium carbonate to form compound I'-1A; Step 3: Compound I'-1A reacts in the presence of lithium hydroxide / hydrogen peroxide to form compound I'-2A. Step 4: Compound I'-2A is reacted with hydrochloric acid to form compound I'-3; 15. A compound of formula IIA or a pharmaceutically acceptable salt thereof, in, R 1 Selected from hydrogen or a protecting group (PG), wherein the protecting group is selected from tert-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), trichloroethoxycarbonyl (Troc), p-toluenesulfonyl (Tos); R 2 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R 2A Replaced by, R 2A Each is independently selected from halogen, hydroxyl, cyano or amino groups; R 3 Selected from OH, OR 4 or R 4 C 1-6 alkyl; R 5 For hydrogen, C 1-6 Alkyl group, (CH2) m R 5A R 5A Selected from phenyl, C 1-6 Alkoxy, wherein the phenyl or alkoxy group is optionally selected from one or more C 1-6 Alkyl, C 1-6 Substitution with alkoxy, halogen, or nitro groups; R 6 R 7 Each is independently selected from hydrogen, C 1-6 Alkyl, phenyl, or benzyl, wherein the alkyl, phenyl, or benzyl group is optionally substituted with one or more R 3A Replaced by, R 3A Each is independently selected from halogen, hydroxyl, cyano or amino groups; D and E are each independently selected from O or S; L A Selected from LG is a leaving group; n is an integer between 0 and 4; m is a number between 0, 1, and 2.

16. The compound according to claim 15, wherein R 3 Selected from R 5 Selected from CH2R 5A R 5A Selected from phenyl, wherein the phenyl is optionally mixed with one or more of C 1-6 Alkyl, C 1-6 Substitution with alkoxy, halogen, or nitro groups.

17. The compound according to claim 15 or 16, wherein LG is selected from halogens or -OSO2R. 8 R 8 Selected from C 1-6 Alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl group is optionally converted to one or more halogens, hydroxyl groups, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkoxy groups are substituted, with LG preferably halogens and -OTs, and more preferably chlorine and -OTs.

18. The compound according to claim 15, wherein the compound of formula IIA is a compound of formula IIA'-1. R 1 R 5 L A As defined in claim 14.

19. Use of the compound or a salt thereof according to any one of claims 15-18 in the preparation of an Lpa inhibitor, wherein the Lpa inhibitor is preferably...

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