Chiral synthesis of fused bicyclic raf inhibitors

Abstract

This disclosure generally relates to the improved synthesis of enantiomers or pharmaceutically acceptable salts, tautomers, or stereoisomers of fused bicyclic Raf inhibitors of formula (I), (Ia), (Ib), (II), (IIa), or (IIb) having a high enantiomer excess (%ee). This disclosure also relates to methods of treating diseases such as cancers, including colorectal cancer, using compounds of formula (I), (Ia), (Ib), (II), (IIa), or (IIb) or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 057,531, filed July 28, 2020, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure generally relates to the improved synthesis of enantiomers of fused bicyclic Raf inhibitors with high enantiomer excess (%ee). Background Technology

[0004] Mutations leading to uncontrolled signaling via the RAS-RAF-MAPK pathway have been found in more than one-third of all cancers. RAF kinases (A-RAF, B-RAF, and C-RAF) are components of this pathway, with B-RAF mutations being clinically common. While most B-RAF V600E-mutant skin cancers are sensitive to approved B-RAF-selective agents, B-RAF V600E-mutant colorectal cancers are unexpectedly insensitive to these agents as monotherapy due to the function of other RAF family members and require combination therapy. B-RAF-selective therapies have failed to demonstrate clinical benefit against atypical B-RAF (non-V600E), other RAF, and RAS-driven tumors.

[0005] U.S. Patent No. 10,183,939 discloses racemic Raf inhibitors exhibiting binding affinity for both B-RAF V600E and C-RAF, the disclosure of which is incorporated herein by reference in its entirety. These pan-RAF inhibitors have been identified as promising candidates for overcoming resistance mechanisms associated with clinically approved selective B-RAF drugs. However, U.S. Patent No. 10,183,939 does not describe a method for selectively synthesizing enantiomers of Raf inhibitors. Summary of the Invention

[0006] This disclosure relates to a method for synthesizing a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or tautomer thereof.

[0007]

[0008] in:

[0009] R 1 Selected from substituted or unsubstituted: C 1-6 Alkyl, C 1-6 Halogenated alkyl, aryl, heterocyclic or heteroaryl;

[0010] R 2 It is H;

[0011] X 1 Is it N or CR? 8 ;

[0012] X 2 Is it N or CR? 9 ;

[0013] R 6 It is hydrogen, halogen, alkyl, alkoxy, -NH2, -NR F C(O)R 5 -NR F C(O)CH2R 5 -NR F C(O)CH(CH3)R 5 or -NR F R 5 ;

[0014] R 7 R 8 and R 9 Each is independently hydrogen, halogen, or alkyl;

[0015] Alternatively, R 6 and R 8 Or R 7 and R 9 Together with the atoms to which they are attached, they form 5- or 6-membered partially unsaturated or unsaturated rings containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the rings are substituted or unsubstituted.

[0016] R 5 It is a substituted or unsubstituted group selected from alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups; and

[0017] R F Selected from H or C 1-3 alkyl.

[0018] The method includes:

[0019] a) Reacting compound 1A with (R)-6-hydroxychroman-3-carboxylic acid or (S)-6-hydroxychroman-3-carboxylic acid to provide compound 2A;

[0020] Compound 2A has (R) or (S) stereochemistry at the carbon indicated by *;

[0021]

[0022] b) React compound 2A with compound 3A or a salt thereof to provide compound 4A;

[0023] Compound of formula 4A has (R) or (S) stereochemistry at the carbon indicated by *; and

[0024]

[0025] c) Cycling the compound of formula 4A from step b) in the presence of ammonia or an ammonium salt to provide a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or tautomer thereof.

[0026]

[0027] This disclosure relates to a method for synthesizing a compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt or tautomer thereof.

[0028]

[0029] in:

[0030] R 3 It is halogen, -OR A -NR A R B -SO2R C -SOR C -CN,C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 Cycloalkyl, wherein the alkyl, haloalkyl, and cycloalkyl groups are optionally substituted by one to three independently selected groups from: -OR A -CN, -SOR C or -NR A R B ;

[0031] R A and R B Each is independently selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0032] R C Selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0033] n is 0, 1, 2, 3 or 4;

[0034] The method includes:

[0035] a) Reaction of 5-fluoro-3,4-dihydro-1,8-naphthidin-2(1H)-one with (R)-6-hydroxy-som-3-carboxylic acid or (S)-6-hydroxy-som-3-carboxylic acid to provide (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy)som-3-carboxylic acid;

[0036]

[0037] b) Reacting (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy)chroman-3-carboxylic acid or (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy)chroman-3-carboxylic acid with 2-amino-1-phenylethyl-1-one or a pharmaceutically acceptable salt thereof to provide a compound of formula 4B.

[0038] 2-Amino-1-phenylethyl-1-one is optionally replaced by R 3 Replace; and

[0039] Compound 4B has (R) or (S) stereochemistry at the carbon indicated by *; and

[0040]

[0041] c) Cycling the compound of formula 4B from step b) in the presence of ammonia or an ammonium salt to provide a compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt or tautomer thereof.

[0042]

[0043] In embodiments of the synthetic method disclosed herein, (R)-6-hydroxychromene-3-carboxylic acid or (S)-6-hydroxychromene-3-carboxylic acid is prepared by chiral hydrogenation of 6-hydroxy-2H-chromene-3-carboxylic acid.

[0044]

[0045] In embodiments of the synthetic method disclosed herein, the chiral hydrogenation is carried out in the presence of a Ru or Rh catalyst and a chiral ligand. In embodiments, the Ru or Rh catalyst is selected from Ru(OAc)₂, [RuCl₂(p-cym)]₂, Ru(COD)(Me-allyl)₂, Ru(COD)(TFA)₂, [Rh(COD)₂]OTf, or [Rh(COD)₂]BF₄. In embodiments, the Ru catalyst is selected from [RuCl₂(p-cym)]₂, Ru(COD)(Me-allyl)₂, or Ru(COD)(TFA)₂. In the implementation scheme, the chiral ligand is selected from (S)- or (R)-BINAP, (S)- or (R)-H8-BI NAP, (S)- or (R)-PPhos, (S)- or (R)-Xyl-PPhos, (S)- or (R)-PhanePhos, (S)- or (R)-Xyl-PhanePhos, (S,S)-Me-DuPhos, (R,R)-Me-DuPhos, (S,S)-iPr-DuPhos, (R,R)-iPr-DuPhos, (S,S)-NorPhos, (R,R)-NorPhos, (S,S)-BPPM or (R,R)-BPPM or Josiphos SL-J002-1. In the implementation scheme, the chiral ligand is selected from (S)- or (R)-PhanePhos or (S)- or (R)-An-PhanePhos.

[0046] In embodiments of the synthetic method disclosed herein, the chiral hydrogenation is carried out in the presence of a chiral Ru-complex or a chiral Rh-complex. In the embodiments, the chiral Ru-complex or the chiral Rh-complex is selected from [(R)-Phanephos-RuCl2(p-cym)], [(S)-Phanephos-RuCl2(p-cym)], [(R)-An-Phanephos-RuCl2(p-cym)], [(S)-An-Phanephos-RuCl2(p-cym)], [(R)-BINAP-RuCl(p-cym)]Cl, [(S)-BINAP-RuCl(p-cym)]Cl, (R)-BINAP-Ru(OAc)2, (S)-BINAP-Ru(OAc)2, [(R)-Phanephos-Rh(COD)]BF4, [(S)-Phanephos-Rh(COD)]BF4, [(R)-Phanephos-RuCl2(p-cym ... [(S)-Phanephos-Rh(COD)]OTf or [(S)-Phanephos-Rh(COD)]OTf. In an embodiment, the chiral Ru-complex is selected from [(R)-Phanephos-RuCl2(p-cym)], [(S)-Phanephos-RuCl2(p-cym)], [(R)-An-Phanephos-RuCl2(p-cym)] or [(S)-An-Phanephos-RuCl2(p-cym)].

[0047] In embodiments of the synthetic method disclosed herein, the chiral hydrogenation is carried out with a substrate / catalyst loading ranging from about 25 / L to about 1,000 / L. In other embodiments, the substrate / catalyst loading ranges from about 200 / L to about 1,000 / L.

[0048] In embodiments of the synthetic method disclosed herein, the chiral hydrogenation is carried out in the presence of a base. In embodiments, the base is triethylamine, NaOMe, or Na₂CO₃. In embodiments, the base is used in an equivalent of about 2.0, about 1.9, about 1.8, about 1.7, about 1.6, about 1.5, about 1.4, about 1.3, about 1.2, about 1.1, about 1.0, about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2, or about 0.1 of 6-hydroxy-2H-chromene-3-carboxylic acid.

[0049] In embodiments of the synthesis method disclosed herein, the chiral hydrogenation is carried out at a temperature in the range of about 30°C to about 50°C.

[0050] In embodiments of the synthetic method disclosed herein, the chiral hydrogenation is carried out at a concentration of 6-hydroxy-2H-chromene-3-carboxylic acid in the range of about 0.2 M to about 0.8 M.

[0051] In embodiments of the synthesis method disclosed herein, the chiral hydrogenation is carried out at a hydrogen pressure ranging from about 2 bar to about 30 bar. In other embodiments, the hydrogen pressure is in the range of about 3 bar to about 10 bar.

[0052] In embodiments of the synthetic method disclosed herein, the chiral hydrogenation is carried out in an alcohol solvent. In these embodiments, the solvent is methanol, ethanol, or isopropanol.

[0053] In embodiments of the synthetic method disclosed herein, (R)-6-hydroxychromium-3-carboxylic acid and (S)-6-hydroxychromium-3-carboxylic acid have an enantiomer excess of at least 90%.

[0054] In embodiments of the synthetic method disclosed herein, (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy)chroman-3-carboxylic acid and (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy)chroman-3-carboxylic acid have at least 90% enantiomeric excess.

[0055] In an embodiment of the synthetic method disclosed herein, the compound of formula 4A in step b) has an enantiomeric excess of at least 90%.

[0056] In an embodiment of the synthetic method disclosed herein, the compound of formula 4B in step b) has an enantiomeric excess of at least 90%.

[0057] In embodiments of the synthetic methods disclosed herein, compounds of formulas (IIa) and (IIb) or pharmaceutically acceptable salts or tautomers thereof have an enantiomer excess of at least 90%.

[0058] In embodiments of the synthetic methods disclosed herein, compounds of formulas (Ia) and (Ib) or their pharmaceutically acceptable salts or tautomers have an enantiomer excess of at least 90%.

[0059] In embodiments of the synthesis method disclosed herein, R in formula (IIa) or (IIb) 3 It is halogen, C 1-4 Alkyl group, -SO2(C 1-4 Alkyl). In the implementation scheme, R 3 It is F, Cl, Br, or I. In the implementation scheme, n is 0, 1, or 2.

[0060] In the embodiments of the synthesis method disclosed herein, R in formula (Ia) or (Ib)1 It is a substituted or unsubstituted heteroaryl group.

[0061] In embodiments of the synthetic method disclosed herein, the compound is selected from...

[0062] Or a pharmaceutically acceptable salt or tautomer thereof. In embodiments of the synthetic methods disclosed herein, the compound is selected from compounds A-1-N-1 or A-2-N-2 prepared by any of the methods disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0063] This disclosure relates to a compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt or tautomer thereof prepared by any of the methods disclosed herein.

[0064] This disclosure relates to a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or tautomer thereof prepared by any of the methods disclosed herein.

[0065] This disclosure relates to compounds A-1-N-1 or A-2-N-2 or pharmaceutically acceptable salts or tautomers thereof prepared by any of the methods disclosed herein.

[0066] This disclosure relates to compounds A-1-N-1 or A-2-N-2, or pharmaceutically acceptable salts or tautomers thereof.

[0067] In embodiments of the compounds disclosed herein, the compound has an enantiomer excess of at least 90%. In embodiments, the compound has an enantiomer excess of at least 95%. In embodiments, the compound has a chemical purity of 85% or higher. In embodiments, the compound has a chemical purity of 90% or higher. In embodiments, the compound has a chemical purity of 95% or higher.

[0068] This disclosure relates to a pharmaceutical composition comprising any of the compounds disclosed herein and a pharmaceutically acceptable excipient or carrier.

[0069] In embodiments of the pharmaceutical composition, the composition further comprises an additional therapeutic agent. In these embodiments, the additional therapeutic agent is selected from antiproliferative or antitumor drugs, cell growth inhibitors, anti-invasive agents, growth factor function inhibitors, anti-angiogenic agents, steroids, targeted therapies, or immunotherapies.

[0070] This disclosure relates to a method for treating a disorder regulated by RAF kinase, the method comprising administering an effective amount of any of the compounds disclosed herein.

[0071] In one implementation of the treatment method, the disease can be treated by inhibiting one or more Raf kinases. In another implementation, the disease is selected from cancer, sarcoma, melanoma, skin cancer, hematologic malignancy, lymphoma, carcinoma, or leukemia. In the implementation plan, the diseases are selected from Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; bile duct cancer; central nervous system tumors; primary CNS tumors; glioblastoma, astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (tumors originating outside the central nervous system that metastasize to the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancer; squamous cell carcinoma of the head and neck; acute lymphoblastic leukemia; acute myeloid leukemia (AML); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; kidney cancer; metastatic melanoma; or thyroid cancer.

[0072] This disclosure relates to a method of treating cancer, the method comprising administering an effective amount of any of the compounds disclosed herein.

[0073] In an embodiment of a method for treating cancer, the cancer includes at least one mutation of the BRAF kinase. In another embodiment, the cancer includes BRAF... V600E mutation.

[0074] In the implementation plan, the cancer is selected from melanoma, thyroid cancer, Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, bile duct cancer, central nervous system tumors, glioblastoma, astrocytoma, ependymoma, colorectal cancer, colon cancer, gastric cancer, head and neck cancer, hematologic cancer, leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryocyte leukemia, multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, kidney cancer, sarcoma, uveal melanoma, or skin cancer. In the implementation plan, the cancer is BRAF. V600E melanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid carcinoma, BRAF V600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAF V600E Hepatobiliary carcinoma, BRAF V600E Hairy cell leukemia, BRAF V600E Non-small cell carcinoma or BRAFV600E Pilocytic astrocytoma. In the implementation scheme, the cancer is colorectal cancer. Attached Figure Description

[0075] Figure 1 The results for the reaction of compound 1 with P1 and / or P2 are shown with the [(S)-BINAP-RuCl(p-cym)]Cl catalyst at different temperatures and substrate concentrations. (Example 1, Part C).

[0076] Figure 2 The hydrogen absorption record from Endeavor software is shown for the reactions disclosed in Table 10.

[0077] Figure 3A The superposition of hydrogen absorption records from Endeavor software is shown for hydrogenation reactions using different substrate concentrations as disclosed in items 1-2 of Table 11. Figure 3B Show Figure 3A The hydrogen absorption record shows that the line for lower substrate concentrations (Table 11, entry 2) shifts (to the right) over time, aligning the first data point with the reaction at higher substrate concentrations.

[0078] Figure 3C The superposition of hydrogen absorption records from the reactions disclosed in Entries 1-3 of Table 11 is shown, where the lines corresponding to Entries 1 and 2 are shifted over time so that the first data point is aligned with the reaction at a higher substrate concentration.

[0079] Figure 3D The superposition of hydrogen absorption records from the reactions disclosed in entries 1 and 4 of Table 11 is shown, where the line corresponding to entry 4 is shifted over time so that the first data point is aligned with the reaction at a higher substrate concentration.

[0080] Figure 4 The diagram shows a comparison of reaction rates between reactions carried out in a Parr vessel (larger scale) and those carried out in an Endeavor vessel (smaller scale), based on hydrogen absorption records.

[0081] Figure 5 The diagram shows a comparison of reaction rates between reactions carried out in a Parr vessel (larger scale) and those carried out in an Endeavor vessel (smaller scale), based on hydrogen absorption records.

[0082] Figure 6 The diagram shows a comparison of reaction rates using different catalyst loadings (S / C 1,000 / 1 vs. S / C 200 / 1) based on hydrogen absorption records.

[0083] Figure 7 Chiral LCMS chromatograms of compounds A-1 and A-2 are shown.

[0084] Figure 8A The image shows an Ortep image of a single crystal of compound P2 obtained by slow evaporation in acetonitrile. Figure 8B An Ortep image of compound P2 single crystals obtained by slow evaporation in THF / water is shown. Detailed Implementation

[0085] All publications, patents and patent applications (including any figures and appendices therein) are incorporated by full reference for all purposes, as if each individual publication, patent or patent application, figure or appendice were expressly and individually incorporated by full reference for all purposes.

[0086] definition

[0087] While it is believed that those skilled in the art will fully understand the following terms, the following definitions are set forth in order to facilitate the interpretation of the subject matter disclosed herein.

[0088] Throughout this specification, the terms “about” and / or “approximately” may be used in conjunction with numerical values ​​and / or ranges. The term “about” is understood to mean those values ​​close to the stated value. Furthermore, the phrases “less than about [a value]” or “greater than about [a value]” should be understood based on the definition of the term “about” provided herein. The terms “about” and “approximately” are used interchangeably.

[0089] Throughout this specification, numerical ranges are provided for certain quantities. It is important to understand that these ranges include all subranges thereof. Thus, the range "50 to 80" includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values ​​within a given range can be endpoints of the ranges thus encompassed (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[0090] The term "a / an" refers to one or more of the aforementioned entities; for example, "a Raf inhibitor" refers to one or more Raf inhibitors or at least one Raf inhibitor. Therefore, the terms "a / an," "a / an or more / an," and "at least one / an" are used interchangeably herein. Furthermore, "a inhibitor" as referred to by the indefinite article "a / an" does not exclude the possibility of more than one inhibitor, unless the context explicitly requires the presence of exactly one inhibitor.

[0091] As used herein, the verb "comprising" and its variations as used in this specification and claims are used in their non-limiting sense to mean including the substance following the word, but not excluding substances not specifically mentioned. The invention may suitably "comprising" the steps, elements, and / or reagents described in the claims, "consisting of the steps, elements, and / or reagents described in the claims," ​​or "consisting substantially of the steps, elements, and / or reagents described in the claims."

[0092] It should be further noted that the claims can be drafted to exclude any optional elements. Thus, such a statement is intended to serve as a basis for a narrative incorporating the elements of the claims, using exclusive terms such as “alone” or “only”, or employing a “negative” limitation.

[0093] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid via any of a number of known methods.

[0094] The term "treatment" means the relief, reduction, delay, lessening, improvement, or control of one or more symptoms of a subject's disease. The term "treatment" may also mean the suppression, delay of onset (i.e., the period prior to the clinical manifestation of the disease), or reduction of the risk of the development or worsening of the disease.

[0095] The compounds of the present invention, or pharmaceutically acceptable salts thereof, contain at least one asymmetric center. Compounds of the present invention having one asymmetric center produce enantiomers, wherein the absolute stereochemistry can be represented as (R)- and (S)-, or (+) and (-). When compounds of the present invention have more than two asymmetric centers, the compounds may exist as diastereomers or other stereoisomers. This disclosure is intended to include all such possible isomers as well as their racemic and optically pure forms, whether or not they are specifically described herein. Optically active (+) and (-), or (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and stepwise crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain an alkene double bond or other geometrically asymmetric center, and unless otherwise stated, the compounds are intended to include both E and Z geometric isomers. Similarly, it aims to include all tautomer forms.

[0096] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This disclosure covers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0097] "Tautomerism" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomerisms of any of the said compounds.

[0098] "Effective amount" means the amount of the formulation according to the invention that is sufficient to achieve such treatment when administered to a patient in a therapeutic state, condition or disease. "Effective amount" will vary depending on the active ingredient, the state to be treated, the condition or disease and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.

[0099] The term “therapeutically effective” when applied to dosage or amount refers to an amount of a compound or pharmaceutical preparation that, when administered to a patient in need, is sufficient to produce the desired clinical benefit.

[0100] As used herein, "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. Subjects may be suspected of having cancer or at risk of developing cancer, including but not limited to colorectal cancer and melanoma.

[0101] "Mammals" include humans and domesticated animals such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits) as well as non-domesticated animals such as wild animals.

[0102] Unless otherwise noted, all weight percentages mentioned herein (i.e., "by weight %" and "wt.%" and w / w) are measured relative to the total weight of the pharmaceutical composition.

[0103] As used herein, “substantially” or “basically” refers to the complete or nearly complete extent or degree of an effect, characteristic, property, state, structure, substance, or result. For example, a “substantially” closed object would mean that the object is completely or nearly completely closed. In some cases, the exact permissible degree of deviation from absolute completeness may depend on the specific context. However, in general, a closeness to completeness will have the same overall result as achieving absolute and complete completion. The use of “substantially” also applies when used in a negative sense, meaning the complete or nearly complete absence of an effect, characteristic, property, state, structure, substance, or result. For example, a composition “substantially free” of other active agents either has no other active agents at all or almost no other active agents, yet its effect is the same as if it had no other active agents at all. In other words, a composition “substantially free” of a certain ingredient or element or another active agent may still contain that substance, as long as it has no measurable effect.

[0104] The term "halogen" refers to a halogen. In particular, the term refers to fluorine, chlorine, bromine, and iodine.

[0105] "alkyl" or "alkyl group" refers to a fully saturated straight-chain or branched hydrocarbon chain group that is connected to the rest of the molecule by a single bond. This includes alkyl groups containing any number of carbon atoms (including but not limited to 1 to 12). Alkyl groups containing up to 12 carbon atoms are C1-C2. 12 Alkyl groups, which contain up to 10 carbon atoms, are C1-C6. 10 Alkyl groups, specifically those containing up to six carbon atoms (C1-C6 alkyl groups) and those containing up to five carbon atoms (C1-C5 alkyl groups), are further categorized as C1-C5 alkyl groups. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include all the portions described above for C1-C5 alkyl groups, but also include C6 alkyl groups. C1-C 10 Alkyl groups include all the portions described above for C1-C5 and C1-C6 alkyl groups, but also include C7, C8, C9, and C6 alkyl groups. 10 Alkyl group. Similarly, C1-C 12 Alkyl groups include all the foregoing portions, but also include C. 11 and C 12Alkyl group. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specifically stated in the specification, alkyl groups may optionally be substituted.

[0106] "Cycloalkyl" refers to a stable, non-aromatic, fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms. It may include fused or bridged ring systems having three to twenty carbon atoms, preferably three to ten, and is connected to the rest of the molecule by single bonds. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, cycloalkyl groups may optionally be substituted.

[0107] "Halogenated alkyl" refers to an alkyl group as defined above that has been substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specifically stated in the specification, halogenated alkyl groups may optionally be substituted.

[0108] "Aryl" refers to a hydrocarbon ring system group containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of this invention, aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl groups include, but are not limited to, those derived from anthracene, acenaphthene, phenanthrene, anthracene, azulene, benzene, etc. Aryl groups of fluoranthene, fluorene, asymmetric indole, symmetric indole, indene, indene, naphthalene, phenanthene, pleiadene, pyrene, and triphenylene. Unless otherwise specified in the specification, the term "aryl" is intended to include optionally substituted aryl groups.

[0109] "Heterocyclic group," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered ring group consisting of two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclic groups or heterocyclic rings include heteroaryl groups as defined below. Unless otherwise specifically stated in the specification, heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the heterocyclic group may optionally be substituted. In the implementation scheme, the heterocyclic group, heterocyclic ring, or heterocycle is a stable 3- to 20-membered non-aromatic ring group composed of two to twelve carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0110] "Heteroaryl" refers to a 5- to 20-membered ring system group comprising a hydrogen atom, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. For the purposes of this invention, the heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heteroaryl can optionally be oxidized; the nitrogen atom can optionally be quaternized. Examples include, but are not limited to, azaheptatrienyl, acridineyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptatrienyl, 1,4-benzodioxylalkyl, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cenylyl, dibenzofuranyl, dibenzothiopheneyl, furanyl, furanoneyl, isothiazolyl The following groups are listed: imidazole, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indolazinyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazacycloheptatrienyl, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and phenylthio (i.e., thiophene). Unless otherwise specified in the specification, heteroaryl groups may optionally be substituted.

[0111] As used herein, the term "substituted" means any of the aforementioned groups (i.e., alkyl, alkylene, alkenyl, alkenylene, ynyl, alkenylene, alkoxy, alkylamino, alkylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloynyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) wherein at least one hydrogen atom is bonded to a non-hydrogen atom such as, but not limited to, a halogen atom, such as F, C L, Br, and I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiols, thioalkyls, sulfones, sulfonyls, and sulfoxides; nitrogen atoms in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl; and other heteroatoms in various other groups. "Substituted" also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., double or triple bond) with a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by -NR. g R h -NR g C(=O)R h -NR g C(=O)NR g R h -NR g C(=O)OR h -NR g SO2R h -OC(=O)NR g R h -OR g -SR g -SOR g -SO2R g -OSO2R g -SO2OR g =NSO2R g and -SO2NR g R h Substitution. "Substitution also refers to any of the aforementioned groups in which one or more hydrogen atoms are replaced by -C(=O)R g -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NR g Rh Permutation. In the foregoing, R g and R h These groups are identical or different, and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further means any of the above groups in which one or more hydrogen atoms are substituted with a bond of amino, cyano, hydroxyl, imino, nitro, oxo, thio, halo, alkyl, alkenyl, alkynyl, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. Furthermore, each of the above groups may optionally be substituted with one or more of the above groups.

[0112] Compounds of the present invention

[0113] This disclosure relates to pan-RAF inhibitors having the structure of formula (I) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof.

[0114]

[0115] Where R 1 Or R 2 One of them is selected from substituted or unsubstituted: C 1-6 Alkyl, C 1-6 Halogenated alkyl, aryl, heterocyclic or heteroaryl, and another R 1 Or R 2 It is H;

[0116] Alternatively, R 1 and R 2 Together with the atoms they are attached to, they form 5- or 6-membered partially unsaturated or unsaturated rings containing 0, 1, or 2 heteroatoms selected from N, O, or S;

[0117] X 1 Is it N or CR? AA ;

[0118] X 2 Is it N or CR? BB ;

[0119] R 6 It is hydrogen, halogen, alkyl, alkoxy, -NH2, -NR F C(O)R 5 -NR F C(O)CH2R5 -NR F C(O)CH(CH3)R 5 or -NR F R 5 ;

[0120] R 7 R 8 and R 9 Each is independently hydrogen, halogen, or alkyl;

[0121] Alternatively, R 6 and R 8 Or R 7 and R 9 Together with the atoms to which they are attached, they form 5- or 6-membered partially unsaturated or unsaturated rings containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the rings are substituted or unsubstituted.

[0122] R 5 It is a substituted or unsubstituted group selected from alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups; and

[0123] R F Selected from H or C 1-3 alkyl.

[0124] In the implementation scheme, the compound of formula (I) has the following stereochemistry:

[0125]

[0126] In the embodiments, the compound of formula (I) has the stereochemistry shown in formula (Ib).

[0127] In the embodiments of compound (I), R 1 and R 2 Halogenated group, -OR A -NR A R B -SO2R C -SOR C -CN,C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 Cycloalkyl substitution, wherein the alkyl, haloalkyl, and cycloalkyl groups are optionally substituted by one to three independently selected groups from the following: -OR A -CN, -SOR C or -NR A R B ;

[0128] Where R A and R B Each is independently selected from H and C.1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0129] Where R C Selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups.

[0130] In embodiments of compounds of formula (I), (Ia), or (Ib), R 1 Or R 2 One of them is selected from substituted or unsubstituted: phenyl, a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms selected from N, O or S, or a fused bicyclic ring having 8, 9 or 10 ring members. In embodiments of compounds of formula (I), (Ia) or (Ib), R 1 Or R 2 One of them is a phenyl group or a 5,6-membered heteroaryl group containing one or two heteroatoms. In embodiments of compounds of formula (I), (Ia), or (Ib), R 1 Or R 2 One of them is phenyl, pyridinyl, imidazole, pyrazole, or thiophene.

[0131] In embodiments of compounds of formula (I), (Ia), or (Ib), R 1 Or R 2 One of them is a fused bicyclic ring having 8, 9, or 10 ring members, wherein 0, 1, 2, or 3 ring atoms are heteroatoms selected from N, O, or S. In embodiments of compounds of formula (I), (Ia), or (Ib), R 1 Or R 2 One of them is a fused bicyclic ring with 8, 9 or 10 ring members, wherein 0, 1, 2 or 3 ring atoms are heteroatoms selected from N, O or S, and both of the fused rings are aromatic rings, or one ring is an aromatic ring and the other ring is a non-aromatic ring.

[0132] In embodiments of compounds of formula (I), (Ia), or (Ib), R 1 and R 2 Together they form a benzene ring (forming a benzimazole ring with the imidazole ring drawn in formula (I)), wherein the benzene ring is optionally substituted. In embodiments of compounds of formula (I), (Ia), or (Ib), R 1 and R 2 Together they form a 5- or 6-membered ring containing a heteroatom selected from N, S, or O, which may optionally be substituted.

[0133] In embodiments of compounds of formula (I), (Ia), or (Ib), R 6 and R 8Together with the atoms they are attached to, they form 5- or 6-membered partially unsaturated or unsaturated rings containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the rings are substituted or unsubstituted. In an embodiment, R 7 and R 9 Together with the atoms to which they are attached, they form 5- or 6-membered partially unsaturated or unsaturated rings containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the rings are substituted or unsubstituted.

[0134] In embodiments of compounds of formula (I), (Ia), or (Ib), R 6 and R 8 Together with the atoms they are attached to, they form a 5- or 6-membered partially unsaturated or unsaturated ring containing one or two heteroatoms selected from N, O, or S, wherein the ring is substituted or unsubstituted. In embodiments of compounds of formula (I), (Ia), or (Ib), R 6 and R 8 Together with the atoms they are attached to, they form a 5- or 6-membered partially unsaturated or unsaturated ring containing a nitrogen atom as a ring member, wherein the ring is substituted or unsubstituted. In embodiments, the ring is substituted with an oxo group. In embodiments, R 7 and R 9 Both are hydrogen.

[0135] In embodiments of compounds of formula (I), (Ia), or (Ib), R 6 and R 8 Together with the rings they connect to form In the implementation plan, X 2 It is CH;R 7 It is H; and R 6 and R 8 Together with the rings they connect to form

[0136] In embodiments of compounds of formula (I), (Ia), or (Ib), R 6 It is a halogen or a C1-C3 alkyl group. In embodiments of compounds of formula (I), (Ia), or (Ib), R 6 It is -NHC(O)R 5 -NHC(O)CH2R 5 -NHC(O)CH(CH3)R 5 or -NHR 5 .

[0137] In embodiments of compounds of formula (I), (Ia), or (Ib), R 7 R 8 and R 9Each is independently hydrogen or methyl. In embodiments of compounds of formula (I), (Ia), or (Ib), R 7 R 8 and R 9 Each is independently hydrogen.

[0138] In embodiments of compounds of formula (I), (Ia), or (Ib), R 5 It is a substituted or unsubstituted group selected from alkyl, 3-6 membered carbocyclic, phenyl, 3-6 membered heterocyclic, or 5-6 membered heteroaryl. In the embodiments, R 5 It is a substituted or unsubstituted group selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, azacyclobutane, pyrrolidine, piperidine, piperazine, morpholine, pyridine, thiazole, imidazole, pyrazole or triazole.

[0139] In embodiments of compounds of formula (I), (Ia), or (Ib), R F It is H or methyl. In embodiments of compounds of formula (I), (Ia), or (Ib), R F It's H.

[0140] In embodiments of compounds of formula (I), (Ia), or (Ib), X 1 and X 2 One of them is N. In the implementation scheme, X 1 It is N and X 2 It is CH. In the implementation plan, X 2 It is N and X 1 It is CH. In the implementation plan, X 1 and X 2 Both are CH.

[0141] In the implementation scheme, the compound of formula (I) has the structure of formula (II) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof:

[0142]

[0143] Among them, R 3 It is halogen, -OR A -NR A R B -SO2R C -SOR C -CN,C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 Cycloalkyl, wherein the alkyl, haloalkyl, and cycloalkyl groups are optionally substituted by one to three independently selected groups from: -OR A -CN, -SOR C or -NRA R B ;

[0144] Where R A and R B Each is independently selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0145] Where R C Selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0146] n is 0, 1, 2, 3 or 4.

[0147] In the implementation scheme, the compound of formula (II) has the following stereochemistry:

[0148]

[0149] In the embodiments, the compound of formula (II) has the stereochemistry shown in formula (IIb).

[0150] In embodiments of compounds of formula (II), (IIa), or (IIb), n is 0, 1, 2, or 3. In embodiments of compounds of formula (II), (IIa), or (IIb), n is 0, 1, or 2. In embodiments of compounds of formula (II), (IIa), or (IIb), n is 0 or 1. In embodiments of compounds of formula (II), (IIa), or (IIb), n is 1.

[0151] In embodiments of compounds of formula (II), (IIa) or (IIb), R 3 It is halogen, C 1-4 Alkyl group, -SO2(C 1-4 Alkyl group). In embodiments of compounds of formula (II), (IIa) or (IIb), R 3 It is a halogen. In embodiments of compounds of formula (II), (IIa), or (IIb), R 3 It is F.

[0152] In the embodiments, the compound of formula (I) or (II) or its pharmaceutically acceptable salt or tautomer has (S)-stereochemistry at the carbon marked with *. In the embodiments, the compound of formula (I) or (II) having (S)-stereochemistry at the carbon marked with * has an enantiomeric excess of greater than 80% (ee or ee), greater than 85% ee, greater than 90% ee, or greater than 95% ee. In the embodiments, the compound of formula (I) or (II) having (S)-stereochemistry at the carbon marked with * has greater than 80% ee, 81% ee, 82% ee, 83% ee, 84% ee, 85% ee, 86% ee, 87% ee, 88% ee, 89% ee, 90% ee, 91% ee, 92% ee, 93% ee, 94% ee, or 95% ee, including all values ​​in between.

[0153] In the embodiments, the compound of formula (I) or (II) or its pharmaceutically acceptable salt or tautomer has (R)-stereochemistry at the carbon marked with *. In the embodiments, the compound of formula (I) or (II) having (R)-stereochemistry at the carbon marked with * has an enantiomeric excess (ee) greater than 80%, greater than 85%, greater than 90%, or greater than 95%. In the embodiments, the compound of formula (I) or (II) having (R)-stereochemistry at the carbon marked with * has greater than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%, including all values ​​in between.

[0154] In the embodiments, the compounds of formula (I), (Ia), (Ib), (II), (IIa) or (IIb) or their pharmaceutically acceptable salts have a chemical purity of greater than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, including all values ​​in between.

[0155] In one embodiment, the compound of formula (I), (Ia), or (Ib) is selected from Table A, or a pharmaceutically acceptable salt or tautomer thereof. In one embodiment, the compound of formula (Ia) or (Ib) is selected from compounds A-1, A-2, B-1, or B-2, or a pharmaceutically acceptable salt or tautomer thereof.

[0156] Table A

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163] Chiral synthesis of the compounds of this invention

[0164] This disclosure relates to the chiral synthesis of compounds of formula (I), (Ia), (Ib), (II), (IIa) or (IIb) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof.

[0165] In embodiments, the chiral synthesis uses (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid. In embodiments, the (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid used in the chiral synthesis has an enantiomer excess of at least 85%, at least 90%, or at least 95%. In embodiments, the (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid used in the chiral synthesis has an enantiomer excess of about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%, including all values ​​in between.

[0166]

[0167] In embodiments, (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid is prepared from 6-hydroxy-2H-chromen-3-carboxylic acid by chiral hydrogenation as shown in Scheme 1. In embodiments, chiral hydrogenation uses a transition metal catalyst. In embodiments, chiral hydrogenation uses a Ru or Rh catalyst. In embodiments, chiral hydrogenation uses a Ru catalyst selected from Ru(OAc)2, [RuCl2(p-cym)]2, Ru(COD)(Me-allyl)2, or Ru(COD)(TFA)2. In embodiments, the Ru catalyst is selected from [RuCl2(p-cym)]2, Ru(COD)(Me-allyl)2, or Ru(COD)(TFA)2. In n embodiments, chiral hydrogenation uses an Rh catalyst selected from [Rh(COD)2]OTf or [Rh(COD)2]BF4.

[0168] Option 1.

[0169]

[0170] In the embodiments, chiral hydrogenation uses chiral ligands. In the embodiments, chiral phosphine ligands are used. In the embodiments, the chiral ligands are selected from Table B or their opposites (i.e., when Table B lists (S)-PhanePhos, the disclosure explicitly includes the opposite chiral ligand (R)-PhanePhos). In the embodiments, the chiral ligands are selected from Table 4A or Table 5, or their opposites.

[0171] In the implementation scheme, the chiral hydrogenation of scheme 1 uses a combination of (R)-PhanePhos and a catalyst. In the implementation scheme, the chiral hydrogenation of scheme 1 uses a combination of (R)-PhanePhos and a Ru catalyst. In the implementation scheme, the chiral hydrogenation of scheme 1 uses (R)-PhanePhos with [RuCl2(p-cym)]2.

[0172] Table B. Chiral Ligands

[0173]

[0174]

[0175] In embodiments of chiral hydrogenation, the chiral ligand is selected from (S)- or (R)-BINAP, (S)- or (R)-H8-BINAP, (S)- or (R)-PPhos, (S)- or (R)-Xyl-PPhos, (S)- or (R)-PhanePhos, (S)- or (R)-Xyl-PhanePhos, (S,S)-Me-DuPhos, (R,R)-Me-DuPhos, (S,S)-iPr-DuPhos, (R,R)-iPr-DuPhos, (S,S)-NorPhos, (R,R)-NorPhos, (S,S)-BPPM or (R,R)-BPPM, and Josiphos SL-J002-1. In the embodiments, the chiral ligand is (S)- or (R)-PhanePhos or (S)- or (R)-An-PhanePhos. In the embodiments, the chiral ligand is (S)- or (R)-PhanePhos. In the embodiments, the chiral ligand is (R)-PhanePhos.

[0176] In embodiments of chiral hydrogenation, a metal catalyst precursor and a chiral ligand are used to form a chiral metal complex in situ. In embodiments, the metal catalyst precursor is selected from any of the Rh or Ru catalysts disclosed herein, and the chiral ligand is selected from any of the chiral ligands disclosed herein. In embodiments, the metal catalyst precursor is Ru(OAc)₂, [RuCl₂(p-cym)]₂, Ru(COD)(Me-allyl)₂, or Ru(COD)(TFA)₂, and the chiral ligand is (S)- or (R)-PhanePhos or (S)- or (R)-An-PhanePhos. In embodiments, the metal catalyst precursor is [RuCl₂(p-cym)]₂, Ru(COD)(Me-allyl)₂, or Ru(COD)(TFA)₂, and the chiral ligand is (S)- or (R)-PhanePhos. In one embodiment, the metal catalyst precursor and the chiral ligand are used in a ratio ranging from about 1:2 to about 1:1, including all values ​​and ranges therebetween. In another embodiment, the metal catalyst precursor and the chiral ligand are used in a ratio ranging from about 1:1 to about 1:1.5, including all values ​​and ranges therebetween. In yet another embodiment, the metal catalyst precursor and the chiral ligand are used in a ratio of about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, or about 1:1.5.

[0177] In this embodiment, the metal catalyst precursor is [RuCl2(p-cym)]2, and the chiral ligand is (R)-PhanePhos. In this embodiment, the metal catalyst precursor and the chiral ligand are used in a ratio ranging from about 1:2 to about 1:1, including all values ​​and ranges therebetween. In this embodiment, the metal catalyst precursor and the chiral ligand are used in a ratio of about 1:2.

[0178] In this embodiment, the metal catalyst precursor and the chiral ligand are premixed to pre-form a chiral metal complex prior to the initiation of the hydrogenation reaction. In this embodiment, the pre-formed chiral metal complex is selected from [(R)-Phanephos-RuCl2(p-cym)], [(S)-Phanephos-RuCl2(p-cym)], [(R)-An-Phanephos-RuCl2(p-cym)], [(S)-An-Phanephos-RuCl2(p-cym)], [(R)-BINAP-RuCl(p-cym)]Cl, [(S)-BINAP-RuCl(p-cym)]Cl, (R)-BINAP-Ru(OAc)2, (S)-BINAP-Ru(OAc)2, [(R)-Phanephos-Rh(CO)2], etc. [(S)-Phanephos-Rh(COD)]BF4, [(R)-Phanephos-Rh(COD)]OTf, or [(S)-Phanephos-Rh(COD)]OTf. In embodiments, the pre-formed chiral metal complex is [(R)-Phanephos-RuCl2(p-cym)], [(S)-Phanephos-RuCl2(p-cym)], [(R)-An-Phanephos-RuCl2(p-cym)], or [(S)-An-Phanephos-RuCl2(p-cym)]. In embodiments, the pre-formed chiral metal complex is [(R)-Phanephos-RuCl2(p-cym)] or [(S)-Phanephos-RuCl2(p-cym)].

[0179] In the implementation scheme, the metal catalyst precursor and the chiral ligand do not need to be premixed to pre-form a chiral metal complex before the hydrogenation reaction begins.

[0180] In embodiments of chiral hydrogenation, a catalyst loading in the range of about 20 / L (substrate / catalyst = S / C) to about 2,000 / L is used, including all values ​​and ranges therebetween. In embodiments, the catalyst loading (S / C) is in the range of about 25 / L to about 1,000 / L, including all values ​​and ranges therebetween. In embodiments, the catalyst loading (S / C) is in the range of about 200 / L to about 1,000 / L, including all values ​​and ranges therebetween. In embodiments, the catalyst loading (S / C) is about 25 / L, about 50 / L, about 100 / L, about 150 / L, about 200 / L, about 250 / L, about 300 / L, about 350 / L, about 400 / L, about 450 / L, about 500 / L, about 550 / L, about 600 / L, about 650 / L, about 700 / L, about 750 / L, about 800 / L. The catalyst loading (S / C) is in the range of approximately 200 / 1 to approximately 500 / 1, including all values ​​and ranges. In an embodiment, the catalyst loading (S / C) is in the range of approximately 300 / 1 to approximately 350 / 1, including all values ​​and ranges. In an embodiment, the catalyst loading (S / C) is in the range of approximately 320 / 1 to approximately 330 / 1, including all values ​​and ranges.

[0181] In embodiments of chiral hydrogenation, a base is used. In embodiments, the base is selected from amines. In embodiments, the base is selected from triethylamine, NaOMe, or Na₂CO₃. In embodiments, the base is triethylamine. In embodiments, the base is used in ≤2 equivalents relative to 6-hydroxy-2H-chromene-3-carboxylic acid. In embodiments, the base is used in ≤2 equivalents relative to 6-hydroxy-2H-chromene-3-carboxylic acid. In embodiments, the base is used in about 1.5 equivalents relative to 6-hydroxy-2H-chromene-3-carboxylic acid.

[0182] In embodiments of chiral hydrogenation, the base is used in a substoichiometric amount relative to 6-hydroxy-2H-chromoside-3-carboxylic acid. In one embodiment, the base is used in amounts of about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 equivalents relative to 6-hydroxy-2H-chromoside-3-carboxylic acid, including all values ​​in between. In one embodiment, the base is used in amounts of about 0.1 equivalents relative to 6-hydroxy-2H-chromoside-3-carboxylic acid.

[0183] In embodiments of chiral hydrogenation, the reaction is carried out at a temperature ranging from about 25°C to about 70°C, including all values ​​and ranges therebetween. In embodiments of chiral hydrogenation, the reaction is carried out at a temperature ranging from about 25°C to about 70°C, including all values ​​and ranges therebetween. In embodiments of chiral hydrogenation, the reaction is carried out at a temperature ranging from about 30°C to about 40°C, including all values ​​and ranges therebetween. In embodiments of chiral hydrogenation, the reaction is carried out at about 40°C.

[0184] In embodiments of chiral hydrogenation, the substrate concentration ([S], i.e., the concentration of 6-hydroxy-2H-chromene-3-carboxylic acid) is in the range of about 0.01 M to about 5 M, inclusive of all values ​​and ranges therebetween. In embodiments, [S] is in the range of about 0.1 M to about 1 M, inclusive of all values ​​and ranges therebetween. In embodiments, [S] is in the range of about 0.2 M to about 0.8 M, inclusive of all values ​​and ranges therebetween. In embodiments, [S] is about 0.2 M, 0.3 M, 0.4 M, 0.5 M, 0.6 M, 0.7 M, or 0.8 M, inclusive of all values ​​therebetween. In embodiments, [S] is about 0.5 M.

[0185] In embodiments of chiral hydrogenation, the pressure of H2 is in the range of about 1 bar to about 50 bar, inclusive. In embodiments, the pressure of H2 is in the range of about 2 bar to about 30 bar, inclusive. In embodiments, the pressure of H2 is in the range of about 3 bar to about 10 bar, inclusive. In embodiments, the pressure of H2 is in the range of about 5 bar to about 6 bar. In embodiments, the pressure of H2 is about 5 bar.

[0186] In embodiments of chiral hydrogenation, the solvent is a protic solvent. In embodiments of chiral hydrogenation, the solvent is an alcohol solvent. In embodiments of chiral hydrogenation, the solvent is methanol, ethanol, isopropanol, or a fluorinated variant thereof (such as trifluoroethanol). In embodiments of chiral hydrogenation, the solvent is methanol. In embodiments of chiral hydrogenation, the solvent is ethanol.

[0187] In embodiments of chiral hydrogenation, to achieve a high %ee of (S)-6-hydroxychromium-3-carboxylic acid or (R)-6-hydroxychromium-3-carboxylic acid, an inert container free of contaminants is required. In embodiments, to achieve a high %ee of the product, the container should be free of metal deposit contaminants.

[0188] In the embodiment of chiral hydrogenation of Scheme 1, the chiral purity of (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid is greater than about 90%. In the embodiment, the chiral purity of (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid is greater than about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, or about 96%. In the embodiment, the chiral purity of (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid is greater than about 95%.

[0189] In the implementation scheme, the chiral synthesis of compounds of formula (I), (Ia), (Ib), (II), (IIa), or (IIb) or their pharmaceutically acceptable salts, tautomers, or stereoisomers comprises a reaction step labeled Scheme 2A, wherein X 1 X 2 R 6 and R 7 As described in this article.

[0190] Option 2A

[0191]

[0192] In the implementation scheme, the chiral synthesis of compounds of formula (I), (Ia), (Ib), (II), (IIa) or (IIb) or their pharmaceutically acceptable salts, tautomers or stereoisomers includes the reaction step labeled Scheme 2B.

[0193] Option 2B.

[0194]

[0195] In embodiments of scheme 2A or 2B, (S)-6-hydroxychromium-3-carboxylic acid or (R)-6-hydroxychromium-3-carboxylic acid has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0196] In embodiments of scheme 2A or 2B, when (R)-6-hydroxychromium-3-carboxylic acid is used, the stereochemistry of (R)-6-hydroxychromium-3-carboxylic acid is retained in the product (e.g., (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid). In embodiments of scheme 2A or 2B, when (S)-6-hydroxychromium-3-carboxylic acid is used, the stereochemistry of (S)-6-hydroxychromium-3-carboxylic acid is retained in the product (e.g., (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid).

[0197] In embodiments of Scheme 2A or 2B, (R)-6-hydroxysom-3-carboxylic acid is used to provide the product as the (R) isomer. In embodiment of Scheme 2B, (R)-6-hydroxysom-3-carboxylic acid is used to provide (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid. In embodiments, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction Scheme B is within 10% of the chiral purity of the (R)-6-hydroxysom-3-carboxylic acid used in the reaction. In the embodiments, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction scheme B is within 5% of the chiral purity of (R)-6-hydroxysom-3-carboxylic acid used in the reaction. In the embodiments, when prepared from (R)-6-hydroxysom-3-carboxylic acid with a chiral purity greater than 90%, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction scheme B is greater than 90%. In the embodiments, when prepared from (R)-6-hydroxysom-3-carboxylic acid with a chiral purity greater than 95%, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction scheme B is greater than 95%. In the embodiments, when prepared from (R)-6-hydroxysom-3-carboxylic acid with a chiral purity greater than about 98%, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction scheme B is greater than about 98%.

[0198] In embodiments of Scheme 2A or 2B, (S)-6-hydroxysom-3-carboxylic acid is used to provide the product as the (S) isomer. In embodiment of Scheme 2B, (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid is used. In embodiments, the chiral purity of the (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction Scheme B is within 10% of the chiral purity of the (S)-6-hydroxysom-3-carboxylic acid used in the reaction. In the embodiments, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction scheme B is within 5% of the chiral purity of (S)-6-hydroxysom-3-carboxylic acid used in the reaction. In the embodiments, when prepared from (S)-6-hydroxysom-3-carboxylic acid with a chiral purity greater than 90%, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction scheme B is greater than 90%. In the embodiments, when prepared from (S)-6-hydroxysom-3-carboxylic acid with a chiral purity greater than 95%, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction scheme B is greater than 95%. In the embodiments, when prepared from (S)-6-hydroxysom-3-carboxylic acid with a chiral purity greater than about 98%, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by reaction scheme B is greater than about 98%.

[0199] In embodiments of scheme 2A or 2B, an alkali is used. In one embodiment, the alkali is potassium carbonate. In another embodiment, the alkali is tripotassium phosphate (K3PO4).

[0200] In embodiments of scheme 2A or 2B, the reactants are heated to a temperature ranging from about 30°C to about 150°C, including all values ​​and ranges therebetween. In embodiments, the reactants of scheme 2A or 2B are heated to a temperature ranging from about 75°C to about 150°C, including all values ​​and ranges therebetween. In embodiments, the reactants of scheme 2A or 2B are heated to a temperature ranging from about 80°C to about 120°C, including all values ​​and ranges therebetween. In embodiments, the reactants of scheme 2A or 2B are heated to a temperature ranging from about 90°C to about 110°C, including all values ​​and ranges therebetween.

[0201] In the implementation scheme, the chiral synthesis of a compound of formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof includes a reaction step labeled Scheme 3A.

[0202] Option 3A

[0203]

[0204] In an embodiment of scheme 3A, the compound of formula 2A has (R) or (S) stereochemistry at the position marked with *. In an embodiment of scheme 3A, the compound of formula 2A has an enantiomer excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0205] In the implementation scheme, the chiral synthesis of a compound of formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof includes a reaction step labeled Scheme 3B.

[0206] Option 3B.

[0207]

[0208] In the implementation scheme, the chiral synthesis of compounds of formula (II), (IIa) or (IIb) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof includes the reaction step labeled scheme 3C.

[0209] Option 3C.

[0210]

[0211] In embodiments of scheme 3B or 3C, compound 3 has (R) or (S) stereochemistry at the position marked with *. In embodiments of scheme 3A or 3B, compound 3 has an enantiomer excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0212] In embodiments of schemes 3A, 3B, or 3C, the reaction is carried out in the presence of propylphosphonic anhydride (T3P) and N,N-diisopropylethylamine. In embodiments of schemes 3A or 3B, compound 3A may be in salt form, such as hydrochloride. In embodiments of scheme 3C, compound 3B may be in salt form, such as hydrochloride.

[0213] In an implementation scheme of scheme 3C, compound 3B is 2-(4-fluorophenyl)-2-oxoethane-1-ammonium chloride.

[0214] In the implementation scheme, the chiral synthesis of a compound of formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof includes a reaction step labeled Scheme 4A.

[0215] Option 4A

[0216]

[0217] In the implementation scheme, the chiral synthesis of a compound of formula (I), (Ia) or (Ib) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof includes a reaction step labeled Scheme 4B.

[0218] Option 4B

[0219]

[0220] In embodiments of scheme 4A or 4B, the compound of formula 4A has (R) or (S) stereochemistry at the position marked with *. In embodiments of scheme 4A or 4B, the compound of formula 4A has an enantiomer excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0221] In embodiments of scheme 4A or 4B, the stereochemistry of compound 4A is retained in the product. In embodiments of scheme 4A or 4B, when the (S) enantiomer of compound 4A is used, compound (Ia) is obtained. In embodiments of scheme 4A or 4B, when the (R) enantiomer of compound 4A is used, compound (Ib) is obtained.

[0222] In an embodiment, the chiral purity of the compound of formula (Ia) prepared by reaction scheme 4A or 4B is within 10% of the chiral purity of the (S) enantiomer of compound 4A used in the reaction. In an embodiment, the chiral purity of the compound of formula (Ia) prepared by reaction scheme 4A or 4B is within 5% of the chiral purity of the (S) enantiomer of compound 4A used in the reaction. In an embodiment, when prepared from the (S) enantiomer of compound 4A with a chiral purity greater than 90%, the chiral purity of the compound of formula (Ia) prepared by reaction scheme 4A or 4B is greater than 90%. In an embodiment, when prepared from the (S) enantiomer of compound 4A with a chiral purity greater than 95%, the chiral purity of the compound of formula (Ia) prepared by reaction scheme 4A or 4B is greater than 95%. In the implementation scheme, when prepared from the (S) enantiomer of compound 4A with a chiral purity greater than 98%, the chiral purity of compound (Ia) prepared by reaction scheme 4A or 4B is greater than 98%.

[0223] In an embodiment, the chiral purity of the compound of formula (Ib) prepared by reaction scheme 4A or 4B is within 10% of the chiral purity of the (R) enantiomer of compound 4A used in the reaction. In an embodiment, the chiral purity of the compound of formula (Ib) prepared by reaction scheme 4A or 4B is within 5% of the chiral purity of the (R) enantiomer of compound 4A used in the reaction. In an embodiment, when prepared from an enantiomer of compound 4A with a chiral purity greater than 90%, the chiral purity of the compound of formula (Ib) prepared by reaction scheme 4A or 4B is greater than 90%. In an embodiment, when prepared from an enantiomer of compound 4A with a chiral purity greater than 95%, the chiral purity of the compound of formula (Ib) prepared by reaction scheme 4A or 4B is greater than 95%. In the implementation scheme, when prepared from the (R) enantiomer of compound 4A with a chiral purity greater than 98%, the chiral purity of compound (Ib) prepared by reaction scheme 4A or 4B is greater than 98%.

[0224] In embodiments 4A or 4B, the reaction is carried out in the presence of ammonia or an ammonium salt. In these embodiments, the ammonium salt is ammonium acetate, ammonium trifluoroacetate, ammonium carbonate, ammonium bicarbonate, or ammonium chloride. In some embodiments, the ammonium salt is ammonium acetate. In embodiments 4A or 4B, the reaction is carried out in the presence of NH4OAc. In embodiments 4A or 4B, the reaction is carried out in acetic acid. In embodiments 4A or 4B, the reaction is carried out at a temperature ranging from about 30°C to about 150°C, including all values ​​and ranges therebetween. In embodiments 4A or 4B, the reaction is carried out at a temperature ranging from about 60°C to about 120°C, including all values ​​and ranges therebetween. In embodiments 4A or 4B, the reaction is carried out at a temperature ranging from about 80°C to about 100°C, including all values ​​and ranges therebetween. In embodiments 4A or 4B, the reaction is carried out at a temperature of about 90°C.

[0225] In the implementation scheme, the chiral synthesis of compounds of formula (II), (IIa) or (IIb) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof includes the reaction step labeled Scheme 4C.

[0226] Option 4C.

[0227]

[0228] In an embodiment of scheme 4C, the compound of formula 4B has (R) or (S) stereochemistry at the position marked with *. In an embodiment of scheme 4C, the compound of formula 4B has an enantiomer excess of at least 85%, at least 90%, or at least 95%.

[0229] In an embodiment of scheme 4C, the stereochemistry of compound 4B is retained in the product. In an embodiment of scheme 4C, when the (S) enantiomer of compound 4B is used, compound (IIa) is obtained. In an embodiment of scheme 4C, when the (R) enantiomer of compound 4B is used, compound (IIb) is obtained.

[0230] In one embodiment, the chiral purity of the compound of formula (IIa) prepared by reaction 4C is within 10% of the chiral purity of the (S) enantiomer of compound 4B used in the reaction. In another embodiment, the chiral purity of the compound of formula (IIa) prepared by reaction 4C is within 5% of the chiral purity of the (S) enantiomer of compound 4B used in the reaction. In another embodiment, when prepared from the (S) enantiomer of compound 4B with a chiral purity greater than 90%, the chiral purity of the compound of formula (IIa) prepared by reaction 4C is greater than 90%. In another embodiment, when prepared from the (S) enantiomer of compound 4B with a chiral purity greater than 95%, the chiral purity of the compound of formula (IIa) prepared by reaction 4C is greater than 95%. In another embodiment, when prepared from the (S) enantiomer of compound 4B with a chiral purity greater than 98%, the chiral purity of the compound of formula (IIa) prepared by reaction 4C is greater than 98%.

[0231] In one embodiment, the chiral purity of the compound of formula (IIb) prepared by reaction 4C is within 10% of the chiral purity of the (R) enantiomer of compound 4B used in the reaction. In another embodiment, the chiral purity of the compound of formula (IIb) prepared by reaction 4C is within 5% of the chiral purity of the (R) enantiomer of compound 4B used in the reaction. In another embodiment, when prepared from the (R) enantiomer of compound 4B with a chiral purity greater than 90%, the chiral purity of the compound of formula (IIb) prepared by reaction 4C is greater than 90%. In another embodiment, when prepared from the (R) enantiomer of compound 4B with a chiral purity greater than 95%, the chiral purity of the compound of formula (IIb) prepared by reaction 4C is greater than 95%. In another embodiment, when prepared from the (R) enantiomer of compound 4B with a chiral purity greater than 98%, the chiral purity of the compound of formula (IIb) prepared by reaction 4C is greater than 98%.

[0232] In an embodiment of Scheme 4C, the reaction is carried out in the presence of ammonia or an ammonium salt. In an embodiment, the ammonium salt is ammonium acetate, ammonium trifluoroacetate, ammonium carbonate, ammonium bicarbonate, or ammonium chloride. In an embodiment of Scheme 4C, the reaction is carried out in the presence of NH4OAc. In an embodiment of Scheme 4C, the reaction is carried out in acetic acid. In an embodiment of Scheme 4C, the reaction is carried out at a temperature ranging from about 30°C to about 150°C, including all values ​​and ranges therebetween.

[0233] In an embodiment, the chiral synthesis of a compound of formula (I), (Ia), or (Ib) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof includes performing the reaction of scheme 1 and the reaction of scheme 2A. In an embodiment, the chiral synthesis of a compound of formula (I), (Ia), or (Ib) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof includes performing the reactions of scheme 1, scheme 2A, and scheme 3A. In an embodiment, the chiral synthesis of a compound of formula (I), (Ia), or (Ib) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof includes performing the reactions of scheme 1, scheme 2A, scheme 3A, and scheme 4A.

[0234] In the implementation scheme, chiral synthesis of compounds of formula (I), (Ia), or (Ib), or their pharmaceutically acceptable salts, tautomers, or stereoisomers, including one or more of the reactions of scheme 1, scheme 2A, scheme 3A, or scheme 4A, before, after, and / or between them, is not excluded. For example, between the reactions of scheme 2A and scheme 3A, another reaction may occur to further functionalize the N-aryl ring, as shown in scheme 5 below. Scheme 5 illustrates, for example, the reaction in R 6 Within the definition, substituent R 6 The reaction is further functionalized.

[0235] Option 5

[0236]

[0237] In the implementation scheme, R in compound 2A of scheme 2A 6 R 7 R 8 and / or R 9 Unlike R in compound 2A of scheme 3A 6 R 7 R 8 and / or R 9 In the implementation scheme, R in compound 4A of scheme 3A... 6 R 7 R 8 and / or R 9 Unlike R in compound 4A of scheme 4A 6 R 7 R 8 and / or R 9 In the implementation scheme, R in compound 4A of scheme 3B 1 Unlike R in compound 4A of scheme 4B 1 In the implementation scheme, R in compound 4A of scheme 3C 3 Unlike R in compound 4A of scheme 4C3 .

[0238] In the embodiments, the chiral synthesis of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts, tautomers, or stereoisomers includes performing the reaction of scheme 1 and the reaction of scheme 2B. In the embodiments, the chiral synthesis of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts, tautomers, or stereoisomers includes performing the reactions of scheme 1, scheme 2B, and scheme 3B. In the embodiments, the chiral synthesis of compounds of formula (I), (Ia), or (Ib) or their pharmaceutically acceptable salts, tautomers, or stereoisomers includes performing the reactions of scheme 1, scheme 2B, scheme 3B, and scheme 4B.

[0239] In an embodiment, the chiral synthesis of a compound of formula (II), (IIa), or (IIb) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof includes performing the reaction of scheme 1 and the reaction of scheme 2B. In an embodiment, the chiral synthesis of a compound of formula (II), (IIa), or (IIb) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof includes performing the reactions of scheme 1, scheme 2B, and scheme 3C. In an embodiment, the chiral synthesis of a compound of formula (II), (IIa), or (IIb) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof includes performing the reactions of scheme 1, scheme 2B, scheme 3C, and scheme 4C.

[0240] In the embodiments, the chiral synthesis of compounds of formula (I), (Ia), (Ib), (II), (IIa) or (IIb) provides a compound having an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0241] In an embodiment, the chiral synthesis of a compound of formula (I) or (II) provides a compound having (R) or (S) stereochemistry at a carbon marked with *, said compound having a value greater than: 80%ee, 81%ee, 82%ee, 83%ee, 84%ee, 85%ee, 86%ee, 87%ee, 88%ee, 89%ee, 90%ee, 91%ee, 92%ee, 93%ee, 94%ee, 95%ee, 96%ee, 97%ee, or 98%ee, including all values ​​in between.

[0242] In embodiments, the chiral synthesis of compounds of formula (Ia), (Ib), (IIa), or (IIb) provides compounds having a value greater than: 80%ee, 81%ee, 82%ee, 83%ee, 84%ee, 85%ee, 86%ee, 87%ee, 88%ee, 89%ee, 90%ee, 91%ee, 92%ee, 93%ee, 94%ee, 95%ee, 96%ee, 97%ee, or 98%ee, including all values ​​in between.

[0243] In embodiments, the chiral synthesis disclosed herein can be used to prepare stereoisomers of the compounds disclosed in U.S. Patent No. 10,183,939, which is hereby incorporated by reference. In embodiments, the compounds disclosed in U.S. Patent No. 10,183,939 can be prepared as (S) or (R) stereoisomers using the chiral synthesis disclosed herein. In embodiments, the compounds disclosed in U.S. Patent No. 10,183,939 can be prepared as (S) or (R) stereoisomers having at least 85% ee using the chiral synthesis disclosed herein.

[0244] This disclosure also relates to compounds of formula (I), (Ia), (Ib), (II), (IIa) or (IIb) or pharmaceutically acceptable salts, tautomers or stereoisomers thereof prepared according to any of the methods disclosed herein.

[0245] Therapeutic uses

[0246] This disclosure also relates to methods of treating various diseases and disorders using compounds of formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof. In embodiments, compounds of formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, can be used to treat diseases or disorders associated with abnormal activity of one or more Raf kinases. In embodiments, compounds of formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, can be used to treat diseases or disorders that can be treated by inhibiting one or more Raf kinases. RAF kinase inhibition is associated with the treatment of many different diseases related to abnormal activity of the MAPK pathway. In embodiments, disorders can be treated by inhibiting RAF kinases such as B-RAF or C-RAF.

[0247] In the implementation plan, the disease or ailment is cancer. In the implementation plan, the disease or ailment is selected from Barrett's adenocarcinoma; bile duct cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma, astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (tumors originating outside the central nervous system that metastasize to the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancer; squamous cell carcinoma of the head and neck; acute lymphoblastic leukemia; acute myeloid leukemia (AML); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryocyte leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; kidney cancer; metastatic melanoma; or thyroid cancer.

[0248] In the implementation plan, the disease or ailment is melanoma, non-small cell carcinoma, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer, or bile duct cancer. In the implementation plan, the disease or ailment is colorectal cancer. In the implementation plan, the disease or ailment is melanoma.

[0249] In the implementation plan, the disease or ailment includes BRAF. V600E Mutated cancer. In the implementation plan, the disease or ailment is addressed via BRAF. V600E Regulation. In the implementation plan, the disease or ailment is BRAF. V600E melanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid carcinoma, BRAF V600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAF V600E Hepatobiliary carcinoma, BRAF V600E Hairy cell leukemia, BRAF V600E Non-small cell carcinoma or BRAF V600E Pilocytic astrocytoma.

[0250] In the implementation plan, the disease or ailment is cardiofacial skin syndrome and polycystic kidney disease.

[0251] Pharmaceutical Composition

[0252] This disclosure also relates to pharmaceutical compositions comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. This disclosure also relates to pharmaceutical compositions comprising a compound of formula (Ia), (Ib), (IIa), or (IIb) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0253] In this embodiment, the pharmaceutical composition may also contain additional pharmaceutically active agents. These additional pharmaceutically active agents may be antitumor agents.

[0254] In the implementation scheme, the additional pharmaceutically active agent is an antiproliferative / antitumor drug. In the implementation scheme, the antiproliferative / antitumor drug is an alkylating agent (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolate agents such as fluoropyrimidines, such as 5-fluorouracil and nitrofluoridine, raltitrexate, methotrexate, pemetrexed, cytarabine, and hydroxyurea); antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, doxorubicin, epididymitis, etc.). Rubicin, idarubicin, mitomycin-C, styromycin, and styromycin; antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as taxol and paclitaxel, and polo-like kinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; or topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, acridine, topotecan, mitoxantrone, and camptothecin).

[0255] In the implementation scheme, the additional pharmaceutically active agent is a cell growth inhibitor. In the implementation scheme, the cell growth inhibitor is an anti-estrogen (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), an anti-androgen (e.g., bicalutamide, flutamide, nilumethoxazole, and cyproterone acetate), an LHRH antagonist or LHRH agonist (e.g., goserelin, leuprorelin, and buserelin), a progestin (e.g., megestrol acetate), an aromatase inhibitor (e.g., anastrozole, letrozole, vorazole, and exemestane), or a 5α-reductase inhibitor such as finasteride.

[0256] In the implementation plan, the additional pharmaceutical active agent is an anti-invasive agent. In the implementation plan, the anti-invasive agent is dasatinib and bosutinib (SKI-606), a metalloproteinase inhibitor or a urokinase plasminogen activator receptor function inhibitor, or an antibody against heparanase.

[0257] In the implementation scheme, the additional pharmaceutical active agent is a growth factor function inhibitor. In the implementation scheme, the growth factor function inhibitor is a growth factor antibody and a growth factor receptor antibody (e.g., the anti-erbB2 antibody trastuzumab [Herceptin]). TM Anti-EGFR antibody palumumab, anti-erbB1 antibody cetuximab); tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI) 1033), ERB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; regulators of protein regulatory factors of apoptosis (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., Ras / RAF signaling inhibitors such as farnesyltransferase inhibitors, such as sorafenib, tilpifanib, and lonafanib); inhibitors of cell signaling via MEK and / or AKT kinases; c-kit inhibitors; abl kinase inhibitors; PI3 kinase inhibitors; Plt3 kinase inhibitors; CSF-1R kinase inhibitors; IGF receptor kinase inhibitors; aurora kinase inhibitors or cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors.

[0258] In the implementation scheme, another pharmaceutically active agent is an anti-angiogenic agent. In the implementation scheme, the anti-angiogenic agent inhibits the action of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin). TM Thalidomide; Lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalani, sunitinib, axitinib, and pazopanib.

[0259] In the implementation scheme, the additional pharmaceutically active agent is cIn, and the cytotoxic agent is fludarabine, cladribine, or pentostatin. TM ).

[0260] In the implementation plan, the additional pharmaceutically active agent is a steroid. In the implementation plan, the steroid is a corticosteroid, including glucocorticoids and mineralocorticoids, such as aclometasone, aclometasone dipropionate, aldosterone, ancinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasone propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycorticosterone, desonide, desoxymethasone, dexamethasone sodium phosphate, isonicotinic acid dexamethasone, diflucolone, fluchlorloron, flumethasone, flunisolone, fluocinolone acetate. (acetonide), fluocinonide, butyl methacrylate, fluorocortisone, fluorocortolone, flucortolone hexanoate, flucortolone neopentanoate, flumethrin, fluprednisolone, fluprednisolone acetate, fluticasone, fluticasone propionate, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate-propionate, hydrocortisone propionate-butionate, hydrocortisone valerate, icometasone, icometasone acetate-butionate, methylprednisolone, methylprednisolone, peramisone-mometasone, mometasone furoate monohydrate, prednicarbamate, prednisolone, prednisone, tecortisone, tecortisone neopentanoate, triamcinolone, triamcinolone acetonide, triamcinolone acetonide, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, for example, combinations of two or more types of steroids as described herein.

[0261] In the implementation scheme, the additional pharmaceutically active agent is a targeted therapeutic agent. In the implementation scheme, the targeted therapeutic agent is a PI3Kd inhibitor, such as idelalisib and perifoxine.

[0262] In the implementation plan, the additional pharmaceutical active agent is an immunotherapeutic agent. Specifically, the immunotherapeutic agent is an antibody therapeutic agent, such as alemtuzumab, rituximab, or tiimomab. And ofumab; interferons, such as interferon-alpha; interleukins, such as IL-2 (aldeleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines, such as HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); Toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and PD-1 antagonists, PDL-1 antagonists, and IDO-1 antagonists.

[0263] In one embodiment, the pharmaceutical composition may be used in combination with another therapy. In another embodiment, the other therapy is gene therapy, including methods such as replacing abnormal genes like abnormal p53 or abnormal BRCA1 or BRCA2.

[0264] In the implementation plan, other therapies are immunotherapy methods, including, for example, antibody therapies such as alemtuzumab, rituximab, and tiemomalidumab. And ofumab; interferons, such as interferon-alpha; interleukins, such as IL-2 (aldeleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines, such as HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); Toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and PD-1 antagonists, PDL-1 antagonists, and IDO-1 antagonists.

[0265] The compounds of the present invention may exist in a single crystalline form or a mixture of multiple crystalline forms, or they may be amorphous. Therefore, the compounds of the present invention intended for pharmaceutical use may be administered as crystalline or amorphous products. The compounds may be obtained, for example, in the form of solid plugs, powders, or films, by methods such as precipitation, crystallization, freeze-drying, or spray drying or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[0266] The dosage of the compounds of the present invention will naturally vary depending on the compound used, the method of administration, the desired treatment, and the indicated condition. For example, if the compounds of the present invention are administered orally, the daily dose of the compounds of the present invention may be in the range of 0.01 micrograms / kg body weight (μg / kg) to 100 milligrams / kg body weight (mg / kg).

[0267] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used alone, but are generally administered in the form of pharmaceutical compositions wherein the compounds of the present invention or pharmaceutically acceptable salts thereof are associated with pharmaceutically acceptable adjuvants, diluents or carriers. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals—The Science of Dosage Form Designs”, MEAulton, Churchill Livingstone, 1988.

[0268] According to the method of administration of the compound of the present invention, the pharmaceutical composition for administering the compound of the present invention will preferably contain 0.05% w to 99% w (weight percentage) of the compound of the present invention, more preferably 0.05% w to 80% w (weight percentage) of the compound of the present invention, still more preferably 0.10% w to 70% w of the compound of the present invention, and even more preferably 0.10% w to 50% w of the compound of the present invention, all weight percentages being based on the total composition.

[0269] The pharmaceutical composition may be applied topically (e.g., to the skin) or systemically, for example, in the form of cream, gel, lotion, solution, or suspension; or orally in the form of tablets, capsules, syrup, powder, or granules; or parenterically (including intravenous, subcutaneous, intramuscular, intravascular, or infusion) in the form of a sterile solution, suspension, or emulsion for injection; or rectally in the form of a suppository; or inhaled as an aerosol.

[0270] For oral administration, the compounds of the present invention can be mixed with adjuvants or carriers, such as lactose, sucrose, sorbitol, mannitol; starches, such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, etc., and then compressed into tablets. If coated tablets are desired, the core prepared as described above can be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide. Alternatively, the tablets can be coated with a suitable polymer dissolved in a volatile organic solvent.

[0271] To prepare soft gelatin capsules, the compounds of the present invention can be mixed with, for example, vegetable oils or polyethylene glycol. Hard gelatin capsules may contain particles of compounds using the excipients described above for tablets. Liquid or semi-solid formulations of the compounds of the present invention may also be filled into hard gelatin capsules. Liquid formulations for oral application may be in the form of syrups or suspensions, such as solutions containing the compounds of the present invention, with the balance being sugar and a mixture of ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain colorants, flavoring agents, sweeteners (such as saccharin), preservatives, and / or carboxymethyl cellulose as thickeners or other excipients known to those skilled in the art.

[0272] For intravenous (parenteral) administration, the compounds of this invention can be administered in sterile aqueous or oily solutions.

[0273] Pharmaceutical compositions can be prepared as liposomes and encapsulated therapeutic agents. Various methods for preparing liposomes and encapsulating therapeutic agents are described, for example, in U.S. Patent Nos. 3,932,657, 4,311,712, 4,743,449, 4,452,747, 4,830,858, 4,921,757, and 5,013,556. Known methods include the reverse-phase evaporation method described in U.S. Patent No. 4,235,871. Furthermore, U.S. 4,744,989 covers the use of liposomes and methods of preparing them for improving the efficiency or delivery of therapeutic compounds, pharmaceuticals, and other agents.

[0274] The compounds of this invention can be passively or actively loaded into liposomes. Active loading is typically accomplished using a pH (ion) gradient or by using encapsulated metal ions. For example, pH gradient loading can be performed according to the methods described in U.S. Patent Nos. 5,616,341, 5,736,155, 5,785,987, and 5,939,096. Furthermore, liposome loading using metal ions can be performed according to the methods described in U.S. Patent Nos. 7,238,367 and 7,744,921.

[0275] The inclusion of cholesterol in liposome membranes has been shown to reduce drug release and / or increase stability after intravenous administration (see, for example, U.S. Patent Nos. 4,756,910, 5,077,056, and 5,225,212). Low-cholesterol liposome membranes containing continuously charged lipids have been shown to provide cryogenic stability and increase circulation after intravenous administration (see, for example, U.S. Patent No. 8,518,437).

[0276] Pharmaceutical compositions may contain nanoparticles. The formation of nanoparticles has been achieved by various methods. Nanoparticles can be prepared by precipitating molecules in an aqueous miscible solvent, followed by drying and pulverizing the precipitate to form nanoparticles (US Patent No. 4,726,955). Similar techniques for preparing nanoparticles for pharmaceutical formulations include wet milling or grinding. Other methods involve mixing a low concentration of polymer dissolved in an aqueous miscible solution with an aqueous phase to alter the local charge of the solvent and forming a precipitate using conventional mixing techniques (US Patent No. 5,766,635). Other methods involve mixing a copolymer in an organic solution with an aqueous phase containing a colloidal protectant or a surfactant for reducing surface tension. Other methods for incorporating additive therapeutic agents into nanoparticles for drug delivery require treating the nanoparticles with liposomes or surfactants prior to drug administration (US Patent No. 6,117,454). Nanoparticles can also be prepared by rapid nanoprecipitation (US Patent No. 8,137,699).

[0277] U.S. Patent No. 7,850,990 covers a combination of screening agents and a method of encapsulating the combination in a delivery medium such as liposomes or nanoparticles.

[0278] Based on well-known medical principles, the dosage of the compounds of this invention for therapeutic purposes will naturally vary depending on the nature and severity of the disease, the age and sex of the animal or patient, and the route of administration.

[0279] The dosage levels, frequency of dosing, and duration of treatment of the compounds of this invention are expected to vary depending on the formulation and the patient's clinical indications, age, and comorbid medical conditions. For most clinical indications, the standard duration of treatment with the compounds of this invention is expected to vary between 1 and 7 days. In cases of recurrent infections or infections associated with poorly vascularized tissues or implanted materials (including bone / joint, respiratory, endocardial, and dental tissues), the duration of treatment may need to be extended beyond seven days.

[0280] Example

[0281] S

[0282] As used herein, the following terms have the given meanings: “Boc” refers to tert-butoxycarbonyl; “Cbz” refers to carboxybenzyl; “dba” refers to dibenzylacetone; “DCM” refers to dichloromethane; “DIPEA” refers to N,N-diisopropylethylamine; “DMA” refers to dimethylacetamide; “DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “dppf” refers to 1,1'-bis(diphenylphosphine)ferrocene; “EtOAc” refers to ethyl acetate; “EtOH” refers to ethanol; “Et2O” refers to diethyl ether; “IPA” refers to isopropanol; “LiHMDS” "MeCN" refers to bis(trimethylsilyl)aminolithium; "mCPBA" refers to m-chloroperoxybenzoic acid; "MeCN" refers to acetonitrile; "MeOH" refers to methanol; "min" refers to minutes; "NMR" refers to nuclear magnetic resonance; "PhMe" refers to toluene; "pTsOH" refers to p-toluenesulfonic acid; "py" refers to pyridine; "rt" refers to room temperature; "SCX" refers to strong cation exchange; "T3P" refers to propylphosphonic anhydride; "Tf2O" refers to trifluoromethanesulfonic anhydride; "THF" refers to tetrahydrofuran; "THP" refers to 2-tetrahydropyranyl; "(UP)LC-MS" refers to (ultra-high performance) liquid chromatography / mass spectrometry. Unless otherwise specified, solvents, reagents, and starting materials were purchased from commercial suppliers and used as is. Unless otherwise specified, all reactions were carried out at room temperature.

[0283] In Examples 3, 6, and 7, compound identification and purity were confirmed by LC-MS UV using a Waters Acquity SQ detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254 nm, and the MS was performed in positive and negative electrospray modes (m / z: 150-800). Two μL aliquots were sequentially injected into a guard column (0.2 μm x 2 mm filter) and a UPLC column (C18, 50 x 2.1 mm, <2 μm) maintained at 40 °C. The samples were eluted at a flow rate of 0.6 mL / min according to the gradient outlined below, where the mobile phase consisted of A (0.1% (v / v) aqueous formic acid) and B (0.1% (v / v) MeCN solution of formic acid). Retention times (RT) were reported in minutes.

[0284]

[0285]

[0286] NMR was also used to characterize the final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay instrument with a 5 mm BBFO probe. Optionally, the Rf values ​​of the compounds on silica thin-layer chromatography (TLC) plates were measured. The identification and purity confirmation of the compounds in the remaining examples are described in the examples.

[0287] Compound purification was performed by rapid column chromatography on silica or by preparative LC-MS. LC-MS purification was performed using a Waters 3100 mass detector in positive and negative electrospray mode (m / z: 150-800) with a Waters 2489 UV / Vis detector. Samples were then purified using Xbridge. TM Elution was performed on a prep C18 5μM OBD 19x100mm column at a flow rate of 20 mL / min according to the gradient outlined below, wherein the mobile phase system consisted of A (0.1% (v / v) aqueous formic acid) and B (0.1% (v / v) MeCN solution of formic acid):

[0288] Time (min) ％A ％B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 15 90 90

[0289] Chemical names in this literature were generated using the mol 2nam– structure-to-name conversion function in OpenEye Scientific Software. Starting materials were purchased from commercial sources or synthesized according to literature procedures.

[0290] The invention has been generally described and disclosed, and will be more readily understood with reference to the following embodiments, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0291] Example 1. Optimization of enantioselective olefin reduction

[0292]

[0293] General procedure:

[0294] Weigh the pre-formed catalyst (4 μmol, substrate / catalyst 25 / 1) or metal precursor (4 μmol metal, S / C 25 / 1) and ligand (4.8 μmol, metal:ligand, 1:1.2) into an Endeavour vial. Add a solution (2 mL, [S] = 0.05 M) of the substrate (19.2 mg, 0.1 mmol) as the specified solvent to each vial. If used, add triethylamine (14 μL, 0.1 mmol, 1 equivalent) to the relevant vial. Transfer the vials to Endeavour, seal Endeavour and set it to stir at 650 rpm, purged 5 times with nitrogen, purged 5 times with hydrogen, and heated to the specified temperature at 30 bar H2. After 16 hours, exhaust Endeavour and purge with nitrogen. Dilute approximately 0.1 mL of the sample from each reaction to approximately 1 mL with MeOH for supercritical fluid chromatography (SFC) analysis. The percentage of each reactant component is measured by integrating all SFC chromatographic peaks and reporting the percentage of each component as identified, such as by comparing the retention time of a reference sample. The percentage of remaining unidentified peaks relative to the total peak area is summarized as "Other". Enantiomer excess of the major product peak is determined by the peak area ratio of the product peaks in the SFC chromatogram.

[0295] SFC method

[0296] Column: Chiralpak IC-3, 4.6 x 250 mm, 3 μM

[0297] Mobile phase: A: CO2; B: 100% methanol

[0298] Injection volume: 3μL

[0299] Total time: 10 minutes

[0300] Detector: 203nm

[0301] Column temperature 40℃

[0302] Sample diluent: methanol

[0303] Flow rate: 2.0 mL / min

[0304]

[0305] Retention time of starting material (SM) = 5.6 min

[0306] The retention time of the first elution product (P2) was 5.8 min.

[0307] The retention time of the second elution product (P1) was 6.1 min.

[0308] A. Catalyst Screening

[0309] Selected catalysts with literature priority in enantioselective olefin reduction were tested in common solvents: MeOH and THF, with and without 1 equivalent of triethylamine, which has been shown to facilitate the successful hydrogenation of other acid substrates in such reactions (Table 1).

[0310] Table 1. Catalyst screening at 70 °C – S / C 25 / 1, [S] = 0.05 M, 70 °C, 30 bar H2, 16 hours

[0311]

[0312]

[0313] Items 1 and 6 in Table 1 result in ≥90% ee. Item 6, in particular, uses (S)-Phanephos and [RuCl2(p-cym.)]2 (forming an in-situ chiral catalyst) in the presence of triethylamine and methanol solvent to provide high conversion (93% P1, 5% P2; total conversion 98%) and high %ee (90%).

[0314] In both MeOH and THF, triethylamine was observed to promote complete conversion for all catalysts. However, in some cases, it was also thought to reduce %ee. Results in MeOH were generally better than those in THF.

[0315] B. Solvent and Temperature Screening

[0316] The effects of varying solvent and temperature on the catalyst system were tested in the presence of 1 equivalence of triethylamine: (S)-Phanephos with [RuCl2(p-cym)]2, which yielded 90% ee and 98% product conversion in the initial catalyst screening (Table 1). Background reaction studies were conducted in the absence of the ligand (Table 2, entry 1). This indicates that significant hydrogenation (70% product) occurred under ligand-free conditions, but with very low enantioselectivity. This suggests that the formation of chiral ligand-metal complexes is crucial for achieving high enantioselectivity. Using a slightly excess of ligand (Table 1, entry 6), thereby allowing a premix of the ligand and metal precursor, or using a pre-formed complex, ensures the formation of chiral ligand-metal complexes.

[0317] Solvents EtOH and IPA do not appear to offer any advantage over MeOH, as the results show %ee values ​​decreasing in the following order: MeOH, EtOH, IPA (Table 2, compare entries 2-4 or 5-7).

[0318] Lowering the temperature from 70°C to 50°C resulted in a slight improvement in enantioselectivity while maintaining complete conversion. The best result was achieved at 50°C with 93% ee in MeOH (entry 5). Further lowering the temperature to 30°C showed no further improvement (entry 8).

[0319] Table 2. Solvent and temperature screening using 1 equivalent of triethylamine – S / C 25 / 1, [S] = 0.05 M, 1 equivalent of NEt3, 30 bar H2, 16 hours

[0320]

[0321] C. Pre-formed catalyst screening

[0322] Two different pre-formed catalysts containing Phanephos ligands were tested to see if further improvements in enantioselectivity could be obtained when using pre-formed catalysts instead of in-situ ligands and metal precursors (Table 3). The Ru-BINAP pre-formed catalyst was also tested at a higher substrate concentration than previously tested at 0.05 M in the initial catalyst screening.

[0323] The pre-formed [(R)-Phanephos RuCl2(p-cym)] catalyst yielded results similar to those obtained from the in-situ reaction (Table 3, item 1 can be compared with Table 1, item 6: 90% ee). Therefore, there was no significant improvement in the use of the pre-formed form with this ligand-metal combination under these reaction conditions.

[0324] Alternative pre-formed catalysts [(S)-Phanephos Ru(CO)Cl2(dmf)] have been found to improve results for similar reaction types; however, this is not the case for this reaction (entries 2 and 6).

[0325] Results from tests using [(S)-BINAP-RuCl(p-cym)]Cl indicate the absence of a linear trend with respect to substrate concentration, conversion, and enantioselectivity; therefore, a trade-off appears to exist between achieving high conversion or high enantioselectivity under these conditions. Figure 1For example, a very high ee of 97% was achieved, but the conversion rate was low, with 63% of the starting material remaining (entry 4). However, the accuracy of this ee value is uncertain due to overlap with impurities. Generally, under these conditions, 70°C produces better conversion and a higher ee compared to 50°C.

[0326] Table 3. Test results for pre-formed catalysts (S / C 25 / 1, [S] = 0.05-0.2 M, MeOH, 30 bar H2, 16 hours)

[0327]

[0328]

[0329] D. Ligand screening using ruthenium catalysts

[0330] A series of chiral ligands with different spatial and electronic properties were tested on a small scale using [RuCl2(p-cym)]2 as a precursor (Table 4A). Ligands (1 μmol) were weighed into CAT-24 vials. Stock solutions of [RuCl2(p-cym)]2 (0.83 μmol of metal, S / C 25 / 1), substrate (21 μmol), and triethylamine (21 μmol, 1 equivalent) were prepared and 0.25 mL were added to each vial ([S] = 0.084 M). A stir bar was added to each vial. CAT-24 was sealed and purged 5 times with nitrogen and 5 times with hydrogen (stirring between each cycle) and set to 800 rpm stirring and heated to 75 °C at 20 bar H2 (internal temperature estimated to be 5 °C lower). After 18 hours, CAT-24 was purged and purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis.

[0331] All reactions showed near or complete inversion, making ligand comparisons easy. The ligand family with the highest enantioselectivity is Phanephos (entries 5 and 7). The more electron-rich variant, An-Phanephos, gave a slight improvement in the ee value (entry 7). Higher ee values ​​were previously obtained using Phanephos and the same Ru precursor (Tables 1 and 2); however, this screening was conducted at different scales and substrate concentrations. Another ligand providing a similarly high ee to Phanephos is the Josiphos ligand SL-J002-1 (entry 10).

[0332] Table 4A. Ligand screening for [RuCl2(p-cym)]2 – S / C 25 / 1, [S] = 0.08 M, MeOH, 1 equivalent of NEt3, 70 °C, 20 bar H2, 18 hours

[0333]

[0334]

[0335] In addition, two different pre-formed Ru-BINAP catalysts were tested in MeOH or 2,2,2-trifluoroethanol (TFE) and with the addition of alternative bases that have higher steric requirements compared to previously tested, such as triethylamine (Table 4B). Appropriate amounts of catalyst (8 μmol, S / C 50 / 1) and substrate (76.8 mg, 0.4 mmol, 0.2 M) were weighed into Endeavor vials. For the appropriate vial, solvent (2 mL) was added, followed by N,N-diisopropylethylamine (69 μL, 0.4 mmol, 1 equivalent). The vials were transferred to Endeavor, which was sealed and set to stir at 650 rpm, purged 5 times with nitrogen, purged 5 times with hydrogen, and heated to 70 °C at 30 bar H₂. After 16 hours, Endeavor was vented and purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis.

[0336] TFE yielded significantly lower conversion and a lower ee value compared to MeOH (items 5-6 compared to items 1-2). Addition of N(iPr)₂Et (Houninger's base) with the [(S)-BINAP-RuCl(p-cym)]Cl catalyst resulted in improved conversion, but with a lower ee (item 3 compared to item 1). The same effect was previously observed when triethylamine was tested as an additive (Table 1).

[0337] Table 4B. Screening of pre-formed Ru-BINAP catalysts - S / C 50 / 1, [S] = 0.2 M, MeOH, 70 °C, 30 bar H2, 16 hours

[0338]

[0339] E. Ligand screening using rhodium catalysts

[0340] As discussed in the ligand screening using ruthenium catalysts, a range of chiral ligands with different steric and electronic properties were tested on a small scale using [Rh(COD)2]OTf as a precursor (Table 5). Each ligand was tested relative to the substrate in the absence and in the presence of 1 equivalent of triethylamine.

[0341] Most reactions showed complete consumption of the starting material, indicating that ligand-metal complexation had occurred. Reactions in the presence of triethylamine generally yielded lower ee values ​​compared to those in the absence of triethylamine. However, triethylamine also gave results with significantly lower amounts of byproducts compared to reactions without triethylamine. One unidentified byproduct, which appeared in large quantities in some reactions, had a retention time of 6.4 minutes according to SFC.

[0342] (R)-Phanephos and (S)-Xyl-Phanephos were found to provide very high ee values ​​in the absence of triethylamine. However, the amount of unknown byproducts (at 6.4 min) was also very high in these reactions (items 4-5). The opposite enantiomers of these ligands also seem unlikely to preferentially form the same product enantiomers, as it appears to have been completed in items 4-5; therefore, the presence of byproducts may affect the ratio of peaks observed in the chromatogram.

[0343] Table 5. Ligand selection using [Rh(COD)2]OTf - S / C 25 / 1, [S] = 0.08M, MeOH, 70℃, 20 bar H2, 16 hours

[0344]

[0345]

[0346] To assess whether the unknown byproducts (at 6.4 min) originated from the substrate (compound 1) or the products (P1 and P2), the stability of the substrate and products was investigated (Table 6). Compound 1 or the racemic product (0.4 mmol) was weighed into an Endeavour vial. 2 mL of MeOH was added to each vial. The vials were transferred to the Endeavour, which was then sealed and set to a stirring speed of 650 rpm, purged five times with nitrogen, five times with hydrogen, and heated to 50 °C or 90 °C at 30 bar H2. After 16 or 56 hours, the Endeavour was degassed and purged with nitrogen. Approximately 0.1 mL of the sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis.

[0347] Heating the substrate at 90 °C for 16 hours did not cause any change in the SFC chromatogram (entries 1 and 3). However, heating the racemic product sample showed a decrease in the second eluting product peak (P1) and a significant increase in the amount of the byproduct appearing at 6.4 min in the SFC chromatogram, from 2% to 16% (entries 2 and 4). Heating the product at 90 °C for a longer time indicated a further increase in the amount of this byproduct (entry 6). Heating at 50 °C provided a smaller amount of this byproduct (entry 5). Therefore, it appears that higher temperatures and the presence of acid promote the formation of this byproduct (while lower temperatures and the presence of base inhibit it, as observed in previous reactions).

[0348] Table 6. Stability of Compound 1 and Racemic Product (P1 / P2) – [S] = 0.2 M, Me OH, 50℃-90℃, 30 bar H2, 16-56 hours

[0349]

[0350] Because ligand screening using [Rh(COD)2]OTf showed that Phanephos provided 97% ee, despite 65% "other" in the SFC chromatogram (Table 5), two different pre-formed Rh-Phanephos catalysts were tested in different solvents and temperatures (Table 7). Appropriate amounts of catalyst (8 μmol, S / C 50 / 1) and substrate (76.8 mg, 0.4 mmol, 0.2 M) were weighed into Endeavor vials. Solvent (2 mL) was added to each vial. The vials were transferred to Endeavor, which was then sealed and set to stir at 650 rpm, purged 5 times with nitrogen, purged 5 times with hydrogen, and heated to 50 °C or 70 °C at 30 bar H2. After 16 hours, Endeavor was purged and purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis.

[0351] The results indicate that the amount of “other” appears to depend primarily on temperature and the catalyst used. Under all tested conditions, the [(S)-Phanephos Rh(COD)]BF4 catalyst yielded the least amount of “other” compared to [(S)-Phanephos Rh(COD)]OTf. The obtained ee values ​​(Table 7) are lower than those obtained in smaller-scale ligand screening (Table 5). This is because the major product appears to be the first elution peak (P2) in both cases, suggesting the possible presence of byproducts co-eluting with the first elution product peak (5.8 min) when using opposite ligand enantiomers, which thus interfere with the calculated ee values. Therefore, the results in Table 7 may have lower ee values ​​compared to those calculated using the relative integrals of the peaks at 5.8 min (P2) and 6.1 min (P1). The reaction in ethanol is more likely to have more accurate ee values ​​because the separation of byproducts from product peaks is better. Byproducts from the reaction in ethanol appear to appear at slightly different retention times compared to the reaction in methanol (see Tables 8A and 8B). NMR analysis showed that for the reaction in methanol or ethanol, the byproducts were methyl ester or ethyl ester (two enantiomers of the product), respectively.

[0352] Table 7. Screening of Rh-Phanephos catalysts under different conditions – S / C 50 / 1, [S] = 0.2 M, MeOH, 50℃-70℃, 30 bar H2, 16 hours

[0353]

[0354] Table 8A. SFC Readout from Table 7, Entrance 2 (MeOH)

[0355] Peak Name RT area area% high 1 5.453 74133 2.52 17977 2 SM 5.600 3 5.734 95521 3.25 25732 4 P2 5.842 1373483 46.76 268748 5 P1 6.151 716744 24.40 110218 6 6.398 677709 23.07 186998

[0356] Table 8B. SFC Readout from Table 7, Entrance 6 (EtOH)

[0357] Peak Name RT area area% high 1 5.341 81971 2.15 27880 2 SM 5.600 3 5.729 1589281 41.76 526310 4 P2 5.860 241850 6.35 40341 5 P1 6.164 172907 4.54 35584 6 6.294 1720143 45.19 410417

[0358] F. Catalyst loading screening

[0359] The (S)-Panephos and [RuCl2(p-cym)]2 combination was tested at lower catalyst loadings and higher substrate concentrations (Table 9). For entries 1–8: Appropriate amounts of substrate (19.2 mg, 0.1 mmol, 0.05 M; 38.4 mg, 0.2 mmol, 0.1 M; or 76.8 mg, 0.4 mmol, 0.2 M) were weighed into Endeavor vials. A stock solution of (S)-Panephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) was prepared in MeOH, and an appropriate volume was added to each vial. More MeOH was added to each vial to make the total volume of MeOH equal to 2 mL. Triethylamine (1 equivalent) was added to each vial. The vials were transferred to Endeavor, which was sealed and set to stir at 650 rpm, purged 5 times with nitrogen, purged 5 times with hydrogen, and heated to 50 °C at 30 bar H2. Sixteen hours later, the Endeavour was degassed and purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis. For entries 9-11: the same procedure as above, but using larger amounts of reagents: (S)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent, 2.9 mg, 1.2 mg), substrate (192 mg, 1 mmol), NEt3 (140 μL, 1 mmol, 1 equivalent), and 5 mL of MeOH.

[0360] All reactions (items 1-8) yielded complete conversion and 91-92% ee values. This indicates that reducing the catalyst loading to S / C 200 / 1 (0.5 mol%) and increasing the substrate concentration to 0.2 M had no effect on the reactions.

[0361] Some reactions were conducted on a slightly larger scale (still in Endeavor) to validate these favorable results at S / C 200 / 1. Two repetitions yielded the same results, with complete conversion and 90% ee (entries 9-10). Background reactions of the metal precursor and substrate were tested at a metal / substrate loading of 200 / 1. The conversion of the hydrogenated product was significantly lower than that previously tested using a loading of 25 / 1 (which provided 70% product), compared to 17% in this case (entry 11). This demonstrates the presence of ligand-accelerated catalysis when Phanephos is bonded to a metal to form a chiral complex. It also suggests that lower loading may help eliminate the possibility of non-selective hydrogenation by any unreacted metal precursor complex.

[0362] Table 9. Catalyst loading and substrate concentration screening – S / C 50 / 1-200 / 1, [S] = 0.05-0.2 M, MeOH, 1 equivalent NEt3, 50 °C, 20 bar H2, 16 hours

[0363]

[0364] *Entry 4 has 2 equivalents of NEt3.

[0365] In summary, screening experiments revealed that MeOH provided the best results in terms of conversion and enantioselectivity. The addition of 1 equivalent of triethylamine was found to improve the results of certain catalyst systems, making it possible to achieve ≥90% ee and ≥98% product. This was achieved using (S)-Phanephos and [RuCl2(pcym)]2.

[0366] Ligand screening using Ru identified (S)-Phanephos and (S)-An-Phanephos as providing the best results. Some tests using a pre-formed Ru-Phanephos catalyst did not improve the results obtained in situ using ligands and metal precursors. Reducing the loading of the (S)-Phanephos and [RuCl2(p-cym)]2 catalyst system to S / C 200 / 1 still showed full conversion and 90% ee of product. Increasing the concentration to 0.2 M also showed no effect on the results.

[0367] Reactions using rhodium-based catalysts are typically found to produce very large amounts of byproducts. The main byproducts are reduced in the presence of triethylamine. However, low ee values ​​are also obtained under those conditions. The main byproducts from these reactions have been provisionally identified by NMR analysis as methyl esters of the saturated product when the reaction is carried out in methanol or ethyl esters when the reaction is carried out in ethanol.

[0368] Furthermore, lowering the temperature from 70°C to 50°C resulted in a slight increase in ee from 90% to 93%. Lowering it to 30°C did not provide further improvement.

[0369] Example 2. Further optimization of enantioselective olefin reduction

[0370]

[0371] Materials and methods: The SFC method described in Example 1 was used.

[0372] Example 1 identified the Phanephos and [RuCl2(p-cym)]2 catalyst system as one of the best for obtaining high product conversion and high %ee. This study aims to further optimize the reaction conditions of the Phanephos and [RuCl2(p-cym)]2 catalyst system.

[0373] A. Catalyst loading and substrate concentration

[0374] In Example 1, it was found that the catalyst loading could be reduced from S / C 25 / 1 to S / C 200 / 1 and the substrate concentration could be increased from 0.05 M to 0.2 M. Within the ranges tested in Example 1, there was no decrease in conversion or enantioselectivity, and complete conversion and ≥90% ee were obtained at S / C 200 / 1 and a substrate concentration of 0.2 M.

[0375] Further studies on catalyst loading and substrate concentration were conducted. For reactions using S / C 1,000 / L or 10,000 / L, stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents) were prepared in DCM, and appropriate volumes of the solution were added to those vials, after which the DCM was purged with N2. Catalyst loadings of 200 / L to 500 / L were obtained by weighing (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents) into vials. Appropriate amounts of substrate (i.e., 192 mg, 1 mmol) were weighed into Endeavour vials. Methanol (2 mL for entries 1–6 and 5 mL for entries 7–8; Table 10) was added to each vial, followed by triethylamine (1 equivalent). Transfer the vials to Endeavor, seal the Endeavor, and set it to stir at 650 rpm, purging with nitrogen 5 times, hydrogen 5 times, and heating to 50°C at 30 bar H₂. After 16 hours, vent the Endeavor and purge with nitrogen. Dilute approximately 0.1 mL of sample from each reaction to approximately 1 mL with MeOH for SFC analysis (Table 10). Hydrogen absorption times were estimated based on data recorded by the Endeavor, which showed the time when absorption stopped, thus assuming that the reaction was ≥90% complete at this point. For entries 4-6, there was a leak in the Endeavor, therefore the absorption was not accurately recorded.

[0376] Further reduction of catalyst loading showed complete conversion of S / C 1,000 / 1 (item 3), while S / C 10,000 / 1 provided only ≤15% of hydrogenation products after 16 hours of reaction (items 5-6). Lower catalyst loading was also found to produce slightly lower ee values. However, increasing substrate concentration showed a greater effect on reducing enantioselectivity (items 1-2).

[0377] By examining the hydrogen absorption recorded by Endeavor software, one can estimate the approximate time when the reaction is likely to be ≥90% complete. Figure 2 Therefore, increasing the substrate concentration from 0.5 M to 1 M significantly affected the reaction rate, making it approximately 2 hours to stop H2 consumption at S / C 200 / 1 with 0.5 M concentration, while it took approximately 5 hours with 1 M concentration. Figure 2 Compare entries 1 and 2, which correspond to entries 1 and 2 in Table 10. As expected, reducing the catalyst loading also reduced the reaction rate, so S / C 1,000 / 1 reached completion in approximately 10 hours. Figure 2 (Item 3).

[0378] Table 10. Catalyst loading screening and substrate concentration studies for (R)-Phanephos and [RuCl2(p-cym)]2 – S / C 200 / L-10,000 / L, [S] = 0.5-1.0 M, MeOH, 1 equivalent NET3, 50 °C, 30 bar H2, 16 hours

[0379]

[0380] B. Kinetic analysis of hydrogenation reaction

[0381] To investigate the reasons behind any difficulties in minimizing catalyst loading, several kinetic analyses were performed. Hydrogen absorption data recorded by Endeavor were converted into the consumption rate of the starting material. Kinetic analyses were performed on reactions using the same catalyst concentration but different initial starting material concentrations. This followed a method used to distinguish the presence of any product inhibition or catalyst deactivation, termed Variable Time Normalization Analysis (VTNA) in Nielsen et al., Chem. Sci., 2019, 10, 348.

[0382] (R)-Panephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 7 mg and 3.1 mg, respectively) were weighed into Endeavor vials. Different amounts of substrate (i.e., 480 mg, 2.5 mmol) were weighed into Endeavor vials to achieve the desired substrate concentration. Methanol (5 mL) was added to each vial, followed by triethylamine (1 equivalent). The vials were transferred to Endeavor, which was then sealed and set to stir at 650 rpm, purged 5 times with nitrogen, purged 5 times with hydrogen, and heated to 50 °C at 30 bar H2. After 16 hours, Endeavor was purged and purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis. The hydrogen absorption time was estimated based on data recorded by Endeavor, which showed the time when absorption stopped, thus assuming that the reaction was ≥90% complete at this point.

[0383] The reaction curves of the first two reactions (Table 11, entries 1-2) using substrate concentrations of 1.0 or 0.5 M are overlaid on the same graph. Figure 3A The reaction with the initial substrate concentration (item 2) then shifts (to the right) in time so that the first data point aligns with the reaction with the higher substrate concentration. Figure 3B Once the reactions at lower concentrations are superimposed by shifting them over time by 2.9 hours, the reaction curves look very similar. Figure 3B According to the logic of VTNA, this indicates a lack of product inhibition or catalyst deactivation.

[0384] Then a third experiment was conducted using even higher substrate concentrations (Table 11, item 3). It is noteworthy that this reaction did not complete within the 16-hour reaction time range. By transferring the lower concentration reaction to this higher concentration reaction, the reaction curves of the three reactions were overlaid on the same graph. Figure 3C ).like Figure 3C As shown, the reaction curves do not overlap. Therefore, this indicates some differences at this increased concentration (Table 11, entry 3), which affect catalysis.

[0385] To distinguish whether catalyst deactivation or product inhibition was the most likely cause of the effects of increased substrate concentration and catalyst loading, a final experiment was conducted in which 0.5 M of the racemic product was added to the starting mixture (Table 11, Item 4). Figure 3DThe presence of the superimposed curves in (Items 1 and 4 of Table 11) suggests that any differences between reactions at different substrate concentrations are likely due to some product inhibition rather than catalyst deactivation. It is noteworthy that in these reactions using different substrate concentrations, although the amount of triethylamine remains 1 molar equivalent relative to the substrate, the pH will differ in each reaction, which could affect catalysis and therefore the analysis of reaction kinetics. However, this is unlikely to affect the main findings of this analysis: at substrate concentrations up to 1.0 M, any product inhibition or catalyst deactivation should be negligible. This means it should be possible to use low catalyst loadings and obtain good results.

[0386] Table 11. Kinetic Analysis – S / C 250 / 1-750 / 1, [S] = 0.5-1.5M, MeOH, 1 equivalent NET3, 50℃, 30 bar H2, 16 hours

[0387]

[0388] *A racemic product was added in this experiment, so a high ee was not expected.

[0389] C. Further optimization of catalyst loading and substrate concentration

[0390] Further investigation was conducted into the effect of substrate concentration at catalyst loadings of 500 / 1 and 1,000 / 1 (Table 12). Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents) were prepared in DCM, and appropriate volumes of the solutions were added to each Endeavor vial, after which the DCM was purged with N2. The substrate (192 mg, 1 mmol) was weighed into the Endeavor vial. Methanol (2 mL, 4 mL, or 5 mL, to achieve the desired [S]) was added to each vial, followed by triethylamine (1 equivalent). The vials were transferred to Endeavor, which was sealed and set to stir at 650 rpm, purged with nitrogen 5 times, purged with hydrogen 5 times, and heated to 50 °C at 30 bar H2. After 16 hours, the Endeavor was purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis.

[0391] These experiments confirmed that, under the tested conditions, increasing the substrate concentration by more than 0.2 M reduced the ee value. Similar results were obtained at the two tested loading levels, except for the experiment using the lowest loading level and the highest substrate concentration (item 4), in which a small amount of substrate remained and the product ee was significantly lower than in the other results.

[0392] Table 12. Screening for lower catalyst loadings and substrate concentrations of (R)-Phanephos and [RuCl2(p-cym)]2 – S / C 500 / L-1,000 / L, [S] = 0.2-0.5 M, MeOH, 1 equivalent NET3, 50 °C, 30 bar H2, 16 h

[0393]

[0394] D. Screening for shorter reaction times

[0395] Up to this point, the reaction time was maintained at 16 hours, so a 3-hour reaction time was used to investigate whether there was any difference in the obtained ee value if the reaction were stopped earlier. Different amounts of triethylamine (1 or 2 equivalents relative to the substrate) were also tested at different substrate concentrations (Table 13). Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents) were prepared in DCM, and appropriate volumes of the solution were added to each Endeavor vial, after which the DCM was purged with N2. The substrate (192 mg, 1 mmol) was weighed into the Endeavor vial. Methanol (2 mL or 5 mL, to achieve the desired [S]) was added to each vial, followed by triethylamine (1 or 2 equivalents, 140 or 280 μL). The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm, purged 5 times with nitrogen, purged 5 times with hydrogen, and heated to 50 °C at 30 bar H2. After 3 hours, the Endeavour was purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis.

[0396] At a higher catalyst loading (S / C 500 / 1), the reaction was ≥95% complete after 3 hours using 1 equivalent of triethylamine. 2 equivalents of triethylamine showed a slower hydrogenation reaction compared to 1 equivalent. Increasing the amount of triethylamine did not improve the ee value.

[0397] Regarding the higher ee and conversion rates obtained under all tested conditions, there is further evidence that the results improved at lower substrate concentrations. By comparing these results (Table 13) with previous results using a 16-hour reaction time in Table 12, the ee values ​​were slightly improved (by up to 2%) at the 3-hour reaction time. However, the reaction was not fully completed in this shorter time, so it was not possible to extract a comparison between the ee value at which the reaction was completed and the extended reaction time from these results.

[0398] Table 13. Screening of reactions at 3 hours – S / C 500 / L-1,000 / L, [S] = 0.2-0.5 M, MeOH, 1-2 equivalents of NET3, 50 °C, 30 bar of H2, 3 hours

[0399]

[0400] E. Screening of temperature and NET3 quantity

[0401] The catalyst was tested at two substrate concentrations and three temperature settings using a lower triethylamine equivalent (0.5 equivalent) with an S / C 1000 / 1 catalyst loading (Table 14). Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) were prepared in DCM, and appropriate volumes of the solution were added to those vials, after which the DCM was purged with N2. The substrate (192 mg, 1 mmol) was weighed into Endeavor vials. Methanol (2 or 5 mL for 0.5 or 0.2 M substrate concentrations, respectively) was added to each vial, followed by triethylamine (1 or 0.5 equivalent, 140 or 70 μL). The vials were transferred to Endeavor, which was sealed and set to stir at 650 rpm, purged with nitrogen 5 times, purged with hydrogen 5 times, and heated to 40 °C–60 °C at 30 bar H2. After 16 hours, the Endeavour was purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis.

[0402] For the test conditions at 50 °C, using 0.5 equivalents of NEt3 instead of 1 equivalent showed that an improvement in ee was obtained for both substrate concentrations, as well as a slight improvement in conversion for higher substrate concentrations (Table 14, entries 3-6). The effect of temperature was less significant, but the optimal ee value for each substrate concentration was obtained at 40 °C (entries 1-2).

[0403] Table 14. Temperature and NET3 equivalent screening – S / C 1,000 / L, [S] = 0.2-0.5 M, MeOH, 0.5-1 equivalent NET3, 40℃-60℃, 30 bar H2, 16 hours

[0404]

[0405] F. Screening of hydrogenation pressure

[0406] So far, the pressure used has been maintained at 30 bar. Therefore, the effect of using a lower pressure on the results was investigated (Table 15). Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents) were prepared in DCM, and appropriate volumes of the solutions were added to those vials, after which the DCM was purged with N2. The substrate (192 mg, 1 mmol) was weighed into Endeavor vials. Methanol (2 or 5 mL for 0.5 or 0.2 M substrate concentrations, respectively) was added to each vial, followed by triethylamine (0.5 equivalents, 70 μL). The vials were transferred to Endeavor, which was sealed and set to stir at 650 rpm, purged with nitrogen 5 times, purged with hydrogen 5 times, and heated to 40-50 °C at 5-30 bar H2. After 16 hours, the Endeavor was purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis. Hydrogen absorption times were estimated based on data recorded by Endeavor, which showed the time when absorption ceased, thus assuming the reaction was ≥90% complete at this point. H2 absorption time data for entries 1-2 were not available because the Endeavor hydrogen absorption curves indicated a leak.

[0407] Very encouragingly, the pressure could be reduced to 5 bar and complete conversion was still achieved at S / C 1,000 / 1. A high ee was also maintained at this pressure and loading (Table 15, entry 6). Reducing the pressure resulted in a decrease in the reaction rate; for example, using S / C 1,000 / 1 at 5 bar instead of 10 bar required 7 hours to achieve complete conversion instead of 3 hours (compare entries 3 and 6). Using a higher catalyst loading reduced the required reaction time (compare entries 6–8).

[0408] Table 15. Screening under different pressure conditions – S / C 200 / L-1,000 / L, [S] = 0.2-0.5M, MeOH, 0.5 equivalent NET3, 40℃-50℃, 5-30 bar H2, 16 hours

[0409]

[0410] G. Design of Experiments (DoE)

[0411] So far, the results indicate that the reaction is successful at a catalyst loading of 5 bar and S / C 1,000 / 1. These conditions were used to further explore the effects of substrate concentration, amount of triethylamine, and temperature. A design-of-experiment (DoE) approach was used to extract trends caused by each of these factors and to attempt to find conditions that optimize conversion and selectivity. Experiments generated by the DoE model were conducted at a 1 mmol substrate scale. The experimental results are shown in Table 16. Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents) were prepared in DCM, and appropriate volumes of the solution were added to those vials, after which the DCM was blown out with N2. The substrate (192 mg, 1 mmol) was weighed into Endeavor vials. Methanol (1, 1.7, or 5 mL for 1.0, 0.6, or 0.2 M substrate concentrations, respectively) was added to each vial, followed by triethylamine (42, 91, or 140 μL for 0.3, 0.65, or 1 equivalent, respectively). The vials were transferred to Endeavor, which was sealed and set to stir at 650 rpm, purged five times with nitrogen, five times with hydrogen, and heated to 40-50 °C at 5 bar H₂. After 16 hours, Endeavor was purged and purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis. The hydrogen absorption time was estimated based on data recorded by Endeavor, which showed the time when absorption stopped, thus assuming that the reaction was ≥90% complete at this point. Due to leakage, H₂ absorption time data for item 3 were not obtained.

[0412] Table 16. DoE Variable Study – S / C 1,000 / 1, [S] = 0.2-1.0 M, MeOH, 0.3-1.0 equivalent NET3, 40℃-50℃, 5 bar H2, 16 hours

[0413]

[0414] *The actual ee value may be lower because there are some methyl ester impurities that overlap with the peak of P2.

[0415] The results (Table 16) were input into the DoE software JMP. The model showed that substrate concentration had the greatest impact among these factors (as seen in the very low p-values ​​in the effects summary table), while other factors had significantly lower effects on the results (Table 17). The predictive profiler predicted that as substrate concentration increased in the range of 0.2 to 1.0 M, "desirability" (i.e., maximizing both conversion and ee) decreased sharply. According to the predictive profiler model, the amount of triethylamine and temperature had a much smaller effect on desirability.

[0416] The DoE software predicts that optimal results will be obtained at the lowest concentration and amount of triethylamine and the lowest temperature within the tested range: 0.2 M, 0.3 equivalents of NEt3, and 40 °C. The optimal results obtained experimentally reflect this: >99% conversion and 93% ee (Table 16, Entry 3).

[0417] Table 17. Overview of DoE Prediction - Summary of the Impact of Variables

[0418]

[0419] ('^' indicates that the effect with | includes the effect above it)

[0420] The predictive profiler can also be used to calculate which conditions will provide optimal results at the desired substrate concentration. These results are shown in Table 18. These results indicate that using concentrations greater than 0.2 M under these conditions is unlikely to achieve >99% conversion and high ee. However, it must be noted that the hydrogen absorption shows that the reaction is slower at higher concentrations, and therefore completion was not reached within the 16-hour timeframe tested in these cases.

[0421] Table 18. Optimization results of DoE at different substrate concentrations

[0422]

[0423] *The desirability value is between 0 and 1. Desirability is set to maximize conversion rate and ee value, which are equally important, and set to 100, 90, and 80 for high, medium, and low responses, respectively.

[0424] H. Screening of reaction time

[0425] Results from the DoE study found that, when using conditions within the explored range (S / C 1,000 / 1, [S] = 0.2–1.0 M, MeOH, 0.3–1.0 equivalents of NET3, 40–50 °C, 5 bar H2, 16 h), it was impossible to simultaneously obtain high conversion (≥95%) and enantioselectivity (≥90%) at substrate concentrations greater than 0.5 M. Therefore, it was tested whether longer reaction times would allow for higher conversions at substrate concentrations of 0.6–1.0 M (Table 19). Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents) were prepared in DCM, and appropriate volumes of the solution were added to the vials, after which the DCM was purged with N2. The substrate (192 mg, 1 mmol) was weighed into Endeavor vials. Methanol (1, 1.3, or 1.7 mL for 1.0, 0.8, or 0.6 M substrate concentrations, respectively) was added to each vial, followed by triethylamine (91, 112, or 140 μL for 0.65, 0.8, or 1 equivalent, respectively). The vials were transferred to Endeavor, which was then sealed and set to stir at 650 rpm, purged five times with nitrogen, five times with hydrogen, and heated to 45–50 °C at 5 bar H₂. After 16 or 24 hours, Endeavor was purged and purged with nitrogen. Approximately 0.1 mL of sample from each reaction was diluted with MeOH to approximately 1 mL for SFC analysis. Due to leakage, H₂ absorption time data for item 1 were not obtained.

[0426] Reactions using substrate concentrations of 0.8 M or 1.0 M were not completed within 24 hours (items 1-2).

[0427] Table 19. Reaction stopped after 24 hours – S / C 1,000 / L, [S] = 0.6-1.0 M, MeOH, 0.65-1.0 equivalent NET3, 45℃-50℃, 5 bar H2, 24 hours

[0428]

[0429] I. Screening of Alkali Type and Amount

[0430] Several other bases were tested to see if they would provide any benefit (Table 20). Temperature screening (H section) followed the same procedure, except that the addition of triethylamine or base was adjusted as shown in Table 20, and the reaction was stopped at 16 hours. Due to leakage, H2 absorption time data for entries 1 and 5 were not obtained.

[0431] When using 0.3 equivalents of base and substrate, both NaOMe and Na2CO3 provided similar results to NEt3 (items 1-3, 5). The conversion provided by using 0.6 equivalents of NaOMe or Na2CO3 was slightly lower than that provided by using 0.3 equivalents (items 3-6). Therefore, no advantage was observed in using NaOMe / Na2CO3 instead of NEt3. Two different substrate batches were tested under the same conditions and similar results were obtained (items 1-2). The substrate batches had similar purities, as indicated by... 1 Detected by ¹H NMR (96% and 95% for batches 1 and 2, respectively). However, it must be noted that SFC analysis of substrate batch 2 showed a late elution peak (8.6 min) with <1% integral, which was not observed in the first batch. The 1% "other" of the reaction using this substrate batch is therefore mainly related to the presence of this peak in the SFC chromatogram.

[0432] Table 20. Screening of bases - S / C 1,000 / L, [S] = 0.4M, MeOH, 0.3-0.6 equivalent bases, 40℃, 5 bar H2, 16 hours

[0433]

[0434] Because the previous reaction was successful at a substrate concentration of 0.4 M, additional conditions were tested using 0.6 M. This included testing with lower amounts of NaOMe and Na2CO3, as well as testing different Ru precursors (Table 21): A = [RuCl2(p-cym)]2, B = Ru(COD)(Me-allyl)2, C = Ru(COD)(TFA)2. Due to leakage, H2 uptake time data for item 7 were not obtained.

[0435]

[0436] The reaction was found to be successful at this relatively high substrate concentration of 0.6 M (i.e., complete conversion and ≥90% ee). This suggests that obtaining these results requires the use of lower amounts of base (0.1–0.3 equivalents) and lower temperatures (40 °C). Alternative bases NaOMe and Na2CO3 again showed similar results to NET3, and the amounts could be reduced to 0.1 equivalents (items 1–6).

[0437] Different Ru precursors B and C yielded results very similar to [RuCl2(p-cym)]2(A), with ee differences of ±1%. Therefore, this ensures that the presence of Cl ligands in the active complex does not affect the maximum ee that this reaction can achieve.

[0438] Table 21. Screening of base and catalyst precursors under 0.6M substrate – S / C 1,000 / L, [S] = 0.6M, MeOH, 0.1–0.3 equivalent base, 40 °C, 5 bar H₂, 16 hours

[0439]

[0440] Reaction screening in J.Parr container (25mL)

[0441] Previous results showed that 0.6 M provided complete conversion with 90%–93% ee values. These conditions were used to scale up to 25 mL Parr containers using 1.6 g of substrate and 14 mL of MeOH (Table 22). (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 5.8 mg and 2.6 mg, respectively) were weighed into a 25 mL Parr container, followed by the substrate (1.614 g, 8.4 mmol). Methanol (14 mL, 0.6 M substrate concentration) was added to the container, followed by triethylamine (118 μL, 0.84 mmol, 0.1 equivalent). The container was sealed and purged five times with nitrogen (at approximately 2 bar) and stirred five times (at approximately 500 rpm). The container was then purged five times with hydrogen (at approximately 10 bar) and stirred five times (at approximately 500 rpm). The container was then pressurized to 5 bar of hydrogen and heated to 40°C (stirring at 500 rpm). The pressure was kept constant, but after sampling, the pressure was vented and refilled to 5 bar. Samples were taken at 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, and 70 hours. After 70 hours, the container was cooled, vented, and purged with nitrogen. Each approximately 0.1 mL sample was diluted with MeOH to approximately 1 mL for SFC analysis.

[0442] Comparing the reaction rates in the Parr vessel with those in the Endeavor vessel shows that the reaction rate is slower on a larger scale. Figure 4 This difference may be due to the difference in mixing efficiency between Endeavor and Parr. Reactions were conducted using low stirring speeds (500 rpm) and extended reaction times to test the robustness of the catalyst system and the scale-up process. This showed a slower rate and a lower ee value compared to that obtained in Endeavor. There is also room to increase the stirring speed in the Parr vessel.

[0443] No reaction samples were taken between 5.5 and 70 hours, so it is unknown whether there was heat-induced ee degradation after the time to complete conversion was reached. By extrapolating the rate profile from the first 6 hours, it appears the reaction may have been completed within approximately 15–20 hours.

[0444] Table 22. Hydrogenation in Parr container – S / C 1,000 / L, [S] = 0.6 M, 114 g / L, MeOH, 0.1 equivalent of NET3, 40 °C, 5 bar H2, 70 hours, 500 rpm

[0445]

[0446] *This sample was obtained when the internal temperature of the container reached 40°C.

[0447] Next, the stirring speed in Parr was increased to the maximum speed (>1500 rpm) to observe whether this would achieve results more similar to Endeavor (Table 23). This Parr reaction using the maximum stirring speed showed a faster rate compared to the reaction with a slower stirring speed, and the reaction appeared to be completed in about 10 hours instead of about 18 hours (500 rpm) (as assessed by hydrogen absorption).

[0448] Higher stirring speeds did not affect the results between Parr and Endeavor, as the Endeavor reaction was completed much faster, in approximately 7 hours. Notably, increasing the stirring speed did not improve enantioselectivity. Both Parr reactions (Tables 22 and 23) yielded the same result of 87% ee at the end of the reaction, compared to 90%–93% ee obtained using the same set of conditions in Endeavor.

[0449] Table 23.25 mL Parr container (1.6 g SM) Hydrogenation – S / C 1,000 / L, [S] = 0.6 M, 114 g / L, MeOH (14 mL), 0.1 equivalent of NET3, 40 °C, 5 bar H2, 20.5 h, >1500 rpm

[0450]

[0451] *Post-processing procedure: Remove MeOH by vacuum concentration, then add EtOAc (10 mL) and 1M HCl (10 mL). Mix the layers before separation. Wash the EtOAc layer with another 4 mL of 1M HCl before removing the aqueous layer to leave the EtOAc organic phase. Then wash the aqueous layer with another 4 mL of EtOAc and combine the organic layers. Remove EtOAc under vacuum to leave a product as a light gray solid.

[0452] The reaction setup shown in Table 23 was repeated in 25 mL Parr with a lower substrate concentration to investigate whether this could achieve greater enantioselectivity, as seen in small-scale screening at substrate concentrations (in Endeavor). This reaction was carried out at 0.4 M, and sampling was only performed at the end of the reaction; however, hydrogen absorption could be used to provide information about the reaction rate (Table 24). Figure 5 ).

[0453] Table 24.25 mL Parr container (1.1 g SM) Hydrogenation – S / C 1,000 / 1, [S] = 0.4 M, 77 g / L, MeOH (14 mL), 0.1 equivalent of NET3, 40 °C, 5 bar H2, 20.5 h, >1500 rpm

[0454]

[0455] *The same post-processing procedure as in Table 23.

[0456] The results showed that this reduction in substrate concentration did not yield higher enantioselectivity; 87% ee was achieved at both concentrations. Based on the recorded hydrogen absorption, the lower concentration reaction appeared to have a faster initial rate and completed in a shorter time (approximately 9 hours) compared to the higher concentration reaction, which appeared to have completed in about 11 hours. Figure 5 This is more similar to the reaction time of the reaction carried out in Endeavor (using 0.3 equivalents of NEt3). However, in Endeavor, the reaction using 0.1 equivalents of 0.4M triethylamine has not been carried out (higher amounts of triethylamine are known to slow down the reaction).

[0457] The difference between the procedures used to establish the reaction in the Endeavor and Parr containers lies in the scale. For the Endeavor reaction, due to the smaller scale, stock solutions of the metal precursor and ligand are prepared in the DCM and added in small volumes to the vial to provide the correct catalyst loading (before evaporating the DCM). In Parr, both the precursor and ligand are weighed directly into the container as solids. Therefore, the Parr reaction can be described as the “in-situ” formation of the metal-ligand complex in the presence of the substrate, whereas for the Endeavor reaction, the metal and ligand are pre-complexed before the addition of the substrate. Therefore, to investigate the resulting difference, a procedure variation was tested in Endeavor (Table 25). All masses of [RuCl2(p-cym)]2 and (R)-Phanephos were weighed to obtain an S / C ratio of 1,000 / 1 and a ligand molar equivalent of 1.2. For the "in-situ" procedure, a stock solution of [RuCl2(pcym)]2 in DCM was added to one side of the Endeavor vial, followed by purging of the DCM with N2, and a stock solution of (R)-Phanephos in DCM was added to the opposite side of the vial, followed by removal of the DCM (so that the metal and ligand do not come into contact before the addition of other reagents). For the premixed procedure, stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents) were prepared in DCM or MeOH, and an appropriate volume of solution was added to the vial, followed by purging of the solvent with N2. The substrate (192 mg, 1 mmol) was weighed into the Endeavor vial. Methanol (1.7 mL, 0.6 M substrate concentration) was added to each vial, followed by triethylamine (14 μL, 0.1 equivalents). Transfer the vial to Endeavor, seal the Endeavor and set it to stir at 650 rpm. Purge with nitrogen 5 times, then with hydrogen 5 times and heat to 40°C at 5 bar H2. After 16 hours, purge Endeavor with nitrogen. Dilute approximately 0.1 mL of each reaction sample with MeOH to approximately 1 mL for SFC analysis.

[0458] The results were very similar, with 91%–92% ee obtained in all cases. This indicates that the lower ee obtained in the Parr vessel was not due to the absence of a premixture of metal precursors and ligands. This leaves the following as potential reasons for the lower ee values: contamination in the Parr vessel leading to a racemic background reaction, insufficient hydrogen due to an imperfect headspace in the reactor, and differences in internal temperature precision meaning that the Endeavor reaction was actually occurring below 40°C.

[0459] It is worth noting that the “in-situ” reaction with exhaust gas at 10 or 16 hours yielded the same result, so there was no ee degradation during the 6 hours after the reaction was completed.

[0460] Table 25. Comparison of different procedures for adding metal precursors and ligands – S / C 1,000 / L, [S] = 0.6 M, MeOH, 0.1 equivalent NET3, 40 °C, 5 bar H2, 16 hours

[0461]

[0462] * Set this container to vent and stop heating after 10 hours (temperature measured from 10-16 hours is 30°C).

[0463] K. Study of background reactions

[0464] Three runs using a 25 mL Parr vessel at S / C 1,000 / 1 (testing two stirring speeds and two substrate concentrations) were found to provide lower results than expected based on Endeavor results. Therefore, the presence of background reactions in the vessel leading to lower enantioselectivity was tested. Thus, conditions were kept identical except for the absence of ligands or metal precursors, and pressure was kept constant, but after sampling, the pressure was vented and refilled to the desired pressure. After 5 hours at 20 bar, the pressure was reduced to 5 bar (Table 26).

[0465] By initially using 20 bar as the hydrogen pressure, 11% low-ee product was measured from the sample after 5 hours (Table 26, entry 2). After 5 hours, the pressure was reduced to 5 bar. After reheating for 15.5 hours and maintaining a pressure of 5 bar, an additional 3% product was produced (Table 26, entry 3).

[0466] Therefore, the rate of the background reaction is lower at lower pressures and has a smaller effect on the ee obtained from the reaction (Table 27). This experiment provides evidence of the presence of a background reaction and explains the lower ee obtained in previous experiments using this particular Parr container.

[0467] Table 26. Background reaction test in 25 mL Parr container – [S] = 0.6 M, MeOH, 0.1 equivalent of NET3, 40 °C, 5-20 bar H2, >1500 rpm, 23 hours

[0468]

[0469] Table 27. Analysis of background reaction rates for specific Parr containers and their impact on ee

[0470]

[0471] a The product rates were calculated based on the background reaction at 5 bar or 20 bar, with 10 hours as the reaction completion time and 93% ee as the maximum ee for the enantioselective hydrogenation product. *In this case, the background reaction was found to provide a lower level of enantioselectivity for the desired product enantiomer (P2).

[0472] To verify that the background reaction was caused by contaminants in the container rather than the substrate, further background reaction studies were conducted at Endeavor—where the previous ≥91% ee results were obtained. A study had been performed to examine for any background reaction earlier in this project (Example 1), but at that stage, 0.2 M was used as the concentration and a different substrate batch was used. Therefore, two different substrate batches were tested in parallel, and the optimal conditions now found for enantioselective hydrogenation were tested in the absence of a catalyst (Table 28). Except as noted in Table 28, the reaction settings were the same as in Table 25.

[0473] Two substrate batches and several different conditions were found to yield <1% product at 50°C (entries 2-5). This suggests that the background reaction observed in the Parr container was likely due to contaminants found in the container rather than in the substrate. The vials containing the substrate, triethylamine, and methanol were returned to Endeavor, but the temperature was increased to 90°C. Under these conditions, small amounts of product were observed after 16 hours (entries 6-8). This was likely due to trace contaminants in the Endeavor that required more stringent conditions to react with the substrate.

[0474] Table 28. Background reaction in Endeavor – [S] = 0.2–0.6 M, MeOH, 0.1 equivalent NET3, 50–90 °C, 5–30 bar H2, 250 rpm, 16 hours

[0475]

[0476] To demonstrate that similar results to Endeavor can be obtained on a larger scale in a Parr vessel in the absence of a background reaction, a glass liner and PTFE stir bar, along with PTFE tape covering the thermocouples, were used (Table 29). The reaction setup was otherwise identical to Table 22, but as noted, the substrate amount (1.845 g, 9.6 mmol) was used and the reaction time was different. For item 1, an error occurred with the heating plate used to heat this reaction overnight, causing the temperature to drop from 40 °C to 22 °C, but after 16 hours, the reaction was reheated to 40 °C.

[0477] Using this setup, a 91% ee was achieved at full conversion, indicating that contaminants in the previously used stainless steel vessel led to a lower ee, and therefore a high ee could be obtained with a catalyst loading of S / C 1,000 / 1 in the absence of any background reaction. The reaction products after methanol removal and post-treatment... 1 1H NMR spectroscopy showed that post-processing successfully removed all triethylamine. A 1% ee loss was observed in the post-processing measurements, but this could be a product of integration errors in the SFC analysis.

[0478] Table 29. Parr container reaction with PTFE tape on PTFE stir bar and thermocouple - S / C 1,000 / L, [S] = 0.6 M, 114 g / L, MeOH, 0.1 equivalent NET3, 40 °C, 5 bar H2, 1500 rpm, 20.5 h

[0479]

[0480] *The same post-processing procedure as shown in Table 23

[0481] L. Expand to 300mL Parr container

[0482] Once the presence of contaminants in the 25 mL Parr container, resulting in a <90% ee, was determined, an initial scale-up was performed in a 300 mL Parr container using S / C 200 / 1 to prevent the container from inducing a background reaction (Table 30). It was predicted that the rapid reaction rate caused by the high loading would be able to provide a >90% ee by minimizing the effects from any background reaction, which would have a much slower rate. (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 322 mg and 142 mg, respectively) were weighed into a 300 mL Parr container, followed by the substrate (17.87 g, 93 mmol). Methanol (155 mL, 0.6 M substrate concentration) was added to the container, followed by triethylamine (1.3 mL, 9.3 mmol, 0.1 equivalent). The container was sealed and purged with nitrogen five times (at approximately 2 bar) and stirred five times (at approximately 500 rpm). The container was then purged five times with hydrogen (at approximately 10 bar) and stirred five times (at approximately 500 rpm). The container was then pressurized to 5 bar of hydrogen and initially heated to 30°C, then increased to 35°C (with maximum stirring, >1500 rpm). The pressure was kept constant, but after sampling, the container was vented and refilled to 5 bar. After 5 hours, the container was cooled. After 6 hours, the container was vented and purged with nitrogen. Each approximately 0.1 mL sample was diluted with MeOH to approximately 1 mL for SFC analysis.

[0483] The reaction was completed within 4–6 hours, with a product yield of 91% ee. During the initial 1.7 hours, the temperature was ≤30°C, during which hydrogen consumption was recorded, indicating that the reaction can occur below 30°C. However, increasing the temperature above 30°C significantly increased the reaction rate; therefore, the temperature was increased to 35°C and maintained until completion. Following post-treatment, high yield and high purity of the product were obtained (according to…). 1 H NMR).

[0484] Table 30.300mL Parr container scale-up - S / C 200 / 1, [S] = 0.6M, 114g / L, MeOH, 0.1 equivalent NET3, 30℃-35℃, 5 bar H2, >1500rpm, 6 hours

[0485]

[0486] *Post-processing procedure: Transfer the contents of the Parr container to a round-bottom flask. Wash the container with MeOH (10 mL) and transfer the washings to the flask. Remove the MeOH by vacuum concentration, then add EtOAc (40 mL) and 1M HCl (40 mL). Wash the round-bottom flask with more parts of EtOAc (2 x 10 mL) and 1M HCl (10 mL) and transfer to a separatory funnel. Vigorously shake the funnel to mix the layers before allowing them to separate. Wash the organic layer of EtOAc with more parts of 1M HCl (2 x 20 mL) and the aqueous layer with more parts of EtOAc (2 x 20 mL), then combine the organic layers. Remove the EtOAc under vacuum to leave a product as a light gray solid (17.5 g, 97% yield).

[0487] The second scale-up reaction, conducted in 300 mL Parr, was carried out at S / C 1,000 / 1 (Table 31). At this point, it was unclear whether any contaminants in the vessel would have contributed to the lower ee value. Except for the catalyst loadings ((R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 64 mg and 28 mg, respectively), the experiment was set at the same substrate scale as the previous 300 mL reaction.

[0488] The results showed a significant background reaction, as evidenced by the <90% ee value. Hydrogen absorption indicates that the reaction was completed in approximately 14 hours at S / C 1,000 / 1, compared to the 4–6 hours observed with S / C 200 / 1. Figure 6 This difference in reaction rate means that background reactions are allowed to have a greater impact on the ee value, and therefore highlights the importance of evaluating each specific vessel based on the catalyst loading and the desired ee result.

[0489] Table 31. Scale-up of 300 mL Parr container - S / C 1,000 / 1, [S] = 0.6 M, 114 g / L, MeOH, 0.1 equivalent NET3, 30℃-35℃, 5 bar H2, >1500 rpm, 19 hours

[0490]

[0491] The post-processing procedure is the same as in Table 30.

[0492] M. Summary of Optimization

[0493] As shown in Table 32, an important finding from this embodiment is that the presence and amount of metal deposit contaminants in the reaction vessel affect the reduction of ee, making it far from the maximum ee achievable under the same conditions in a completely inert vessel. Increasing the catalyst loading in the vessel where the background reaction was observed has proven to be a way to overcome this effect on ee (items 4-5).

[0494] Table 32. Summary of optimal conditions in different containers – (R)-Phanephos+[RuCl2(p-cym)]2 (1.2:1 metal equivalents), [S] = 0.6M, MeOH, 0.1 NET equivalents, 5 bar H2, 30℃-40℃

[0495]

[0496] This example focuses on optimizing conditions using (R)-Phanephos+[RuCl2(p-cym)]2 with an S / C ratio of 1,000 / 1 to provide >90% P2 (the desired product enantiomer). Encouragingly, the reaction conditions were found to be successful at a pressure of 5 bar H2. Therefore, optimization was carried out using an S / C ratio of 1,000 / 1 and a pressure of 5 bar. This included DoE studies to investigate the effects of parameters: substrate concentration, amount of triethylamine, and temperature.

[0497] Increasing the substrate concentration had the greatest impact on reducing the obtained conversion and ee value. Reducing the amount of triethylamine used to 0.1 equivalents (relative to the substrate) was found to successfully allow complete conversion and >90% ee at a substrate concentration of 0.6 M. It was also found that using a temperature of 30–40 °C helped achieve the maximum ee value.

[0498] The optimized conditions found on a small scale were then transferred to separate Parr vessels to demonstrate hydrogenation reactions on a larger scale. Four different vessels were used in this work (Endeavor, 25 mL stainless steel Parr, 50 mL glass-lined Parr, and 300 mL stainless steel Parr) and it was found that the ee values ​​obtained in different vessels could vary due to the presence or absence of diastereoselective background reactions. To overcome this issue of achieving <90% ee, it has been shown that an S / C 200 / 1 loading is sufficient to compensate for the presence of any background reaction. Alternatively, inert vessels (i.e., glass-lined) have proven to achieve >90% ee using an S / C 1,000 / 1.

[0499] Example 3. Chiral synthesis of compounds A-1 and A-2

[0500] Synthesis of A.P2

[0501]

[0502] Step 1: Over 10 minutes, 3,4-dihydro-2H-pyran (165 mL, 1810 mmol) was added dropwise to a solution of 2,5-dihydroxybenzaldehyde (200 g, 1448 mmol) and p-toluenesulfonic acid pyridinium (18.2 g, 72.4 mmol) in DCM (3.75 L), and the reaction temperature was raised to 30 °C. The reaction was stirred for 2 hours and examined by UPLC-MS, which indicated that the reaction was 92% complete (approximately 5% of the starting material and approximately 3% of the later run unknown). The reaction was then terminated. The reaction was washed with water (1.5 L), and the DCM solution was passed through a 750 g silica pad, followed by another 2.5 L of DCM. The DCM solution was concentrated under vacuum, and the crude product was slowly diluted with petroleum ether to approximately 1 L of total volume. The mixture was stirred and cooled to approximately 10 °C to obtain a viscous yellow slurry. The product was filtered, washed with petroleum ether (2 x 150 mL), and pressed dry for 3 hours to give 2-hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (265 g, 1192 mmol, 82% yield) as a bright yellow solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ / ppm: 10.35 (s, 1H), 10.23 (s, 1H), 7.32–7.19 (m, 2H), 6.94 (d, J = 8.9 Hz, 1H), 5.36 (t, J = 3.3 Hz, 1H), 3.77 (ddd, J = 11.2, 8.8, 3.6 Hz, 1H), 3.59–3.49 (m, 1H), 1.94–1.45 (m, 6H). UPLC-MS (ES⁺, short acid): 1.64 min, m / z 223.0 [M⁺H] + (100%).

[0503] Step 2: 2-Hydroxy-5-tetrahydropyran-2-yloxy-benzaldehyde (107 g, 481 mmol) was dissolved in diethylene glycol dimethyl ether (750 mL), and K₂CO₃ (133 g, 963 mmol) was added in a single addition with stirring to give a bright yellow suspension. The reaction mixture was then heated to 140 °C, and tert-butyl acrylate (155 mL, 1059 mmol) in DMF (75 mL) was added over 10 minutes, starting at approximately 110 °C and continuing up to 130 °C. This temperature was maintained for another 1 hour. UPLC-MS indicated that the reaction had proceeded to 75%. After another hour, this indicated complete conversion to 85% of the product with few or no byproducts. After another 3 hours, UPLC-MS showed 88% of the product (previous reactions showed that further heating would not provide a higher conversion). The dark brown reaction mixture was cooled to room temperature overnight and filtered to remove inorganic matter. The reactants were suspended in EtOAc (2.5 L) and water (2.5 L) and the phases were separated. The aqueous layer was re-extracted with EtOAc (2.5 L), and the combined organic fractions were washed with brine (2 x 1.5 L) and concentrated under vacuum. The crude product was then purified on silica (2 kg) loaded with a minimum volume of DCM. A gradient of EtOAc in petroleum ether (10%–25%) was run and the clean product fractions were combined and concentrated under vacuum to provide tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate as a yellow solid (93.5 g, 281 mmol, 58% yield). 1 H NMR (400MHz, DMSO-d6) δ / ppm: 7.37 (q, J=1.2Hz, 1H), 7.05 (d, J=2.9Hz, 1H), 6.94 (dd, J=8.8, 2.9Hz, 1H), 6.79 (dd, J=8.7, 0.7Hz, 1H), 5.35 (t, J=3.3Hz, 1H), 4.82 (d, J=1.4Hz, 2H), 3.77 (ddt, J=13.3, 8.3, 4.2Hz, 1H), 3.59–3.48 (m, 1H), 1.93–1.49 (m, 6H), 1.49 (s, 9H). UPLC-MS (ES+, short acidic): 2.18min, m / z([M+H] + Not detected (100%).

[0504] Step 3: 215 g (647 mmol) of tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate was suspended in 1.6 L of MeOH at room temperature (not immediately dissolved), and pyridinium p-toluenesulfonate (16.3 g, 64.7 mmol) was added. The reaction was heated to 40 °C in a hot water bath, and the progress was monitored by UPLC-MS after 1 hour, indicating completion and a clear orange solution. The reactants were concentrated under vacuum, and the crude product was dissolved in DCM (2 L) and washed with water (1 L). The organic layer was dried (MgSO4), filtered, and concentrated under vacuum to give a crude product as a yellow solid. This crude product was suspended in petroleum ether and stirred in an ice bath before filtration to give a bright yellow solid. The solid was dried under high vacuum at 50 °C for 2 hours to give tert-butyl 6-hydroxy-2H-chromene-3-carboxylate (144.4 g, 582 mmol, 90% yield). 1 ¹H NMR (400 MHz, DMSO-d⁶) δ / ppm: 9.17 (s, 1H), 7.33 (s, 1H), 6.76–6.64 (m, 3H), 4.77 (d, J = 1.4 Hz, 2H), 1.49 (s, 9H). UPLC-MS (ES⁺, short acid): 1.71 min, m / z 247.2 [MH]⁻ (100%).

[0505] Step 4: 6-Hydroxy-2H-chromene-3-carboxylic acid tert-butyl ester (84 g, 338.34 mmol) was dissolved in DCM (500 mL), and trifluoroacetic acid (177.72 mL, 2320.9 mmol) was added at room temperature. The reaction was stirred to give a brown solution. Initially, gas escaping was observed, and the reaction was stirred at room temperature for several days. DCM and TFA were removed under vacuum, and finally, the mixture was azeotropically reacted with 200 mL of toluene, then slurried with diethyl ether and filtered to give crude 6-hydroxy-2H-chromene-3-carboxylic acid (53.15 g, 276.58 mmol, 81.745% yield) as a cream-colored solid. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.77 (s, 1H), 9.14 (s, 1H), 7.37 (t, J=1.4Hz, 1H), 6.72 (dd, J=2.4, 0.9Hz, 1H), 6.70–6.64 (m, 2H), 4.78 (d, J=1.4Hz, 2H).

[0506] Step 5: Weigh (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 6.6 mg and 3.0 mg respectively) into a 50 mL glass-lined Parr container, followed by the substrate (1.845 g, 9.6 mmol). Add methanol (16 mL, 0.6 M substrate concentration) to the container, then add triethylamine (135 μL, 0.96 mmol, 0.1 equivalent). Add a PTFE stir bar and cover the thermocouple with PTFE tape. Seal the container and purge it five times with nitrogen (at approximately 2 bar) and stir five times (at approximately 500 rpm). Then purge the container five times with hydrogen (at approximately 10 bar) and stir five times (at approximately 500 rpm). Then pressurize the container to 5 bar hydrogen pressure and heat it to 40°C (using a stirring speed of 1500 rpm). Maintain a constant pressure, but vent and refill to 5 bar after sampling. After 21.5 hours, the container was cooled. After 22.5 hours, the container was vented and purged with nitrogen. Each approximately 0.1 mL sample was diluted with MeOH to approximately 1 mL for SFC analysis. Post-processing procedure: MeOH was removed by vacuum concentration, followed by the addition of EtOAc (10 mL) and 1 M HCl (10 mL). The layers were mixed before separation. The EtOAc layer was washed with another 4 mL of 1 M HCl before removing the aqueous layer to leave the EtOAc organic phase. The aqueous layer was then washed with another 4 mL of EtOAc and the organic layers were combined. The EtOAc was then removed under vacuum to leave the product as a light gray solid (see Table 29). P2 was the first elution product with a retention time of 5.8 min, and P1 was the second elution product with a retention time of 6.1 min, using the SFC method as described in Example 1.

[0507] Synthesis of B. 5-fluoro-3,4-dihydro-1,8-naphthidium-2(1H)-one

[0508]

[0509] Step 1: 2-Amino-4-fluoropyridine (400 g, 3568 mmol) was loaded into a 10 L stationary reactor vessel and dissolved as a slurry in DCM (4 L) under a nitrogen atmosphere. DMAP (43.6 g, 357 mmol) was added and the mixture was cooled to 10 °C. Di-tert-butyl dicarbonate (934 g, 4282 mmol) was added over 1.5 hours as a solution in DCM (1 L). The reaction mixture was stirred at room temperature for 2 hours, and the complete consumption of the starting material was confirmed by NMR. N,N-dimethylethylenediamine (390 mL, 3568 mmol) was added to the reaction mixture and the mixture was heated to 40 °C overnight (to convert any di-BOC material back to the desired mono-BOC product). The mixture was cooled to room temperature, diluted with another 2 L of DCM, and washed with water (2 L). The mixture was extracted with another 2 L of DCM, washed with water (1 L), brine (1.2 L), and dried (MgSO4) before filtration. The solvent was removed under vacuum, and the resulting product was slurried in DCM / petroleum ether (1:1) (500 mL). The mixture was filtered, washed with another layer of petroleum ether, and pressed dry to give a creamy solid of N-(4-fluoro-2-pyridyl)carbamate tert-butyl ester (505 g, 2380 mmol, 67% yield). A second batch of material was separated from the mother liquor after passing through a short silica pad and subsequently grinding with DCM / petroleum ether (1:1) (approximately 200 mL) to give N-(4-fluoro-2-pyridyl)carbamate tert-butyl ester (46.7 g, 220 mmol, 6% yield). 1 ¹H NMR (400MHz, DMSO-d⁶) δ / ppm: 10.13 (d, J = 1.7Hz, 1H), 8.26 (dd, J = 9.4, 5.7Hz, 1H), 7.60 (dd, J = 12.3, 2.4Hz, 1H), 6.94 (ddd, J = 8.2, 5.7, 2.4Hz, 1H), 1.47 (s, 9H). UPLC-MS (ES⁺, short acid): 1.64 min, m / z 213.1 [M⁺H]⁺ (98%).

[0510] Step 2: Dissolve tert-butyl N-(4-fluoro-2-pyridyl)carbamate (126 g, 594 mmol) and TMEDA (223 mL, 1484 mmol) in anhydrous THF (1.7 L), and then cool to -78 °C under a nitrogen atmosphere. Add n-butyllithium solution (2.5 M in hexane) (285 mL, 713 mmol) to this solution, and then stir for 10 min. Add sec-butyllithium solution (1.2 M in cyclohexane) (509 mL, 713 mmol), maintaining the reaction temperature below -70 °C while stirring for 1 h. Thereafter, slowly and dropwise add iodine (226 g, 891 mmol) from THF (300 mL) over 30 min, maintaining the temperature below -65 °C. The mixture was stirred for another 10 minutes at -70°C, then quenched by adding saturated NH4Cl aqueous solution (400 mL), followed by adding a solution of sodium thiosulfate (134 g, 848 mmol) dissolved in water (600 mL). This addition raised the temperature to approximately -25°C. The reactants were heated to room temperature, then transferred to a 5 L separator and extracted with EtOAc (2 x 1.5 L), washed with brine (500 mL), dried (MgSO4), and then vacuum evaporated to obtain crude material (approximately 200 g). This was dissolved in hot DCM (500 mL) (the slurry was added to a silica pad), and then passed through a 2 kg silica pad. The product was thoroughly washed with DCM (10 x 1 L fractions), and then eluted from the column with EtOAc in petroleum ether (10% to 100%) (each 10% increase in 1 L fractions). This yielded two mixed fractions and a fraction containing a clean product, which were combined and evaporated under vacuum to give N-(4-fluoro-3-iodo-2-pyridyl)carbamate tert-butyl ester as a white solid (113.4 g, 335.4 mmol, 57% yield). The solid was cleaned by UPLC-MS and NMR. The mixed fraction was combined with the previous crude product to give a total of 190 g of cream-colored solid, which consisted of approximately 50% of the desired product. This was re-columned as described above to give a second batch of the combined product from all four batches, N-(4-fluoro-3-iodo-2-pyridyl)carbamate tert-butyl ester as a cream-colored solid (107.5 g, 318 mmol, 54% yield). 1 ¹H NMR (400 MHz, DMSO-d⁶) δ / ppm: 9.47 (s, 1H), 8.33 (dd, J = 8.7, 5.5 Hz, 1H), 7.19 (dd, J = 7.3, 5.5 Hz, 1H), 1.46 (s, 9H). UPLC-MS (ES⁺, short acid): 1.60 min, m / z 339.1 [M⁺H]⁺ (100%).

[0511] Step 3: N-(4-fluoro-3-iodo-2-pyridyl)carbamate tert-butyl ester (300 g, 887 mmol), 3,3-dimethoxyprop-1-ene (137 mL, 1153 mmol), and DIPEA (325 mL, 1863 mmol) were suspended in DMF (2 L) and water (440 mL) to obtain a yellow slurry. This slurry was degassed at 30 °C for 20 min. Then, palladium(II) acetate (19.92 g, 89 mmol) was added to this mixture in a single addition, followed by degassed again for 15 min. The reactants were slowly and carefully heated to 100 °C. Gases escaped at approximately 85 °C (a large amount of gas was released, possibly due to the loss of the Boc group as CO2 and isobutylene). Once the gas release was complete and complete dissolution was achieved, the reactants became darker. The reactants were then heated at 100°C for 3 hours and examined by UPLC-MS (70% desired product, 18% uncyclized intermediate, and 7% deiodinated BOC). The reactants were heated again for 2 hours, and this showed 81% desired product, 12% uncyclized intermediate, and 8% deiodinated BOC. After 7 hours, the reaction showed 89% desired product, 4% uncyclized intermediate, and 7% deiodinated BOC. The reactants were heated overnight. The reaction solution was cooled and filtered through diatomaceous earth and evaporated under vacuum to a thick, deep orange slurry, which was then suspended in water (1 L) and acidified with an aqueous HCl (4N) solution to approximately pH 1–2. It was then alkalized with a saturated aqueous NaHCO3 solution to approximately pH 9. Extraction was performed with DCM (2 x 2 L), washed with brine, and dried (MgSO4). EtOAc (2 L) was added to the solution, and the organic matter was then passed through a 500 g silica plug. This was followed by DCM / EtOAc (1:1) (2 L) and finally EtOAc (2 L) (the last wash included only the baseline). Fractions containing the product were combined and concentrated under vacuum to give an orange slurry, which was then suspended in hot diethyl ether (300 mL) and cooled to approximately 10 °C with stirring in an ice bath. The slurry was then filtered and washed with 150 mL of ice-cold diethyl ether. The slurry was pressed to dryness to give 5-fluoro-3,4-dihydro-1H-1,8-naphthidium-2-one (58.4 g, 351.5 mmol, 39.6% yield) as a creamy, fluffy solid. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ / ppm: 10.69 (s, 1H), 8.29–7.90 (m, 1H), 6.92 (dd, J = 8.8, 5.7 Hz, 1H), 2.88 (dd, J = 8.3, 7.1 Hz, 2H), 2.57–2.47 (m, 2H). UPLC-MS (ES⁺, short acid): 1.04 min, m / z 167.0 [M⁺H]⁺ (100%).

[0512] C. Synthesis of compounds A-1 and A-2

[0513]

[0514] Step 1: Potassium carbonate (832 mg, 6.02 mmol) was added to a stirred solution of 5-fluoro-3,4-dihydro-1H-1,8-naphthid-2-one (250 mg, 1.5 mmol), P2 (see Step A, 292 mg, 1.5 mmol; 85% ee), and DMSO (2 mL) at room temperature. The reaction mixture was degassed and washed three times with nitrogen, then stirred at 100 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (20 mL), and the resulting mixture was extracted with EtOAc (20 mL). A solution of citric acid (1156.3 mg, 6.02 mmol) in water (10 mL) was then added to the aqueous layer, yielding a solid precipitate. The precipitate was filtered and dried under vacuum to give (S)- or (R)-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthid-4-yl)oxy]chroman-3-carboxylic acid (345 mg, 1.01 mmol, 67% yield) as a white solid. UPLC-MS (ES+, short acid): 1.29 min, m / z 341.1 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.71 (1H, br s), 10.47 (1H, s), 7.95 (1H, d, J = 6.0Hz), 6.97 (1H, d, J = 2.4Hz), 6.89 (1H, dd, J = 8.4Hz, 2.4Hz), 6.83 (1H, d, J = 8.4Hz), 6.24 ( 1H, d, J=6.0Hz), 4.33 (1H, dd, J=11.2Hz, 3.2Hz), 4.15 (1H, dd, J=11.2Hz, 7.2Hz), 3.05-2.89 (5H, m), 2.53 (2H, t, J=7.6Hz).

[0515] Step 2: Propylphosphonic anhydride (0.91 mL, 1.52 mmol) was added to a stirred solution of (S)-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthid-4-yl)oxy]chromium-3-carboxylic acid (345 mg, 1.01 mmol), 2-amino-1-(4-fluorophenyl)ethyl ketone hydrochloride (288 mg, 1.52 mmol), N,N-diisopropylethylamine (0.88 mL, 5.07 mmol), and DCM (10 mL). After stirring for 2 hours, the reaction was complete as indicated by LC-MS. Water (50 mL) and DCM (50 mL) were added, and the organic layer was separated and washed with a saturated aqueous solution of NaHCO3 (50 mL). The organic layer was dried over sodium sulfate and the solvent was removed under vacuum. The residue was purified by column chromatography using 0%–5% MeOH in DCM as eluent to give (S)- or (R)-N-[2-(4-fluorophenyl)-2-oxo-ethyl]-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthid-4-yl)oxy]chroman-3-carboxamide (300 mg, 0.63 mmol, 62% yield) as a yellow solid. UPLC-MS (ES+, short acid): 1.52 min, m / z 476.4 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 10.47 (1H, s), 8.60-8.54 (1H, m), 8.08 (1H, dd, J=8.8Hz, 5 .6Hz), 7.95 (1H, d, J = 5.6Hz), 7.41-7.37 (2H, m), 7.01-6.97 (1H, m), 6.90 (1H, dd, J = 8.8 Hz, 3.2Hz), 6.86 (1H, d, J = 8.8Hz), 6.25 (1H, d, J = 5.6Hz), 4.65 (2H, d, J = 6.0Hz), 4.42-4.35 (1H, m), 3.96 (1H, t, J = 9.6Hz), 3.03-2.87 (5H, m), 2.55-2.52 (2H, m), No exchangeable protons were observed.

[0516] Step 3: Combine (S)- or (R)-N-[2-(4-fluorophenyl)-2-oxo-ethyl]-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthid-4-yl)oxy]chromium-3-carboxamide (300 mg, 0.63 mmol), ammonium acetate (1216 mg, 15.77 mmol), and acetic acid (5 mL) in a sealable vial. Seal the vial and stir the reaction mixture, then heat to 130 °C for 18 hours. The reaction is then confirmed to be complete by LC-MS. Cool the reaction mixture to room temperature and remove AcOH under vacuum. Add DCM (50 mL) to the residue and then add saturated NaHCO3 aqueous solution (50 mL). Separate the organic layer and wash with brine, dry over sodium sulfate, and remove the solvent under vacuum. The residue was purified by column chromatography using an eluent of 0%-10% MeOH in DCM to give (R)- or (S)-5-[3-[4-(4-fluorophenyl)-1H-imidazol-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthid-2-one as a yellow solid (141 mg, 0.31 mmol, 49% yield).

[0517] Chiral LCMS of the product and chiral LCMS of compounds A-1 and A-2 indicate that the product is mainly compound A-1 ( Figure 7 It has an ee similar to that of the starting acid (85% ee), but cannot be accurately analyzed due to peak overlap. UPLC-MS (ES+, short acid): 1.36 min, m / z 457.2 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 12.31 (0.2H, s), 12.10 (0.8H, s), 10.47 (1H, s), 7.96 (1H, d, J=6.0Hz), 7.80-7.75 (1.8H, m), 7.69-7.65 (0.2H, m), 7.59-7.78 (0.8H, m), 7.29-7.23 (0.4H, m), 7.19-7.13 (1.8H, m), 7.03-7.00 (1H , m), 6.92 (1H, dd, J = 8.8Hz, 2.8Hz), 6.89 (1H, d, J = 8.8Hz), 6.27 (1H, d, J = 6.0Hz), 4.55-4.48 (1H, m), 4.16-4.09 (1H, m), 3.44-3.36 (1H, m), 3.30-3.21 (1H, m), 3.16-3.09 (1H, m), 2.94 (2H, t, J = 7.2Hz), 2.54 (2H, t, J = 7.2Hz).

[0518] Chiral LCMS:

[0519] Chiracel OZ-RH

[0520] 150mm x 4.6mm, 5um

[0521] Mobile phase A: 20 mM ammonium bicarbonate

[0522] Mobile phase B: Acetonitrile

[0523] isocratic rate 1.2 ml / min

[0524] 50% A; 50% B

[0525] Sample diluted in methanol (1 mg / ml)

[0526] P1 can be used instead of P2 for the synthesis of the main preparative compound A-2 (see step A).

[0527] The enantiomers of the product can be separated using the following conditions:

[0528] Instrument: Thar 200 preparative SFC (SFC-7)

[0529] Column: ChiralPak AS, 300×50mm ID, 10μm

[0530] Mobile phase: A represents CO2, and B represents ethanol.

[0531] Gradient: B 50%

[0532] Flow rate: 200 mL / min

[0533] Back pressure: 100 bar

[0534] Column temperature: 38℃

[0535] Wavelength: 220nm

[0536] Cycle time: Approximately 5 minutes

[0537] Example 4. Large-scale chiral synthesis of compounds A-1 and A-2

[0538] Liquid chromatography-mass spectrometry: Unless otherwise stated, the following ultra-high performance LCMS methods and parameters are used to characterize the products of each step described in this embodiment.

[0539]

[0540]

[0541] Synthesis of A.P2

[0542]

[0543] Step 1: Dry 2,5-dihydroxybenzaldehyde (13.6 kg, 98.18 mol) at a maximum temperature of 35°C using 2x azeotropic concentration and 2x 125-130 kg of THF, concentrating to 27-41 kg under vacuum each time. Then remove THF at a maximum temperature of 35°C using 4x azeotropic concentration and 4x 179-187 kg of DCM, concentrating to 27-41 kg under vacuum each time. Dilute the concentrate with DCM (284 kg) and add pyridine p-toluenesulfonic acid (PPTS; 1.25 kg, 4.97 mol). Slowly add 3,4-dihydro-2H-pyran (10.4 kg, 123.63 mol) between 25°C and 35°C, and stir the reaction mixture at 30°C for 90 minutes. The mixture was added to a solution of Na₂CO₃ (7.1 kg) in water (138 kg) at -15°C, and the solution was heated to 25°C and stirred for 6 hours. The mixture was then transferred through... (33 kg) Filter and wash with DCM (92.5 kg). Let the filtrate stand for 1 hour, then separate the organic phase and concentrate to 27-41 kg. Then remove DCM with 3x azeotropic concentration and 3x 105 kg n-heptane at a maximum temperature of 35°C, concentrating to 27-41 kg under vacuum each time. Dilute the concentrate with n-heptane (210 kg) and heat to 30°C-40°C and stir for 6 hours. Then cool the solution to -5°C to -15°C for 4 hours, stir for 9 hours and filter, washing the filter cake with n-heptane (39.5 kg). Dry the wet filter cake under vacuum at 30°C-40°C for 24 hours to give 2-hydroxy-5-(oxane-2-yloxy)benzaldehyde (9.38 kg, 40.6%). The additional product (8.00 kg, 34.3%) was recovered by dissolving the solid adhering to the wall of the reaction vessel with 42 kg of DCM and concentrating the resulting solution under vacuum, yielding another 8.00 kg (34.3% yield) of product, for a total yield of 74.9% (17.38 kg). LCMS (ES-): 15.18 min, m / z 221.12 [MH]-.

[0544] Step 2: Add K₂CO₃ (21.4 kg, 154.83 mol) to a stirred solution of 2-hydroxy-5-(oxan-2-yloxy)benzaldehyde (16.95 kg, 76.27 mol) in diethylene glycol dimethyl ether (113.4 kg), and heat the mixture to between 80°C and 90°C. Add tert-butyl propionate (20.0 kg, 156.04 mol), and heat the mixture to between 120°C and 130°C and stir for 18 hours. Cool the mixture and filter it, and wash the filter cake with EtOAc (80.0 kg). Dilute the filtrate with EtOAc (238.0 kg) and water (338.0 kg) and stir at 20°C-30°C for 1 hour, then let it stand for 2 hours. Pass the mixture through... The filtrate was filtered (40.0 kg) and the filter cake was washed with EtOAc (84.0 kg). The filtrate was allowed to stand for 2 hours, and the aqueous layer was extracted with EtOAc (312.0 kg), stirred for 1 hour at 0-30°C, and allowed to stand for 2 hours. The organic layers were combined and washed with 2 x 345 kg of water, stirred for 1 hour at 20-30°C, and allowed to stand for 2 hours after each wash. The combined organic matter was then concentrated to 182.4 kg and kept at a temperature below 50°C under vacuum. This yielded tert-butyl 6-(oxan-2-yloxy)-2H-chromene-3-carboxylate (66.9% yield) as a 9.3% solution in diethylene glycol dimethyl ether / EtOAc, and was ready for use in the next stage without further separation. LCMS (ES-): 20.26 min, m / z 247.12 [M-THP]-.

[0545] Step 3: 16.9 kg (50.84 mol) of tert-butyl 6-(oxan-2-yloxy)-2H-chromene-3-carboxylic acid, which was a solution in 181.8 kg of diethylene glycol dimethyl ether / EtOAc, was concentrated to 68 kg under vacuum at 50 °C. TFA (110.3 kg, 1002.46 mol) was added, and the reaction mixture was heated to 40 °C under a nitrogen stream and stirred for 8 hours. The mixture was then diluted with DCM (222.0 kg) and cooled to between -5 °C and -15 °C, and stirred for 7 hours. The solid was filtered, and the filter cake was washed with DCM (67.0 kg). The wet filter cake was dried under vacuum at 30 °C–40 °C for 24 hours to give 6-hydroxy-2H-chromene-3-carboxylic acid (8.75 kg, 78.5% yield). LCMS (ES-): 0.85 min, m / z 191.11 [MH]-.

[0546] Step 4: Add (R)-Phanephos (131 g, 0.227 mol), [RuCl2(p-cym)]2 (70 g, 0.114 mol), and Et3N (5.6 kg, 55.3 mol) to a stirred solution of 6-hydroxy-2H-chromene-3-carboxylic acid (7.19 kg, 37.4 mol) in N2-degassed EtOH (60 kg). Replace the reaction atmosphere with 3x N2, then with 3x H2, adjusting the H2 pressure to between 0.5 and 0.6 MPa, and stir at 40°C for 18 hours. Then replace the atmosphere with 3x N2, then with 3x H2, again adjusting the H2 pressure to between 0.5 and 0.6 MPa, and stir the mixture for another 18 hours.

[0547] The mixture was concentrated under vacuum to approximately 30 kg at a temperature not exceeding 40 °C. The reactants were diluted with MTBE (53 kg) and cooled to between 15 °C and 25 °C. 5% Na₂CO₃ (80 kg) was added dropwise while stirring the mixture for 2 hours, and then allowed to stand for 2 hours at 15 °C and 25 °C. The aqueous layer was collected, and 5% Na₂CO₃ (48 kg) was added to the organic layer, followed by stirring at 15 °C and 25 °C for 2 hours. Filter (10.0 kg). Wash the wet filter cake with water (20 kg), and dilute the combined aqueous filtrate and aqueous layer with IPAc (129.0 kg). Adjust the pH of the mixture to 1-3 by dropwise addition of 6N HCl (29 kg) at 15-25°C and stir for 2 hours. Filter the mixture through... Filter (10 kg), wash the filter cake with IPAc (34 kg), and let the filtrate stand at 15°C-25°C for 2 hours. Then extract the aqueous layer with IPAc (34 kg) and concentrate the combined organic layers to approximately 35 kg under vacuum not exceeding 40°C. Add Me-cyclohexane (21 kg) dropwise at 15°C-25°C and concentrate to approximately 35 kg under vacuum not exceeding 40°C. Add another 20 kg of Me-cyclohexane dropwise at 15°C-25°C and stir for 3 hours. Then stir the mixture at 40°C-50°C for 4 hours and cool to 15°C-25°C over 3 hours, then stir for another 2 hours.

[0548] The mixture was then filtered, and the filter cake was washed with 16.4 kg of IPAc / Me-cyclohexane (1 / 4, v / v). The wet filter cake was vacuum dried at 35-45 °C for 24 h to give (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (5.2 kg, 68.6% yield, 95.5% chiral purity). Further products were separated by washing the solid from the reaction vessel wall with EtOH (42 kg) and concentrating to dryness. The resulting solid was suspended in IPAc (875 mL) and Me-cyclohexane (2625 mL) and stirred at 40 °C for 5 h, then cooled to 20 °C over 2 h and stirred for 16 h before filtration. The filter cake was then divided into two equal batches, and each batch was suspended in IPAc (912 mL) and Me-cyclohexane (2737 mL). The resulting mixture was stirred at 45 °C for 18 hours, then filtered, and the filter cake was dried at 45 °C to give (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (1.27 kg, 17% yield, chiral purity 96.2%). LCMS (ES-): 1.74 min, m / z 193.03 [MH]-.

[0549] Chiral separation to improve chiral purity:

[0550] (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (P2; 5.94 kg, 30.59 mol) (chiral purity = 95.5%) was dissolved in IPAc (138.2 kg) and stirred at 20-30 °C for 2 hours. The resulting solution was then subjected to... (12 kg) Filter and wash thoroughly with IPAc (25 kg). In a separate container, (S)-(+)-2-phenylglycine (4.4 kg, 32.07 mol) was dissolved in IPAc (56 kg) and stirred at 40-50°C for 1 hour. The filtrate was added to this solution after 4 hours at 40-50°C and stirred for 1 hour. The mixture was then stirred at 15-25°C for 1 hour and concentrated to approximately 120 kg under vacuum not exceeding 40°C. The concentrate was stirred at 15-25°C for 3 hours and filtered, and washed thoroughly with IPAc (12 kg). (Chiral purity = 96.2%).

[0551] The wet filter cake was redissolved in EtOH (29 kg), heated to 40-50°C, and diluted with IPAc (64 kg). 30 g of the dried product was added and stirred at 15-25°C for 30 min. The mixture was concentrated under vacuum to approximately 42 kg at no more than 40°C and redissolved with IPAc (64 kg). This step was repeated twice, followed by stirring at 40-50°C for 8 hours. The mixture was filtered and thoroughly washed with IPAc (13 kg) (chiral purity = 97.7%). This recrystallization process was repeated twice, for a total of 3 recrystallization cycles, yielding a material with a chiral purity of 98.9%.

[0552] The wet filter cake (10.7 kg) was then dissolved in 1 N HCl (45.4 kg) and stirred at 20-30°C for 1 hour. The mixture was then passed through... Filter (11.5 kg) and wash thoroughly with IPAc (28 kg). Extract the aqueous layer with IPAc (28.8 kg) and wash the combined organic layers with water (30 kg), then concentrate under vacuum at 40 °C to approximately 24 kg. Add Me-cyclohexane (19 kg) at 20 °C and concentrate the mixture under vacuum at 40 °C to approximately 24 kg. Repeat this step twice. Dilute the concentrate with Me-cyclohexane (29 kg) and stir at 15 °C–25 °C for 1 hour. Filter the mixture and wash the wet filter cake with Me-cyclohexane (59 kg). Dry the wet filter cake under vacuum at 35 °C–45 °C for 16 hours to give (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (3.02 kg, 50.2% yield).

[0553] The chiral purity of compound P2 was determined by supercritical fluid chromatography (SFC):

[0554]

[0555]

[0556] Synthesis of B. 5-fluoro-3,4-dihydro-1,8-naphthidium-2(1H)-one

[0557]

[0558] Step 1: Add DMAP (0.59 kg, 4.82 mol) to a stirred solution of 4-fluoro-2-pyridinylamine (10.6 kg, 94.55 mol) in THF (104.0 kg), maintaining the temperature between 8°C and 12°C. In a separate reaction vessel, dissolve Boc₂O (24.9 kg, 114.09 mol) in THF (19 kg) with stirring, maintaining the temperature between 20°C and 30°C and stirring for 30 minutes. Then, slowly transfer this solution to a vessel containing 4-fluoro-2-pyridinylamine at 10°C and stir the mixture for 7 hours.

[0559] N',N'-dimethylethane-1,2-diamine (10.05 kg, 114.01 mol) was then slowly added to the reaction mixture at 10 °C, and the mixture was stirred while maintaining the temperature between 38 °C and 42 °C for 22 hours. Water (42 kg) was then added over 2 hours at 25 °C, and the mixture was stirred between 20 °C and 30 °C for 2 hours. Water (202 kg) was then added over 6 hours, and the temperature was maintained at 25 °C while stirring between 20 °C and 30 °C for 1 hour. The container was then cooled to 10 °C over 2 hours and stirred for 5 hours. The mixture was filtered at 10 °C, and the wet filter cake was washed with 38.6 kg of water / THF 1 / 3 (v / v). The wet filter cake was dried at 45 °C–55 °C for 23 hours to give tert-butyl (4-fluoro-pyridin-2-yl)-carbamate (15.98 kg, 78.4% yield). LCMS (ES+): 16.59 min, m / z 156.97 [M-tBu]+.

[0560] Step 2: Dissolve (4-fluoro-pyridin-2-yl)-tert-butyl carbamate (12.6 kg, 59.36 mol) and TMEDA (17.78 kg, 153.0 mol) in THF (130 kg, 12 volumes) at -40 °C at 111.4 mL / min. -1 n-BuLi (1.6 M in n-hexane) (45.25 kg, 168.8 mol) was added at a rate of 40 mL / min. -1 Each feedstock is fed into a separate flow reactor. The residence time in this flow reactor is 14 min, after which the solution is fed into another flow reactor at -55°C to -40°C. Simultaneously, I₂ (26.7 kg, 95.3 mol) from THF (105.3 kg) is added at a rate of 70 mL / min. -1 The feed is introduced into this flow reactor. The residence time for iodization is 14 min at -55°C to -40°C, then adjusted to 0°C to 10°C and quenched with 5.0 equivalents of AcOH in water for 10 min, and then transferred to a separation vessel.

[0561] The organic layer was separated and treated with 2.0 equivalents of Na₂S₂O₃ (16.7% in water), and the organic layer was separated and diluted with EtOAc (88.2 L) and water (37.8 L). The organic matter was collected, washed with water (3 x 38.2 kg), and concentrated under vacuum to 50 L at below 30 °C. IPAc (58 kg) was added, and the resulting mixture was concentrated under vacuum to approximately 4 volumes. This process was repeated to remove residual THF to below 1%, and the resulting mixture was stirred at 10 °C to 25 °C for 3 hours, filtered, and the filter cake was washed with IPAc (37 kg). The wet filter cake was vacuum dried at 30 °C–40 °C to give the product (4-fluoro-3-iodo-pyridin-2-yl)-tert-butyl carbamate (15.1 kg, 75.2% yield). LCMS (Method A, ES+): 14.49 min, m / z 282.73 [M-tBu]⁺.

[0562] Step 3a: Mechanically stir N,N-dimethylacetamide (132 kg) and bubble N2 through the reaction vessel for 12 hours. Add Et3N (10.8 kg, 106.73 mol), butyl propionate (10.4 kg, 81.149 mol), tert-butyl (4-fluoro-3-iodopyridin-2-yl)carbamate (14.4 kg, 42.59 mol), and 10% wet Pd / C (1.45 kg), and evacuate the reaction vessel and replace the atmosphere with N2 three times. Under N2, heat the mixture to 95°C–105°C and stir for 16 hours. Then cool the mixture and pass it through the reaction vessel. (19.95kg) Filtered and thoroughly washed with EtOAc (63.6kg).

[0563] The filtrate was diluted with EtOAc (33 kg) and water (106 kg), and the mixture was stirred for 2 hours, allowed to stand for 2 hours, and then the layers were separated. The aqueous layer was extracted with 3 x 65 kg of EtOAc, each extraction being stirred for 1 hour at 20-30°C and allowed to stand for 2 hours. The combined organic matter was washed with 3 x 71 kg of water at 20-30°C, each wash being stirred for 1 hour and allowed to stand for 2 hours at 20-30°C. The organic layer was concentrated to 30-45 kg, diluted with THF (75 kg), and then THF (80 kg) was added, concentrating the solution to approximately one-sixth of its volume. This was repeated 3 times to reduce the EtOAc content to approximately 1%. This yielded (2E)-3-(2-amino-4-fluoropyridin-3-yl)prop-2-enoate butyl ester as a solution in THF (total 50.4 kg, 8.52 kg, 84% product yield). LCMS (ES+): 17.69 min, m / z 239.08 [M+H]+.

[0564] Step 3b: Two identical reactions were performed. 10% wet Pd / C (0.80 kg) was added to a stirred solution of (2E)-3-(2-amino-4-fluoropyridin-3-yl)prop-2-enoate (4.19 kg, 17.58 mol) in THF (20.61 kg). The reaction atmosphere was evacuated and replaced three times with argon, then evacuated and replaced three times with H2. The H2 pressure was adjusted to between 30 and 40 psi, and the reactants were heated to between 35°C and 45°C and stirred for 18 hours. The mixture was then passed through… (8.2 kg) Filtered and thoroughly washed with THF (21 kg) to obtain butyl 3-(2-amino-4-fluoropyridin-3-yl)propionate as a solution in THF.

[0565] Step 3c: Combine the two butyl 3-(2-amino-4-fluoropyridin-3-yl)propionate solutions in THF and concentrate to approximately one-fifth of their volume. Add EtOH (51 kg) and concentrate the resulting solution to approximately one-fifth of its volume. Repeat this process four times to reduce the residual THF to approximately 0.5%. Add EtOH (11 kg) and t-BuOK (0.20 kg, 1.8 mol), and stir at 35°C for 8 hours. Neutralize the mixture with 1 M HCl (1.6 kg) at 25°C and dilute with water (42 kg). Cool the mixture to between 5°C and 15°C and stir for 3 hours. Filter the precipitate and wash the filter cake with 2 x 27 kg of 1 / 3 (v / v) EtOH / water. The wet filter cake was vacuum dried at 40-50°C for 24 hours to give 5-fluoro-1,2,3,4-tetrahydro-1,8-naphthidin-2-one (4.9 kg, 79% yield in two steps). LCMS (ES+): 7.83 min, m / z 166.99 [M+H]+.

[0566] C. Synthesis of compound A-1

[0567]

[0568] Step 1: Add 5-fluoro-1,2,3,4-tetrahydro-1,8-naphthyl-2-one (1.54 kg, 9.27 mol) and K3PO4 (7.7 kg, 36.27 mol) to a stirred suspension of (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (1.73 kg, 8.91 mol, 98.9% chiral purity) in N2-degassed NMP (54 kg), and stir the reaction mixture at 95 °C–105 °C for 24 hours.

[0569] The reactants were then cooled to 20°C–30°C and diluted with THF (15.8 kg), followed by stirring at -15°C to -5°C for 4 hours. The reaction mixture was filtered, and the filter cake was washed with THF (19.8 kg). The wet filter cake was stirred in water (79 kg) at 15°C–25°C for 2 hours, and then adjusted to pH 1 by dropwise addition of 2N HCl (40 kg). The resulting suspension was stirred at 15°C–25°C for 3 hours, filtered, and the filter cake was washed with water (44 kg). The wet filter cake was vacuum dried at 50℃-60℃ for 36 hours, and then dried again at 55℃-65℃ for 30 hours to obtain (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (2.80 kg, 87.5% yield, 99.2% chiral purity). LCMS (ES+): 8.79 min, m / z 341.08 [M+H]+.

[0570] The chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid was determined by SFC:

[0571]

[0572]

[0573] Step 2: Add 2-(4-fluorophenyl)-2-oxoethane-1-ammonium chloride (2.32 kg, 12.24 mol) and T3P (8.50 kg, 13.36 mol) to a stirred mixture of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (2.758 kg, 8.10 mol, 99.2% chiral purity) in N2-degassed DCM (73 kg), and wash the reaction mixture with DCM (10 kg). Add DIPEA (5.80 kg, 44.88 mol) dropwise over 3 hours, and stir the reaction mixture at 20-30°C for 8 hours.

[0574] The reactants were then diluted with MTBE (42 kg) and concentrated under vacuum to 38 L at a temperature not exceeding 40 °C. The concentrate was diluted with MTBE (16 kg) and DCM (7.5 kg) and then reconcentrated under vacuum to 41 L at a temperature not exceeding 40 °C. The concentrate was stirred at 15 °C–25 °C for 1.5 hours and filtered, and the wet filter cake was washed with 12 kg of MTBE / DCM (2 / 1, v / v). The wet filter cake was resuspended in 38 kg of MTBE / DCM (2 / 1, v / v) and stirred at 15 °C–25 °C for 7 hours. The mixture was then filtered, and the filter cake was washed with 13 kg of MTBE / DCM (2 / 1, v / v). The wet filter cake was then vacuum dried at 55℃-65℃ for 24 hours to obtain (3R)-N-[2-(4-fluorophenyl)-2-oxoethyl]-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxamide (3.40 kg, 87.1%, 99.1% chiral purity). LCMS (ES+): 15.01 min, m / z 476.01 [M+H]+.

[0575] The chiral purity of (3R)-N-[2-(4-fluorophenyl)-2-oxoethyl]-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxamide was determined by SFC:

[0576]

[0577] Step 3: Under a nitrogen atmosphere at 40°C, add CF3SO2NH2 (1570 g, 25 equivalents) to an AcOH (1900 g, 9.5 vol.) solution for 30 minutes. Then, under a nitrogen atmosphere at 35°C-40°C, add NH4OAc (811 g, 25 equivalents) to the reaction vessel for 1 hour. Then, under a nitrogen atmosphere at 35°C-40°C, add P2O5 (106 g, 1.78 equivalents) to the reaction vessel for 30 minutes, followed by the addition of another AcOH (150 g, 0.75 vol.). The mixture is then stirred at 35°C-40°C for 2 hours.

[0578] Then, under a nitrogen atmosphere, P2O5 (13.5 g, 0.23 equivalents) was added to the mixture, followed by AcOH (50 g, 0.25 volume) under a nitrogen atmosphere. The mixture was then stirred at 35°C–40°C for 18 hours.

[0579] Then, (3R)-N-[2-(4-fluorophenyl)-2-oxoethyl]-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxamide (200.05 g, 1 equivalent) was added to the reaction mixture at 35-40°C under a nitrogen atmosphere for 30 minutes. The reaction temperature was raised to 90-95°C and stirred for 24 hours under a nitrogen atmosphere before being lowered to 40-50°C. NH4OAc (486.5 g, 15 equivalents) was added to the reaction mixture under a nitrogen atmosphere, and the reaction temperature was raised to 90-95°C and stirred for 24 hours.

[0580] The temperature was lowered again to 40-50°C. Under a nitrogen atmosphere, 486.5 g of NH4OAc (15 equivalents) was added to the reaction mixture, and the reaction temperature was raised to 90-95°C and stirred for 24 hours. Afterward, the temperature was lowered again to 40-50°C. Under a nitrogen atmosphere, 486.5 g of NH4OAc (15 equivalents) was added to the reaction mixture, and the reaction temperature was raised to 90-95°C and stirred for 24 hours.

[0581] The reaction temperature was then raised to 20-30°C, and an aqueous solution of NaOH (50 volumes, 5 wt.%) was added to a separate reaction vessel. 0.7 g of 5-{[(3S)-3-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl]oxy}-1,2,3,4-tetrahydro-1,8-naphthidin-2-one was added as a seed to the cooled reaction mixture. The reaction mixture was then slowly transferred to a vessel containing the NaOH solution, and the resulting mixture was stirred at 20-30°C for 12 hours. The reaction mixture was then filtered, and the filter cake was washed with water (20 volumes).

[0582] The filter cake was then dissolved in TFA (0.25 v / L), water (12.5 v / L), MeCN (7.5 v / L), and THF (2.5 v / L), and the resulting solution was purified by preparative HPLC under the following conditions:

[0583] Column: YMC Triart 250 x 50 mm, 7 μm

[0584] Mobile phase: A represents H2O (0.1% TFA), and B represents MeCN.

[0585] Flow rate: 80 mL / min

[0586] Column temperature: room temperature

[0587] Wavelength: 220nm, 254nm

[0588] Cycle time: Approximately 31 minutes

[0589] Injection: 40 mL per injection

[0590] Adding NH3·H2O to the combined fractions resulted in the precipitation of a solid. The resulting mixture was filtered, and the filtrate was concentrated under vacuum to give a grayish-white solid of 5-{[(3S)-3-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl]oxy}-1,2,3,4-tetrahydro-1,8-naphthidin-2-one (146.4 g, 75% yield, 98.6% chiral purity). LCMS (ES+): 23.00 min, m / z 457.40 [M+H]+.

[0591] The chiral purity of 5-{[(3S)-3-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl]oxy}-1,2,3,4-tetrahydro-1,8-naphthidium-2-one was determined by SFC:

[0592]

[0593]

[0594] LCMS method and parameters for 5-{[(3S)-3-[4-(4-fluorophenyl)-1H-imidazol-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl]oxy}-1,2,3,4-tetrahydro-1,8-naphthidin-2-one:

[0595]

[0596] MS parameters

[0597]

[0598]

[0599] Example 5. Single crystal analysis of (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (P2)

[0600]

[0601] Compound P2, with a 90% ee, was used for single-crystal cultivation. Single-crystal growth experiments were conducted using various solvents and through slow evaporation, vapor diffusion, and slow cooling methods. Single crystals suitable for structural analysis were obtained by slow evaporation in acetonitrile or tetrahydrofuran (THF) / water solvent systems. The crystal structures were determined using single crystals obtained in acetonitrile and THF / water solvent systems.

[0602] Slow evaporation in acetonitrile Add approximately 5-10 mg of compound P2 to a 40 mL glass vial containing 10 mL of acetonitrile. Sonicate for approximately 30 seconds, centrifuge the vial, and then evaporate the solvent under ambient conditions.

[0603] Slow evaporation in a tetrahydrofuran (THF) / water (v:v = 2:1) solvent system Add approximately 5-10 mg of compound P2 to a 1 mL glass vial containing 0.4 mL of THF / water (v:v = 2:1) solvent. After sonicating for approximately 30 seconds, filter the resulting solution or suspension through a 0.45 μm membrane filter. Transfer the filtrate to a 1 mL glass vial. Then cap the vial with a plastic cap with a pinhole. Place the vial in a fume hood to allow slow evaporation under ambient conditions.

[0604] The single-crystal structure of compound P2 was determined at 170(2) K. For single crystals obtained from both solvent systems, the absolute configuration of the chiral C atom was determined to be "R". Crystals from vials and single crystals were also collected during slow evaporation in acetonitrile for chiral purity testing. The chiral purity of the sample was 97%. Furthermore, the retention time of the main peak was consistent with that of the desired enantiomer, indicating that the absolute configuration of the desired enantiomer of compound P2 is R.

[0605] Single crystal X-ray diffractometer

[0606]

[0607] The crystal form obtained from acetonitrile is monoclinic, space group P21, R int =3.4%, absolute structural parameter =0.05 and final R1 = at 170(2) K [I>2σ(I)] =3.6% (Table 33A). The asymmetric unit contains no solvent molecules. Single crystal Or tep images of compound P2 obtained from acetonitrile are shown Figure 8A middle.

[0608] Table 33A: Crystal data of crystal forms obtained from acetonitrile

[0609]

[0610] The crystal form obtained from the THF / water solvent system is monoclinic, space group P21, R int =4.9%, absolute structural parameter = -0.04 and final R1 = at 170(2) K [I>2σ(I)] = 3.9% (Table 33B). The asymmetric unit contains no solvent molecules. Single-crystal Ortep images of compound P2 obtained from the THF / water solvent system are shown Figure 8B middle.

[0611] Table 33B: Crystal data of crystal forms obtained from THF / water

[0612]

[0613] Example 6.5 Substitute Synthesis of fluoro-3,4-dihydro-1,8-naphthidium-2(1H)-one

[0614]

[0615] Step 1: N-(4-fluoro-3-iodo-2-pyridyl)carbamate tert-butyl ester (6.4 g, 18.9 mmol), K₂CO₃ (7.9 g, 57 mmol), and [(E)-2-(ethoxycarbonyl)vinyl]boronic acid-pinacol ester (4.92 g, 21.8 mmol) were dissolved in 1,4-dioxane (120 mL) and water (25 mL), and then degassed for 15 min. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) chloride DCM complex (1.55 g, 1.9 mmol) was added to this mixture, and the reaction mixture was heated to 90 °C overnight. Initial deprotection of the 2-Boc position was observed first and proceeded cleanly; thereafter, the Suzuki product conversion took effect. The reaction mixture was evaporated to dryness and dissolved in DCM (150 mL) and treated with a saturated NH₄Cl aqueous solution (50 mL). Extracted with a separate DCM (2 x 150 mL), washed with brine, dried (MgSO4) and filtered, then evaporated to dryness under vacuum. The residue was subjected to rapid column chromatography (120 g silica), eluted with EtOAc in petroleum ether (25% to 75%). The desired compound was eluted cleanly with about 60% EtOAc in petroleum ether to give ethyl (E)-3-(2-amino-4-fluoro-3-pyridyl)prop-2-enoate as a waxy yellow solid (3.10 g, 14.8 mmol, 78% yield). 1 ¹H NMR (400 MHz, DMSO-d⁶), δ / ppm: 7.98 (dd, J = 8.9, 5.6 Hz, 1H), 7.57 (d, J = 16.1 Hz, 1H), 6.72 (s, 2H), 6.56–6.48 (m, 1H), 6.45 (dd, J = 16.2, 1.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). UPLC-MS (ES⁺, short acid): 1.1 min, m / z 211.1 [M⁺H]⁺ (100%).

[0616] Step 2: Ethyl (E)-3-(2-amino-4-fluoro-3-pyridyl)propion-2-enoate (1.0 g, 4.8 mmol) was dissolved in EtOH (10 mL) and thoroughly purged with nitrogen. Palladium (10 wt.% on carbon powder, 50% wet) (225 mg, 0.21 mmol) was added, and the reaction mixture was placed under a hydrogen atmosphere and stirred overnight at room temperature. The reaction mixture appeared primarily as reduced side chains (approximately 90%) and the desired final cyclized hinge material (8%). The reaction mixture was filtered to remove the Pd catalyst and evaporated to dryness to give a crude mixture containing the desired product ethyl 3-(2-amino-4-fluoro-3-pyridyl)propionate (900 mg, 4.09 mmol, 86% yield) and 5-fluoro-3,4-dihydro-1H-1,8-naphthidium-2-one (64 mg, 0.46 mmol, 10% yield) as components. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 7.79 (dd, J=9.1, 5.6Hz, 1H), 6.38 (dd, J=9.2, 5.7Hz, 1H), 6.11 (s, 2H), 4.0 4 (q, J=7.1Hz, 2H), 2.73 (ddd, J=8.1, 6.8, 1.3Hz, 2H), 2.45 (dd, J=8.4, 7.0Hz, 2H), 1.16 (t, J=7.1Hz, 3H).

[0617] Step 3: Ethyl 3-(2-amino-4-fluoro-3-pyridyl)propionate (950 mg, 4.5 mmol) was dissolved in THF (10 mL), then treated with KOtBu (754 mg, 6.7 mmol) and stirred at room temperature for 30 min. The reaction was quenched by adding saturated NH4Cl aqueous solution (2 mL), evaporated to dryness under vacuum, then dissolved in water and sonicated thoroughly. The precipitate was slurried in water for 1 hour and the solid was filtered off, washed with water and dried in a vacuum oven to give 5-fluoro-3,4-dihydro-1H-1,8-naphthidium-2-one (691 mg, 4.2 mmol, 93% yield) as a fluffy white solid. ¹H NMR (400 MHz, DMSO-d6) δ / ppm: 10.69 (s, ¹H), 8.23–7.96 (m, ¹H), 6.91 (dd, J = 8.8, 5.7 Hz, ¹H), 2.88 (dd, J = 8.3, 7.1 Hz, 2H), 2.50 (s, 2H). UPLC-MS (ES+, short acid): 1.07 min, m / z 166.9 [M+H]+ (100%).

[0618] Example 7.5-Alternative Synthesis of fluoro-3,4-dihydro-1,8-naphthidium-2(1H)-one

[0619]

[0620] Step 1: N-(4-fluoro-3-iodo-2-pyridyl)carbamate tert-butyl ester (150 g, 444 mmol) was suspended in 1,4-dioxane (1.25 L) containing butyl acrylate (159 mL, 1109 mmol) and TEA (155 mL, 1109 mmol) was added. Palladium (10 wt.% on carbon powder, 50% wet) (10.6 g, 99.8 mmol) was added, and the reaction mixture was stirred and heated to reflux overnight, then cooled. UPLC-MS indicated 94% of the desired product. The reaction mixture was diluted with water (750 mL) and EtOAc (500 mL) and filtered through diatomaceous earth to remove the catalyst. The mixture was washed thoroughly with EtOAc (500 mL). The layers were separated, and the aqueous layer was re-extracted with EtOAc (500 mL). The combined organic layers were washed with water (500 mL), dried (MgSO4), filtered, and concentrated under vacuum to give (E)-3-(2-amino-4-fluoro-3-pyridyl)prop-2-enoate butyl ester (117.5 g, 439 mmol, 99% yield), which was a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 7.98 (dd, J=8.9, 5.5Hz, 1H), 7.56 (d, J=16.1Hz, 1H), 6.71 (s, 2H), 6.56–6. 40 (m, 2H), 4.15 (t, J=6.6Hz, 2H), 1.63 (dq, J=8.4, 6.7Hz, 2H), 1.45–1.29 (m, 2H), 0.92 (t, J=7.3Hz, 3H). UPLC-MS(ES + (Short acidic): 1.47 min, m / z 239.3 [M+H] + (100%).

[0621] Step 2: Ethyl (E)-3-(2-amino-4-fluoro-3-pyridyl)propion-2-enoate (1.0 g, 4.8 mmol) was dissolved in EtOH (10 mL) and thoroughly purged with nitrogen. Palladium (10 wt.% on carbon powder, 50% wet) (225 mg, 0.21 mmol) was added, and the reaction mixture was placed under a hydrogen atmosphere and stirred overnight at room temperature. The reaction mixture appeared primarily to have reduced side chains (approximately 90%) and the desired final cyclized material (8%). The reaction mixture was filtered to remove the Pd catalyst and evaporated to dryness to give a crude mixture containing the desired product ethyl 3-(2-amino-4-fluoro-3-pyridyl)propionate (900 mg, 4.09 mmol, 86% yield) and 5-fluoro-3,4-dihydro-1H-1,8-naphthidium-2-one (64 mg, 0.46 mmol, 10% yield) as components. 1H NMR (400MHz, DMSO-d6) δ / ppm: 7.79 (dd, J=9.1, 5.6Hz, 1H), 6.38 (dd, J=9.2, 5.7Hz, 1H), 6.11 (s, 2H), 4.0 4 (q, J=7.1Hz, 2H), 2.73 (ddd, J=8.1, 6.8, 1.3Hz, 2H), 2.45 (dd, J=8.4, 7.0Hz, 2H), 1.16 (t, J=7.1Hz, 3H).

[0622] Step 3: Dissolve ethyl 3-(2-amino-4-fluoro-3-pyridyl)propionate (950 mg, 4.5 mmol) in THF (10 mL), then use KO... t The mixture was treated with Bu (754 mg, 6.7 mmol) and stirred at room temperature for 30 min. The reaction was quenched by adding saturated NH4Cl aqueous solution (2 mL), evaporated to dryness under vacuum, dissolved in water, and thoroughly sonicated. The precipitate was slurried in water for 1 hour and the solid was filtered off, washed with water, and dried in a vacuum oven to give 5-fluoro-3,4-dihydro-1H-1,8-naphthid-2-one (691 mg, 4.2 mmol, 93% yield) as a fluffy white solid. 1 H NMR (400MHz, DMSO-d6) δ / ppm: 10.69 (s, 1H), 8.23–7.96 (m, 1H), 6.91 (dd, J=8.8, 5.7Hz, 1H), 2.88 (dd, J=8.3, 7.1Hz, 2H), 2.50 (s, 2H). UPLC-MS(ES + (Short acidic): 1.07 min, m / z 166.9 [M+H] + (100%).

[0623] Example 8. Biological assay

[0624] HCT-116AlphaLISA SureFire pERK1 / 2 Cell Assay

[0625] Human HCT-116 colorectal cancer cell line (ATCC CCL-247) endogenously expresses KRAAS G13D The mutation leads to constitutive activation of the MAP kinase pathway and phosphorylation of ERK. To determine whether the compound inhibits constitutive ERK phosphorylation in HCT-116 cells, a assay was performed using... The assays were performed using the Perkin Elmer p-ERK1 / 2p-T202 / Y204 assay kit (ALSU-PERK-A10K). Readouts were taken 2 or 24 hours after compound administration. On day 1, HCT-116 cells were harvested, resuspended in growth medium (McCoys 5A containing Glutamax (Life Technologies 36600021) and 10% heat-inactivated fetal bovine serum (Sigma F9665)) and counted. Cells were plated at 100 μl per well in each well of a 96-well culture dish (Sigma CLS3598) to a final density of 30,000 cells per well (2-hour readout) or 15,000 cells per well (24-hour readout) and incubated overnight at 37°C and 5% CO2. On day 2, the growth medium was replaced with drug-treated medium (McCoys5A containing Glutamax (Life Technologies 36600021) and 1% heat-inactivated fetal bovine serum (Sigma F9665)) and the compound was administered to cells to produce a 10-point dose-response, with the highest concentration being 1 μM and subsequent concentrations at 1 / 3 logarithmic dilution intervals. A matched DMSO control was included. Cells were then incubated at 37°C and 5% CO2 for 2 or 24 hours. After incubation, the medium was removed and cells were incubated at room temperature for 15 minutes with lysis buffer containing a phosphatase inhibitor. Cell lysates were transferred to 96-well white Optiplate cells at half area. TM In PerkinElmer 6005569, the mice were incubated with anti-mouse IgG receptor beads (a biotinylated anti-ERK1 / 2 rabbit antibody that recognizes phosphorylated and non-phosphorylated ERK1 / 2), a mouse antibody targeting the Thr202 / Tyr204 epitope and recognizing only phosphorylated ERK protein, and streptavidin-coated donor beads. The biotinylated antibody bound to the streptavidin-coated donor beads, and the phosphate-ERK1 / 2 antibody bound to the receptor beads. The plate was read on an EnVision reader (Perkin Elmer), and laser excitation at 680 nm induced the release of singlet oxygen molecules from the donor beads, triggering energy transfer to nearby receptor beads, generating a signal measurable at 570 nm. Both antibodies bound to phosphorylated ERK protein, ensuring close proximity between the donor and receptor beads. All data were analyzed using Dotmatics or GraphPad Prism software packages. Absolute IC50 was measured. 50 The absolute IC50 value is used to evaluate the inhibition of ERK phosphorylation. 50 The value was defined as the concentration of the compound required to reduce phosphorylated ERK protein levels by 50% compared to the DMSO control.

[0626] WiDr AlphaLISA SureFire pERK1 / 2 Cell Assay

[0627] Human WiDr colorectal adenocarcinoma cell line (ATCC CCL-218) endogenously expresses BRAF. V600E Mutations lead to constitutive activation of the MAP kinase pathway and phosphorylation of ERK. To determine whether the compound inhibits constitutive ERK phosphorylation in WiDr cells, A... The technology (Perkin Elmer p-ERK1 / 2p-T202 / Y204 assay kit ALSU-PERK-A10K) was used to test them. The main procedure was basically the same as that used for HCT-116 cells (as described above), with the following adjustments made to the growth medium (Iger's minimum essential medium (Sigma M2279) containing 1x Glutamax (Life Technologies 35050038), 1x sodium pyruvate (Sigma S8636), and 10% heat-inactivated fetal bovine serum (Sigma F9665)), the administration medium (Iger's minimum essential medium (Sigma M2279) containing 1x Glutamax (Life Technologies 35050038), 1x sodium pyruvate (Sigma S8636), and 1% heat-inactivated fetal bovine serum (Sigma F9665)) and the seeding density (2 hours: 50,000 cells per well; 24 hours: 35,000 cells per well). In addition, the compound was administered at 1 / 2 logarithmic dilution intervals, with a maximum concentration of 10 μM.

[0628] HCT-116AlphaLISA SureFire pERK1 / 2 Cell Assay (Dimer)

[0629] Human HCT-116 colorectal cancer cell line (ATCC CCL-247) endogenously expresses KRAS. G13D Mutations lead to constitutive activation of the MAP kinase pathway and phosphorylation of ERK. First-generation RAF inhibitors promote RAF dimer formation in KRAS-mutant tumors, resulting in paradoxical activation of this pathway. To determine whether compounds can address this issue and inhibit RAF dimerization in HCT-116 cells, [the following was performed] using [a specific method / technology]. The technology (Perkin Elmer p-ERK1 / 2p-T202 / Y204 assay kit ALSU-PERK-A10K) was used to test them. The main procedure was basically the same as described above, with the following adjustments: cells were seeded at a density of 30,000 cells per well. No medium change was performed on the second day (the day of administration), and the cells were administered 1 μM enoxacin for 1 hour (at 37°C and 5% CO2) to induce RAF dimerization and promote paradoxical dimer-dependent pERK signaling. After incubation, the cells were washed, 100 μL of fresh growth medium was added, and the target compound was administered to the cells to produce a 10-point dose response, with the highest concentration being 10 μM and subsequent concentrations at 1 / 2 logarithmic dilution intervals. The cells were incubated again at 37°C and 5% CO2 for 1 hour before lysis and pERK was administered as described above. The reagent kit is processed.

[0630] A375 AlphaLISA SureFire pERK1 / 2 Cell Assay (Single Cell)

[0631] Human A375 melanoma cell line (ATCC CRL-1619) endogenously expresses BRAF. V600E Mutations lead to constitutive activation of the MAP kinase pathway and phosphorylation of ERK. In BR AF V600E In mutant tumors, BRAF acts as a monomer to signal and activate ERK. To determine whether a compound could inhibit BRAF monomers in A375 cells, AlphaLI was used. The technology (Perkin Elmer p-ERK1 / 2p-T202 / Y204 assay kit ALSU-PERK-A10K) was used to test them. The main procedure was essentially the same as described above for HCT-116 cells, with the following adjustments: A375 cells were cultured and drugged in DuPont modified Eagle's medium containing 4.5 g / L L-glucose (Sigma D6546), 10% heat-inactivated fetal bovine serum (Sigma F9665), and 1% sodium pyruvate (Sigma S8636) at a seeding density of 30,000 cells per well. No medium exchange was performed before drug administration of the compound to produce a 10-point dose response, with the highest concentration being 10 μM and subsequent concentrations at 1 / 2 logarithmic dilution intervals. Subsequently, the cells were incubated at 37°C and 5% CO2 for 1 hour before lysis.

[0632] HCT-116CellTiter-Glo 3D Cell Proliferation Assay

[0633] Human HCT-116 colorectal cancer cell line (ATCC CCL-247) endogenously expresses KRAS. G13D Mutations that lead to enhanced survival and proliferation signaling. To determine whether the compound inhibits the proliferation of HCT-116 cells, [the following was performed] using [a specific method / technology]. The cells were tested using a 3D cell viability assay kit (Promega G9683). On day 1, HCT-116 cells were harvested, resuspended in growth medium (McCoys 5A containing Glutamax (Life Technologies 36600021) and 10% heat-inactivated fetal bovine serum (Sigma F9665)) and counted. Cells were plated at 100 μl per well to a final density of 1000 cells per well in each well of a Corning 7007 96-well clear round-bottom ultra-low adhesion plate (VWR 444-1020). Seeding was used for pre-treatment and post-treatment readouts. The cells were then incubated at 37°C and 5% CO2 for 3 days (72 hours) to form spheroids. After 72 hours, the plates seeded for pre-treatment readouts were removed from the incubator and allowed to equilibrate at room temperature for 30 minutes before being seeded. Reagent was added to each well. The plate was incubated at room temperature with shaking at 300 rpm for 5 minutes, then on a workbench for 25 minutes, followed by reading on an Envision reader (Perkin Elmer) as described below. On the same day, the compound was administered to cells plated for post-treatment reading to produce a 9-point dose response, with the highest concentration being 15 μM and subsequent concentrations at 1 / 2 logarithmic dilution intervals. These cells were then incubated at 37°C and 5% CO2 for another 4 days (96 hours). After 4 days, the plate was removed from the incubator to allow equilibration to room temperature for 30 minutes and read as described above. Reagent treatment. The method allows for the quantification of ATP present in the wells, which is proportional to the number of live cells in the 3D cell culture and therefore possesses metabolic activity. The reagent lyses cells and contains luciferin and luciferase (Ultra-Glo). TM Recombinant luciferase (RF) generates bioluminescence from luciferin in the presence of ATP and oxygen. Therefore, the plate was read and the luminescence signal recorded using an EnVision reader (Perkin Elmer). Cell proliferation was determined 4 days after drug administration, relative to pre-treatment readings. All data were analyzed using Dotmatics or GraphPad Prism software packages. GI was measured... 50 The value was used to assess the inhibition of proliferation, and the value was defined as the concentration of the compound required to reduce the cell proliferation level by 50% compared with the DMSO control.

[0634] WiDr CellTiter-Glo 3D Cell Proliferation Assay

[0635] Human WiDr colorectal adenocarcinoma cell line (ATCC CCL-218) endogenously expresses BRA F V600E Mutations that lead to enhanced survival and proliferation signaling. To determine whether the compound inhibits the proliferation of WiDr cells, [the following was used]. The 3D cell viability assay kit (Promega G9683) was used to test HCT-116 cells as described for the cells, with the growth medium adjusted as follows: Eagle's minimum essential medium (Sigma M2279) containing 1x Glutamax (Life Technologies 35050038), 1x sodium pyruvate (Sigma S8636), and 10% heat-inactivated fetal bovine serum (Sigma F9665).

[0636] Table 34A. Cell assay results

[0637]

[0638]

[0639] Table 34B. Cell assay results

[0640]

[0641] Microparticle stability determination

[0642] Stability studies were performed manually using a substrate reduction method. The test compound was administered at 37°C with cryopreserved mouse or human liver microsomes (Corning) at a dose of 0.5 mg / mL. -1 The mixture was incubated with a protein concentration of 1 μM and a final substrate concentration of 1 μM. Aliquots were removed from the incubator at defined time points, and the reaction was terminated by adding an ice-cold organic solvent. Compound concentrations were determined by LC-MS / MS analysis. The natural logarithm of the percentage of remaining compound was plotted for each time point, and the slope was determined. Half-life (t) 1 / 2 ) and CL int Calculate using Equations 1 and 2 respectively. Perform data analysis using Excel (Microsoft, USA).

[0643] t 1 / 2 (min)=0.693 / - slope(1)

[0644] CL int (μL / min / mg)=(LN(2) / t 1 / 2(min))*1000 / microsomal protein (mg / mL) (2)

[0645] The results of the stability assays for HLM (human liver microsomes) and MLM (mouse liver microsomes) are described in Table 34C.

[0646] Hepatocyte stability assay

[0647] Hepatocyte stability studies were performed manually using a substrate reduction method. The compound was mixed with cryopreserved mouse (Bioreclamation) or human (Corning) hepatocytes at 0.5 x 10⁻⁶ at 37°C. 6 Incubation was performed at a cell density of 1 cell / mL and a final compound concentration of 1 μM. Sampling was conducted at defined time points, and the reaction was terminated by adding an ice-cold organic solvent. Compound concentrations were determined by LC-MS / MS analysis. The natural logarithm of the percentage of remaining compound was plotted for each time point, and the slope was determined. Half-life (t) 1 / 2 ) and CL int Calculate using Equations 1 and 3 respectively. Perform data analysis using Excel (Microsoft, USA).

[0648] CL int (μL / min / 10 6 (number of cells) = (LN(2) / t) 1 / 2 (min))*1000 / cell density(10 6 (3) cells / mL

[0649] The results of the HLH (human hepatocytes) and MLH (mouse hepatocytes) stability assays are described in Table 34C.

[0650] Table 34C. Stability

[0651]

[0652]

[0653] Plasma protein binding assay

[0654] Plasma protein binding was determined by balanced dialysis. Compounds (5 μM) at known concentrations in previously frozen human or mouse plasma (Sera Labs) were dialyzed against phosphate-buffered saline for 4 hours at 37°C using a RED device (Life Technologies). Compound concentrations on the protein-containing (PC) and protein-free (PF) sides of the dialysis membrane were determined by LC-MS / MS, and the percentage of free compound was determined by Equation 4. Data analysis was performed using Excel (Microsoft, USA).

[0655] Free % = (1 - ((PC - PF) / PC)) x 100 (4)

[0656] The results for hPPB (human plasma protein binding) and mPPB (mouse plasma protein binding) are described in Table 34D.

[0657] FeSSIF solubility determination

[0658] 1 mL of a fed-state simulated intestinal fluid (FeSSIF) prepared using FaSSIF / FeSSIF / FaSSGF powder (Biorelevant.com) and pH 5 acetate buffer was added to 1.0 mg of the compound, and then incubated for 24 h (Bioshake iQ, 650 rpm, 37 °C). After filtration under positive pressure, the concentration of the compound in the solution was assessed by LC-UV and compared with the response of a calibration standard at a known concentration (250 μM). The FeSSIF solubility results are described in Table 34D.

[0659] Table 34D. Plasma protein binding and solubility

[0660]

[0661] The publications discussed herein are provided solely for the purposes of their prior disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the invention is not entitled to such prior disclosure due to prior invention.

[0662] While the invention has been described in conjunction with specific embodiments proposed herein, it is to be understood that further modifications can be made to the invention, and this application is intended to cover any variations, uses, or alterations generally made in accordance with the principles of the invention, including deviations from known or conventional practices in the field to which the invention pertains, as well as from the essential features set forth above and the scope of the appended claims.

[0663] Implementation plan with numbering

[0664] Implementation Scheme 1. A method for synthesizing a compound of formula (IIb) or a pharmaceutically acceptable salt or tautomer thereof,

[0665]

[0666] in:

[0667] R 3 It is halogen, -OR A -NR A R B -SO2R C -SOR C -CN,C 1-4 Alkyl, C1-4 Halogenated alkyl or C 3-6 Cycloalkyl, wherein the alkyl, haloalkyl, and cycloalkyl groups are optionally substituted by one to three independently selected groups from: -OR A -CN, -SOR C or -NR A R B ;

[0668] R A and R B Each is independently selected from H and C. 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0669] R C Selected from C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0670] n is 0, 1, 2, 3 or 4;

[0671] The method includes:

[0672] a) React 5-fluoro-3,4-dihydro-1,8-naphthidin-2(1H)-one with (R)-6-hydroxy-som-3-carboxylic acid to provide (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy)som-3-carboxylic acid;

[0673]

[0674] b) Reacting (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy)chroman-3-carboxylic acid with 2-amino-1-phenylethyl-1-one or a salt thereof to provide a compound of formula 4B-(R).

[0675] 2-Amino-1-phenylethyl-1-one is optionally replaced by R 3 Replace; and

[0676]

[0677] c) Cyclate the compound of formula 4B-(R) from step b) in the presence of ammonia or an ammonium salt to provide the compound of formula (IIb) or a pharmaceutically acceptable salt or tautomer thereof.

[0678]

[0679] Implementation Scheme 2. The method as described in Implementation Scheme 1, wherein (R)-6-hydroxychromene-3-carboxylic acid is prepared by the chiral hydrogenation of 6-hydroxy-2H-chromene-3-carboxylic acid.

[0680]

[0681] Implementation Scheme 3. The method as described in Implementation Scheme 2, wherein the chiral hydrogenation is carried out in the presence of a Ru or Rh catalyst and a chiral ligand.

[0682] Implementation Scheme 4. The method as described in Implementation Scheme 3, wherein the Ru or Rh catalyst is selected from Ru(OAc)2, [RuCl2(p-cym)]2, Ru(COD)(Me-allyl)2, Ru(COD)(TFA)2, [Rh(COD)2]OTf or [Rh(COD)2]BF4.

[0683] Implementation Scheme 5. The method as described in Implementation Scheme 3 or 4, wherein the Ru catalyst is selected from [RuCl2(p-cym)]2, Ru(COD)(Me-allyl)2 or Ru(COD)(TFA)2.

[0684] Implementation Scheme 6. The method of any one of Implementation Schemes 3-5, wherein the chiral ligand is selected from (R)-PhanePhos or (R)-An-PhanePhos.

[0685] Implementation Scheme 7. The method of Implementation Scheme 3, wherein the chiral hydrogenation is carried out in the presence of a chiral Ru-complex or a chiral Rh-complex.

[0686] Implementation Scheme 8. The method as described in Implementation Scheme 7, wherein the chiral Ru-complex or the chiral Rh-complex is selected from [(R)-Phanephos-RuCl2(p-cym)] or [(R)-An-Phanephos-RuCl2(p-cym)].

[0687] Implementation Scheme 9. The method of any one of Implementation Schemes 2-8, wherein the chiral hydrogenation is carried out with a substrate / catalyst loading in the range of about 25 / 1 to about 1,000 / 1.

[0688] Implementation Scheme 10. The method of any one of Implementation Schemes 2-8, wherein the chiral hydrogenation is carried out with a substrate / catalyst loading in the range of about 200 / L to about 1,000 / L.

[0689] Implementation Scheme 11. The method of any one of Implementation Schemes 2-10, wherein the chiral hydrogenation is carried out in the presence of a base.

[0690] Implementation Scheme 12. The method as described in Implementation Scheme 11, wherein the base is triethylamine, NaOMe, or Na2CO3.

[0691] Implementation Scheme 13. The method of Implementation Scheme 11 or 12, wherein the base is used in an equivalent of about 2.0, about 1.9, about 1.8, about 1.7, about 1.6, about 1.5, about 1.4, about 1.3, about 1.2, about 1.1, about 1.0, about 0.9, about 0.8, about 0.7, about 0.6, about 0.5, about 0.4, about 0.3, about 0.2 or about 0.1 of 6-hydroxy-2H-chromene-3-carboxylic acid.

[0692] Implementation Scheme 14. The method of any one of Implementation Schemes 2-13, wherein the chiral hydrogenation is carried out at a temperature in the range of about 30°C to about 50°C.

[0693] Implementation Scheme 15. The method of any one of Implementation Schemes 2-14, wherein the chiral hydrogenation is carried out at a concentration of 6-hydroxy-2H-chromene-3-carboxylic acid in the range of about 0.2 M to about 0.8 M.

[0694] Implementation Scheme 16. The method of any one of Implementation Schemes 2-15, wherein the chiral hydrogenation is carried out at a hydrogen pressure in the range of about 2 bar to about 30 bar.

[0695] Implementation Scheme 17. The method of any one of Implementation Schemes 2-15, wherein the chiral hydrogenation is carried out at a hydrogen pressure in the range of about 3 bar to about 10 bar.

[0696] Implementation Scheme 18. The method of any one of Implementation Schemes 2-17, wherein the chiral hydrogenation is carried out in an alcohol solvent.

[0697] Implementation Scheme 19. The method as described in Implementation Scheme 18, wherein the solvent is methanol, ethanol or isopropanol.

[0698] Implementation Scheme 20. The method of any one of Implementation Schemes 1-19, wherein (R)-6-hydroxychroman-3-carboxylic acid has an enantiomeric excess of at least 90%.

[0699] Implementation Scheme 21. The method of any one of Implementation Schemes 1-19, wherein (R)-6-hydroxychroman-3-carboxylic acid has an enantiomeric excess of at least 95%.

[0700] Implementation Scheme 22. The method of any one of Implementation Schemes 1-21, wherein (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy)chroman-3-carboxylic acid has an enantiomeric excess of at least 90%.

[0701] Implementation Scheme 23. The method of any one of Implementation Schemes 1-21, wherein (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy)chroman-3-carboxylic acid has at least 95% enantiomeric excess.

[0702] Implementation Scheme 24. The method of any one of Implementation Schemes 1-23, wherein the formula 4B-(R) compound in step b) has an enantiomeric excess of at least 90%.

[0703] Implementation Scheme 25. The method of any one of Implementation Schemes 1-23, wherein the formula 4B-(R) compound in step b) has at least 95% enantiomeric excess.

[0704] Implementation Scheme 26. The method of any one of Implementation Schemes 1-25, wherein the compound of formula (IIb) or a pharmaceutically acceptable salt or tautomer thereof has an enantiomer excess of at least 90%.

[0705] Implementation Scheme 27. The method of any one of Implementation Schemes 1-25, wherein the compound of formula (IIb) or a pharmaceutically acceptable salt or tautomer thereof has an enantiomer excess of at least 95%.

[0706] Implementation Scheme 28. The method of any one of Implementation Schemes 1-25, wherein the compound of formula (IIb) or a pharmaceutically acceptable salt or tautomer thereof has an enantiomer excess of at least 98%.

[0707] Implementation Scheme 29. The method as described in any one of Implementation Schemes 1-28, wherein R 3 It is halogen, C 1-4 Alkyl group, -SO2(C 1-4 alkyl).

[0708] Implementation Scheme 30. The method as described in any one of Implementation Schemes 1-28, wherein R 3 It is F, Cl, Br, or I.

[0709] Implementation scheme 31. The method as described in any one of implementation schemes 1-30, wherein n is 0, 1 or 2.

[0710] Implementation Scheme 32. The method of any one of Implementation Schemes 1-31, wherein the compound is Or its pharmaceutically acceptable salts or tautomers.

[0711] Implementation Scheme 33. A compound of formula (IIb) or a pharmaceutically acceptable salt or tautomer thereof, prepared by any one of Implementation Schemes 1-32.

[0712] Implementation Scheme 34. A structure The compound or its pharmaceutically acceptable salt or tautomer, prepared by any one of embodiments 1-32.

[0713] Implementation Scheme 35. The compound as described in Implementation Scheme 33 or 34, wherein the compound has an enantiomer excess of at least 90%.

[0714] Implementation Scheme 36. The compound of any one of Implementation Schemes 33-35, wherein the compound has at least 95% enantiomer excess.

[0715] Implementation Scheme 37. The compound of any one of Implementation Schemes 33-36, wherein the compound has an enantiomer excess of at least 98%.

[0716] Implementation Scheme 38. The compound of any one of Implementation Schemes 33-37, wherein the compound has a chemical purity of 85% or higher.

[0717] Implementation Scheme 39. The compound of any one of Implementation Schemes 33-38, wherein the compound has a chemical purity of 90% or higher.

[0718] Implementation Scheme 40. The compound of any one of Implementation Schemes 33-39, wherein the compound has a chemical purity of 95% or higher.

[0719] Implementation Scheme 41. A pharmaceutical composition comprising a compound as described in any one of Implementation Schemes 33-40 and a pharmaceutically acceptable excipient or carrier.

[0720] Implementation Scheme 42. The pharmaceutical composition as described in Implementation Scheme 41, wherein the pharmaceutical composition further comprises an additional therapeutic agent.

[0721] Implementation Scheme 43. The pharmaceutical composition of Implementation Scheme 42, wherein the additional therapeutic agent is selected from antiproliferative or antitumor drugs, cell growth inhibitors, anti-invasive agents, growth factor function inhibitors, anti-angiogenic agents, steroids, targeted therapeutic agents, or immunotherapeutic agents.

[0722] Implementation Scheme 44. A method for treating a disorder regulated by RAF kinase, the method comprising administering to a subject in need an effective amount of a compound as described in any one of Implementation Schemes 33-40.

[0723] Implementation Scheme 45. The method as described in Implementation Scheme 44, wherein the disease can be treated by inhibiting one or more Raf kinases.

[0724] Implementation Scheme 46. The method as described in Implementation Scheme 44 or 45, wherein the disease is selected from cancer, sarcoma, melanoma, skin cancer, hematologic malignancy, lymphoma, carcinoma, or leukemia.

[0725] Implementation Scheme 47. The method described in Implementation Scheme 44 or 45, wherein the disease is selected from Barrett's adenocarcinoma; bile duct cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma, astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (tumors originating outside the central nervous system that metastasize to the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancer; squamous cell carcinoma of the head and neck; acute lymphoblastic leukemia; acute myeloid leukemia (AML); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; kidney cancer; metastatic melanoma; or thyroid cancer.

[0726] Implementation Scheme 48. A method for treating cancer, the method comprising administering to a subject in need an effective amount of a compound as described in any one of Implementation Schemes 33-40.

[0727] Implementation Scheme 49. The method as described in Implementation Scheme 48, wherein the cancer includes at least one mutation of BRAF kinase.

[0728] Implementation Scheme 50. The method as described in Implementation Scheme 49, wherein the cancer includes BRAF. V600E mutation.

[0729] Implementation Scheme 51. The method as described in Implementation Scheme 49, wherein the cancer is selected from melanoma, thyroid cancer, Barrett's adenocarcinoma, bile duct cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumors, glioblastoma, astrocytoma, ependymoma, colorectal cancer, colon cancer, gastric cancer, head and neck cancer, hematologic cancers, leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryocyte leukemia, multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, kidney cancer, sarcoma, uveal melanoma, or skin cancer.

[0730] Implementation Scheme 52. The method as described in Implementation Scheme 50, wherein the cancer is BRAF. V600E melanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid carcinoma, BRAFV600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAF V600E Hepatobiliary carcinoma, BRAF V600E Hairy cell leukemia, BRAF V600E Non-small cell carcinoma or BRAF V600E Pilocytic astrocytoma.

[0731] Implementation scheme 53. The method of any one of implementation schemes 2 46-52, wherein the cancer is colorectal cancer.

Claims

1. A method for synthesizing a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, in: R 1 selected from substituted or unsubstituted: C 1-6 alkyl, C 1-6 haloalkyl, aryl, heterocyclyl, or heteroaryl; R 2 is H; X 1 is N or CR 8 ; X 2 is N or CR 9 ; R 6 is hydrogen, halogen, alkyl, alkoxy, -NH2, -NR F C(O)R 5 , -NR F C(O)CH2R 5 , -NR F C(O)CH(CH3)R 5 or -NR F R 5 ; R 7 R 8 and R 9 Each is independently hydrogen, halogen, or alkyl; Alternatively, R 6 and R 8 or R 7 and R 9 Together with the atoms to which they are attached, they form 5- or 6-membered partially unsaturated or unsaturated rings containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the rings are substituted or unsubstituted. R 5 It is a substituted or unsubstituted group selected from alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups; and R F Selected from H or C 1-3 alkyl; The method includes: a) Reacting compound 1A with (R)-6-hydroxychroman-3-carboxylic acid or (S)-6-hydroxychroman-3-carboxylic acid to provide compound 2A; Compound 2A has (R) or (S) stereochemistry at the carbon indicated by *; b) React compound 2A with compound 3A or a salt thereof to provide compound 4A; Compound of formula 4A has (R) or (S) stereochemistry at the carbon indicated by *; and c) Cycling the compound of formula 4A from step b) in the presence of ammonia or an ammonium salt to provide the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the method synthesizes compound (IIa) or (IIb) or a pharmaceutically acceptable salt thereof. in: R 3 It is halogen, -OR A -NR A R B -SO2R C -SOR C -CN,C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 3-6 Cycloalkyl, wherein the alkyl, haloalkyl, and cycloalkyl groups are optionally substituted by one to three independently selected groups from: -OR A -CN, -SOR C or -NR A R B ; R A and R B Each independently represents H and C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups; R C C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; and n is 0, 1, 2, 3 or 4; The method includes: a) Reaction of 5-fluoro-3,4-dihydro-1,8-naphthidin-2(1H)-one with (R)-6-hydroxy-som-3-carboxylic acid or (S)-6-hydroxy-som-3-carboxylic acid to provide (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy)som-3-carboxylic acid; b) Reacting (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy)chroman-3-carboxylic acid or (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)oxy)chroman-3-carboxylic acid with 2-amino-1-phenylethyl-1-one or a salt thereof to provide a compound of formula 4B. The 2-amino-1-phenylethyl-1-one is optionally R 3 Replace; and The compound of formula 4B has (R) or (S) stereochemistry at the carbon indicated by *; and c) Cycling the compound of formula 4B from step b) in the presence of ammonia or an ammonium salt to provide the compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein (R)-6-hydroxychromene-3-carboxylic acid or (S)-6-hydroxychromene-3-carboxylic acid is prepared by chiral hydrogenation of 6-hydroxy-2H-chromene-3-carboxylic acid in the presence of a chiral catalyst and hydrogen pressure in the range of 2 bar to 30 bar. in: The chiral catalyst comprises a Ru catalyst or a Rh catalyst and a chiral ligand, wherein the Ru catalyst or Rh catalyst is selected from Ru(OAc)2, [RuCl2(p-cym)]2, Ru(COD)(Me-allyl)2, Ru(COD)(TFA)2, [Rh(COD)2]OTf, or [Rh(COD)2]BF. 4， The chiral ligand is selected from (S)- or (R)-BINAP, (S)- or (R)-H8-BINAP, (S)- or (R)-PPhos, (S)- or (R)-Xyl-PPhos, (S)- or (R)-PhanePhos, (S)- or (R)-Xyl-PhanePhos, (S,S)-Me-DuPhos, (R,R)-Me-DuPhos, (S,S)-iPr-DuPhos, (R,R)-iPr-DuPhos, (S,S)-NorPhos, (R,R)-NorPhos, (S,S)-BPPM or (R,R)-BPPM or Josiphos SL-J002-1; or The chiral catalyst comprises a chiral Ru-complex or a chiral Rh-complex, wherein the chiral Ru-complex or chiral Rh-complex is selected from [(R)-Phanephos-RuCl2(p-cym)], [(S)-Phanephos-RuCl2(p-cym)], [(R)-An-Phanephos-RuCl2(p-cym)], [(S)-An-Phanephos-RuCl2(p-cym)], [(R)-BINAP-RuCl2(p-cym)], [(R)-BINAP-RuCl2(p-cym)], and [(R)-BINAP-RuCl2(p-cym)]. l(p-cym)]Cl, [(S)-BINAP-RuCl(p-cym)]Cl, (R)-BINAP-Ru(OAc)2, (S)-BINAP-Ru(OAc)2, [(R)-Phanephos-R h(COD)]BF4, [(S)-Phanephos-Rh(COD)]BF4, [(R)-Phanephos-Rh(COD)]OTf or [(S)-Phanephos-Rh(COD)]OTf.

4. The method of claim 3, wherein the Ru catalyst is selected from [RuCl2(p-cym)]2, Ru(COD)(Me-allyl)2 or Ru(COD)(TFA)2.

5. The method of claim 3, wherein the chiral ligand is selected from (S)- or (R)-PhanePhos or (S)- or (R)-An-PhanePhos.

6. The method of claim 3, wherein the chiral Ru-complex is selected from [(R)-Phanephos-RuCl2(p-cym)], [(S)-Phanephos-RuCl2(p-cym)], [(R)-An-Phanephos-RuCl2(p-cym)] or [(S)-An-Phanephos-RuCl2(p-cym)].

7. The method of claim 3, wherein the chiral hydrogenation is performed with a substrate / catalyst loading in the range of 25 / 1 to 1,000 / 1.

8. The method of claim 3, wherein the chiral hydrogenation is performed with a substrate / catalyst loading in the range of 200 / L to 1,000 / L.

9. The method of claim 3, wherein the chiral hydrogenation is carried out in the presence of a base.

10. The method of claim 9, wherein the base is triethylamine, NaOMe, or Na2CO3.

11. The method of claim 9, wherein the base is used in an amount not greater than 2.0 equivalents relative to 6-hydroxy-2H-chromene-3-carboxylic acid.

12. The method of claim 3, wherein the chiral hydrogenation is performed at a temperature in the range of 30°C to 50°C.

13. The method of claim 3, wherein the chiral hydrogenation is carried out at a concentration of 6-hydroxy-2H-chromene-3-carboxylic acid in the range of 0.2 M to 0.8 M.

14. The method of claim 3, wherein the chiral hydrogenation is carried out at a hydrogen pressure in the range of 3 bar to 10 bar.

15. The method of claim 3, wherein the chiral hydrogenation is carried out in an alcohol solvent.

16. The method of claim 15, wherein the solvent is methanol, ethanol or isopropanol.

17. The method of claim 1 or 2, wherein (R)-6-hydroxychromium-3-carboxylic acid and (S)-6-hydroxychromium-3-carboxylic acid have at least 90% enantiomeric excess.

18. The method of claim 1 or 2, wherein (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy)chroman-3-carboxylic acid and (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)oxy)chroman-3-carboxylic acid have at least 90% enantiomeric excess.

19. The method of claim 2, wherein the compound of formula 4B in step b) has an enantiomeric excess of at least 90%.

20. The method of claim 2, wherein the compounds of formula (IIa) and (IIb) or pharmaceutically acceptable salts thereof have an enantiomeric excess of at least 90%.

21. The method of claim 2, wherein R 3 It is halogen, C 1-4 Alkyl group, -SO2(C 1-4 alkyl).

22. The method of claim 2, wherein R 3 It is F, Cl, Br, or I.

23. The method of claim 2, wherein n is 0, 1, or 2.

24. The method of claim 1, wherein the compound of formula 4A in step b) has an enantiomer excess of at least 90%.

25. The method of claim 1, wherein R 1 It is a substituted or unsubstituted heteroaryl group.

26. The method of claim 1, wherein the compound of formula (Ia) is Or its pharmaceutically acceptable salt.

27. The method of claim 1, wherein the compound of formula (Ib) is Or its pharmaceutically acceptable salt.

28. The method of claim 1, wherein the compound formula (Ia) is Or its pharmaceutically acceptable salt.

29. The method of claim 1, wherein the compound of formula (Ib) is Or its pharmaceutically acceptable salt.

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