A process for the synthesis of 3-ethoxy-8-azabicyclo[3.2.1]octan-1-yl-benzoic acid and derivatives thereof

Abstract

The present disclosure provides a method of synthesizing 3-ethoxy-8-azabicyclo[3.2.1]octan-1-yl-benzoic acid and derivatives thereof. In particular, the present disclosure provides a method of synthesizing 4-((1S,3S,5R)-3-ethoxy-8-azabicyclo[3.2.1]octan-1-yl)benzoic acid and derivatives thereof, and the use of this intermediate in the preparation of Factor B inhibitors.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a method for preparing a synthetic 3-ethoxy-8-azabicyclo[3.2.1]octane-1-ylbenzoic acid and its derivatives. Background Technology

[0002] The complement system is a crucial component of the body's innate immunity, responsible for resisting infections from exogenous pathogens, bacteria, and parasites. It also plays a vital role in the transition between innate and adaptive immunity. Complement is composed of plasma proteins, including soluble proteins, membrane-bound proteins, and complement receptors. It is primarily produced by membrane proteins expressed on the liver or cell surface and functions in plasma, tissues, or cells. The complement system is activated mainly through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0003] Complement factor B acts on the AP pathway. Inhibiting Factor B activity can prevent API pathway activation without interfering with the CP and LP pathways, thus avoiding increased infection risk due to complement system inhibition.

[0004] Ipatecan, the first marketed Factor B inhibitor, is used to treat IgA nephropathy. Meanwhile, several other small-molecule Factor B inhibitors have been reported, such as:

[0005] The chiral compound methyl 4-((1S,3S,5R)-3-ethoxy-8-azabicyclo[3.2.1]octane-1-yl)benzoate is a key intermediate in the preparation of the aforementioned Factor B inhibitor.

[0006] Chiral intermediates are often obtained through chiral column resolution or chiral reagent resolution. This method is not only inefficient, but also inevitably results in at least half of the isomers being wasted, leading to a low overall yield. For example, WO2022143845 discloses a process for preparing the target product from 4-(4-bromophenyl)-4-oxobutyraldehyde as a starting material through seven reaction steps. In this process, chiral intermediates are obtained through chiral column resolution, resulting in low yields and making it difficult to industrialize.

[0007] WO2023237041 discloses a process for preparing the target product from 4-(4-oxobutyryl)benzonitrile via a 7-step reaction, in which chiral intermediates are obtained by resolution with chiral reagents. However, this process has low yields and high production costs.

[0008] Summary of the Invention

[0009] This disclosure provides a method for processing the compound of formula D or a salt thereof.

[0010] The method includes the step of reacting the compound of formula C to form the compound of formula D.

[0011] Z and Y are each independently selected from CH and N;

[0012] R 1 Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4 and -CONR 5 R 6 ;

[0013] R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0014] R 4 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted by one or more groups selected from halogen, nitro, or cyano groups; R 5 R 6 Each is independently selected from hydrogen and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano groups;

[0015] P 1 P 2 Each was independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0016] P 3 Selected from C 1-6 Alkyl, the C1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano.

[0017] In some embodiments, the compound shown in formula C reacts under acidic conditions to form the compound shown in formula D.

[0018] In some embodiments, the acid used in the reaction of the compound represented by Formula C is selected from, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, or p-toluenesulfonic acid.

[0019] In some embodiments, the amount of acid used in the reaction is 10 to 15 times the molar amount of the compound shown in Formula C, including 10, 11, 12, 13, 14, 15 times or any two of these values.

[0020] In some embodiments, the reaction temperature of the compound represented by Formula C is selected from 40 to 80°C, including 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or any value between any two numbers.

[0021] In some embodiments, the reaction solvent for the compound represented by Formula C is selected from protic solvents, including but not limited to one or more of methanol, ethanol, isopropanol, or water.

[0022] In some embodiments, the compound shown in formula C reacts under hydrochloric acid conditions to form the compound shown in formula D or a salt thereof.

[0023] In some embodiments, the compound shown in formula C reacts under acetic acid conditions to form the compound shown in formula D or a salt thereof.

[0024] In some embodiments, the method for preparing the compound of formula D or a salt thereof further includes reacting the compound of formula A with a sulfinamide to form the compound of formula B, and reacting the compound of formula B with the compound of formula W to form the compound of formula C.

[0025]

[0026] Where R 1 R 2 Z, Y, P 1 P 2 P 3 As defined above; R 1a Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4a and -CONR 5a R 6a R 4a Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted by one or more groups selected from halogen, nitro, or cyano groups; R5a R 6a Each is independently selected from hydrogen and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano.

[0027] In some embodiments, the compound represented by Formula A reacts with sulfinamide in the presence of a titanate, such as tetraethyl titanate or tetraisopropyl titanate.

[0028] When R 1a Selected from ester group - COOR 4a The compound shown in Formula A undergoes ester exchange in the presence of titanate, for example, methyl ester is converted to ethyl ester or isopropyl ester.

[0029] In some embodiments, the compound shown in Formula A reacts with sulfinamide in the presence of a titanate ester.

[0030] In some embodiments, the amount of titanate used is 2 to 5 times the molar amount of the compound shown in Formula A, including 2, 3, 4, 5 times or any two of these values.

[0031] In some embodiments, the compound of formula B reacts with the compound of formula W under alkaline conditions, wherein the base is selected from, but not limited to, butyllithium and diisopropylaminolithium.

[0032] In some embodiments, the reaction temperature of the compound represented by Formula B with the compound represented by Formula W is selected from -30 to 0°C, including -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, or any value between any two numbers.

[0033] In some embodiments, the reaction temperature between the compound of formula B and the compound of formula W is selected from -70 to 0°C, including -70°C, -65°C, -60°C, -55°C, -50°C, -45°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, or any two of these values. In some embodiments, the reaction solvent between the compound of formula B and the compound of formula W is selected from aprotic solvents, including but not limited to tetrahydrofuran or toluene.

[0034] In some embodiments, P in the compound represented by formula W 3 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl.

[0035] In some embodiments, the compound represented by formula W is tert-butyl acetoacetate.

[0036] In some embodiments, the compound represented by formula W is methyl acetoacetate.

[0037] In some embodiments, the compound represented by formula W is ethyl acetoacetate.

[0038] In some embodiments, Z is CH and Y is CH in the compound shown in Formula D; or Z is CH and Y is N.

[0039] In some embodiments, R in the compound shown in formula D 1 It is a halogen, such as bromine.

[0040] In some embodiments, R in the compound shown in formula D 1 It is a cyano group.

[0041] In some embodiments, R in the compound shown in formula D 1 -COOR 4 R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl.

[0042] In some embodiments, R in the compound shown in formula D 1 For -CONR 5 R 6 R 5 R 6 Each is independently selected from hydrogen.

[0043] In some embodiments, R in the compound shown in formula D 1 For -CONR 5 R 6 R 5 R 6 Each is independently selected from methyl groups.

[0044] In some embodiments, the compound represented by formula D is the compound represented by formula D-1. A method for preparing the compound of formula D-1 or a salt thereof includes the step of reacting the compound of formula C-1 under acidic conditions to form the compound of formula D-1.

[0045] Where R 1 R 2 P 1 P 2 P 3 As defined above.

[0046] In some embodiments, the compound represented by formula C is the compound represented by formula C-1a. R 1 Defined in the compound shown in Formula C.

[0047] In some embodiments, the method for preparing the compound of formula D-1 or a salt thereof includes the step of reacting the compound of formula C-1a under acidic conditions to form the compound of formula D-1.

[0048] Where R 1 As defined above.

[0049] In other embodiments, the compound shown in Formula D-1 is obtained as an optically pure compound by chiral column preparation or chiral reagent resolution, for example... For chiral column preparation or chiral reagent resolution methods / conditions, please refer to WO2022143845, WO2023237041, and WO2024017299, and the relevant content is incorporated into this document for illustrative purposes.

[0050] In some embodiments, the compound represented by formula D is the compound represented by formula Da-1. A method for preparing the compound of formula Da-1 or a salt thereof includes the step of reacting the compound of formula Ca-1 under acidic conditions to form the compound of formula Da-1.

[0051] Where R 1 R 2 P 1 P 2 P 3 As defined above.

[0052] In some embodiments, the compound represented by formula D is the compound represented by formula Da-1a. Where X is a halogen, such as bromine.

[0053] In some embodiments, the method for preparing the compound of formula Da-1a or a salt thereof includes the step of reacting the compound of formula Ca-1a under acidic conditions to form the compound of formula Da-1a.

[0054] Where R 2 P 1 P 2 P 3 As defined above; X is a halogen, such as bromine.

[0055] In some embodiments, the method for preparing the compound of formula Da-1a or a salt thereof further includes the steps of reacting the compound of formula A-1a with a sulfinamide to form the compound of formula B-1a, and reacting the compound of formula Ba-1a with the compound of formula W to form the compound of formula Ca-1a.

[0056]

[0057] Where R2 P 1 P 2 P 3 As defined above; X is a halogen, such as bromine.

[0058] In some embodiments, the compound represented by formula D-1 is selected from...

[0059] In some embodiments, the compound represented by formula D is the compound represented by formula Da-2a.

[0060] In some embodiments, the method for preparing the compound of formula Da-2a or a salt thereof includes the step of reacting the compound of formula Ca-2a to form the compound of formula Da-2a.

[0061] Where R 2 P 1 P 2 P 3 As defined above.

[0062] In some embodiments, the method for preparing the compound of formula Da-2a or a salt thereof further includes reacting the compound of formula A-2a with a sulfinamide to form the compound of formula B-2a, and reacting the compound of formula Ba-2a with the compound of formula W to form the compound of formula Ca-2a.

[0063]

[0064] Where R 2 P 1 P 2 P 3 As defined above.

[0065] On the other hand, in some implementation schemes, the compound represented by formula D is the compound represented by formula Da-3a. Where R 4 As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0066] In some embodiments, the method for preparing the compound of formula Da-3a or a salt thereof includes the step of reacting the compound of formula Ca-3a to form the compound of formula Da-3a.

[0067] Where R 2 P 1 P 2 P 3 As defined above; R 4 As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0068] In some embodiments, the method for preparing the compound of formula Da-3a or a salt thereof further includes reacting the compound of formula A-3a with a sulfonamide to form the compound of formula B-3a, and reacting the compound of formula Ba-3a with the compound of formula W to form the compound of formula Ca-3a.

[0069]

[0070] Where R 2 P 1 P 2 P 3 As defined above; R 4 R 4a As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0071] In some embodiments, the compound represented by formula D-3 is selected from...

[0072] On the other hand, in some implementation schemes, P in the compound shown in formula C 1 P 2 Each was independently selected from C 1-3 Alkyl groups, such as methyl groups.

[0073] In some implementation schemes, P is present in the compound shown in formula C. 1 P 2 Each was independently selected from C 1-3 Acyl groups, such as acetyl groups.

[0074] In other implementations, P is present in the compound of formula C. 1 P 2 Each was independently selected from P 1 P 2 Together with adjacent atoms, they form 5-6 membered heterocyclic alkyl groups.

[0075] In some implementation schemes, R in the compound of formula C 2 Selected from methyl or ethyl.

[0076] In some implementation schemes, R in the compound of formula C 2 Selected from phenyl or naphthyl.

[0077] In some implementation schemes, P is present in the compound shown in formula C. 3 Selected from methyl, ethyl, isopropyl or tert-butyl.

[0078] In some embodiments, the compounds represented by formula C or C-1 are selected from... Where X is a halogen, such as bromine.

[0079] In some implementation schemes, the compounds represented by formula C or C-2 are selected from... Some embodiments show compounds represented by formula C or C-3 selected from... R 4 As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0080] In some embodiments, the method for preparing the compound of formula Da-1a or a salt thereof includes the step of reacting the compound of formula Ca-1aa under acidic conditions to form the compound of formula D-1.

[0081] X is selected from halogens, such as bromine.

[0082] In some embodiments, the method for preparing the compound of formula Da-1a or a salt thereof includes the steps of reacting the compound of formula Aa-1a with R-tert-butylsulfinamide to form the compound of formula Ba-1a, and reacting the compound of formula Ba-1a with tert-butyl acetoacetate to form the compound of formula Ca-1aa.

[0083]

[0084] Where X is a halogen, such as bromine.

[0085] On the other hand, a method for preparing the compound of formula Da-2a or a salt thereof includes the step of reacting the compound of formula Ca-2aa under acidic conditions to form the compound of formula Da-2a.

[0086]

[0087] In some embodiments, the method for preparing the compound of formula Da-2a or a salt thereof includes the steps of reacting the compound of formula Aa-2a with R-tert-butylsulfinamide to form the compound of formula Ba-2a, and reacting the compound of formula Ba-2a with tert-butyl acetoacetate to form the compound of formula Ca-2aa.

[0088]

[0089] In other embodiments, the method for preparing the compound of formula Da-3a or a salt thereof includes the step of reacting the compound of formula Ca-3aa under acidic conditions to form the compound of formula Da-3a.

[0090] R 4 As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0091] In some embodiments, the method for preparing the compound of formula Da-3a or a salt thereof includes the steps of reacting the compound of formula Aa-3a with R-tert-butylsulfinamide to form the compound of formula Ba-3a, and reacting the compound of formula Ba-3a with tert-butyl acetoacetate to form the compound of formula Ca-3aa.

[0092]

[0093] Where R 4 R 4a As defined above, such as methyl, ethyl, isopropyl, or tert-butyl.

[0094] In another aspect, this disclosure provides a method for preparing the compound of formula G or a salt thereof.

[0095] The method includes the steps described above for preparing the compound of formula D or its salt.

[0096] In some embodiments, the method for preparing the compound of formula G or a salt thereof further includes the step of converting the compound of formula D into the compound of formula G.

[0097] Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0098] In some embodiments, a method for preparing the compound of formula G or a salt thereof includes the steps of reacting the compound of formula Da in the presence of a reducing agent to form the compound of formula E, reacting the compound of formula E with an amino protecting agent to form the compound of formula F, and reacting the compound of formula F with an alkylating agent to form the compound of formula G.

[0099] Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0100] In some embodiments, a compound of formula E or a salt thereof reacts with an amino protecting agent under basic conditions to form a compound of formula F or a salt thereof, wherein the base includes, but is not limited to, triethylamine, isopropylamine, imidazole, or pyridine. Specific procedures are described in Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2006, and the relevant content is incorporated herein by reference.

[0101] In some implementations, the amino protecting agent is selected from, but not limited to, di-tert-butyl dicarbonate.

[0102] On the other hand, in some other embodiments, the method for preparing the compound of formula G or a salt thereof includes the steps of reacting the compound of formula Da with an amino protecting agent to form the compound of formula EL, reacting the compound of formula EL in the presence of a reducing agent to form the compound of formula F, and reacting the compound of formula F with an alkylating agent to form the compound of formula G.

[0103] Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0104] In some embodiments, a compound of formula Da or a salt thereof reacts with an amino protecting agent under organic base conditions to form a compound of formula EL or a salt thereof, wherein the organic base includes, but is not limited to, triethylamine, isopropylamine, imidazole, or pyridine. Specific operational procedures are described in Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2006, and the relevant content is incorporated herein for illustrative purposes.

[0105] In some embodiments, the amount of organic base used is 1 to 3 times the molar amount of the compound represented by formula Da, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0106] In some embodiments, the reducing agent used in the reduction reaction of the compound represented by formula EL is selected from lithium trisec-butylborohydride or (-)diisopinepine chloroborane.

[0107] In some implementations, the amount of reducing agent used is 1 to 3 times the molar amount of the compound shown in Formula EL, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0108] In some embodiments, Z is CH and Y is CH in the compound of formula G or its salt.

[0109] In some embodiments, the compound represented by formula G is the compound represented by formula G-1. Where X is selected from halogens, such as bromine; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0110] In some embodiments, the compound represented by formula G-1 is the compound represented by formula G-1a. X is a halogen, such as bromine.

[0111] In some embodiments, the method for preparing the compound of formula G-1 or a salt thereof includes the step of converting the compound of formula Da-1a into the compound of formula G-1.

[0112] Where X is selected from halogens, such as bromine; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0113] In some embodiments, the method for preparing the compound of formula G-1 or a salt thereof includes the steps of reacting the compound of formula Da-1a in the presence of a reducing agent to form the compound of formula E-1, reacting the compound of formula E-1 with an amino protecting agent to form the compound of formula F-1, and reacting the compound of formula F-1 with an ethylating agent to form the compound of formula G-1.

[0114]

[0115] Where X is selected from halogens, such as bromine; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0116] In some embodiments, the reducing agent used in the reduction reaction of the compound represented by formula Da-1a is selected from lithium trisec-butylborohydride or (-)diisopinepine chloroborane.

[0117] In some embodiments, the amount of reducing agent used is 1 to 3 times the molar amount of the compound shown in formula Da-1a, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0118] In some embodiments, the ethylating agent includes a haloethane (e.g., iodoethane) or diethyl sulfate. The ethylation reaction is carried out under basic conditions, wherein the base is selected from, but not limited to, sodium tert-butoxide or sodium hydride. For specific procedures / dosages, see WO2023237041 and WO2022143845, the relevant content of which is incorporated herein for illustrative purposes.

[0119] On the other hand, in some embodiments, the method for preparing the compound of formula G-1a or a salt thereof includes the steps of reacting the compound of formula Da-1a in the presence of a reducing agent to form the compound of formula E-1, reacting the compound of formula E-1 with di-tert-butyl dicarbonate to form the compound of formula F-1a, and reacting the compound of formula F-1a with iodoethane or diethyl sulfate to form the compound of formula G-1.

[0120]

[0121] X is selected from halogens, such as bromine.

[0122] In some embodiments, the compound shown in Formula E-1 reacts with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0123] In some embodiments, the amount of organic base used is 1 to 3 times the molar amount of the compound shown in Formula E-1, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0124] In some embodiments, the compound of formula F-1a is reacted with iodoethane under sodium tert-butyl or sodium hydride conditions to introduce an ethyl group. For specific procedures / dosages, see WO2022143845, the relevant content of which is incorporated herein for illustration.

[0125] In some embodiments, the method for preparing the compound of formula G-1 or a salt thereof includes the steps of reacting the compound of formula Da-1a with an amino protecting agent to form the compound of formula E-1L, reacting the compound of formula E-1L with a reducing agent to form the compound of formula F-1, and reacting the compound of formula F-1 with an ethylating agent to form the compound of formula G-1.

[0126]

[0127] Where X is selected from halogens, such as bromine; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0128] In some embodiments, a method for preparing the compound of formula G-1a or a salt thereof includes the steps of reacting the compound of formula Da-1a with di-tert-butyl dicarbonate to form the compound of formula E-1La, reacting the compound of formula E-1La in the presence of a reducing agent to form the compound of formula F-1a, and reacting the compound of formula F-1a with iodoethane or diethyl sulfate to form the compound of formula G-1a.

[0129]

[0130] X is selected from halogens, such as bromine.

[0131] In some embodiments, the compound of formula Da-1a is reacted with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0132] In some embodiments, the reducing agent used in the reduction reaction of the compound represented by formula E-1La is selected from lithium trisec-butylborohydride or (-)diisopinepine chloroborane.

[0133] In some embodiments, the compound represented by formula F-1a reacts with iodoethane under sodium tert-butyl or sodium hydride conditions. For specific procedures / dosages, please refer to WO2022143845, the relevant content of which is incorporated herein for illustrative purposes.

[0134] In other embodiments, the compound represented by formula G is the compound represented by formula G-2. Where P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0135] In some embodiments, the compound represented by formula G-2 is the compound represented by formula G-2a.

[0136] In some embodiments, the method for preparing the compound of formula G-2 or a salt thereof includes the step of converting the compound of formula Da-2a into the compound of formula G-2.

[0137] Where P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0138] In some embodiments, the method for preparing the compound of formula G-2 or a salt thereof includes the steps of reacting the compound of formula Da-2a in the presence of a reducing agent to form the compound of formula E-2, reacting the compound of formula E-2 with an amino protecting agent to form the compound of formula F-2, and reacting the compound of formula F-2 with an ethylating agent to form the compound of formula G-2.

[0139]

[0140] Where P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0141] In some embodiments, the method for preparing the compound of formula G-2a or a salt thereof includes the steps of reacting the compound of formula Da-2a in the presence of a reducing agent to form the compound of formula E-2, reacting the compound of formula E-2 with di-tert-butyl dicarbonate to form the compound of formula F-2a, and reacting the compound of formula F-2a with iodoethane or diethyl sulfate to form the compound of formula G-2a.

[0142]

[0143] In some embodiments, the reducing agent used in the reduction reaction of the compound represented by formula Da-2a is selected from lithium trisec-butylborohydride or (-)diisopinepine chloroborane.

[0144] In some implementations, the amount of reducing agent used is 1 to 3 times the molar amount of the compound shown in formula Da-2a, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0145] In some embodiments, the ethylating agent includes a haloethane (e.g., iodoethane) or diethyl sulfate. The ethylation reaction is carried out under basic conditions, wherein the base is selected from, but not limited to, sodium tert-butoxide or sodium hydride. For specific procedures / dosages, see WO2023237041 and WO2022143845, the relevant content of which is incorporated herein for illustrative purposes.

[0146] In some embodiments, the compound shown in Formula E-2 reacts with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0147] In some embodiments, the amount of organic base used is 1 to 3 times the molar amount of the compound shown in Formula E-2, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0148] In some embodiments, the compound shown in formula F-2a is reacted with iodoethane under sodium tert-butyl or sodium hydride conditions. For specific procedures / dosages, please refer to WO2022143845, the relevant content of which is incorporated herein for illustrative purposes.

[0149] In some embodiments, the method for preparing the compound of formula G-2 or a salt thereof includes the steps of reacting the compound of formula Da-2a with an amino protecting agent to form the compound of formula E-2L, reacting the compound of formula E-2L with a reducing agent to form the compound of formula F-2, and reacting the compound of formula F-2 with an ethylating agent to form the compound of formula G-2.

[0150]

[0151] Where P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0152] In some embodiments, the method for preparing the compound of formula G-2a or a salt thereof includes the steps of reacting the compound of formula Da-2a with di-tert-butyl dicarbonate to form the compound of formula E-2La, reacting the compound of formula E-2La in the presence of a reducing agent to form the compound of formula F-2a, and reacting the compound of formula F-2a with iodoethane or diethyl sulfate to form the compound of formula G-2a.

[0153]

[0154] In some embodiments, the compound of formula Da-2a is reacted with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0155] In other embodiments, the compound represented by formula G is the compound represented by formula H-1. Where R 4 As defined in compounds of formula C, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0156] In some embodiments, the compound represented by formula H-1 is of formula Ha.

[0157] In some embodiments, the compound represented by formula H-1 is selected from...

[0158] In some embodiments, the method for preparing the compound of formula H-1 or a salt thereof includes the step of converting the compound of formula Da-3a into the compound of formula H-1.

[0159] Where P 4Amino protecting groups, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl; R 4 As defined in compounds of formula C, such as methyl, ethyl, isopropyl, or tert-butyl.

[0160] In some embodiments, the method for preparing the compound of formula H-1 or a salt thereof includes the steps of reacting the compound of formula Da-3a in the presence of a reducing agent to form the compound of formula E-3, reacting the compound of formula E-3 with an amino protecting agent to form the compound of formula F-3, and reacting the compound of formula F-3 with an ethylating agent to form the compound of formula H-1.

[0161]

[0162] Where R 4 As defined in the compound shown in formula C; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0163] In some embodiments, the ethylating agent includes a haloethane (e.g., iodoethane) or diethyl sulfate. The ethylation reaction is carried out under basic conditions, wherein the base (1) is selected from, but not limited to, sodium tert-butoxide or sodium hydride. For specific procedures / dosages, see WO2023237041 and WO2022143845, the relevant contents of which are incorporated herein for illustrative purposes.

[0164] In some embodiments, the method for preparing the compound of formula H-1 or a salt thereof includes the steps of reacting the compound of formula Da-3a in the presence of a reducing agent to form the compound of formula E-3, reacting the compound of formula E-3 with di-tert-butyl dicarbonate to form the compound of formula F-3a, and reacting the compound of formula F-3a with iodoethane or diethyl sulfate to form the compound of formula H-1a.

[0165]

[0166] Where R 4 Defined in the compound shown in Formula C.

[0167] In some embodiments, the compound shown in Formula E-3 reacts with ditert-butyl dicarbonate in the presence of an organic base selected from, but not limited to, triethylamine and N,N-diisopropylethylamine.

[0168] In some embodiments, the amount of organic base used is 1 to 3 times the molar amount of the compound shown in Formula E-3, including 1, 1.5, 2, 2.5, 3 times or any two of these values.

[0169] In some embodiments, the compound shown in formula F-3a reacts with iodoethane under sodium tert-butyl or sodium hydride conditions. For specific procedures / dosages, please refer to WO2022143845, the relevant content of which is incorporated herein for illustrative purposes.

[0170] In some embodiments, the method for preparing the compound of formula H-1 or a salt thereof includes the steps of reacting the compound of formula Da-3a with an amino protecting agent to form the compound of formula E-3L, reacting the compound of formula E-3L with a reducing agent to form the compound of formula F-3, and reacting the compound of formula F-3 with an ethylating agent to form the compound of formula H-1.

[0171]

[0172] Where R 4 As defined in the compound shown in formula C; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0173] In some embodiments, the method for preparing the compound shown in G or a salt thereof includes the following steps:

[0174] a) The compound shown in formula C reacts under acidic conditions to form the compound shown in formula D.

[0175] b) The compound shown in formula D reacts in the presence of a reducing agent to form the compound shown in formula E.

[0176] c) The compound shown in formula E reacts with an amino protecting agent to form the compound shown in formula F, and,

[0177] d) The compound shown in formula F reacts with an alkylating agent to form the compound shown in formula G.

[0178]

[0179] In some embodiments, the method for preparing the compound shown in G-1a or a salt thereof includes the following steps:

[0180] a) The compound represented by formula Ca-1aa reacts under acidic conditions to form the compound represented by formula Da-1a.

[0181] b) The compound shown in formula Da-1a reacts with the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-1.

[0182] c) The compound shown in formula E-1 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-1a, and,

[0183] d) The compound shown in formula F-1a reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1a.

[0184] Where X is a halogen, such as bromine or chlorine.

[0185] In some embodiments, the method for preparing the compound shown in G-2a or a salt thereof includes the following steps:

[0186] a) The compound represented by formula Ca-2aa reacts under acidic conditions to form the compound represented by formula Da-2a.

[0187] b) The compound shown in formula Da-2a reacts with the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-2.

[0188] c) The compound shown in formula E-2 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-2a, and,

[0189] d) The compound shown in formula F-2a reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1a.

[0190]

[0191] In some embodiments, the method for preparing the compound shown in H-1a or a salt thereof includes the following steps:

[0192] a) The compound represented by formula Ca-3aa reacts under acidic conditions to form the compound represented by formula Da-3a.

[0193] b) The compound shown in formula Da-3a reacts with the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-3.

[0194] c) The compound shown in formula E-3 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-3a, and,

[0195] d) The compound shown in formula F-3a reacts with iodoethane or diethyl sulfate to form the compound shown in formula H-1a.

[0196] Where R 4 C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl.

[0197] This disclosure also provides a method for preparing the compound of formula I or a salt thereof.

[0198] Z and Y are each independently selected from CH and N; R 3 Selected from C1-3 Alkyl and deuterated C 1-3 Alkyl; R 7 Selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano groups.

[0199] The method includes the steps of the aforementioned method for preparing the compound of formula D or its salt, and / or the steps of the aforementioned method for preparing the compound of formula G or its salt.

[0200] In some embodiments, Z is CH and Y is CH in the compound of Formula I or its salt.

[0201] In some embodiments, the method for preparing the compound of formula I or a salt thereof further includes the step of converting the compound of formula G into the compound of formula I.

[0202] Z and Y are each independently selected from CH and N; R 1 Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4 and -CONR 5 R 6 ;R 4 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted by one or more groups selected from halogen, nitro, or cyano groups; R 5 R 6 Each is independently selected from hydrogen and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano groups;

[0203] R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 alkyl;

[0204] P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0205] In some embodiments, Z is CH and Y is CH in the compound of Formula I or its salt.

[0206] In some embodiments, the compound represented by Formula I is the same as the compound represented by Formula II-1. Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl.

[0207] In some embodiments, the compound represented by Formula II-1 is selected from...

[0208] In some embodiments, the compound represented by Formula I is compound II-2.

[0209] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the step of removing the amino protecting group from the compound of formula H-1 to form the compound of formula I.

[0210] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0211] The conditions for removing the amino protecting group disclosed herein are selected according to the type of protecting group. See the corresponding conditions for removing the protecting group in (Protective Groups in Organic Synthesis, 5th Ed. TW Greene & P. ​​GMWuts), and the relevant content is incorporated herein for illustration. For example, the compound of formula H-1 or its salt is deamino protecting the -Boc under acid (1) conditions, wherein the acid (1) is selected from trifluoroacetic acid, acetic acid or hydrochloric acid.

[0212] In some embodiments, the compound of formula H-1 or its salt is deprotected under metal reducing conditions such as hydrogen / Pd / c by removing the amino protecting group -Bn or -Cbz.

[0213] On the one hand, in some embodiments, the method for preparing the compound of formula II-1 or a salt thereof further includes the step of converting the compound of formula G-1 into the compound of formula H-1.

[0214] Where X is a halogen, such as bromine; R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0215] In some embodiments, the compound of formula G-1 reacts with carbon monoxide in the presence of divalent palladium to form the compound of formula H-1, wherein the divalent palladium is selected from, but not limited to, palladium acetate, palladium chloride, or Pd(dppf)Cl2.

[0216] In some embodiments, the compound shown in formula G-1 reacts with carbon monoxide in the presence of palladium acetate or Pd(dppf)Cl2 to form the compound shown in formula H-1. For specific procedures, see WO2022218429A (Example 5) and WO2022143845A (Example 3), the relevant contents of which are incorporated herein by reference. The solvent used in the aforementioned reactions is selected from fatty alcohols, such as methanol or ethanol.

[0217] In some embodiments, the compound represented by formula H-1 is selected from...

[0218] In some embodiments, the compound represented by Formula II-1 is selected from...

[0219] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the steps of converting the compound of formula G-1 into the compound of formula H-1, and removing the amino protecting group from the compound of formula H-1 to form the compound of formula II-1.

[0220] Where X is a halogen, such as bromine; R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0221] In other embodiments, the compound shown in formula G-1 reacts with carbon dioxide in the presence of a Grignard reagent and / or an organolithium reagent to form the compound shown in formula HZ. Or its salt.

[0222] In some embodiments, the Grignard reagent is selected from, but not limited to, isopropyl magnesium chloride, cyclohexyl magnesium chloride, methyl magnesium chloride, ethyl magnesium chloride, isopropyl magnesium bromide, cyclohexyl magnesium bromide, methyl magnesium bromide, and ethyl magnesium bromide.

[0223] In other embodiments, the organolithium reagent is selected from, but not limited to, n-butyllithium, tert-butyllithium, isobutyllithium, phenyllithium, methyllithium, diisopropylaminolithium, and bis(trimethylsilyl)aminolithium.

[0224] In some embodiments, the compound shown in formula G-1 reacts with carbon dioxide in the presence of isopropyl magnesium chloride (i-PrMgCl) / n-butyllithium (n-BuLi) to form the compound shown in formula HZ. Or its salt.

[0225] Furthermore, the compound represented by formula HZ or its salt reacts with C 1-6Fatty alcohols react to form compounds with the corresponding formula H-1.

[0226] In some embodiments, the compound represented by formula HZ or its salt reacts with methanol in the presence of thionyl chloride to form the corresponding methyl ester compound.

[0227] In some embodiments, the compound represented by formula HZ or its salt reacts with ethanol in the presence of thionyl chloride to form the corresponding ethyl ester compound.

[0228] In some embodiments, the compound represented by formula HZ or its salt reacts with tert-butanol in the presence of thionyl chloride to form the corresponding tert-butyl ester compound.

[0229] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the steps of converting the compound of formula G-1 to the compound of formula HZ, subjecting the compound of formula HZ to esterification to form the compound of formula H-1, and removing the amino protecting group from the compound of formula H-1 to form the compound of formula II-1.

[0230] Where X is a halogen, such as bromine; R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0231] On the other hand, some methods for preparing the compound shown in Formula II-1 or its salts also include the step of converting the compound shown in Formula G-2 into the compound shown in Formula H-1.

[0232] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0233] In some embodiments, the compound shown in formula G-2 undergoes a hydrolysis reaction to form the compound shown in formula H-Z1, and the compound shown in formula H-Z1 is converted into the compound shown in formula H-1.

[0234] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0235] In some embodiments, the compound shown in formula H-Z1 is in sulfone chloride / C 1-6 The reaction in the presence of fatty alcohols forms the compound shown in formula H-1.

[0236] In some embodiments, the compounds shown in formula H-Z1 react in the presence of sulfone chloride / methanol to form methyl ester compounds.

[0237] In some embodiments, the compounds shown in formula H-Z1 react in the presence of sulfone chloride / ethanol to form ethyl ester compounds.

[0238] In some embodiments, the compounds shown in formula H-Z1 react in the presence of dimethylformamide dimethyl acetal (DMFDMA) / methanol to form methyl ester compounds.

[0239] In some embodiments, the compound shown in formula G-2 reacts in the presence of hydrogen peroxide / potassium carbonate to form the compound shown in formula H-Z1.

[0240] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the steps of converting the compound of formula G-2 into the compound of formula H-1, and removing the amino protecting group from the compound of formula H-1 to form the compound of formula II-c.

[0241] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0242] In other embodiments, the compound of formula G-2 undergoes hydrolysis to form the compound of formula HZ, and formula HZ undergoes esterification to form the compound of formula H-1.

[0243] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0244] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the following steps:

[0245] a) The compound represented by formula Ca-1a reacts under acidic conditions to form the compound represented by formula Da-1a.

[0246] b) The compound shown in formula Da-1a is reduced in the presence of a reducing agent to form the compound shown in formula E-1.

[0247] c) The compound shown in formula E-1 reacts with an amino protecting agent to form the compound shown in formula F-1.

[0248] d) The compound shown in formula F-1 reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1.

[0249] e) The compound shown in formula G-1 is converted into the compound shown in formula H-1.

[0250] f) The compound shown in formula H-1 is deamino protected to form the compound shown in formula II-1.

[0251]

[0252] In some embodiments, the method for preparing the compound of formula II-1 or a salt thereof includes the following steps:

[0253] a) The compound represented by formula Ca-1a reacts under acidic conditions to form the compound represented by formula Da-1a.

[0254] b) The compound shown in formula Da-1a is reduced in the presence of a reducing agent to form the compound shown in formula E-1.

[0255] c) The compound shown in formula E-1 reacts with an amino protecting agent to form the compound shown in formula F-1.

[0256] d) The compound shown in formula F-1 reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1.

[0257] e) The compound shown in formula G-1 is converted into the compound shown in formula HZ.

[0258] f) The compound shown in formula HZ undergoes an esterification reaction to form the compound shown in formula H-1, and the compound shown in formula H-1 undergoes the removal of an amino protecting group to form the compound shown in formula II-1.

[0259]

[0260] In some embodiments, the method for preparing the compound of formula II-1a or a salt thereof includes the following steps:

[0261] a) The compound represented by formula Ca-1aa reacts under acidic conditions to form the compound represented by formula Da-1a.

[0262] b) The compound shown in formula Da-1a reacts with the reducing agent trisec-butylborohydride or (-)-diisopinepine chloroborane to form the compound shown in formula E-1.

[0263] c) The compound shown in formula E-1 reacts with di-tert-butyl dicarbonate to form the compound shown in formula F-1a.

[0264] d) The compound shown in formula F-1a reacts with iodoethane or diethyl sulfate to form the compound shown in formula G-1a.

[0265] e) The compound shown in formula G-1a reacts with carbon dioxide in the presence of isopropyl magnesium chloride (i-PrMgCl) / n-butyllithium (n-BuLi) to form the compound shown in formula H-Za.

[0266] f) The compound shown in formula H-Za undergoes esterification in the presence of sulfone chloride / methanol to form the compound shown in formula H-1a, and the compound shown in formula H-1a undergoes deamino protecting group removal to form the compound shown in formula II-1.

[0267]

[0268] The esterification and deprotection steps of the compounds represented by formula H-Za are not sequential. For example, esterification followed by deprotection of the compound represented by formula H-Za, or deprotection followed by esterification of the compound represented by formula H-Za, can yield the target product, such as compound II-1a. In some embodiments, deprotection and esterification can be performed in a one-pot process without separation steps.

[0269] On the other hand, this disclosure also provides the following compounds or salts thereof, said compounds being selected from:

[0270] Z and Y are each independently selected from CH and N;

[0271] R 1 Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4 and -CONR 5 R 6 ;

[0272] R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0273] R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 alkyl;

[0274] R 4 Selected from C 1-6 Alkyl, the C1-6 The alkyl group may be optionally substituted by one or more groups selected from halogen, nitro, or cyano groups; R 5 R 6 Each is independently selected from hydrogen and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano groups;

[0275] P 1 P 2 Each was independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0276] P 3 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano.

[0277] In some embodiments, the compound represented by formula B is selected from... Where X is selected from halogens, such as bromine; P 1 P 2 Each was independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0278] R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0279] R 4 Selected from C1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano.

[0280] In some embodiments, the compound represented by formula C is selected from... Where R 1 As defined above.

[0281] In some embodiments, the compound represented by formula C is selected from... Where X is selected from halogens, such as bromine; P 1 P 2 Each was independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted;

[0282] P 3 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano groups;

[0283] R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0284] R 4 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano.

[0285] This disclosure also provides, in another aspect, steps of the method for preparing the compound of formula D or its salt, or / and the method for preparing the compound of formula G or its salt, or / and the method for preparing the compound of formula I or its salt, or the use of the aforementioned compound or its salt in the preparation of Factor B inhibitors.

[0286] In this disclosure, the Factor B inhibitors are selected from, but are not limited to:

[0287]

[0288] This disclosure also provides a method for preparing compound AA or a salt thereof, the method comprising the steps of the aforementioned methods for preparing the compound of formula D or a salt thereof, the compound of formula G or a salt thereof, and the compound of formula I or a salt thereof.

[0289]

[0290] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting the compound of formula II-1 with the compound of formula DD-1 to form the compound of formula EE.

[0291] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 5 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0292] In some embodiments, the method for preparing compound AA or a salt thereof includes reacting compound II-1a with compound DD-1a in the presence of trimethylchlorosilane, phenylsilane, and pyridine to form compound EE-a.

[0293] For specific reaction procedures, please refer to WO2023 / 237041 (Example 2), and the relevant content is incorporated herein for illustration.

[0294] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting the compound of formula II-1 with the compound of formula DD-2 to form the compound of formula EE.

[0295] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 5 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

[0296] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting compound II-1a with compound DD-2a in the presence of triphenylphosphine and carbon tetrachloride to form a compound shown in formula EE-b.

[0297] For specific reaction procedures, please refer to WO2022143845A (Example 3), and the relevant content is incorporated herein for illustration.

[0298] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting the compound of formula II-1 with the compound of formula DD-3 to form the compound of formula EE.

[0299] Where R 4 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, isopropyl, or tert-butyl; P 5 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl; X1 is selected from halogens, such as bromine.

[0300] In some embodiments, the method for preparing compound AA or a salt thereof includes the step of reacting compound II-1a with compound DD-3a in the presence of a base (4) to form compound EE-c, wherein the base (4) is selected from, but is not limited to, cesium carbonate or potassium carbonate.

[0301] For specific reaction procedures, please refer to WO2022218429A (Example 5), and the relevant content is incorporated herein for illustration.

[0302] In some embodiments, the method for preparing compound AA or its salts further includes a deprotection of the compound represented by formula EE and an ester hydrolysis step. The deprotection step and the ester hydrolysis step may be performed in any order. In some embodiments, the deprotection and ester hydrolysis can be performed in a one-pot process without any separation steps. Example operations are described in WO2022218429A, WO2022143845A, and WO2023 / 237041, the contents of which are incorporated herein by reference.

[0303] This disclosure also provides a method for preparing compound BB or a salt thereof, the method comprising the steps of the aforementioned methods for preparing the compound of formula D or a salt thereof, the compound of formula G or a salt thereof, and the compound of formula I or a salt thereof.

[0304]

[0305] On the other hand, the preparation method described in this disclosure also includes one or more steps such as filtration, concentration, column chromatography purification and drying.

[0306] "Formation" and "conversion" do not specifically refer to a single-step conversion 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 to remove the protecting agent, and then reacts with the corresponding substrate to obtain the corresponding target product.

[0307] 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%.

[0308] The compounds described in this disclosure may be pharmaceutical salts or salts thereof, which may be selected from inorganic or organic salts. These include acid addition salts and base addition salts. For example, salts formed by an acid-base reaction with a basic group (amino group), wherein the acid includes organic or inorganic acids.

[0309] 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.

[0310] "alkyl" refers to a saturated aliphatic hydrocarbon group, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Alkyl groups can be substituted or unsubstituted.

[0311] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 6 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, excluding the ring moiety of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Heterocyclic alkyl groups can be substituted or unsubstituted.

[0312] "Aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl. Aryl groups can be substituted or unsubstituted.

[0313] "Heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 6 to 10-membered, such as naphthyl. More preferably, it is 5- or 6-membered. The heteroaryl group can be substituted or unsubstituted.

[0314] "Acyl" refers to -C(O)R a R a Selected from hydrogen or C 1-2 alkyl.

[0315] "Hydroxy" refers to the -OH group.

[0316] “Cyano” refers to the -CN group.

[0317] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0318] "Amino" refers to -NH2.

[0319] The "amino protecting group" disclosed herein is a group known in the art that can be used to protect amino groups, see the amino protecting groups in the literature (Protective Groups in Organic Synthesis, 5th Ed. TW Greene & P. ​​GMWuts). As examples, it includes, but is not limited to, tert-butoxycarbonyl (Boc).

[0320] When the functional group of this disclosure is substituted, the substituent is preferably one or more of the following groups: halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl group. Detailed Implementation

[0321] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0322] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0323] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm).

[0324] The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (d6-DMSO) as the solvent.

[0325] MS measurements were performed using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer, scanning in positive / negative ion mode, with a mass scan range of 120–1300.

[0326] HPLC column: YMC-Pack ODS-A (3μm, 4.6mm x 150mm)

[0327] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.2mm ± 0.03mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm-0.5mm.

[0328] Example 1

[0329]

[0330] Step 1:

[0331] Compound 1a (5.03 g, 49.96 mmol, purchased from Aladdin) was added to DCE (100 mL), cooled to 5-15 °C, and aluminum trichloride (14.66 g, 109.92 mmol, purchased from Merrill) was added. The mixture was then allowed to rise naturally to room temperature for 1 hour. Compound 1b (11.77 g, 74.95 mmol) was added dropwise to the reaction solution, and the mixture was allowed to rise naturally to room temperature for 22 hours. The mixture was then filtered after adding 600 mL of 9% HCl. The filtrate was separated, and the aqueous phase was extracted once with DCM. The DCM, organic phase, and filter cake were combined and concentrated to dryness. The concentrated solid was dissolved in toluene by heating, then cooled to room temperature and stirred for 1 hour. The mixture was filtered, and the filter cake was dried to give 7.55 g of compound 1c (yield 58.80%).

[0332] MS(ESI): m / z 256.9 [M+1] + .

[0333] Step 2:

[0334] Compound 1c (7.51 g, 29.21 mmol) was added to methanol (75 mL), cooled to 5-10 °C, and thionyl chloride (4.52 g, 37.98 mmol, purchased from Kelon) was added. The mixture was then heated to 60 °C and reacted for 2 hours. After cooling to room temperature, the mixture was concentrated to dryness, dissolved in ethyl acetate, washed once with saturated sodium carbonate solution, separated, and the organic phase was concentrated to dryness to give 11.17 g of compound 1d (yield over 100%).

[0335] MS(ESI): m / z 270.9 [M+1] + .

[0336] 1 H NMR (400MHz, CDCl3): δ7.85 (d, J = 8.4Hz, 2H), 7.61 (d, J = 8.4Hz, 2H), 3.71 (s, 3H), 3.28 (t, 2H), 2.77 (t, 2H).

[0337] Step 3:

[0338] Compound 1d (5.01 g, 18.44 mmol), compound 1e (11.50 g, 184.43 mmol, purchased from Xilong Chemical), sulfuric acid (191 mg, 1.84 mmol, purchased from Xilong Chemical), and triethyl orthoformate (3.28 g, 22.13 mmol, purchased from Kelon) were added to toluene (50 mL) and reacted at 80 °C for 20 hours. After cooling to room temperature, the mixture was concentrated to dryness and purified by column chromatography (PE:EA = 100:0-90:10) to give 1.66 g of compound 1f (yield 28.57%).

[0339] MS(ESI): m / z 314.9 [M+1] + .

[0340] 1 H NMR (400MHz, DMSO-d6): δ7.55(d,J=6.6Hz,2H),7.33(d,J=6.6Hz,2H),3.96(t,2H),3.67(t,2H),3.54(s,3H),2.29(t,2H),2.09(t,2H).

[0341] Step 4:

[0342] Compound 1f (1.50 g, 4.76 mmol) and sodium borohydride (360 mg, 9.52 mmol, purchased from Kelon) were added to tetrahydrofuran (12 mL) and methanol (1.5 mL), and reacted at 55 °C for 4.5 h. After cooling to room temperature, the mixture was concentrated to dryness and purified by column chromatography (PE:EA = 100:0-90:10) to give 580 mg of compound 1 g (yield 41.43%).

[0343] Step 5:

[0344] Dimethyl sulfoxide (950 mg, 12.16 mmol, purchased from Kelon) was added to dichloromethane (8.4 mL), purging the argon gas, and the mixture was cooled to -70 °C in a dry ice-ethanol bath. Oxaloyl chloride (1.109 g, 8.74 mmol, purchased from Energi) was slowly added dropwise. After the addition, the mixture was kept warm and stirred for 20 minutes. 1 g (488 mg, 1.70 mmol) of the compound was dissolved in dichloromethane (1.4 mL) and added dropwise to the reaction mixture. Then, triethylamine (2.131 g, 21.06 mmol, purchased from Kelon) was added dropwise to the reaction mixture, with the temperature controlled not to exceed -65 °C during the addition process. The reaction was carried out at -65 °C for 2 hours, then brought to room temperature. A saturated sodium bicarbonate aqueous solution was added, the mixture was separated, and the organic phase was concentrated to dryness. The solution was purified by column chromatography (PE:EA = 100:0-90:10) to give 294 mg of the compound in 1 h (yield 60.67%).

[0345] MS(ESI): m / z 284.9 [M+1] + .

[0346] 1 H NMR (400MHz, DMSO-d6): δ9.59(t,1H),7.57(d,2H),7.34(d,2H),3.94(t,2H),3.67(t,2H),2.40(t,2H),2.15(t,2H).

[0347] Example 2

[0348]

[0349] Step 1:

[0350] Compound 1h (2.50 g, 8.77 mmol) and compound 1i (4.26 g, 35.15 mmol, purchased from Bio-Pharmaceutical) were added to tetrahydrofuran (50 mL), followed by tetraethyl titanate (20.01 g, 87.72 mmol, purchased from Anage). The mixture was purged with argon gas and heated to 65 °C for 18 hours. After cooling to room temperature, water and ethyl acetate were added, followed by extraction, separation, concentration of the organic phase, and purification by column chromatography (PE:EA = 100:0-90:10) to give 3.05 g of compound 1j (yield 89.71%).

[0351] 1 H NMR (400MHz, DMSO-d6): δ7.96(t,1H),7.57(d,2H),7.36(d,2H),4.00-3.9 7(m,2H),3.71-3.67(m,2H),2.54-2.50(m,2H),2.15(t,2H),1.09(s,9H).

[0352] Step 2:

[0353] Compound 1k (4.10 g, 25.75 mmol, purchased from Bio-Pharmaceutical) was added to tetrahydrofuran (30 mL), purged with argon, and cooled to 0-5 °C. Diisopropylaminolithium (4 M in THF, 26 mL, purchased from Adamas) was added dropwise, maintaining a temperature not exceeding 10 °C. After addition, the mixture was stirred for 15 minutes, then cooled to -45 °C. Compound 1j (4.95 g, 12.88 mmol) was dissolved in tetrahydrofuran (30 mL) and added dropwise to the 1k reaction solution. The reaction was carried out at -45 to -60 °C for 10 minutes. Saturated ammonium chloride aqueous solution was added, and the mixture was heated to room temperature. Extraction was performed twice with ethyl acetate, and the liquid was separated. The organic phase was concentrated and purified by column chromatography (PE:EA = 70:30-30:70) to give 5.49 g of compound 1l (yield 80.03%).

[0354] MS(ESI): m / z 546.1 [M+1] +.

[0355] 1 H NMR (400MHz, DMSO-d6): δ7.57-7.53(m,2H),7.34-7.28(m,2H),5.05-5.01(m,1H),3.97-3.94(m,2H)3.68-3.65(m ,2H),3.45-3.32(m,3H),2.50(d,1H),2.10-1.70(m,2H),1.43-1.39(m,1H),1.39-1.38(m,9H),1.08-1.03(m,9H).

[0356] Step 3:

[0357] Compound 1 (106 mg, 199.44 μmol) was added to ethanol (13 mL), followed by glacial acetic acid (13 mL) and ammonium acetate (355 mg, 4.61 mmol, purchased from Kelon). The mixture was heated to 70 °C and reacted for 6 hours. The reaction solution was concentrated, water and dichloromethane were added, and the pH was adjusted to 12–13 with 1 M sodium hydroxide. The mixture was separated, the organic phase was concentrated, and purified by column chromatography (PE:EA = 80:30–50:40) to give 11 mg of compound 1 (yield 20%).

[0358] MS(ESI): m / z 281.7 [M+1] + .

[0359] 1 H NMR (500MHz, DMSO-d6): δ11.49(s,1H),10.34(s,1H),7.70~7.60(dd,4H),4.39(m,1H),3.29~3.25(m ,1H),3.13~3.09(m,1H),2.76~2.72(m,1H),2.56~2.50(m,2H),2.30~2.22(m,2H),1.91~1.86(m,1H).

[0360] In addition, HPLC analysis showed that compound a accounted for approximately 60% of compound 1.

[0361]

Claims

1. A method for preparing compound D or its salt, The method includes the step of reacting the compound of formula C to form the compound of formula D. in, Z and Y are each independently selected from CH and N; R 1 Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4 and -CONR 5 R 6 ; R 2 Selected from C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, nitro, cyano, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R 4 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano groups; R 5 R 6 Each is independently selected from hydrogen and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano groups; P 1 P 2 Each was independently selected from C 1-3 Alkyl and C 1-3 Acyl group, the C 1-3 Alkyl or C 1-3 The acyl group may be optionally substituted with one or more halogens or phenyl groups, or P 1 P 2 Together with adjacent atoms, they form a 5-6 membered heterocyclic alkyl group, which is optionally bonded by one or more atoms selected from halogens or C. 1-3 Alkyl groups are substituted; P 3 Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano.

2. The method according to claim 1, wherein the compound of formula C reacts under acidic conditions to form the compound of formula D, wherein the acid is preferably hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, hydrobromic acid or p-toluenesulfonic acid, more preferably hydrochloric acid.

3. The method according to any one of claims 1 or 2, wherein the compound represented by formula D is the compound represented by formula D-1. A method for preparing the compound of formula D-1 or a salt thereof includes the step of reacting the compound of formula C-1 under acidic conditions to form the compound of formula D-1. Where R 1 R 2 P 1 P 2 P 3 As defined in claim 1.

4. The method according to any one of claims 1-3, further comprising reacting the compound of formula A with a sulfinamide to form the compound of formula B, and reacting the compound of formula B with the compound of formula W to form the compound of formula C. Where R 1 R 2 Z, Y, P 1 P 2 P 3 As defined in claim 1; R 1a Selected from halogen, cyano, C 1-6 Alkyl, -COOR 4a and -CONR 5a R 6a R 4a Selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano; R 5a R 6a Each is independently selected from hydrogen and C. 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano.

5. The method according to any one of claims 1-4, wherein the compound represented by formula C is selected from... Where R 1 As defined in claim 1.

6. The method according to any one of claims 1-5, wherein R 1 Selected from halogen, cyano, -COOR 4 R 4 As defined in claim 1.

7. A method for preparing the compound of formula G or a salt thereof, The method comprises the steps of the method for preparing the compound of formula D or a salt thereof as described in any one of claims 1-6, wherein R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

8. The method of claim 7, further comprising the step of converting the compound of formula D into the compound of formula G. Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

9. The method according to claim 7 or 8, further comprising the steps of reacting the compound of formula Da in the presence of a reducing agent to form the compound of formula E, reacting the compound of formula E with an amino protecting agent to form the compound of formula F, and reacting the compound of formula F with an alkylating agent to form the compound of formula G. Where R 1 Z, Y are defined as shown in the compound of formula C; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

10. A method for preparing the compound of formula I or a salt thereof, Z and Y are each independently selected from CH and N; R 3 Selected from C 1-3 Alkyl and deuterated C 1-3 Alkyl; R 7 Selected from hydrogen, C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more groups selected from halogen, nitro, or cyano groups. The method includes the steps of the method for preparing the compound of formula D or a salt thereof as described in any one of claims 1-6, or / and the steps of the method for preparing the compound of formula G or a salt thereof as described in any one of claims 7-9.

11. The method of claim 10, further comprising the step of converting the compound of formula G into the compound of formula I. Among them, Z, Y, and R 3 R 7 As defined in claim 10; P 4 It is an amino protecting group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, p-toluenesulfonyl, and trifluoroacetyl.

12. A compound or a salt thereof, said compound being selected from: Where R 1 R 2 P 1 P 2 P 3 Z and Y are as defined in claim 1.

13. The method for preparing the compound of formula D or a salt thereof according to any one of claims 1-6; the method for preparing the compound of formula G or a salt thereof according to any one of claims 7-9; the method for preparing the compound of formula I or a salt thereof according to claim 10; the use of the compound or a salt thereof according to claim 12 in the preparation of a Factor B inhibitor, wherein the Factor B inhibitor is preferably...

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