Chiral synthesis of condensed bicyclic RAF inhibitors

Abstract

The present disclosure generally relates to fused bicyclic Raf inhibitor enantiomers of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, having high enantiomeric excess (ee%). The present disclosure also relates to methods of using compounds of Formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, to treat diseases such as cancer, including colorectal cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the rights of U.S. Provisional Application No. 63 / 057,531, filed on 28 July 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] This disclosure relates to improved synthesis of condensed bicyclic Raf inhibitors with generally high enantiomeric excess (ee%). [Background technology]

[0003] Mutations resulting in uncontrolled signaling via the RAS-RAF-MAPK pathway are found on one-third of all cancers. RAF kinases (A-RAF, B-RAF, and C-RAF) are integral parts of this pathway and are commonly associated with B-RAF mutations in clinical settings. While most skin cancers with the V600E mutation in B-RAF are sensitive to approved B-RAF selective agents, colorectal cancers with the V600E mutation in B-RAF are surprisingly unresponsive to these agents as monotherapy due to the function of other RAF family members and require combination therapy. B-RAF selective therapy has not shown clinical benefit for atypical B-RAF (non-V600E), other RAFs, and RAS-driven tumors.

[0004] U.S. Patent No. 10,183,939 discloses racemic Raf inhibitors that exhibit binding affinity of B-RAF to 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 to overcome resistance mechanisms associated with clinically approved B-RAF selective agents. However, methods for selectively synthesizing enantiomers of Raf inhibitors were not described in U.S. Patent No. 10,183,939. [Overview of the project]

[0005] The present disclosure relates to a method for synthesizing a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt or tautomer thereof, [Chemical formula]

[0006] wherein,

[0007] R 8 is selected from substituted or unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, aryl, heterocyclyl, or heteroaryl;

[0008] R 2 is H;

[0009] X 1 is N or CR 8 ;

[0010] X 2 is N or CR 9 ;

[0011] 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 ;

[0012] R 7 , R 8 , and R 9 are each independently hydrogen, halogen, or alkyl;

[0013] Alternatively, R 6 and R 8 together, or R 7 and R 9Together, they form a five- or six-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, along with the atoms to which they are bonded, and the ring is substituted or unsubstituted;

[0014] R 5 is a substituted or unsubstituted group selected from alkyl, carbocyryl, aryl, heterocyclyl, or heteroaryl;

[0015] R F is H or C 1-3 Selected from alkyl groups,

[0016] The method is:

[0017] a) Reacting the compound of formula 1A with (R)-6-hydroxychroman-3-carboxylic acid or (S)-6-hydroxychroman-3-carboxylic acid to obtain compound 2A.

[0018] (The compound of formula 2A has (R) or (S) stereochemistry at the carbon indicated by *); [ka]

[0019] b) Reacting compound 2A with the compound of formula 3A or a salt thereof to obtain compound 4A.

[0020] (The compounds of formula 4A have (R) or (S) stereochemistry at the carbon indicated by *); [ka]

[0021] c) Cyclizing 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. [ka]

[0022] This disclosure relates to compounds of formula (IIa) or (IIb), or pharmaceutically acceptable salts or tautomers thereof. [ka]

[0023] Regarding the method of synthesis, in the formula,

[0024] R 3 is halogen, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 It is a cycloalkyl, alkyl is a haloalkyl, and cycloalkyl is -OR A -CN, -SOR C , or -NR A R B It is optionally replaced by 1 to 3 elements that are independently selected from it;

[0025] R A and R B These are H and C, respectively, independently. 1-4 Alkyl and C 1-4 Selected from haloalkyl groups;

[0026] R C C 1-4 Alkyl and C 1-4 Selected from haloalkyl groups;

[0027] n is 0, 1, 2, 3, or 4,

[0028] The method is:

[0029] a) Reacting 5-fluoro-3,4-dihydro-1,8-naphthyridine-2(1H)-one with (R)-6-hydroxychroman-3-carboxylic acid or (S)-6-hydroxychroman-3-carboxylic acid to provide (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid or (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid; [ka]

[0030] b) Reacting (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid or (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid with 2-amino-1-phenylethane-1-one or a pharmaceutically acceptable salt thereof to provide the compound of formula 4B.

[0031] (2-amino-1-phenylethane-1-one is R 3 It is replaced by an optional choice;

[0032] (The compounds of formula 4B have (R) or (S) stereochemistry at the carbon indicated by *); [ka]

[0033] c) Cyclizing 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. [ka]

[0034] In embodiments of the synthesis methods disclosed herein, (R)-6-hydroxychroman-3-carboxylic acid or (S)-6-hydroxychroman-3-carboxylic acid is prepared by chiral hydrogenation of 6-hydroxy-2H-chromen-3-carboxylic acid. [ka]

[0035] In embodiments of the synthesis methods disclosed herein, 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 embodiment, 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. In the embodiment, the chiral ligand is selected from (S)- or (R)-PhanePhos, or (S)- or (R)-An-PhanePhos.

[0036] In embodiments of the synthesis methods disclosed herein, chiral hydrogenation is carried out in the presence of a chiral Ru complex or a chiral Rh complex. In embodiments, the chiral Ru complex or chiral Rh complex is [(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-Rh(COD)]OTf, or [(S)-Phanephos-Rh(COD)]OTf. In embodiments, 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)].

[0037] In embodiments of the synthesis methods disclosed herein, chiral hydrogenation is carried out with substrate / catalyst loading in the range of about 25 / 1 to about 1,000 / 1. In embodiments, the substrate / catalyst loading is in the range of about 200 / 1 to about 1,000 / 1.

[0038] In embodiments of the synthesis methods disclosed herein, chiral hydrogenation is carried out in the presence of a base. In some embodiments, the base is triethylamine, NaOMe, or Na2CO3. In embodiments, the base is used in amounts 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 equivalents relative to 6-hydroxy-2H-chromene-3-carboxylic acid.

[0039] In embodiments of the synthesis methods disclosed herein, chiral hydrogenation is carried out at a temperature in the range of about 30°C to about 50°C.

[0040] In embodiments of the synthesis methods disclosed herein, chiral hydrogenation is carried out at concentrations of 6-hydroxy-2H-chromene-3-carboxylic acid ranging from about 0.2 M to about 0.8 M.

[0041] In embodiments of the synthesis methods disclosed herein, chiral hydrogenation is carried out at a hydrogen pressure in the range of about 2 bar to about 30 bar. In embodiments, the hydrogen pressure is in the range of about 3 bar to about 10 bar.

[0042] In embodiments of the synthesis methods disclosed herein, chiral hydrogenation is carried out in an alcohol solvent. In embodiments, the solvent is methanol, ethanol, or isopropanol.

[0043] In embodiments of the synthesis methods disclosed herein, (R)-6-hydroxychroman-3-carboxylic acid and (S)-6-hydroxychroman-3-carboxylic acid have an enantiomer excess of at least 90%.

[0044] In embodiments of the synthesis methods disclosed herein, (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid and (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid have an enantiomer excess of at least 90%.

[0045] In embodiments of the synthesis methods disclosed herein, the compound of formula 4A in step b) has an enantiomeric excess of at least 90%.

[0046] In embodiments of the synthesis methods disclosed herein, the compound of formula 4B in step b) has an enantiomeric excess of at least 90%.

[0047] In embodiments of the synthesis methods disclosed herein, the compounds of formulas (IIa) and (IIb), or their pharmaceutically acceptable salts or tautomers, have an enantiomeric excess of at least 90%.

[0048] In embodiments of the synthesis methods disclosed herein, the compounds of formulas (Ia) and (Ib), or their pharmaceutically acceptable salts or tautomers, have an enantiomeric excess of at least 90%.

[0049] In embodiments of the synthesis methods disclosed herein, R in formula (IIa) or (IIb) 3 is halogen, C 1-4 Alkyl, -SO2(C 1-4 It is alkyl. In this embodiment, R 3 n is F, Cl, Br, or I. In the embodiment, n is 0, 1, or 2.

[0050] In embodiments of the synthesis methods disclosed herein, R in formula (Ia) or (Ib) 1 It is a substituted or unsubstituted heteroaryl compound.

[0051] In certain embodiments of the methods and compositions disclosed herein, the compound is [ka] or selected from pharmaceutically acceptable salts or stereoisomers thereof. In embodiments of the synthesis methods disclosed herein, the compound is selected from compound A-1-N-1 or A-2-N-2, or pharmaceutically acceptable salts or tautomers thereof, prepared by any of the methods disclosed herein.

[0052] This disclosure relates to compounds of formula (IIa) or (IIb), or pharmaceutically acceptable salts or tautomers thereof, prepared by any of the methods disclosed herein.

[0053] This disclosure relates to compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts or tautomers thereof, prepared by any of the methods disclosed herein.

[0054] This disclosure relates to compound A-1-N-1 or A-2-N-2, or a pharmaceutically acceptable salt or tautomer thereof, prepared by any of the methods disclosed herein.

[0055] This disclosure relates to compound A-1-N-1 or A-2-N-2, or a pharmaceutically acceptable salt or tautomer thereof.

[0056] In embodiments of the compounds of this disclosure, the compounds have an enantiomeric excess of at least 90%. In embodiments, the compounds have an enantiomeric excess of at least 95%. In embodiments, the compounds have a chemical purity of 85% or more. In embodiments, the compounds have a chemical purity of 90% or more. In embodiments, the compounds have a chemical purity of 95% or more.

[0057] This disclosure relates to a pharmaceutical composition comprising one of the compounds disclosed herein and a pharmaceutically acceptable excipient or carrier.

[0058] In embodiments of the pharmaceutical composition, the composition further comprises an additional therapeutic agent. In embodiments, the additional therapeutic agent is selected from antiproliferative agents or antineoplastic agents, cell proliferation inhibitors, anti-infiltration agents, growth factor function inhibitors, anti-angiogenic agents, steroids, targeted therapy agents, or immunotherapy agents.

[0059] This disclosure relates to a method for treating a RAF kinase-mediated condition, comprising administering an effective amount of any one of the compounds disclosed herein.

[0060] In embodiments of the treatment method, the condition is treatable by inhibition of one or more Raf kinases. In embodiments, the condition is selected from cancer, sarcoma, melanoma, skin cancer, hematological malignancies, lymphoma, carcinoma, or leukemia. In the embodiment, the condition is selected from Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma; astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (metastases to the central nervous system from tumors originating outside the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancers; 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.

[0061] This disclosure relates to a method for treating cancer, comprising administering an effective amount of any one of the compounds disclosed herein.

[0062] In embodiments of a method for treating cancer, the cancer comprises at least one mutation in BRAF kinase. In embodiments, the cancer comprises BRAF V600E Includes mutations.

[0063] In embodiments, cancer is selected from melanoma, thyroid cancer, Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumors, glioblastoma, astrocytoma, ependymoma, colorectal cancer, colon cancer, gastric cancer, head and neck cancer, hematological cancers, leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, megakaryoblastic leukemia, multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, kidney cancer, sarcoma, uveal melanoma, or skin cancer. In embodiments, cancer is BRAF V600E Melanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid cancer, BRAF V600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAFV600E Hepatobiliary cancer, BRAF V600E hairy cell leukemia, BRAF V600E Non-small cell lung cancer, or BRAF V600E It is a pilocytic astrocytoma. In some embodiments, the cancer is colorectal cancer. [Brief explanation of the drawing]

[0064] [Figure 1] Results from the reaction of compound 1 to P1 and / or P2 using the [(S)-BINAP-RuCl(p-cym)]Cl catalyst at different temperatures and substrate concentrations are shown (Example 1, Part C). [Figure 2] Table 10 shows the hydrogen uptake records from the Endeavor software for the reactions disclosed. [Figure 3A] Table 11, entries 1-2) shows an overlay of hydrogen uptake records from Endeavor software for hydrogenation reactions at different substrate concentrations. [Figure 3B] Figure 3A shows the hydrogen uptake record. The line for low substrate concentration (Table 11, entry 2) has been shifted temporally (to the right) so that the first data point coincides with the reaction at higher substrate concentration. [Figure 3C] Table 11 shows an overlay of hydrogen uptake records from the reactions disclosed in entries 1-3. The lines corresponding to entries 1 and 2 have been shifted in time so that the first data point coincides with the reaction with a higher substrate concentration. [Figure 3D] Table 11 shows an overlay of hydrogen uptake records from the reactions disclosed in entries 1 and 4. The line corresponding to entry 4 has been shifted in time so that the first data point coincides with the reaction at a higher substrate concentration. [Figure 4] Based on hydrogen uptake records, this shows a comparison of reaction rates between a large-scale reaction conducted in a Parr container and a small-scale reaction conducted in an Endeavor container. [Figure 5]Based on hydrogen uptake records, this shows a comparison of reaction rates between a large-scale reaction conducted in a Parr container and a small-scale reaction conducted in an Endeavor container. [Figure 6] This shows a comparison of reaction rates under different catalyst loading conditions (S / C 1,000 / 1 vs. S / C 200 / 1) based on hydrogen uptake records. [Figure 7] The chiral LC-MS chromatograms of compound A-1 and compound A-2 are shown. [Figure 8A] The Ortep image of a single crystal of compound P2 obtained by slow evaporation in acetonitrile is shown. [Figure 8B] This image shows an Ortep image of a compound P2 single crystal obtained by slow evaporation in THF / water. [Modes for carrying out the invention]

[0065] All publications, patents, and patent applications, including drawings and appendices, are incorporated by reference for all purposes to the same extent that each publication, patent, and patent application, including drawings and appendices, is specifically and individually indicated as being incorporated by reference in whole for all purposes.

[0066] definition The following terms are expected to be easily understood by those skilled in the art, but their definitions are provided below to facilitate the explanation of the subject matter currently disclosed.

[0067] Throughout this specification, the terms “about” and / or “approximately” may be used in conjunction with numbers and / or ranges. The term “about” is understood to mean a value close to the listed values. Furthermore, the phrases “less than approximately [value]” or “greater than approximately [value]” should be understood in consideration of the definition of the term “about” provided herein. The terms “about” and “approximately” may be used interchangeably.

[0068] Throughout this specification, numerical ranges are provided for a particular quantity. It should be understood that these ranges include all subranges within that range. Thus, the range "50-80" includes all possible ranges within that range (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 contained within that range (e.g., the range 50-80 includes ranges with endpoints such as 55-80, 50-75, etc.).

[0069] The terms "a" or "an" refer to one or more entities. For example, "Raf inhibitor" refers to one or more Raf inhibitors or at least one Raf inhibitor. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein. In addition, references to "inhibitors" with the indefinite article "a" or "an" do not preclude the possibility of more than one inhibitor unless the context clearly requires that only one inhibitor exists.

[0070] As used herein, the verb “comprise” and its variations as used in this description and in the claims are used in the non-limiting sense that the items following the word are included, but not that items not specifically mentioned are excluded. The present invention may suitably “comprise,” “consist of,” or “consist essentially of” the steps, elements, and / or reagents described in the claims.

[0071] It should be further noted that claims may be drafted to exclude optional elements. In such cases, this statement is intended to function as an antecedent to the use of exclusive terms such as “alone” or “only” in relation to the enumeration of elements in the claims or the use of “negative” restrictions.

[0072] The term "pharmaceutically acceptable salt" includes both acid and base addition salts. Examples of pharmaceutically acceptable salts include those obtained by reacting an active compound acting as a base with an inorganic or organic acid to form salts, such as those 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, and carbonate. 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 one of many known methods.

[0073] The term “to treat” means to reduce, alleviate, delay, decrease, improve, or manage at least one symptom of the condition in question. The term “to treat” may also mean to prevent, delay the onset of the condition (i.e., the period before the clinical symptoms of the condition appear), or reduce the risk of progression or worsening of the condition.

[0074] The compounds of the present invention, or their pharmaceutically acceptable salts, contain at least one chiral center. Compounds of the present invention having one chiral center yield enantiomers, whose absolute stereochemistry can be expressed as (R)- and (S)-, or (+) and (-). If a compound of the present invention has more than two chiral centers, the compound can exist as a diastereomer or other stereoisomer. This disclosure is intended to include all such possible isomers, whether or not they are specifically shown herein, as well as their racemic and optically pure forms. Optically active (+) and (-), or (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or they can be separated using conventional techniques, e.g., chromatography and split crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include, for example, chiral synthesis from the decomposition of a suitable optically pure precursor or racemate (or racemate of a salt or derivative) using chiral high-pressure liquid chromatography (HPLC). Where a compound described herein contains an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compound is intended to include both E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included.

[0075] A "stereoisomer" refers to a compound composed of the same atoms bonded together by the same bonds, but having different three-dimensional structures and being incompatible. This disclosure intends to describe various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are mirror images of each other and cannot be superimposed.

[0076] "Tautomerism" refers to a proton shift from one atom in a molecule to another atom in the same molecule. This disclosure includes tautomers of any of the aforementioned compounds.

[0077] “Effective dose” means the amount of the formulation according to the present invention that, when administered to a patient to treat a condition, disorder, or condition, is sufficient to achieve such treatment. The “effective dose” varies depending on the active ingredient, the condition, disorder, or condition being treated and its severity, as well as the age, weight, physical condition and responsiveness of the mammal being treated.

[0078] The term "therapeutically effective" as applied to dosage or quantity refers to the amount of compound or pharmaceutical formulation sufficient to produce the desired clinical benefit after administration to a patient who needs it.

[0079] As used herein, “Subjects” may include humans, non-human primates, mammals, rats, mice, cattle, horses, pigs, sheep, goats, dogs, cats, etc. Subjects may have suspected cancer or be at risk of having cancer, including but not limited to colorectal cancer and melanoma.

[0080] "Mammals" include humans, as well as domesticated animals such as laboratory animals (e.g., mice, rats, monkeys, dogs, etc.) and pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and wild animals.

[0081] All weight percentages referenced herein (i.e., "weight %", "wt%", and "weight / weight") are measured relative to the total weight of the pharmaceutical composition unless otherwise specified.

[0082] As used herein, “substantially” or “substantial” means the complete or near-complete range or degree of an action, characteristic, property, state, structure, item, or result. For example, an object “substantially” enclosed means that the object is completely enclosed or nearly completely enclosed. The exact range of deviation from absolute completeness may, in some cases, depend on the specific context. However, generally, proximity to completion is to ensure that the overall result is the same as if complete completion had been achieved. The use of “substantially” also applies when used in a negative sense to indicate the complete or near-complete absence of an action, characteristic, property, state, structure, item, or result. For example, a composition “substantially” free of another activator will have the same effect as one completely free of the other activator, because it is either completely or nearly completely free of the other activator. In other words, a composition “substantially” free of an ingredient or element or another activator may still contain such an item, as long as its measurable effect is not significant.

[0083] The term "halo" refers to halogens. In particular, this term refers to fluorine, chlorine, bromine, and iodine.

[0084] "Alkyl" or "alkyl group" refers to a fully saturated, linear or branched hydrocarbon chain group that is bonded to the rest of the molecule by a single bond. Alkyl groups include any number of carbon atoms, from 1 to 12, but not limited to these. Alkyl groups containing up to 12 carbon atoms are C1-C 12 Alkyl alkyl groups, which contain up to 10 carbon atoms, are C1-C 10Alkyl groups containing up to six carbon atoms are C1-C6 alkyl groups, and alkyl groups containing up to five carbon atoms are C1-C5 alkyl groups. C1-C5 alkyl groups include C5 alkyl groups, C4 alkyl groups, C3 alkyl groups, C2 alkyl groups, and C1 alkyl groups (i.e., methyl groups). C1-C6 alkyl groups include all the parts described above for C1-C5 alkyl groups, but also include C6 alkyl groups. 10 Alkyl includes all the parts described above for C1-C5 alkyl and C1-C6 alkyl, but also C7, C8, C9, and C 10 It also includes alkyl groups. Similarly, C1-C 12 Alkyl includes all the parts mentioned above, but C 11 and C 12 Includes alkyl groups. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentene, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specified herein, alkyl groups may be optionally substituted.

[0085] "Cycloalkyl" refers to a non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon group consisting only of carbon and hydrogen atoms, having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, and may include fused or cross-linked ring systems, bonded to the rest of the molecule by single bonds. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl groups include adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified herein, cycloalkyl groups may be optionally substituted.

[0086] "Haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halo groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. Unless otherwise specified herein, haloalkyl groups may be optionally substituted.

[0087] "Aryl" refers to a hydrocarbon ring group comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of the present invention, the aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include a fused ring system or a bridged ring system. Examples of aryl groups include, but are not limited to, acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, the term "aryl" means that the aryl group may be optionally substituted.

[0088] A "heterocyclyl," "heterocycle," or "heterocycle" refers to a stable 3- to 20-membered ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heterocyclyls or heterocycles include the heteroaryls defined below. Unless otherwise specified herein, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridging ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl group may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclyl group may be partially or completely saturated. Examples of heterocyclyl groups include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxothiomorpholinil, and 1,1-dioxothiomorpholinil. Unless otherwise specified herein, the halocyclyl group may be optionally substituted. In the embodiments, heterocyclyl, heterocycle, or heterocycle refers to a stable 3- to 20-membered non-aromatic ring group consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0089] "Heteroaryl" refers to a 5-20 membered cyclic group comprising a hydrogen atom, 1-13 carbon atoms, a heteroatom selected from the group consisting of 1-6 nitrogen atoms, oxygen atoms, and sulfur atoms, and at least one aromatic ring. For the purposes of the present invention, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic system, and may include a fused or bridging cyclic system. The nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, in Examples include, but are not limited to, dolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl groups may be optionally substituted.

[0090] As used herein, the term "substituted" means that at least one hydrogen atom is a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; or in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups. "Substituted" also means that one or more hydrogen atoms are replaced by a higher-order bond (such as a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. For example, "substituted" means that one or more hydrogen atoms are replaced by a higher-order bond (such as a double or triple bond) to a heteroatom, such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imine, oxime, hydrazone, and nitrile. 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 -SORg 、 -SO2R g 、 -OSO2R g 、 -SO2OR g 、 =NSO2R g 、 and -SO2NR g R h includes any of the above groups substituted with. "Substitution" also means that one or more hydrogen atoms are replaced with C(=O)R g 、 -C(=O)OR g 、 -C(=O)NR g R h 、 -CH2SO2R[[ID=2^]] g 、 -CH2SO2NR g R h also means any of the above groups substituted with. In the above, R g and R h are the same or different and independently are hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N - heterocyclyl, heterocyclylalkyl, heteroaryl, N - heteroaryl, and / or heteroarylalkyl. "Substituted" further means that one or more hydrogen atoms are replaced with amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N - heterocyclyl, heterocyclylalkyl, heteroaryl, N - heteroaryl, and / or heteroarylalkyl groups. Furthermore, each of the aforementioned groups may be optionally substituted with one or more of the above groups.

[0091] The compounds of the present invention This disclosure relates to formula (I) [Chemical formula] Regarding pan-RAF inhibitors having the structure, or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof,

[0092] In the formula, R 1 or R 2 One of them is substitution or non-substitution, C 1-6 Alkyl, C 1-6 Selected from haloalkyl, aryl, heterocyclyl, or heteroaryl, R 1 or R 2 The other side is H;

[0093] Alternatively, R 1 and R 2 Together, they form a five- or six-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, along with the atoms to which they are bonded;

[0094] X 1 is N or CR AA and;

[0095] X 2 is N or CR BB and;

[0096] R 6 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 and;

[0097] R 7 , R 8 , and R 9 Each of these is independently hydrogen, halogen, or alkyl;

[0098] Alternatively, R 6 and R 8together, or R 7 and R 9 Together, they form a five- or six-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, along with the atoms to which they are bonded, and the ring is substituted or unsubstituted;

[0099] R 5 is a substituted or unsubstituted group selected from alkyl, carbocyryl, aryl, heterocyclyl, or heteroaryl;

[0100] R F is H or C 1-3 Selected from alkyl groups.

[0101] In this embodiment, the compound of formula (I) has the following stereochemistry:

[0102] [ka]

[0103] In this embodiment, the compound of formula (I) has the stereochemistry shown in formula (Ib).

[0104] In embodiments of the compound of formula (I), R 1 and R 2 is, halo, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 It is a cycloalkyl, alkyl is haloalkyl, and cycloalkyl is :-OR A -CN, -SOR C , or -NR A R B It is optionally replaced by 1 to 3 elements that are independently selected from it;

[0105] RA and R B These are H and C, respectively, independently. 1-4 Alkyl and C 1-4 Selected from haloalkyl groups;

[0106] R C C 1-4 Alkyl and C 1-4 Selected from haloalkyl groups;

[0107] In embodiments of the compounds of formula (I), (Ia), or (Ib), R 1 or R 2 One of these is selected from a 5- or 6-membered heteroaryl ring containing one or two heteroatoms selected from substituted or unsubstituted phenyl, N, O, or S, or from a condensed biring with 8, 9, or 10 ring members. In embodiments of the compounds of formula (I), (Ia), or (Ib), R 1 or R 2 One of these is a phenyl or a 5,6-membered heteroaryl containing one or two heteroatoms. In embodiments of the compounds of formula (I), (Ia), or (Ib), R 1 or R 2 One of these is phenyl, pyridyl, imidazole, pyrazole, or thiophene.

[0108] In embodiments of the compounds of formula (I), (Ia), or (Ib), R 1 or R 2 One of these is a fused diring with 8, 9, or 10 ring members, where 0, 1, 2, or 3 ring atoms are heteroatoms selected from N, O, or S. 1 or R 2 One of these is a fused diring having 8, 9, or 10 ring members, where 0, 1, 2, or 3 ring atoms are heteroatoms selected from N, O, or S, and both fused rings are aromatic rings, or one ring is aromatic and the other is non-aromatic.

[0109] In embodiments of the compounds of formula (I), (Ia), or (Ib), R 1 and R 2 Together they form a phenyl ring (forming a benzimidazole having the imidazole ring depicted in formula (I)), which is optionally substituted. In embodiments of the compounds of formula (I), (Ia), or (Ib), R 1 and R 2 These elements combine to form a five- or six-membered ring containing one heteroatom selected from N, S, or O, which is optionally substituted.

[0110] In embodiments of the compounds of formula (I), (Ia), or (Ib), R 6 and R 8 Together, they form a 5-membered or 6-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, along with the atoms to which they are bonded, and the ring is substituted or unsubstituted. In embodiments, R 7 and R 9 Together, they form a 5-membered or 6-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, along with the atoms to which they are bonded, and the ring is substituted or unsubstituted.

[0111] In embodiments of the compounds of formula (I), (Ia), or (Ib), R 6 and R 8 Together, they form a five- or six-membered partially unsaturated or unsaturated ring containing one or two heteroatoms selected from N, O, or S, along with the atoms to which they are bonded, and the ring is substituted or unsubstituted. In embodiments of the compounds of formula (I), (Ia), or (Ib), R 6 and R 8 Together, they form a 5- or 6-membered partially unsaturated or unsaturated ring containing a nitrogen atom as a ring member, along with the atoms to which they are bonded, and the ring is substituted or unsubstituted. In embodiments, the ring is substituted with an oxo. In embodiments, R 7 and R 9 Both are hydrogen.

[0112] In other embodiments of the compounds of formula (I), (Ia), or (Ib), R 6 and R 8 They come together, along with the ring that binds them together. [ka] Forms X 2 is CH; R 7 H is R 6 and R 8 They come together, along with the rings that bind them together. [ka] It forms.

[0113] In embodiments of compounds of formula (IA), (IB), or (IC), R 6 is a halogen or a C1-C3 alkyl. In embodiments of the compounds of formula (I), (Ia), or (Ib), R 6 is -NHC(O)R 5 -NHC(O)CH2R 5 ,-NHC(O)CH(CH3)R 5 , or -NHR 5 That is the case.

[0114] In embodiments of the compounds of formula (I), (Ia), or (Ib), R 7 , R 8 , and R 9 R is independently either hydrogen or methyl. In embodiments of the compounds of formula (I), (Ia), or (Ib), R 7 , R 8 , and R 9 Each of them is independently hydrogen.

[0115] In embodiments of the compounds of formula (I), (Ia), or (Ib), R 5R is a substituted or unsubstituted group selected from alkyl, 3-6 membered carbocyryl, phenyl, 3-6 membered heterocyclyl, or 5-6 membered heteroaryl. In embodiments, R 5 is a substituted or unsubstituted group selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyridine, thiazole, imidazole, pyrazole, or triazole.

[0116] In embodiments of the compounds of formula (I), (Ia), or (Ib), R F is H or methyl. In embodiments of the compounds of formula (I), (Ia), or (Ib), R F H is H.

[0117] In embodiments of the compounds of formula (I), (Ia), or (Ib), X 1 and X 2 One of them is N. In this embodiment, X 1 is N, and X 2 is CH. In this embodiment, X 2 is N, and X 1 is CH. In this embodiment, X 1 and X 2 Both are CH.

[0118] In this embodiment, the compound of formula (I) has the structure of formula (II): [ka] or having a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

[0119] In the formula, R 3 is halogen, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-4 Alkyl, C 1-4 Haloalkyl, or C3-6 It is a cycloalkyl, alkyl is a haloalkyl, and cycloalkyl is -OR A -CN, -SOR C , or -NR A R B It is optionally replaced by 1 to 3 elements that are independently selected from it;

[0120] R A and R B These are H and C, respectively, independently. 1-4 Alkyl and C 1-4 Selected from haloalkyl groups;

[0121] R C C 1-4 Alkyl and C 1-4 Selected from haloalkyl groups;

[0122] n is 0, 1, 2, 3, or 4.

[0123] In this embodiment, the compound of formula (II) has the following stereochemistry: [ka]

[0124] In this embodiment, the compound of formula (II) has the stereochemistry shown in formula (IIb).

[0125] In embodiments of the compound of formula (II), (IIa), or (IIb), n is 0, 1, 2, or 3. In embodiments of the compound of formula (II), (IIa), or (IIb), n is 0, 1, or 2. In embodiments of the compound of formula (II), (IIa), or (IIb), n is 0 or 1. In embodiments of the compound of formula (II), (IIa), or (IIb), n is 1.

[0126] In embodiments of the compounds of formula (II), (IIa), or (IIb), R 3 is halogen, C 1-4 Alkyl, -SO2(C1-4 It is alkyl. In embodiments of the compounds of formula (II), (IIa), or (IIb), R 3 is a halogen. In embodiments of the compounds of formula (II), (IIa), or (IIb), R 3 It is F.

[0127] In the embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, has (S)-stereochemistry at the carbon marked with *. In the embodiments, the compound of formula (I) or (II) has (S)-stereochemistry at the carbon marked with * with an enantiomer excess of *80%, *81%, *82%, *83%, *84%, *85%, *86%, *87%, *88%, *89%, *90%, *91%, *92%, *93%, *94%, *95

[0128] In the embodiments, the compound of formula (I) or (II), or a pharmaceutically acceptable salt or tautomer thereof, has (R)-stereochemistry at the carbon marked with *. In the embodiments, the compound of formula (I) or (II) has (R)-stereochemistry at the carbon marked with * with an enantiomer 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) has (R)-stereochemistry at the carbon marked with * with an ee 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 greater than 95% ee (including all values ​​in between).

[0129] In an embodiment, the compound of formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof, has a chemical purity 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 therebetween).

[0130] In one embodiment, the compound of formula (I), (Ia), or (Ib) is selected from Table A, or is a pharmaceutically acceptable salt or tautomer thereof. In one embodiment, the compound of (Ia) or (Ib) is selected from compound A-1, A-2, B-1, or B-2, or a pharmaceutically acceptable salt or tautomer thereof.

[0131] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0132] Chiral synthesis of the compounds of the present invention The present 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.

[0133] In embodiments, the chiral synthesis uses (S)-6-hydroxy chroman-3-carboxylic acid or (R)-6-hydroxy chroman-3-carboxylic acid. In embodiments, the (S)-6-hydroxy chroman-3-carboxylic acid or (R)-6-hydroxy chroman- carboxylic acid used in the chiral synthesis has an enantiomeric excess of at least 85%, at least 90%, or at least 95%. In embodiments, the (S)-6-hydroxy chroman-3-carboxylic acid or (R)-6-hydroxy chroman-3-carboxylic acid used in the chiral synthesis has an enantiomeric excess of about 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 therebetween).

Chemical formula

[0134] In the embodiment, (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid is prepared from 6-hydroxy-2H-chromene-3-carboxylic acid by chiral hydrogenation as shown in Scheme 1. In the embodiment, the chiral hydrogenation uses a transition metal catalyst. In the embodiment, the chiral hydrogenation uses a Ru or Rh catalyst. In the embodiment, the 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 the embodiment, the Ru catalyst is selected from [RuCl2(p-cym)]2, Ru(COD)(Me-allyl)2, or Ru(COD)(TFA)2. In the embodiment, the chiral hydrogenation uses an Rh catalyst selected from [Rh(COD)2]OTf or [Rh(COD)2]BF4.

[0135] [ka]

[0136] In embodiments, chiral hydrogenation uses a chiral ligand. In embodiments, it is a chiral phosphine ligand. In embodiments, the chiral ligand is selected from Table B or the opposite chiral ligand (i.e., if Table B lists (S)-PhanePhos, this disclosure expressly includes the opposite chiral ligand (R)-PhanePhos). In embodiments, the chiral ligand is selected from Table 4A or Table 5 or the opposite chiral ligand.

[0137] In the embodiment, the chiral hydrogenation of scheme 1 uses (R)-PhanePhos in combination with a catalyst. In the embodiment, the chiral hydrogenation of scheme 1 uses (R)-PhanePhos in combination with a Ru catalyst. In the embodiment, the chiral hydrogenation of scheme 1 uses (R)-PhanePhos together with [RuCl2(p-cym)]2.

[0138] [ka] [ka]

[0139] In the chiral hydrogenation embodiment, 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, Josiphos SL-J002-1. In the embodiment, the chiral ligand is (S)- or (R)-PhanePhos, or (S)- or (R)-An-PhanePhos. In the embodiment, the chiral ligand is (S)- or (R)-PhanePhos. In the embodiment, the chiral ligand is (R)-PhanePhos.

[0140] In the chiral hydrogenation embodiment, a metal catalyst precursor and a chiral ligand are used to form a chiral metal complex in situ. In the embodiment, the metal catalyst precursor is selected from either the Rh or Ru catalysts disclosed herein, and the chiral ligand is selected from any of the chiral ligands disclosed herein. In the embodiment, 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 the embodiment, 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 the embodiments, 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 ​​in between). In the embodiments, 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 ​​in between). In the embodiments, 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.

[0141] In the embodiment, the metal catalyst precursor is [RuCl2(p-cym)]2 and the chiral ligand is (R)-PhanePhos. In the 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 ​​in between). In the embodiment, the metal catalyst precursor and the chiral ligand are used in a ratio of about 1:2.

[0142] In the embodiment, the metal catalyst precursor and the chiral ligand are pre-mixed to pre-form a chiral metal complex before setting up the hydrogenation reaction. In the 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(COD)]BF4, [(S)-Phanephos-Rh(COD)]BF4, [(R)-Phanephos-Rh(COD)]OTf, or [(S)-Phanephos-Rh(COD)]OTf. In the embodiment, 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 the embodiment, the pre-formed chiral metal complex is [(R)-Phanephos-RuCl2(p-cym)] or [(S)-Phanephos-RuCl2(p-cym)].

[0143] In this embodiment, the metal catalyst precursor and the chiral ligand do not need to be pre-mixed to pre-form a chiral metal complex before setting up the hydrogenation reaction.

[0144] In the chiral hydrogenation embodiment, catalyst loading is transferred in the range of approximately 20 / 1 (substrate / catalyst = S / C) to approximately 2,000 / 1 (including all values ​​in between). In the embodiment, catalyst loading (S / C) is in the range of approximately 25 / 1 to approximately 1,000 / 1 (including all values ​​in between). In the embodiment, catalyst loading (S / C) is in the range of approximately 200 / 1 to approximately 1,000 / 1 (including all values ​​in between). In the embodiment, the catalyst loading (S / C) is approximately 25 / 1, approximately 50 / 1, approximately 100 / 1, approximately 150 / 1, approximately 200 / 1, approximately 250 / 1, approximately 300 / 1, approximately 350 / 1, approximately 400 / 1, approximately 450 / 1, approximately 500 / 1, approximately 550 / 1, approximately 600 / 1, approximately 650 / 1, approximately 700 / 1, approximately 750 / 1, approximately 800 / 1, The values ​​are approximately 850 / 1, 900 / 1, 950 / 1, 1,000 / 1, 1,100 / 1, 1,200 / 1, 1,300 / 1, 1,400 / 1, 1,500 / 1, 1,600 / 1, 1,700 / 1, 1,800 / 1, 1,900 / 1, or approximately 2,000 / 1 (including all values ​​in between). In embodiments, the catalyst loading (S / C) is in the range of approximately 200 / 1 to approximately 500 / 1 (including all values ​​in between). In embodiments, the catalyst loading (S / C) is in the range of approximately 300 / 1 to approximately 350 / 1 (including all values ​​in between). In embodiments, the catalyst loading (S / C) is in the range of approximately 320 / 1 to approximately 330 / 1 (including all values ​​in between).

[0145] In the chiral hydrogenation embodiment, a base is used. In the embodiment, the base is selected from amines. In some embodiments, the base is selected from triethylamine, NaOMe, or Na2CO3. In some embodiments, the base is triethylamine. In the embodiment, the base is used in an amount of 2 equivalents or less relative to 6-hydroxy-2H-chromene-3-carboxylic acid. In the embodiment, the base is used in an amount of 2 equivalents or less relative to 6-hydroxy-2H-chromene-3-carboxylic acid. In the embodiment, the base is used in an amount of about 1.5 equivalents relative to 6-hydroxy-2H-chromene-3-carboxylic acid.

[0146] In embodiments of chiral hydrogenation, the base is used in a sub-stoichiometric amount relative to 6-hydroxy-2H-chromene-3-carboxylic acid. In one embodiment, the base is used at about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 equivalents (including all values therebetween) relative to 6-hydroxy-2H-chromene-3-carboxylic acid. In one embodiment, the base is used at about 0.1 equivalents relative to 6-hydroxy-2H-chromene-3-carboxylic acid.

[0147] In embodiments of chiral hydrogenation, the reaction is carried out at a temperature in the range of about 25 °C to about 70 °C (including all values therebetween). In embodiments of chiral hydrogenation, the reaction is carried out at a temperature in the range of about 25 °C to about 70 °C (including all values therebetween). In embodiments of chiral hydrogenation, the reaction is carried out at a temperature in the range of about 30 °C to about 40 °C (including all values therebetween). In embodiments of chiral hydrogenation, the reaction is carried out at about 30 °C to about 40 °C. In embodiments of chiral hydrogenation, the reaction is carried out at about 40 °C.

[0148] 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 (including all values therebetween). In embodiments, [S] is in the range of about 0.1 M to about 1 M (including all values therebetween). In embodiments, [S] is in the range of about 0.2 M to about 0.8 M (including all values 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 (including all values therebetween). In embodiments, [S] is about 0.5 M.

[0149] In the chiral hydrogenation embodiment, the H2 pressure is in the range of about 1 bar to about 50 bar (including all values ​​in between). In the embodiment, the H2 pressure is in the range of about 2 bar to about 30 bar (including all values ​​in between). In the embodiment, the H2 pressure is in the range of about 3 bar to about 10 bar (including all values ​​in between). In the embodiment, the H2 pressure is in the range of about 5 bar to about 6 bar. In the embodiment, the H2 pressure is about 5 bar.

[0150] In the chiral hydrogenation embodiment, the solvent is a protic solvent. In the chiral hydrogenation embodiment, the solvent is an alcoholic solvent. In the chiral hydrogenation embodiment, the solvent is methanol, ethanol, isopropanol, or their fluorinated variants (such as trifluoroethanol). In the chiral hydrogenation embodiment, the solvent is methanol. In the chiral hydrogenation embodiment, the solvent is ethanol.

[0151] In the chiral hydrogenation embodiment, a contaminant-free inert vessel is desirable to achieve a high ee% of (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid. In the embodiment, the vessel should not contain metal deposit contaminants in order to achieve a high ee% of the product.

[0152] In the chiral hydrogenation embodiment 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%.

[0153] In the embodiment, the chiral synthesis of a compound of formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer thereof, comprises a reaction step labeled Scheme 2A, X 1 , X 2 , R 6 , and R 7 This is as described in this specification.

[0154] [ka]

[0155] In embodiments, 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 2B.

[0156] Scheme 2B [ka]

[0157] In embodiments of Scheme 2A or 2B, the (S)-6-hydroxychroman-3-carboxylic acid or (R)-6-hydroxychroman-3-carboxylic acid has an enantiomer excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0158] In embodiments of Scheme 2A or 2B, if (R)-6-hydroxychroman-3-carboxylic acid is used, the stereochemistry of (R)-6-hydroxychroman-3-carboxylic acid is retained in the product (e.g., (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid). In embodiments of Scheme 2A or 2B, if (S)-6-hydroxychroman-3-carboxylic acid is used, the stereochemistry of (S)-6-hydroxychroman-3-carboxylic acid is retained in the product (e.g., (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid).

[0159] In embodiments of Scheme 2A or 2B, using (R)-6-hydroxychroman-3-carboxylic acid yields the product as the (R) isomer. In embodiments of Scheme 2B, using (R)-6-hydroxychroman-3-carboxylic acid yields (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-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-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of Scheme B is within 10% of the chiral purity of (R)-6-hydroxychroman-3-carboxylic acid used in the reaction. In the embodiment, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of Scheme B is within 5% of the chiral purity of (R)-6-hydroxychroman-3-carboxylic acid used in the reaction. In the embodiment, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of Scheme B is greater than 90% when prepared from (R)-6-hydroxychroman-3-carboxylic acid having a chiral purity of greater than 90%. In the embodiment, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of scheme B is greater than 95% when prepared from (R)-6-hydroxychroman-3-carboxylic acid having a chiral purity of greater than 95%.In the embodiment, the chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of Scheme B is greater than about 98% when prepared from (R)-6-hydroxychroman-3-carboxylic acid which has a chiral purity of greater than about 98%.

[0160] In embodiments of Scheme 2A or 2B, using (S)-6-hydroxychroman-3-carboxylic acid yields the product as the (S) isomer. In embodiments of Scheme 2B, using (S)-6-hydroxychroman-3-carboxylic acid yields (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid. In embodiments, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of Scheme B is within 10% of the chiral purity of (S)-6-hydroxychroman-3-carboxylic acid used in the reaction. In the embodiment, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of Scheme B is within 5% of the chiral purity of (S)-6-hydroxychroman-3-carboxylic acid used in the reaction. In the embodiment, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of Scheme B is greater than 90% when prepared from (S)-6-hydroxychroman-3-carboxylic acid having a chiral purity of greater than 90%. In the embodiment, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of scheme B is greater than 95% when prepared from (S)-6-hydroxychroman-3-carboxylic acid having a chiral purity of greater than 95%.In the embodiment, the chiral purity of (3S)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid prepared by the reaction of scheme B is greater than about 98% when prepared from (S)-6-hydroxychroman-3-carboxylic acid which has a chiral purity of greater than about 98%.

[0161] In embodiments of scheme 2A or 2B, a base is used. In embodiments, the base is potassium carbonate. In embodiments, the base is tripotassium phosphate (K3PO4).

[0162] In embodiments of scheme 2A or 2B, the reaction is heated to a temperature in the range of about 30°C to about 150°C (including all values ​​in between). In embodiments, the reaction of scheme 2A or 2B is heated to a temperature in the range of about 75°C to about 150°C (including all values ​​in between). In embodiments, the reaction of scheme 2A or 2B is heated to a temperature in the range of about 80°C to about 120°C (including all values ​​in between). In embodiments, the reaction of scheme 2A or 2B is heated to a temperature in the range of about 90°C to about 110°C (including all values ​​in between).

[0163] In the embodiment, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer, comprises a reaction step labeled as scheme 3A.

[0164] [ka]

[0165] In the embodiment of Scheme 3A, the compound of formula 2A has (R) or (S) stereochemistry at the position labeled with *. In the 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%.

[0166] In the embodiment, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer, comprises a reaction step labeled as scheme 3B.

[0167] [ka]

[0168] In the embodiment, the chiral synthesis of a compound of formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer, comprises a reaction step labeled Scheme 3C.

[0169] [ka]

[0170] In embodiments of Scheme 3B or Scheme 3C, compound 3 has (R) or (S) stereochemistry at the position labeled with *. In embodiments of Scheme 3A or Scheme 3B, compound 3 has an enantiomer excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0171] In embodiments of Scheme 3A, Scheme 3B, or Scheme 3C, the reaction is carried out in the presence of propylphosphonic anhydride (T3P) and N,N-diisopropylethylamine. In embodiments of Scheme 3A or Scheme 3B, compound 3A may be in the form of a salt, such as a hydrochloride salt. In embodiments of Scheme 3C, compound 3B may be in the form of a salt, such as a hydrochloride salt.

[0172] In the embodiment of Scheme 3C, compound 3B is 2-(4-fluorophenyl)-2-oxoethane-1-aminium chloride.

[0173] In the embodiment, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer, comprises a reaction step labeled as scheme 4A.

[0174] [ka]

[0175] In the embodiment, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer, comprises a reaction step labeled Scheme 4B.

[0176] [ka]

[0177] In embodiments of scheme 4A or 4B, the compound of formula 4A has (R) or (S) stereochemistry at the position labeled with *. In embodiments of scheme 4A or 4B, the compound of formula 4A has an enantiomeric excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0178] 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, the compound of formula (Ia) is obtained. In embodiments of scheme 4A or 4B, when the (R) enantiomer of compound 4A is used, the compound of formula (Ib) is obtained.

[0179] In the embodiment, the chiral purity of the compound of formula (Ia) prepared by the reaction of scheme 4A or 4B is within 10% of the chiral purity of the (S) enantiomer of compound 4A used in the reaction. In the embodiment, the chiral purity of the compound of formula (Ia) prepared by the reaction of scheme 4A or 4B is within 5% of the chiral purity of the (S) enantiomer of compound 4A used in the reaction. In the embodiment, the chiral purity of the compound of formula (Ia) prepared by the reaction of scheme 4A or 4B is greater than 90% when prepared from the (S) enantiomer of compound 4A having a chiral purity of greater than 90%. In the embodiment, the chiral purity of the compound of formula (Ia) prepared by the reaction of scheme 4A or 4B is greater than 95% when prepared from the (S) enantiomer of compound 4A having a chiral purity of greater than 95%. In the embodiment, the chiral purity of the compound of formula (Ia) prepared by the reaction of scheme 4A or 4B is greater than 98% when prepared from the (S) enantiomer of compound 4A which has a chiral purity of greater than 98%.

[0180] In the embodiment, the chiral purity of the compound of formula (Ib) prepared by the reaction of scheme 4A or 4B is within 10% of the chiral purity of the (R) enantiomer of compound 4A used in the reaction. In the embodiment, the chiral purity of the compound of formula (Ib) prepared by the reaction of scheme 4A or 4B is within 5% of the chiral purity of the (R) enantiomer of compound 4A used in the reaction. In the embodiment, the chiral purity of the compound of formula (Ib) prepared by the reaction of scheme 4A or 4B is greater than 90% when prepared from the (R) enantiomer of compound 4A having a chiral purity of greater than 90%. In the embodiment, the chiral purity of the compound of formula (Ib) prepared by the reaction of scheme 4A or 4B is greater than 95% when prepared from the (R) enantiomer of compound 4A having a chiral purity of greater than 95%. In the embodiment, the chiral purity of the compound of formula (Ib) prepared by the reaction of scheme 4A or 4B is greater than 98% when prepared from the (R) enantiomer of compound 4A which has a chiral purity of greater than 98%.

[0181] In embodiments of Scheme 4A or 4B, the reaction is carried out in the presence of ammonia or an ammonium salt. In embodiments, the ammonium salt is ammonium acetate, ammonium trifluoroacetate, ammonium carbonate, ammonium bicarbonate, or ammonium chloride. In embodiments, the ammonium salt is ammonium acetate. In embodiments of Scheme 4A or 4B, the reaction is carried out in the presence of NH4OAc. In embodiments of Scheme 4A or 4B, the reaction is carried out in acetic acid. In embodiments of Scheme 4A or 4B, the reaction is carried out at a temperature in the range of about 30°C to about 150°C (including all values ​​in between). In embodiments of Scheme 4A or 4B, the reaction is carried out at a temperature in the range of about 60°C to about 120°C (including all values ​​in between). In embodiments of Scheme 4A or 4B, the reaction is carried out at a temperature in the range of about 80°C to about 100°C (including all values ​​in between). In embodiments of Scheme 4A or 4B, the reaction is carried out at a temperature of about 90°C.

[0182] In the embodiments, the chiral synthesis of a compound of formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer, comprises a reaction step labeled as scheme 4C.

[0183] [ka]

[0184] In the embodiment of Scheme 4C, the compound of formula 4B has (R) or (S) stereochemistry at the position labeled with *. In the embodiment of Scheme 4C, the compound of formula 4B has an enantiomer excess of at least 85%, at least 90%, or at least 95%.

[0185] In the embodiment of Scheme 4C, the stereochemistry of compound 4B is retained in the product. In the embodiment of Scheme 4C, when the (S) enantiomer of compound 4B is used, the compound of formula (Ia) is obtained. In the embodiment of Scheme 4C, when the (R) enantiomer of compound 4B is used, the compound of formula (IIb) is obtained.

[0186] In the embodiment, the chiral purity of the compound of formula (IIa) prepared by the reaction of scheme 4C is within 10% of the chiral purity of the (S) enantiomer of compound 4B used in the reaction. In the embodiment, the chiral purity of the compound of formula (IIa) prepared by the reaction of scheme 4C is within 5% of the chiral purity of the (S) enantiomer of compound 4B used in the reaction. In the embodiment, the chiral purity of the compound of formula (IIa) prepared by the reaction of scheme 4C is greater than 90% when prepared from the (S) enantiomer of compound 4B having a chiral purity of greater than 90%. In the embodiment, the chiral purity of the compound of formula (IIa) prepared by the reaction of scheme 4C is greater than 95% when prepared from the (S) enantiomer of compound 4B having a chiral purity of greater than 95%. In the embodiment, the chiral purity of the compound of formula (IIa) prepared by the reaction of scheme 4C is greater than 98% when prepared from the (S) enantiomer of compound 4B, which has a chiral purity of greater than 98%.

[0187] In the embodiment, the chiral purity of the compound of formula (IIb) prepared by the reaction of scheme 4C is within 10% of the chiral purity of the (R) enantiomer of compound 4B used in the reaction. In the embodiment, the chiral purity of the compound of formula (IIb) prepared by the reaction of scheme 4C is within 5% of the chiral purity of the (R) enantiomer of compound 4B used in the reaction. In the embodiment, the chiral purity of the compound of formula (IIb) prepared by the reaction of scheme 4C is greater than 90% when prepared from the (R) enantiomer of compound 4B having a chiral purity of greater than 90%. In the embodiment, the chiral purity of the compound of formula (IIb) prepared by the reaction of scheme 4C is greater than 95% when prepared from the (R) enantiomer of compound 4B having a chiral purity of greater than 95%. In the embodiment, the chiral purity of the compound of formula (IIb) prepared by the reaction of scheme 4C is greater than 98% when prepared from the (R) enantiomer of compound 4B, which has a chiral purity of greater than 98%.

[0188] In the embodiment of Scheme 4C, the reaction is carried out in the presence of ammonia or an ammonium salt. In the embodiment, the ammonium salt is ammonium acetate, ammonium trifluoroacetate, ammonium carbonate, ammonium bicarbonate, or ammonium chloride. In the embodiment of Scheme 4C, the reaction is carried out in the presence of NH4OAc. In the embodiment of Scheme 4C, the reaction is carried out in acetic acid. In the embodiment of Scheme 4C, the reaction is carried out at a temperature in the range of about 30°C to about 150°C (including all values ​​in between).

[0189] In the embodiments, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reaction of Scheme 1 and the reaction of Scheme 2A. In the embodiments, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reactions of Scheme 1, Scheme 2A, and Scheme 3A. In the embodiments, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reactions of Scheme 1, Scheme 2A, Scheme 3A, and Scheme 4A.

[0190] In embodiments, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, including carrying out one or more of the reactions of Scheme 1, Scheme 2A, Scheme 3A, or Scheme 4A, does not exclude additional reactions before, after, and / or between them. For example, between the reactions of Scheme 2A and Scheme 3A, another reaction may be carried out to further functionalize the N-aryl ring, such as the reaction shown below in Scheme 5. Scheme 5 involves substituent R 6 However, R 6 Examples of reactions that are further functionalized within the definition are given below.

[0191] [ka]

[0192] In the embodiment, in the compound of formula 2A in scheme 2A, R 6 , R 7 , R 8 , and / or R 9 In the compound of formula 2A in scheme 3A, R 6 , R 7 , R 8 , and / or R 9 This is different. In the embodiment, in the compound of formula 4A in scheme 3A, R6 , R 7 , R 8 , and / or R 9 In the compound of formula 4A in scheme 4A, R 6 , R 7 , R 8 , and / or R 9 This is different. In the embodiment, R in the compound of formula 4A in scheme 3B 1 This is R in the compound of formula 4A in scheme 4B. 1 This is different. In the embodiment, R in the compound of formula 4A in scheme 3C 3 R in the compound of formula 4A in scheme 4C 3 It is different.

[0193] In the embodiments, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reaction of Scheme 1 and the reaction of Scheme 2B. In the embodiments, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reactions of Scheme 1, Scheme 2B, and Scheme 3B. In the embodiments, the chiral synthesis of a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reactions of Scheme 1, Scheme 2B, Scheme 3B, and Scheme 4B.

[0194] In the embodiments, the chiral synthesis of a compound of formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reaction of Scheme 1 and the reaction of Scheme 2B. In the embodiments, the chiral synthesis of a compound of formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reactions of Scheme 1, Scheme 2B, and Scheme 3C. In the embodiments, the chiral synthesis of a compound of formula (II), (IIa), or (IIb), or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof, includes carrying out the reactions of Scheme 1, Scheme 2B, Scheme 3C, and Scheme 4C.

[0195] In the embodiment, the chiral synthesis of compounds of formula (I), (Ia), (Ib), (II), (IIa), or (IIb) yields compounds having an enantiomer excess of at least 85%, at least 90%, at least 95%, or at least 98%.

[0196] In the embodiments, the chiral synthesis of the compounds of formula (I) or (II) yields compounds having (R) or (S) stereochemistry at the carbon marked with *, having values ​​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).

[0197] In the embodiments, the chiral synthesis of compounds (Ia), (Ib), (IIa), or (IIb) yields compounds having values ​​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).

[0198] In embodiments, the chiral synthesis disclosed herein can be used to prepare stereoisomers of compounds disclosed in U.S. Patent No. 10,183,939, which is incorporated herein by reference. In embodiments, compounds disclosed in U.S. Patent No. 10,183,939 can be prepared as (S) or (R) stereoisomers by the chiral synthesis disclosed herein. In embodiments, compounds disclosed in U.S. Patent No. 10,183,939 can be prepared as (S) or (R) stereoisomers having at least 85% ee by the chiral synthesis disclosed herein.

[0199] 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.

[0200] therapeutic use This disclosure also relates to methods for using compounds of formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, to treat a variety of diseases and conditions. In embodiments, compounds of formula (I), (Ia), (Ib), (II), (IIa), or (IIb), or pharmaceutically acceptable salts, tautomers, or stereoisomers thereof, are useful for treating diseases or conditions involving 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, are useful for treating diseases or conditions treatable by inhibition of 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 this embodiment, the condition is treatable by inhibiting RAF kinases such as B-RAF or C-RAF.

[0201] In the embodiments, the disease or condition is cancer. In the embodiments, the disease or condition is selected from Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma; astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (metastases to the central nervous system from tumors originating outside the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancers; 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.

[0202] In the embodiments, the disease or condition is melanoma, non-small cell carcinoma, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer, or bile duct cancer. In the embodiments, the disease or condition is colorectal cancer. In the embodiments, the disease or condition is melanoma.

[0203] In the embodiment, the disease or condition is BRAF V600E It is a cancer that includes mutations. In embodiments, the disease or condition is BRAF V600E It is regulated by. In the embodiment, the disease or condition is BRAF V600E Melanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid cancer, BRAF V600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAF V600E Hepatobiliary cancer, BRAF V600E hairy cell leukemia, BRAF V600E Non-small cell carcinoma, or BRAF V600E It is a pilocytic astrocytoma.

[0204] In this embodiment, the disease or condition is cardiac facial cutaneous syndrome and polycystic kidney disease.

[0205] Pharmaceutical composition The 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. The 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.

[0206] In some embodiments, the pharmaceutical composition may further contain additional pharmaceutically active agents. These additional pharmaceutically active agents may be antitumor agents.

[0207] In embodiments, additional pharmaceutically active agents are antiproliferative / antiteconjugate agents. In embodiments, antiproliferative / antiteconjugate agents include alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustine, melphalan, chlorambucil, busulfan, temozolamide, and nitrosourea); antimetabolites (e.g., fluoropyrimidines such as gemcitabine, 5-fluorouracil, and tegafur, larcitrexed, methotrexate, pemetrexed, cytosine arabinoside, and folate antagonists such as hydroxyurea); and antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin). Anthracyclines such as mitomycin-C, dactinomycin, and mitramycin; mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine; taxoids such as TAXOL® (paclitaxel); and taxoteres and polokinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; or topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrin, topotecan, mitoxantrone, and camptothecin).

[0208] In embodiments, additional pharmaceutically active agents are cell proliferation inhibitors. In embodiments, cell proliferation inhibitors are anti-estrogenic agents (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), anti-androgenic agents (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), or 5α-reductase inhibitors such as finasteride.

[0209] In the embodiment, the other pharmaceutically active agent is an anti-infiltration agent. In the embodiment, the anti-infiltration agent is dasatinib and bosutinib (SKI-606), a metalloproteinase inhibitor, or an inhibitor of urokinase plasminogen activator receptor function, or an antibody against heparanase.

[0210] In embodiments, additional pharmaceutically active agents are growth factor function inhibitors. In embodiments, growth factor function inhibitors include growth factor antibodies and growth factor receptor antibodies, e.g., anti-erbB2 antibody trastuzumab [Herceptin®], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., gefitinib, erlotinib, and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazoline-4-amine (CI) 1033); erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; regulators of protein regulators of cell 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., farnesyltransferase inhibitors, Ras / RAF signaling inhibitors such as sorafenib, tipifarnib and ronafarnib); inhibitors of cell signaling mediated by 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; cyclin-dependent kinase inhibitors such as aurora kinase inhibitors or CDK2 and / or CDK4 inhibitors.

[0211] In some embodiments, other pharmacoactive agents are anti-angiogenic agents. In embodiments, anti-angiogenic agents inhibit the effects of vascular endothelial growth factor and include, for example, the anti-vascular endothelial growth factor antibody bevacizumab (Avastin®); thalidomide; lenalidomide; and VEGF receptor tyrosine kinase inhibitors such as vandetanib, batalanib, sunitinib, axitinib, and pazopanib.

[0212] In the embodiments, the additional pharmaceutically active agent, in the embodiments, the cytotoxic agent, is fludarivine (Fuldara), cladribine, or pentostatin (Nipent®).

[0213] In some embodiments, the additional pharmacoactive agent is a steroid. In embodiments, the steroid is a corticosteroid, including glucocorticoids and mineralocorticoids, for example, acrometasone, acrometasone dipropionate, aldosterone, amcinonide, beclometasone, beclometasone dipropionate, betamethasone, betamethasone dipropionate, sodium betamethasone phosphate, betamethasone valerate, budesonide, clobetazone, clobetazone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortibazole, deoxycorton, desonide, deoxymetasone, dexamethasone, sodium dexamethasone phosphate, dexamethasone isonicotinate, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluocinolone, fluocinolone acetonide, f These include luocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, flucortolone caproate, fluocortolone pivalate, fluorometholone, flupredniden, flupredniden acetate, flulandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, icometasone embutate, meprednisone, methylprednisolone, parametasone mometasone, mometasone fluate monohydrate, prednicarbate, prednisolone, prednisone, thixocortol, thixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and their respective pharmaceutically acceptable derivatives. Combinations of steroids, for example, combinations of two or more steroids described herein, can be used.

[0214] In the embodiment, the additional pharmacoactive agent is a targeted therapy agent. In the embodiment, the targeted therapy agent is a PI3Kd inhibitor, such as idelalisib and perifosin.

[0215] In some embodiments, other pharmaceutically active agents are immunotherapeutic agents. In embodiments, immunotherapeutic agents include antibody therapies such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), and ofatumumab; interferons such as interferon-α; interleukins such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines such as HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Ciproisel-T (Provenge); Toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; PD-1 antagonists, PDL-1 antagonists, and IDO-1 antagonists.

[0216] In embodiments, the pharmaceutical composition may be used in combination with another therapy. In embodiments, the other therapy may be gene therapy, which may include, for example, an approach to replace an abnormal gene such as an abnormal p53 or an abnormal BRCA1 or BRCA2.

[0217] In embodiments, other treatments include immunotherapeutic approaches such as antibody therapies including alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), and ofatumumab; interferons such as interferon-alpha; interleukins such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, such as prophylactic and therapeutic vaccines including HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Ciproisel-T (Provenge); Toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; PD-1 antagonists, PDL-1 antagonists, and IDO-1 antagonists.

[0218] The compounds of the present invention may exist in single-crystalline form, as a mixture of crystalline forms, or in amorphous form. Therefore, for pharmaceutical use, the compounds of the present invention can be administered as crystalline or amorphous products. They can be obtained as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze-drying, spray-drying, or evaporative drying. For this purpose, microwave or high-frequency drying may be used.

[0219] The dosage of the compounds of the present invention described above will naturally vary depending on the compound used, the method of administration, the desired treatment, and the specified disorder. For example, when the compounds of the present invention are administered orally, the daily dose of the compounds disclosed may range from about 0.01 micrograms (μg / kg) to about 100 milligrams (mg / kg) per kilogram of body weight.

[0220] The compounds of the present invention or their pharmaceutically acceptable salts may be used on their own, but are generally administered in the form of pharmaceutical compositions in which the compounds of the present invention or their pharmaceutically acceptable salts are conjugated with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are described, for example, in “Pharmaceuticals—The Science of Dosage Form Designs”, ME Aulton, Churchill Livingstone, 1988.

[0221] Depending on the method of administration of the compound of the present invention, the pharmaceutical composition used to administer the compound of the present invention preferably contains 0.05 to 99% by weight (weight percent) of the compound of the present invention, more preferably 0.05 to 80% by weight, even more preferably 0.10 to 70% by weight, and still more preferably 0.10 to 50% by weight, all weight percents being based on the whole composition.

[0222] Pharmaceutical compositions may be administered topically (e.g., on the skin) in the form of, for example, creams, gels, lotions, solutions, or suspensions; systemically by oral administration in the form of, for example, tablets, capsules, syrups, powders, or granules; parenterally by sterile solutions, suspensions, or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion); rectally by suppositories; or by inhalation in the form of aerosols.

[0223] For oral administration, the compounds of this disclosure may be mixed with an adjuvant or carrier, e.g., lactose, saccharose, sorbitol, mannitol; starch, e.g., potato starch, corn starch, or amylopectin; cellulose derivative; binder, e.g., gelatin or polyvinylpyrrolidone; and / or lubricant, e.g., magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in an easily volatile organic solvent.

[0224] For the preparation of soft gelatin capsules, the compounds of the Disclosure may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compounds using any of the above-mentioned tablet excipients. Hard gelatin capsules may also be filled with liquid or semi-solid formulations of the compounds of the Disclosure. Liquid formulations for oral administration are in the form of syrup or suspension, for example, a solution containing the compounds of the Disclosure, the remainder being sugar, as well as a mixture of ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain colorants, flavorings, thickeners (e.g., saccharin), preservatives, and / or carboxymethylcellulose as a thickener, or other excipients known to those skilled in the art.

[0225] For intravenous (parenteral) administration, the compounds of the present invention can be administered as a sterile aqueous solution or an oily solution.

[0226] Pharmaceutical compositions can be prepared as liposomes and encapsulated therapeutic agents. For various methods of preparing liposomes and encapsulating therapeutic agents, see, for example, U.S. Patents 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 reversed-phase evaporation method described in U.S. Patent 4,235,871. U.S. Patent 4,744,989 also encompasses the use and preparation of liposomes to improve the efficiency or delivery of therapeutic compounds, drugs, and other agents.

[0227] The compounds of the present invention can be loaded into liposomes passively or actively. Active loading is typically performed using a pH (ion) gradient or using encapsulated metal ions. For example, pH gradient loading can be carried out according to the methods described in U.S. Patents No. 5,616,341, 5,736,155, 5,785,987, and 5,939,096. Similarly, loading into liposomes using metal ions can be carried out according to the methods described in U.S. Patents No. 7,238,367 and 7,744,921.

[0228] Inclusion of cholesterol in the liposome membrane has been shown to reduce drug release and / or enhance stability after intravenous administration (see, for example, U.S. Patents 4,756,910, 5,077,056, and 5,225,212). Inclusion of low-cholesterol liposome membranes with continued charged lipids has been shown to provide low-temperature stability and increase circulation after intravenous administration (see U.S. Patent 8,518,437).

[0229] Pharmaceutical compositions may contain nanoparticles. The formation of nanoparticles is achieved by various methods. Nanoparticles can be prepared by precipitating molecules in a water-miscible solvent, then drying and grinding the precipitate to form nanoparticles (U.S. Patent No. 4,726,955). Similar techniques for preparing nanoparticles for pharmaceutical formulations include wet grinding or milling. Other methods involve mixing a low concentration of polymer dissolved in a water-miscible solution with an aqueous phase to alter the local charge of the solvent and form a precipitate by conventional mixing techniques (U.S. 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 to reduce surface tension. Other methods for incorporating excipient therapeutic agents into nanoparticles for drug delivery require the nanoparticles to be treated with liposomes or surfactants before drug administration (U.S. Patent No. 6,117,454). Nanoparticles can also be prepared by flash nanoprecipitation (U.S. Patent No. 8,137,699).

[0230] U.S. Patent No. 7,850,990 encompasses a method for screening combinations of agents and encapsulating those combinations in a delivery vehicle such as liposomes or nanoparticles.

[0231] The therapeutic dose of the compound of the present invention will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0232] The dosage level, frequency of administration, and duration of treatment of the compounds of the present invention are expected to vary depending on the patient's formulation and clinical indication, age, and comorbidities. The standard duration of treatment with the compounds of the present invention is expected to vary between 1 and 7 days for most clinical indications. In cases of recurrent infections or infections associated with tissues or graft materials with insufficient blood supply to bone / joints, airways, endocardium, and dental tissue, the treatment period may need to be extended beyond 7 days. [Examples]

[0233] As used herein, the following terms have the meanings given: "Boc" refers to tert-butyloxycarbonyl; "Cbz" refers to carboxybenzyl; "dba" refers to dibenzylideneacetone; "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(diphenylphosphin)ferrocene; "siRNA" refers to ethyl acetate; "EtOH" refers to ethanol; "Et2O" refers to diethyl ether; "IPA" refers to isopropyl alcohol; "LiHM "DS" refers to lithium bis(trimethylsilyl)amide; "mCPBA" refers to metachloroperoxybenzoic 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. Solvents, reagents, and starting materials were purchased from commercial vendors and used as received, unless otherwise stated. Unless otherwise stated, all reactions were carried out at room temperature.

[0234] In Examples 3, 6, and 7, the identity and purity of the compounds 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 MS was performed in positive and negative electrospray mode (m / z: 150-800). 2 μL aliquots were maintained at 40°C on a guard column (0.2 μm × 2 mm filter) and a UPLC column (C18, 50 × 2.1 mm, <2 μm). The samples were eluted at a flow rate of 0.6 mL / min in a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in MeCN) according to the gradient outlined below. Retention time RT is reported in minutes. [Table 2]

[0235] NMR was also used to characterize the final compounds. NMR spectra were obtained using a Bruker AVIII 400 Nanobay equipped with a 5 mm BBFO probe. Optionally, the Rf values ​​of the compounds on silica thin-layer chromatography (TLC) plates were measured. Compound identification and purity verification for the remaining examples are described within the examples themselves.

[0236] The compounds were purified by flash 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 with a Waters 2489 UV / Vis detector (m / z: 150-800). Samples were eluted at a flow rate of 20 mL / min on an Xbridge® prep C18 5 μM OBD 19 × 100 mm column in a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in MeCN) according to the gradient outlined below: [Table 3]

[0237] Chemical names in this document were generated using mol2nam (structure-to-name conversion by OpenEye Scientific Software). Starting materials were purchased from commercial sources or synthesized according to literature procedures.

[0238] While this disclosure is generally described herein, it will be more readily understood by referring to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0239] Example 1. Optimization of enantioselective alkene reduction [ka]

[0240] General procedure

[0241] The pre-formed catalyst (4 μmol, substrate / catalyst 25 / 1) or metal precursor (4 μmol of metal, S / C 25 / 1) and ligand (4.8 μmol, metal:ligand, 1:1.2) were weighed into Endeavor vials. The substrate (19.2 mg, 0.1 mmol) was added to each vial as a solution in the specified solvent (2 mL, [S] = 0.05 M). If ready for use, triethylamine (14 μL, 0.1 mmol, 1 equivalent) was added to the appropriate vial. The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm. The mixture was purged 5 times with nitrogen and 5 times with hydrogen, and heated to the specified temperature with H2 at 30 bar. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For supercritical fluid chromatography (SFC) analysis, approximately 0.1 mL of each reaction sample was diluted to approximately 1 mL with MeOH. The percentage of each reaction component was measured by integrating all SFC chromatogram peaks and reporting the percentage of each component identified by comparing the retention times of the reference sample. The percentage of the total peak area of ​​the remaining unidentified peaks was summed as "other". The enantiomeric excess of the major product peak was determined by the peak area ratio of the product peak in the SFC chromatogram.

[0242] SFC method

[0243] Column: Chiralpak IC-3, 4.6 × 250 mm, 3 μM

[0244] Mobile phase: A: CO2; B: 100% methanol

[0245] Injection volume: 3μL

[0246] Total time: 10 minutes

[0247] Detector: 203nm

[0248] Column temperature 40°C

[0249] Sample diluent: methanol

[0250] Flow rate: 2.0mL / min [Table 4]

[0251] Retention time of starting material (SM) = 5.6 minutes

[0252] Retention time (P2) of the first product to elute = 5.8 minutes

[0253] Retention time of the second eluted product (P1) = 6.1 minutes

[0254] A. Catalytic screening

[0255] Selected catalysts for enantioselective alkene reduction, for which the literature has preceded, were tested in the commonly used solvents MeOH and THF, with or without 1 equivalent of triethylamine, which has been shown to help successfully hydrogenate other acidic substrates in this type of reaction (Table 1).

[0256] [Table 5-1] [Table 5-2]

[0257] In entries 1 and 6 of Table 1, ee% of over 90% was obtained. In particular, in entry 6, (S)-Phanephos and [RuCl2(p-cym.)]2 formed an in situ chiral catalyst, resulting in a high conversion rate (93% P1, 5% P2; total conversion rate 98%) and a high ee% (90%) in the presence of triethylamine and methanol solvent.

[0258] In both MeOH and THF, the effect of triethylamine was observed with all catalysts, promoting complete conversion. However, in some cases, it also appeared to decrease the ee%. The results with MeOH were generally superior to those with THF.

[0259] B. Screening of solvents and temperatures

[0260] The effect of the catalyst system on changes in solvent and temperature in the presence of 1 equivalent of triethylamine (:S)-Phanephos and [RuCl2(p-cym)]2 was tested, and it was found that the initial catalyst screening yielded 90% ee with a 98% product conversion rate (Table 1). Background reaction studies were performed in the absence of ligands (Table 2, entry 1). This showed that a considerable amount of hydrogenation (70% product) occurred under ligand-free conditions, but the enantioselectivity was very low. This indicates that the formation of a chiral ligand-metal complex is important to achieve high enantioselectivity. Using a slightly excess ligand (Table 1, entry 6) to allow pre-mixing of the ligand and metal precursor, or using a pre-formed complex, ensures the formation of a chiral ligand-metal complex.

[0261] The results show that the ee% value decreases in the order of MeOH, EtOH, and IPA, indicating that the solvents EtOH and IPA offered no advantages over MeOH (Table 2, compare entries 2-4 or 5-7).

[0262] Lowering the temperature from 70°C to 50°C slightly improved enantioselectivity while maintaining complete conversion. The best result was 93% ee obtained with MeOH at 50°C (Entry 5). Further lowering the temperature to 30°C did not yield any further improvement (Entry 8).

[0263] [Table 6]

[0264] C. Screening of pre-formed catalysts

[0265] To determine whether enantioselectivity would be further improved by using pre-formed catalysts instead of ligands and metal precursors in situ, two different pre-formed catalysts containing Phanephos ligands were tested (Table 3). The Ru-BINAP pre-formed catalysts were also tested at higher substrate concentrations than in previous tests using 0.05 M in the initial catalyst screening.

[0266] The pre-formed [(R)-Phanephos RuCl2(p-cym)] catalyst showed similar results to those obtained from in-situ reactions (Table 3, entry 1 is comparable to Table 1, entry 6: 90% ee). Therefore, under these reaction conditions, there is no apparent improvement in using the pre-formed version of this ligand-metal combination.

[0267] An alternative pre-formed catalyst, [(S)-Phanephos Ru(CO)Cl2(dmf)], has been shown to improve the results of similar types of reactions, but this was not the case in this reaction (entries 2 and 6).

[0268] Tests using [(S)-BINAP-RuCl(p-cym)]Cl showed no linear trend with respect to substrate concentration, conversion, and enantioselectivity; therefore, there appears to be a trade-off between achieving high conversion or high ee under these conditions (Figure 1). For 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, due to overlap with impurities, there is uncertainty in the accuracy of this ee value. Generally, under these conditions, conversion rates are better and ee is higher at 70°C than at 50°C.

[0269] [Table 7-1] [Table 7-2]

[0270] D. Ruthenium-catalyzed ligand screening

[0271] The selection of chiral ligands with various steric and electronic properties was tested on a small scale using [RuCl2(p-cym)]2 as a precursor (Table 4A). Ligand (1 μmol) was weighed and placed in a CAT-24 vial. 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 was added to each vial ([S] = 0.084 M). A stirring bar was added to each vial. The CAT-24 was sealed and purged 5 times with nitrogen and 5 times with hydrogen (stirring between each cycle), and heated to 75°C with 20 bar H2 at a stirring speed of 800 rpm (the internal temperature is estimated to be 5°C lower). After 18 hours, the CAT-24 was evacuated and purged with nitrogen. For use in SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH.

[0272] Since all reactions showed near-complete or complete conversion, the ligands could be easily compared. The ligand family that showed the greatest enantioselectivity was Phanephos (entries 5 and 7). The more electron-rich variation, An-Phanephos, showed a slight improvement in ee value (entry 7). Higher ee values ​​were obtained previously using the same Ru precursor as Phanephos (Tables 1 and 2), although this screening was performed at different scales and substrate concentrations. Another ligand that gave a similarly high ee to Phanephos was the Josiphos ligand SL-J002-1 (entry 10).

[0273] [Table 8-1] [Table 8-2]

[0274] Furthermore, two different pre-formed Ru-BINAP catalysts were tested in MeOH or 2,2,2-trifluoroethanol (TFE) with the addition of a different sterically more demanding base than those previously tested, e.g., 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. Solvent (2 mL), followed by N,N-diisopropylethylamine (69 μL, 0.4 mmol, 1 equivalent) was added to the appropriate vials. The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm, purged 5 times with nitrogen and 5 times with hydrogen, and heated to 70°C with 30 bar H2. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH.

[0275] TFE showed significantly lower conversion rates and lower ee values ​​than MeOH (entries 5-6 compared to entries 1-2). The addition of N(iPr)2Et (Hünig base) improved the addition with the [(S)-BINAP-RuCl(p-cym)]Cl catalyst, but resulted in a lower ee (entry 3 compared to entry 1). The same effect was previously observed when triethylamine was used as an additive (Table 1).

[0276] [Table 9]

[0277] E. Rhodium-catalyzed ligand screening

[0278] The selection of chiral ligands with various steric and electronic properties was tested on a small scale, along with [Rh(COD)2]OTf as a precursor, as described in the ruthenium-catalyzed ligand screening (Table 5). Each ligand was tested with respect to the substrate both in the absence and in the presence of one equivalent of triethylamine.

[0279] Most of the reactions showed complete consumption of the starting materials, indicating that complex formation from the ligand to the metal occurred. Reactions in the presence of triethylamine generally showed lower ee values ​​than those obtained in the absence of triethylamine. However, triethylamine also resulted in 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 by SFC.

[0280] (R)-Phanephos and (S)-Xyl-Phanephos were found to exhibit very high ee values ​​in the absence of triethylamine. However, the amount of an unknown byproduct (6.4 min) was also very high in these reactions (entries 4-5). Furthermore, as demonstrated in entries 4-5, it seems unlikely that the opposite enantiomers of these ligands would preferentially form the same enantiomer of the product. Therefore, the presence of byproducts may be influencing the ratio of peaks observed in the chromatogram.

[0281] [Table 10-1] [Table 10-2]

[0282] To assess whether the unknown by-product (6.4 min) originated from the substrate (compound 1) or the products (P1 and P2), the stability of the substrate and products was examined (Table 6). Compound 1 or the racemic product (0.4 mmol) was weighed and placed in an Endeavor vial. MeOH (2 mL) was added to each vial. The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm. The mixture was purged 5 times with nitrogen and 5 times with hydrogen, and heated to 50°C or 90°C with 30 bar H2. After 16 hours or 56 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH.

[0283] Heating the substrate at 90°C for 16 hours did not change the SFC chromatogram at all (entries 1 and 3). However, heating the racemic product sample showed a decrease in the second product peak (P1) and a significant increase of 2% to 16% in the by-product appearing at 6.4 min of the SFC chromatogram (entries 2 and 4). Heating the product at 90°C for a longer period showed a further increase in the amount of this by-product (entry 6). Heating at 50°C yielded a small amount of this by-product (entry 5). Therefore, it appears that the formation of this by-product is promoted at higher temperatures and in the presence of acid (and inhibited at lower temperatures and in the presence of base, as seen in previous reactions).

[0284] [Table 11]

[0285] Ligand screening using [Rh(COD)2]OTf showed that Phanephos yielded 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 the Endeavor, which was sealed and set to stir at 650 rpm, purged 5 times with nitrogen and 5 times with hydrogen, and heated to 50°C or 70°C with H2 at 30 bar. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH.

[0286] The results showed that the amount of "other" appeared to depend primarily on temperature and the catalyst used. Under all conditions tested, the lowest amount of "other" was obtained with [(S)-Phanephos Rh(COD)]BF4 compared to [(S)-Phanephos Rh(COD)]OTf. The obtained ee values ​​(Table 7) were lower than those obtained from small-scale ligand screening (Table 5). In both cases, the main product appeared to be the first eluting peak (P2), so using the opposite ligand enantiomer suggests that there may be by-products co-eluting with the first eluting product peak (5.8 min), and therefore this interferes with the calculated ee value. Thus, the results in Table 7 may have lower ee values ​​than those calculated using the relative integral of the peaks at 5.8 min (P2) and 6.1 min (P1). Reactions in ethanol are likely to have more accurate ee values ​​because by-products are better separated from the product peak. By-products from the reaction in ethanol appear with slightly different retention times than those from the reaction in methanol (see Tables 8A and 8B). NMR analysis suggests that the by-products are methyl or ethyl esters of the products from the reaction in methanol or ethanol, respectively.

[0287] [Table 12]

[0288] [Table 13]

[0289] [Table 14]

[0290] F. Catalytic Loading Screening

[0291] The combination of (S)-Phanephos and [RuCl2(p-cym)]2 was tested at lower catalyst loading and higher substrate concentrations (Table 9). For entries 1-8: Appropriate amounts of substrate (19.2 mg, 0.1 mmol for 0.05 M; 38.4 mg, 0.2 mmol for 0.1 M; or 76.8 mg, 0.4 mmol for 0.2 M) were weighed into Endeavor vials. A stock solution of (S)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) was prepared in MeOH, and appropriate amounts were added to each vial. Further MeOH was added to each vial to make a total volume of MeOH 2 mL. Triethylamine (1 equivalent) was added to each vial. The vials were transferred to the Endeavor, the Endeavor was sealed, and set to stir at 650 rpm. The mixture was purged 5 times with nitrogen and 5 times with hydrogen, and heated to 50°C with 30 bar H2. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH. For entries 9-11: The procedure is the same as above, but with 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.

[0292] In all reactions (entries 1-8), complete conversion and ee values ​​of 91-92% were obtained. 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.

[0293] To validate these favorable results at S / C 200 / 1, several reactions were performed on a slightly larger scale (still at Endeavor). The same results were obtained in two repetitions, with complete conversion at 90% ee (entries 9-10). Background reactions of the metal precursor and substrate were tested with a 200 / 1 metal / substrate loading. The conversion rate of the hydrogenation product was significantly lower than in previous tests using a 25 / 1 loading, which yielded 70% product, compared to 17% obtained in this case (entry 11). This indicates ligand-promoting catalysis when Phanephos binds to the metal to form a chiral complex. It also suggests that lower loading may help eliminate the possibility of non-selective hydrogenation performed by unreacted metal precursor complexes.

[0294] [Table 15]

[0295] In summary, screening experiments revealed that MeOH yielded the best results in terms of conversion and enantioselectivity. The addition of one equivalent of triethylamine improved the results in certain catalytic systems, for example, making it possible to achieve over 90% ee with over 98% product. This was achieved with (S)-Phanephos and [RuCl2(pcym)]2.

[0296] Ligand screening using Ru identified (S)-Phanephos and (S)-An-Phanephos as yielding the best results. Several tests with pre-formed Ru-Phanephos catalysts did not improve upon the results obtained using ligands and metal precursors in situ. Loading of the (S)-Phanephos and [RuCl2(p-cym)]2 catalyst system was shown to decrease to S / C 200 / 1, yet still yielding complete conversion and 90% product ee. It was also demonstrated that increasing the concentration to 0.2 M did not affect the results.

[0297] Reactions using rhodium-based catalysts generally produced very large amounts of byproducts. The major byproduct was reduced in the presence of triethylamine. However, low ee values ​​were also obtained under these conditions. The major byproducts from these reactions were tentatively assigned by NMR analysis as the methyl ester of the saturated product when the reaction was carried out in methanol, or as the ethyl ester when the reaction was carried out in ethanol.

[0298] Similarly, lowering the temperature from 70°C to 50°C resulted in a slight improvement in ee from 90% to 93%. No further improvement was observed when the temperature was lowered to 30°C.

[0299] Example 2. Further optimization of enantioselective alkene reduction [ka]

[0300] Materials and methods: The SFC method described in Example 1 was used.

[0301] Example 1 identified the Phanephos and [RuCl2(p-cym)]2 catalyst system as the best for obtaining high conversion rates and high ee% of the product. This study was conducted to further optimize the reaction conditions of the Phanephos and [RuCl2(p-cym)]2 catalyst.

[0302] A. Catalyst loading and substrate concentration

[0303] In Example 1, it was found that the catalyst loading could be reduced from S / C 25 / 1 to S / C 200 / 1. The substrate concentration could be increased from 0.05 M to 0.2 M. Across those ranges tested in Example 1, there was no decrease in conversion and enantioselectivity, with complete conversion and over 90% ee obtained at substrate concentrations of S / C 200 / 1 and 0.2 M.

[0304] Further catalyst loading and substrate concentration studies were performed. Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) were prepared in DCM for reactions using S / C 1,000 / 1 and 10,000 / 1. Appropriate amounts of the solution were added to these vials, and the DCM was then blown off with N2. (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) were weighed and placed in vials, and the catalyst was loaded at 200 / 1 to 500 / 1. Appropriate amounts of substrate (i.e., 192 mg, 1 mmol) were weighed and placed in Endeavor vials. Methanol (2 mL for entries 1-6, 5 mL for entries 7-8, Table 10) was added to each vial, followed by triethylamine (1 equivalent). The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm. The system was purged five times with nitrogen and five times with hydrogen, and heated to 50°C with 30 bar H2. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH (Table 10). The hydrogen uptake time was estimated from the data recorded by the Endeavor, which indicated the time when uptake stopped, so it was assumed that the reaction was more than 90% complete at this point. Uptake was not accurately recorded for entries 4-6 due to leakage in the Endeavor.

[0305] Reducing the catalyst loading resulted in complete conversion of S / C 1,000 / 1 (Entry 3), while S / C 10,000 / 1 yielded less than 15% hydrogenation product after 16 hours of reaction (Entry 5-6). It was also found that slightly lower catalyst loading resulted in lower ee values. However, increasing the substrate concentration had a significant impact on the decrease in enantioselectivity (Entry 1-2).

[0306] By examining hydrogen uptake recorded from the Endeavor software, the approximate time at which the reaction is likely to be more than 90% complete was estimated (Figure 2). Thus, increasing the substrate concentration from 0.5 M to 1 M significantly affected the reaction rate, showing that at S / C 200 / 1, it took approximately 2 hours for H2 consumption to stop at 0.5 M, compared to approximately 5 hours at 1 M (Figure 2, comparing entries 1 and 2, corresponding to entries 1 and 2 in Table 10). As expected, reducing the catalyst loading also decreased the reaction rate, and therefore at S / C 1,000 / 1, it was completed in approximately 10 hours (Figure 2, entry 3).

[0307] [Table 16]

[0308] B. Kinetic Analysis of Hydrogenation Reactions

[0309] Several kinetic analyses were performed to investigate the reasons underlying any difficulties in minimizing catalyst loading. Hydrogen absorption data recorded by Endeavor could be converted into starting material consumption rates. Dynamical analyses of the reaction were performed using the same catalyst concentration but with different initial starting material concentrations. This followed a method called Variable Time Normalization Analysis (VTNA) in Nielsen, et al. Chem. Sci., 2019, 10, 348, which is used to distinguish whether there is product inhibition or catalyst deactivation.

[0310] (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent, 7 mg and 3.1 mg respectively) were weighed and placed in an Endeavor vial. Different amounts of substrate (i.e., 480 mg and 2.5 mmol) were weighed into the Endeavor vial to prepare the required substrate concentrations. Methanol (5 mL) was added to each vial, followed by triethylamine (1 equivalent). The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm. The mixture was purged 5 times with nitrogen and 5 times with hydrogen, and heated to 50°C with 30 bar H2. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH. The hydrogen uptake time is estimated from the data recorded by the Endeavor, which indicates the time when uptake stopped, so it is assumed that the reaction is more than 90% complete at this point.

[0311] The reaction curves for the first two reactions were superimposed on the same graph at substrate concentrations of 1.0 or 0.5 M (Table 11, entries 1-2) (Figure 3A). The reaction with the lower substrate starting concentration (entry 2) was then shifted temporally (to the right) so that the first data point coincided with the reaction at the higher substrate concentration (Figure 3B). When the lower concentration reaction was shifted by 2.9 hours and superimposed, the reaction curves appeared very similar (Figure 3B). This suggests, according to VTNA logic, that there was no inhibition of the product or deactivation of the catalyst.

[0312] Next, a third experiment was conducted using an even higher substrate concentration (Table 11, Entry 3). It is noteworthy that this reaction did not complete within the 16-hour reaction time frame. The reaction curves of these three reactions were superimposed on the same graph by shifting the low-concentration reaction to this high-concentration reaction (Figure 3C). As shown in Figure 3C, the reaction curves did not overlap. Therefore, this suggests that some differences arise at this increased concentration that affect the catalytic activity (Table 11, Entry 3).

[0313] To distinguish whether catalyst deactivation or product inhibition is the most likely cause of the effects with increasing substrate concentration and catalyst loading, a final experiment was performed adding 0.5 M racemic product to the starting mixture (Table 11, entry 4). The presence of overlapping curves in Figure 3D (entries 1 and 4 in Table 11) suggests that the difference in reaction rates at different substrate concentrations may be due to some product inhibition rather than catalyst deactivation. It is worth noting that in these reactions at different substrate concentrations, the amount of triethylamine is maintained at 1 molar equivalent relative to the substrate, but the pH differs in each reaction, which may affect the catalytic activity and, therefore, the analysis of this reaction kinetics. However, this is unlikely to affect the main findings of this analysis: up to a substrate concentration of 1.0 M, product inhibition or catalyst deactivation is not significant. This means that good results can be obtained using low catalyst loading.

[0314] [Table 17]

[0315] C. Further optimization of catalyst loading and substrate concentration.

[0316] Further investigations were conducted into the effects of substrate concentration on catalyst loading of S / C 500 / 1 and 1,000 / 1 (Table 12). Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) were prepared in DCM, and appropriate amounts of the solution were added to each Endeavor vial, after which the DCM was blown off with N2. Substrates (192 mg, 1 mmol) were weighed into the Endeavor vials. Methanol (2 mL, 4 mL, or 5 mL to prepare the desired [S]) was added to each vial, followed by the addition of triethylamine (1 equivalent). The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm, purged 5 times with nitrogen and 5 times with hydrogen, and heated to 50°C with H2 at 30 bar. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH.

[0317] These experiments confirmed that increasing the substrate concentration beyond 0.2 M under the tested conditions resulted in a decrease in the ee value. Similar results were obtained with the two loadings tested, with the exception of the experiment using the lowest loading and highest substrate concentration (entry 4), where a small amount of substrate remained and the product's ee was considerably lower than the other results.

[0318] [Table 18]

[0319] D. Screening for shorter reaction times

[0320] Up to this point, the reaction length had been maintained at 16 hours, so a 3-hour reaction length was used to investigate whether there was a difference in the ee value obtained if the reaction was stopped earlier. Different amounts of triethylamine (1 equivalent 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 equivalent) were prepared in DCM, and appropriate amounts of the solution were added to each Endeavor vial, after which the DCM was blown off with N2. The substrate (192 mg, 1 mmol) was weighed into the Endeavor vial. Methanol (2 mL or 5 mL to prepare the desired [S]) was added to each vial, followed by triethylamine (1 equivalent or 2 equivalents, 140 μL or 280 μL). The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm. The mixture was purged five times with nitrogen and five times with hydrogen, and heated to 50°C with 30 bar H2. After 3 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH.

[0321] In the S / C 500 / 1 reaction with higher catalyst loading, it was shown that when 1 equivalent of triethylamine was used, more than 95% of the reaction was completed after 3 hours, while when 2 equivalents of triethylamine were used, the hydrogenation reaction was slower compared to when 1 equivalent was used. Increasing the amount of triethylamine did not improve the ee value.

[0322] Regarding the higher ee and higher conversion obtained under all tested conditions, there was more evidence of improved results at lower substrate concentrations. Comparing these results (Table 13) with the previous results in Table 12 using a 16-hour reaction time, the ee values ​​obtained with a 3-hour reaction time show a slight improvement (up to 2%). However, since the reaction is not fully complete at this short time, it is not possible to draw a comparison from these results between the ee values ​​at the point of reaction completion and those with extended reaction times.

[0323] [Table 19]

[0324] E. Screening of temperature and NET3 quantity

[0325] Low triethylamine equivalents (0.5 equivalents) were tested at two substrate concentrations and three temperature settings using 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 amounts of the solution were added to these vials, after which the DCM was blown off with N2. Substrates (192 mg, 1 mmol) were weighed into Endeavor vials. Methanol (2 mL or 5 mL for 0.5 M or 0.2 M substrate concentrations, respectively) was added to each vial, followed by triethylamine (1 equivalent or 0.5 equivalents, 140 μL or 70 μL). The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm. The mixture was purged five times with nitrogen and five times with hydrogen, and heated to 40-60°C with 30 bar H2. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH.

[0326] Using 0.5 equivalents of NEt3 instead of 1 under conditions tested at 50°C resulted in improved ee at both substrate concentrations, as well as a slight improvement in conversion at higher substrate concentrations (Table 14, entries 3-6). The effect of temperature is not very clear, but the best ee values ​​for each substrate concentration were obtained at 40°C (entries 1-2).

[0327] [Table 20]

[0328] F. Screening of pressure for hydrogenation

[0329] Up to this point, a pressure of 30 bar was maintained as the pressure used. Therefore, the effect of using lower pressures on the results was investigated (Table 15). Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) were prepared in DCM, and appropriate amounts of the solutions were added to these vials, after which the DCM was blown off with N2. The substrate (192 mg, 1 mmol) was weighed into Endeavor vials. Methanol (2 mL or 5 mL for 0.5 M or 0.2 M substrate concentrations, respectively) was added to each vial, followed by triethylamine (0.5 equivalent, 70 μL). The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm, purged 5 times with nitrogen and 5 times with hydrogen, and heated to 40–50°C with H2 at 5–30 bar. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of each reaction sample was diluted to approximately 1 mL with MeOH. Since the hydrogen uptake time is estimated from the data recorded by Endeavor, which indicates the time when uptake stopped, it is assumed that the reaction is more than 90% complete at this point. Because the Endeavor hydrogen uptake curve showed leakage, data for H2 uptake time for entries 1-2 could not be obtained.

[0330] Encouragingly, the pressure could be reduced to 5 bar, and complete conversion was still achieved at S / C 1,000 / 1. High ee was maintained even at this pressure and loading (Table 15, Entry 6). It was found that reducing the pressure decreased the reaction rate. For example, at 5 bar instead of 10 bar, it took 7 hours instead of 3 hours to achieve complete addition at S / C 1,000 / 1 (compare Entries 3 and 6). Using higher catalyst loading shortened the required reaction time (compare Entries 6-8).

[0331] [Table 21]

[0332] G. Design of Experiment (DoE)

[0333] Previous results showed that the reaction was successful at 5 bar with a catalyst loading of S / C 1,000 / 1. Using these conditions, the effects of factors such as substrate concentration, amount of triethylamine, and temperature were further investigated. A Design of Experiments (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 performed on 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 equivalent) were prepared in DCM, appropriate amounts of the solution were added to these vials, and the DCM was then blown off with N2. The substrate (192 mg, 1 mmol) was weighed into Endeavor vials. Methanol (1 mL, 1.7 mL, or 5 mL for substrate concentrations of 1.0 M, 0.6 M, or 0.2 M, respectively) was added to each vial, followed by triethylamine (42 μL, 91 μL, or 140 μL for 0.3 equivalents, 0.65 equivalents, or 1 equivalent, respectively). The vials were transferred to an Endeavor, which was sealed and set to stir at 650 rpm. The mixture was purged five times with nitrogen and five times with hydrogen, and heated to 40–50°C with 5 bar H2. After 16 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH. The hydrogen uptake time is estimated from the data recorded by the Endeavor, which indicates the time when uptake stopped, so it is assumed that the reaction is more than 90% complete at this point. Data for H2 uptake time for entry 3 was not obtained due to leakage.

[0334] [Table 22]

[0335] The results (Table 16) were entered into the DoE software JMP. This model shows that substrate concentration has the greatest effect among the factors (as seen in the effect summary table by very low P values), and that the other factors have a significantly smaller influence on the outcome (Table 17). The predictive profiler predicted that "desirability" (i.e., maximizing both conversion and ee simultaneously) would decrease sharply as the substrate concentration increased in the range of 0.2–1.0 M. According to the predictive profiler model, the amount of triethylamine and temperature had little effect on desirability.

[0336] The DoE software predicted that the best results would be obtained at the lowest concentration with the smallest amount of triethylamine, at the lowest temperature in the tested range (0.2 M, 0.3 equivalents of NEt3, 40°C). This is reflected in the best experimentally obtained results (over 99% conversion and 93% ee) (Table 16, Entry 3).

[0337] [Table 23]

[0338] A predictive profiler can also be used to calculate the conditions that yield the best results at the desired substrate concentration. These generated results are shown in Table 18. These results suggest that using concentrations above 0.2 M under these conditions is unlikely to achieve conversion above 99% and high ee. However, it should be noted that hydrogen uptake indicates that the reaction at high concentrations is slow and therefore does not reach completion within the 16-hour timeframe tested.

[0339] [Table 24]

[0340] H. Screening of reaction times

[0341] The results of the DoE study revealed that, using the conditions within the investigated range (S / C 1,000 / 1, [S] = 0.2~1.0 M, methanol, 0.3~1.0 equivalents, NET3, 40~50°C, 5 bar H2, 16 hours), it was impossible to simultaneously obtain high addition (≥95%) and enantioselectivity (≥90%) at substrate concentrations higher than 0.5 M. Therefore, we tested whether longer reaction times at substrate concentrations of 0.6~1.0 M would allow for greater conversion (Table 19). Stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) were prepared in DCM, appropriate amounts of the solution were added to these vials, and the DCM was then blown off with N2. The substrate (192 mg, 1 mmol) was weighed into Endeavor vials. Methanol (1 mL, 1.3 mL, or 1.7 mL, respectively, for substrate concentrations of 1.0 M, 0.8 M, or 0.6 M) was added to each vial, followed by triethylamine (91 μL, 112 μL, or 140 μL, respectively, for 0.65 equivalents, 0.8 equivalents, or 1 equivalent). The vials were transferred to an Endeavor, which was sealed and set to stir at 650 rpm. The mixture was purged five times with nitrogen and five times with hydrogen, and heated to 45–50°C with 5 bar H2. After 16 or 24 hours, the Endeavor was evacuated and purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH. Data for H2 uptake time for entry 1 could not be obtained due to leakage.

[0342] Reactions using substrate concentrations of 0.8 M or 1.0 M did not complete within 24 hours (entries 1-2).

[0343] [Table 25]

[0344] I. Screening for the type and amount of bases

[0345] Several other bases were tested to see if they offered any advantages (Table 20). The same procedure was followed for temperature screening (Section H), except that the addition of triethylamine or base was adjusted as shown in Table 20, and the reaction was stopped at 16 hours. Data for H2 uptake time for entries 1 and 5 were not obtained due to leakage.

[0346] Both NaOMe and Na2CO3 showed similar results to NEt3 when 0.3 equivalents of base were used relative to the substrate (entries 1-3, 5). Using 0.6 equivalents of NaOMe or Na2CO3 resulted in slightly lower conversion than using 0.3 equivalents (entries 3-6). Therefore, no advantage was observed in using NaOMe / Na2CO3 instead of NEt3. Similar results were obtained when two different substrate batches were tested under the same conditions (entries 1-2). The substrate batches were: 1 As determined by 1H NMR, they had similar purities (96% and 95% for batches 1 and 2). However, it should be noted that SFC analysis of substrate batch 2 showed the appearance of a slow-eluting peak (8.6 min) with an integral value of less than 1%, which was not observed in batch 1. Therefore, the 1% "other" in the reaction using this substrate batch is mainly related to the presence of this peak on the SFC chromatogram.

[0347] [Table 26]

[0348] Since 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 concentrations of NaOMe and Na2CO3, and testing with different Ru precursors (Table 21). A=[RuCl2(p-cym)]2, B=Ru(COD)(Me-allyl)2, C=Ru(COD)(TFA)2. Data for H2 uptake time for entry 7 were not obtained due to leakage. [ka]

[0349] The reaction was found to be successful at a higher substrate concentration of 0.6 M (i.e., complete conversion and over 90% ee). This indicates that the requirements for obtaining these results are to use smaller amounts of base (0.1–0.3 equivalents) and lower temperatures (40°C). Alternative bases, NaOMe and Na2CO3, were again shown to yield similar results to NEt3, and their amounts could be reduced to 0.1 equivalents (entries 1–6).

[0350] Different Ru precursors, B and C, yielded very similar results to [RuCl2(p-cym)]2(A), with a difference of ±1% ee. Therefore, this ensures that it is not the Cl ligand present in the active complex that is influencing the maximum ee obtainable in this reaction.

[0351] [Table 27]

[0352] Reaction screening in a J. Parr container (25 mL)

[0353] Previous results showed that 0.6M yielded complete conversion with an ee value of 90–93%. These conditions were used to scale up to a 25mL Parr container using 1.6g of substrate and 14mL of MeOH (Table 22). (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 5.8mg and 2.6mg respectively) were weighed into a 25mL Parr container, followed by the substrate (1.614g, 8.4mmol). Methanol (14mL, 0.6M substrate concentration) was added to the container, followed by triethylamine (118μL, 0.84mmol, 0.1 equivalent). The container was sealed and purged 5 times with nitrogen (approximately 2 bar), and then purged 5 times with stirring (approximately 500rpm). The container was purged five times with hydrogen (approximately 10 bar), and then purged five more times while stirring (approximately 500 rpm). Next, the container was pressurized to a hydrogen pressure of 5 bar and heated to 40°C (with stirring set to 500 rpm). The pressure was kept constant, but after sampling, the container was evacuated and refilled to 5 bar. The reaction was sampled at 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, and 70 hours. After 70 hours, the container was allowed to cool, evacuated, and purged with nitrogen. Approximately 0.1 mL of each sample was diluted to approximately 1 mL with MeOH used for SFC analysis.

[0354] Comparing the reaction rates of the reactions conducted in the Parr vessel and the Endeavor vessel, it was found that the reaction was slower in large-scale reactions (Figure 4). This difference may stem from the difference in mixing efficiency between the Endeavor and Parr. The reaction was performed using a low stirring speed (500 rpm) and an extended reaction time to test the robustness of the catalyst system and process during scale-up. This showed slower rates and lower ee values ​​than those obtained with the Endeavor. There is room to increase the stirring speed in the Parr vessel.

[0355] Since no reaction samples were taken between 5.5 and 70 hours, it is unclear whether decomposition of ee due to heating occurred beyond the time it took for complete conversion to occur. Estimating the rate curve after the first 6 hours, it appears likely that the reaction was completed in approximately 15-20 hours.

[0356] [Table 28]

[0357] Next, to see if this would achieve similar results to Endeavor, the stirring speed in the Parr was increased to the maximum speed (over 1500 rpm) (Table 23). This Parr reaction using the maximum stirring speed showed a faster rate compared to the reaction with a low stirring speed, and the reaction appeared to be completed in about 10 hours instead of about 18 hours (500 rpm) (when evaluated by hydrogen uptake).

[0358] The Endeavor reaction completed quickly, within approximately 7 hours, and increasing the stirring speed did not significantly alter the results between Parr and Endeavor. In particular, enantioselectivity was not improved by increasing the stirring speed. Both Parr reactions yielded the same result of 87% ee at the end of the reaction, compared to the 90-93% ee obtained using the same set of conditions in Endeavor (Tables 22 and 23).

[0359] [Table 29]

[0360] The reaction setup shown in Table 23 was repeated with lower substrate concentrations in 25 mL of Parr to investigate whether this could achieve greater enantioselectivity, as observed during the small-scale screening of substrate concentrations (in Endeavor). This reaction was carried out at 0.4 M, and sampling was performed only at the end of the reaction. However, information regarding the reaction rate can be obtained using hydrogen uptake (Table 24, Figure 5).

[0361] [Table 30]

[0362] The results showed an ee of 87% at both concentrations, indicating that lower substrate concentrations did not result in higher enantioselectivity. From the recorded hydrogen uptake, the reaction at lower concentrations appeared to have a faster initial rate, completing in a shorter time of approximately 9 hours compared to the reaction at higher concentrations, which completed in approximately 11 hours (Figure 5). This is more similar to the reaction time performed in Endeavor (using 0.3 equivalents of NEt3). However, in Endeavor, the reaction using 0.1 equivalents of triethylamine at 0.4 M was not performed (it is known that higher amounts of triethylamine slow down the reaction).

[0363] The difference in the procedures used to set up the reaction in the Endeavor and Parr containers is that, in the Endeavor reaction, because it is small-scale, the stock solution of metal precursor and ligand is prepared in DCM and a small amount is added to the vial (before the DCM evaporates) to achieve proper catalyst loading, whereas in Parr, both the precursor and ligand were weighed directly into the container as solids. Thus, the reaction in Parr can be described as undergoing "in situ" formation of the metal-ligand complex in the presence of the substrate, whereas in the Endeavor reaction, the metal and ligand are pre-complexed before the substrate is added. Therefore, to investigate the difference that this was causing, various procedures were tested in the Endeavor (Table 25). All masses of [RuCl2(p-cym)]2 and (R)-Phanephos were weighed to obtain ligands with S / C 1,000 / 1 and 1.2 molar equivalents. For the "in situ" procedure in DCM, the stock solution of [RuCl2(pcym)]2 was added to one side of the Endeavor vial, the DCM was blown off with N2, the stock solution of (R)-Phanephos in DCM was added to the other side of the vial, and then the DCM was removed (so that the metal and ligands do not come into contact before other reagents are added). For the procedure of pre-mixing the stock solutions of (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalent) in DCM or MeOH, an appropriate volume of the solution was added to the vial and the solvent was blown off 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 equivalent). The vials were transferred to the Endeavor, which was sealed and set to stir at 650 rpm. The mixture was purged five times with nitrogen and five times with hydrogen, and heated to 40°C with 5 bar of H2. After 16 hours, the Endeavor was purged with nitrogen. For SFC analysis, approximately 0.1 mL of the sample from each reaction was diluted to approximately 1 mL with MeOH.

[0364] The results were all very similar, with ee values ​​of 91–92% obtained in all cases. This suggests that the low ee values ​​obtained in the Parr vessel were not due to the absence of a prior mixture of metal precursors and ligands. Possible causes of the low ee values ​​include: contamination of the Parr vessel resulting in a racemic background reaction; hydrogen deficiency due to insufficient optimal headspace in the reactor; and differences in the precision of the internal temperature, meaning the Endeavor reaction actually took place below 40°C.

[0365] Importantly, the "in situ" reaction, whether evacuated at 10 or 16 hours, yields the same result, and therefore, there is no decomposition of ee during this 6-hour period after the reaction is complete.

[0366] [Table 31]

[0367] K. Investigation of background reactions

[0368] Three runs using a 25 mL Parr container at S / C 1,000 / 1 (testing two stirring speeds and two substrate concentrations) were found to yield lower results than expected based on Endeavor results. Therefore, we tested whether background reactions causing low enantioselectivity were present in the container. Accordingly, conditions were kept the same except that no ligand or metal precursor was added, and the pressure was kept constant, but after sampling, the container was evacuated and refilled to the desired pressure. After 5 hours at 20 bar, the pressure decreased to 5 bar (Table 26).

[0369] Initially, using a hydrogen pressure of 20 bar resulted in a product with a low ee of 11%, as measured from a sample taken after 5 hours (Table 26, Entry 2). After 5 hours, the pressure was reduced to 5 bar. After heating for a further 15.5 hours while maintaining a pressure of 5 bar, an additional 3% of the product was produced (Table 26, Entry 3).

[0370] Therefore, the rate of background reactions decreases with lower pressure, and has less impact on the ee obtained from the reaction (Table 27). This experiment provides evidence of background reactions and explains the low ee obtained in previous experiments using this particular Parr container.

[0371] [Table 32]

[0372] [Table 33]

[0373] To confirm that the background reaction originates from the container rather than from contaminants in the substrate, further background reaction studies were conducted in Endeavor, where previous results had yielded over 91% ee. While a study to confirm the presence of background reactions had already been performed earlier in this project (Example 1), that stage used a concentration of 0.2 M and different substrate batches. Therefore, two different substrate batches were tested in parallel, and the conditions found to be optimal for the enantioselective hydrogenation reaction were tested without the catalyst (Table 28). Except as described in Table 28, the reaction setup was the same as in Table 25.

[0374] Less than 1% product was observed in both substrate batches and under several different conditions at 50°C (entries 2-5). This suggests that the background reaction observed in the Parr container was likely due to contaminants present in the container rather than the substrate. Vials containing the substrate, triethylamine, and methanol were again subjected to the Endeavor, but the temperature was increased to 90°C. In this case, a small amount of product was observed after 16 hours (entries 6-8). This may be due to trace amounts of contaminants in the Endeavor that required these harsher conditions to react with the substrate.

[0375] [Table 34]

[0376] To demonstrate that similar results to Endeavor can be obtained on a large scale in a Parr vessel when there is no background reaction, a glass liner with PTFE stirring rods and PTFE tape covering the thermocouple was used (Table 29). Otherwise, the reaction setup was the same as in Table 22, but the substrate amount was (1.845 g, 9.6 mmol) and the reaction time was different as described. In entry 1, there was an error with the hot plate used to heat this reaction overnight, causing the temperature to drop from 40 to 22°C, but the reaction was heated back up to 40°C after 16 hours.

[0377] Using this setup, a 91% ee was obtained with complete conversion, indicating that contaminants in the previously used stainless steel vessel were the cause of the low ee, and therefore, if no background reaction was present, a high ee could be obtained with a catalyst loading of S / C 1,000 / 1. After methanol removal and post-treatment of the reaction product 1 The 1H NMR spectrum indicated that the post-treatment successfully removed all triethylamine. A 1% loss of ee was observed after post-treatment, which may be an artifact of an error in the integration of the SFC analysis.

[0378] [Table 35]

[0379] L. Scale up to 300mL Parr containers.

[0380] After confirming the presence of contaminants in a 25 mL Parr container that resulted in an ee of less than 90%, the initial scale-up to a 300 mL Parr container was performed using S / C 200 / 1, even if there were background reactions caused by this container (Table 30). The fast reaction rate caused by high loading resulted in an ee of over 90% by minimizing the impact of any much slower background reactions. (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 322 mg and 142 mg, respectively) were weighed and placed in 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 vial, followed by triethylamine (1.3 mL, 9.3 mmol, 0.1 equivalent). The container was sealed and purged five times with nitrogen (approximately 2 bar) while stirring (approximately 500 rpm). The container was then purged five times with hydrogen (approximately 10 bar) while stirring (approximately 500 rpm). The container was then pressurized to a hydrogen pressure of 5 bar, heated first to 30°C, and then raised to 35°C (with maximum stirring exceeding 1500 rpm). The pressure was kept constant, but after sampling, the container was evacuated and refilled to 5 bar. After 5 hours, the container was allowed to cool. After 6 hours, the container was evacuated and purged with nitrogen. For SFC analysis, each of the approximately 0.1 mL samples was diluted to approximately 1 mL with MeOH.

[0381] The reaction was completed in 4-6 hours, yielding a product with 91% ee. The temperature was below 30°C for the first 1.7 hours, during which hydrogen consumption was recorded, thus indicating that the reaction can occur below 30°C. However, as the temperature rose and exceeded 30°C, the reaction rate increased significantly, so the temperature was raised to 35°C and maintained until the reaction was complete. After workup, high-purity ( 1 High yields of the product were obtained by 1H NMR.

[0382] [Table 36]

[0383] The second scale-up reaction, performed in a 300 mL Parr, was carried out at an S / C ratio of 1,000 / 1 (Table 31). At this point, it was unknown whether any contaminants causing the low ee value were present in the container. The experiment was set up with the same substrate scale as the previous 300 mL half-bag, except for catalyst loading ((R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 64 mg and 28 mg, respectively)).

[0384] The results showed a significant amount of background reaction, as evidenced by an ee value of less than 90%. From hydrogen uptake, it was noted that the reaction completed in approximately 14 hours with S / C 1,000 / 1, compared to 4-6 hours when using S / C 200 / 1. This difference in reaction rate means that background reaction has a greater influence on the ee value, thus highlighting the importance of evaluating each specific vessel in relation to catalyst loading selection and desired ee results.

[0385] [Table 37]

[0386] M. Summary of Optimization

[0387] A key finding from this example, as shown in Table 32, was that the presence and amount of metal deposit contaminants in the reaction vessel affected the decrease in ee from the maximum ee obtained in a completely inert vessel under the same conditions. Increasing the catalyst loading in the vessel where background reactions were observed was shown to be a way to overcome this effect on ee (entries 4-5).

[0388] [Table 38]

[0389] In this example, we focused on optimizing conditions to yield over 90% P2 (the enantiomer of the desired product) using (R)-Phanephos+[RuCl2(p-cym)]2 at S / C 1,000 / 1. Encouragingly, the reaction conditions were found to be successful at an H2 pressure of 5 bar. Therefore, optimization was carried out using S / C 1,000 / 1 and a pressure of 5 bar. This included DoE studies to investigate the effects of parameters such as substrate concentration, amount of triethylamine, and temperature.

[0390] Increasing the substrate concentration had the greatest impact on the conversion rate and the resulting ee value. Reducing the amount of triethylamine used to 0.1 equivalents (relative to the substrate) was found to successfully enable complete conversion of over 90% ee at a 0.6 M substrate concentration. Using a temperature of 30-40°C was also found to help achieve the maximum ee value.

[0391] The optimized conditions found on a small scale were transferred to standalone Parr vessels to demonstrate the hydrogenation reaction 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 presence or absence of non-enantioselective background reactions resulted in variability in the ee values ​​obtained in the different vessels. To overcome this problem of achieving an ee of less than 90%, S / C 200 / 1 was shown to be sufficient loading to compensate for the presence of any background reactions. Alternatively, it was demonstrated that an ee of more than 90% could be achieved using an inert vessel (i.e., glass-lined) with S / C 1,000 / 1.

[0392] Example 3. Chiral synthesis of compounds A-1 and A-2

[0393] A. Synthesis of P2 [ka]

[0394] Step 1: To a solution of 2,5-dihydroxybenzaldehyde (200 g, 1448 mmol) and pyridinium p-toluenesulfonate (18.2 g, 72.4 mmol) in DCM (3.75 L), 3,4-dihydro-2H-pyran (165 mL, 1810 mmol) was added dropwise over 10 minutes, and the reaction temperature was raised to 30°C. The reaction mixture was stirred for 2 hours, and UPLC-MS confirmed that the reaction was 92% complete (approximately 5% starting material and the remainder of approximately 3% unknown). The reaction was stopped. The reaction mixture was washed with water (1.5 L), the DCM solution was passed through a 750 g silica pad, and then through DCM (2.5 L). The DCM solution was reduced under vacuum, and the crude product was slowly diluted with petroleum ether to a total volume of approximately 1 L, stirred, and cooled to approximately 10°C to obtain a thick yellow slurry. The product was filtered, washed with petroleum ether (2 x 150 mL), and dried by suction for 3 hours to obtain 2-hydroxy-5-tetrahydropyran-2-yloxybenzaldehyde (265 g, 1192 mmol, yield 82%) as a bright yellow solid. 1 H 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 acidic): 1.64 min, m / z 223.0[M+H] + (100%)

[0395] Step 2: 2-hydroxy-5-tetrahydropyran-2-yloxybenzaldehyde (107 g, 481 mmol) was dissolved in diglym (750 mL), and K2CO3 (133 g, 963 mmol) was added all at once with stirring to obtain 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, from approximately 110°C to 130°C. This temperature was maintained for a further 1 hour. UPLC-MS showed that the reaction had proceeded 75%. After another 1 hour, it showed that it had completely converted to 85% of the product with little to no by-products. After another 3 hours, UPLC-MS showed 88% of the product (previous reactions had shown that further heating would not result in further conversion). The dark brown reaction mixture was cooled overnight to room temperature and filtered to remove inorganic matter. The reaction products were suspended in Depositphotos (2.5 L) and water (2.5 L), and the phases were separated. The aqueous phase was re-extracted with Depositphotos (2.5 L), and the combined organic phase was washed with brine (2 × 1.5 L), and the organic phase was reduced under vacuum. The crude product was then purified on silica (2 kg) loaded into the smallest amount of DCM. A gradient of Depositphotos in petroleum ether (10–25%) was performed, and the complete product fractions were combined and reduced under vacuum to obtain tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (93.5 g, 281 mmol, yield 58%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ / ppm: 7.37 (q, J = 1.2 Hz, 1H), 7.05 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.8, 2.9 Hz, 1H), 6.79 (dd, J = 8.7, 0.7 Hz, 1H), 5.35 (t, J = 3.3 Hz, 1H), 4.82 (d, J = 1.4 Hz, 2H), 3.77 (ddt, J = 13.3, 8.3, 4.2 Hz, 1H), 3.59 - 3.48 (m, 1H), 1.93 - 1.49 (m, 6H), 1.49 (s, 9H). UPLC-MS (ES+, short acidic): 2.18 min, m / z([M+H] + ) was not detected (100%)

[0396] Step 3: Tert-butyl 6-tetrahydropyran-2-yloxy-2H-chromene-3-carboxylate (215 g, 647 mmol) was suspended in MeOH (1.6 L) at room temperature (it did not dissolve immediately), and p-pyridinium toluenesulfonate (16.3 g, 64.7 mmol) was added. The reaction mixture was heated to 40°C in a water bath, and the progress was checked by UPLC-MS after 1 hour. This indicated that the reaction was complete and the solution was a clear orange. The reaction mixture was reduced under vacuum, the crude product was dissolved in DCM (2 L), and washed with water (1 L). The organic layer was dried in (MgSO4), filtered, and reduced under vacuum to obtain the crude product as a yellow solid. This was suspended in petroleum ether, stirred in an ice bath, and then filtered to obtain a bright yellow solid. This was dried under high vacuum at 50°C for 2 hours to obtain tert-butyl 6-hydroxy-2H-chromene-3-carboxylate (144.4 g, 582 mmol, 90% yield). 1 H 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 acidic): 1.71 min, m / z 247.2[MH]-(100%).

[0397] Step 4: Dissolve tert-butyl 6-hydroxy-2H-chromene-3-carboxylate (84 g, 338.34 mmol) in DCM (500 mL), add trifluoroacetic acid (177.72 mL, 2320.9 mmol) at room temperature, and stir the reaction to obtain a brown solution. Gas generation was initially observed, and the reaction was stirred at room temperature for several days. Remove the DCM and TFA under vacuum, and finally azeotrope with 200 mL of toluene, followed by slurrying with diethyl ether. Filter the mixture to obtain the crude product 6-hydroxy-2H-chromene-3-carboxylic acid as a creamy solid (53.15 g, 276.58 mmol, yield 81.745%). 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 12.77 (s, 1H), 9.14 (s, 1H), 7.37 (t, J = 1.4 Hz, 1H), 6.72 (dd, J = 2.4, 0.9 Hz, 1H), 6.70 - 6.64 (m, 2H), 4.78 (d, J = 1.4 Hz, 2H).

[0398] Step 5: (R)-Phanephos and [RuCl2(p-cym)]2 (1.2:1 equivalents, 6.6 mg and 3.0 mg respectively) were weighed into a 50 mL glass-lined Parr container, followed by the addition of the substrate (1.845 g, 9.6 mmol). Methanol (16 mL, 0.6 M substrate concentration) was added to the vial, followed by the addition of triethylamine (135 μL, 0.96 mmol, 0.1 equivalent). A PTFE stirring rod was added, and the thermocouple was covered with PTFE tape. The container was sealed and purged 5 times with nitrogen (approximately 2 bar), followed by 5 more purges with stirring (approximately 500 rpm). The container was then purged 5 times with hydrogen (approximately 10 bar), followed by 5 more purges with stirring (approximately 500 rpm). The container was then pressurized to a hydrogen pressure of 5 bar and heated to 40°C (at a stirring speed of 1500 rpm). The pressure was kept constant, but after sampling, the container was evacuated and refilled to 5 bar. After 21.5 hours, the container was allowed to cool. After 22.5 hours, the container was evacuated and purged with nitrogen. For SFC analysis, each of the approximately 0.1 mL samples was diluted to approximately 1 mL with MeOH. Workup procedure: After removing MeOH by concentration under vacuum, Depositphotos (10 mL) and 1 M HCl (10 mL) were added. The layers were mixed before separation. After washing the Depositphotos layer with a further portion of 1 M HCl (4 mL), the aqueous layer was removed to leave the Depositphotos organic phase. The aqueous layer was then washed with a further portion of Depositphotos (4 mL), and the organic layers were combined. Then, Depositphotos was removed under vacuum, leaving the product as a grayish solid (see Table 29). Using the SFC method described in Example 1, P2 was the first eluted product with a retention time of 5.8 minutes, and P1 was the second eluted product with a retention time of 6.1 minutes.

[0399] B. Synthesis of 5-fluoro-3,4-dihydro-1,8-naphthyridine-2(1H)-one [ka]

[0400] Step 1: 2-amino-4-fluoropyridine (400 g, 3568 mmol) was placed in a 10 L stationary reaction vessel and then 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 as a solution in DCM (1 L) over 1.5 hours. After stirring the reaction mixture at room temperature for 2 hours, NMR confirmed that the starting materials had been completely consumed. N,N-dimethylethylenediamine (390 mL, 3568 mmol) was added to the reaction mixture and the mixture was heated to 40°C overnight (to convert the di-BOC substance back to the desired mono-BOC product). The mixture was cooled to room temperature, then further diluted with DCM (2 L) and washed with water (2 L). Further extraction with DCM (2 L), washed with water (1 L) and brine (1.2 L), dried (MgSO4), and then filtered. The solvent was removed under vacuum, and the resulting product was slurryed with DCM / petroleum ether (1:1) (500 mL). Filtered, further washed with petroleum ether, and dried by vacuum to obtain tert-butyl N-(4-fluoro-2-pyridyl)carbamate (505 g, 2380 mmol, yield 67%) as a cream-colored solid product. The second product of the material was separated from the mother liquor after passing through a short pad of silica, and subsequently ground with DCM / petroleum ether (1:1) (approximately 200 mL) to obtain tert-butyl N-(4-fluoro-2-pyridyl)carbamate (46.7 g, 220 mmol, yield 6%). 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 10.13 (d, J = 1.7 Hz, 1H), 8.26 (dd, J = 9.4, 5.7 Hz, 1H), 7.60 (dd, J = 12.3, 2.4 Hz, 1H), 6.94 (ddd, J = 8.2, 5.7, 2.4 Hz, 1H), 1.47 (s, 9H). UPLC-MS (ES+, short acidic): 1.64 min, m / z 213.1[M+H]+ (98%)

[0401] Step 2: Dissolve tert-butyl-N-(4-fluoro-2-pyridyl)carbamate (126 g, 594 mmol) and TMEDA (223 mL, 1484 mmol) in dry THF (1.7 L) and then cool to -78°C under a nitrogen atmosphere. Add n-butyllithium solution (2.5 M solution in hexane) (285 mL, 713 mmol) to this solution and stir for a further 10 minutes. Add sec-butyllithium solution (1.2 M solution in cyclohexane) (509 mL, 713 mmol) and stir for 1 hour while maintaining the reaction temperature below -70°C. After this, add iodine (226 g, 891 mmol) in THF (300 mL) dropwise over 30 minutes while maintaining the temperature below -65°C. The mixture was stirred at -70°C for a further 10 minutes, then quenched by adding saturated NH4Cl aqueous solution (400 mL), followed by a solution of sodium thiosulfate (134 g, 848 mmol) dissolved in water (600 mL). This addition raised the temperature to approximately -25°C. The reaction mixture was warmed to room temperature, then transferred to a 5 L separator, extracted with dimethyl (2 × 1.5 L), washed with brine (500 mL), dried (MgSO4), then evaporated under vacuum to obtain the crude product (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 mixture was washed with DCM (10 × 1 L fraction), and the product was eluted from the column with dimethyl (10% to 100%) in petroleum ether (1 L for every 10% increase, 1 L fraction). This yielded two mixed fractions and a complete product containing both fractions, which were combined and evaporated under vacuum to obtain tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate (113.4 g, 335.4 mmol, 57% yield) as a white solid. Completeness was confirmed by UPLC-MS and NMR. The mixed fraction was combined with the previous crude material to obtain 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, and a second product, combined from all four batches, was obtained as tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate (107.5 g, 318 mmol, 5% yield) as a cream-colored solid. 1¹H 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%)

[0402] Step 3: Tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate (300 g, 887 mmol), 3,3-dimethoxypropa-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 was degassed at 30°C for 20 minutes. Then, palladium(II) acetate (19.92 g, 89 mmol) was added all at once to this mixture, and it was degassed again for a further 15 minutes. The reaction mixture was slowly and carefully heated to 100°C. Gas generation occurred around 85°C (a large amount of gas was released, probably due to the loss of Boc groups as CO2 and isobutylene). Once the evacuating was complete and complete dissolution was achieved, the reaction became darker. Next, the reaction mixture was heated at 100°C for 3 hours and confirmed by UPLC-MS (70% desired product, 18% uncyclized intermediate, and 7% des-iodoBOC). Further heating of the reaction mixture for 2 hours yielded 81% desired product, 12% uncyclized intermediate, and 8% des-iodoBOC. After 7 hours, the reaction showed 89% desired product, 4% uncyclized intermediate, and 7% des-iodoBOC. The reaction mixture was heated overnight. The reaction solution was cooled, filtered through Celite, and evaporated under vacuum to a thick, dark orange slurry, which was then suspended in water (1 L) and acidified to approximately pH 1-2 with HCl(4N) aqueous solution. This was then based to approximately pH 9 with saturated NaHCO3 aqueous solution. Extraction was performed with DCM (2 × 2 L), washed with brine, and dried (MgSO4). Depositphotos (2 L) was added to the solution, and the organic matter was then passed through a 500 g silica plug. This was then followed with DCM / Depositphotos (1:1) (2 L), and finally with Depositphotos (2 L) (final wash including only the baseline). The fractions containing the product were combined and an orange slurry was obtained under reduced pressure, then suspended in hot diethyl ether (300 mL), cooled to approximately 10°C in an ice bath with stirring, filtered, and washed with 150 mL of ice-cold diethyl ether. By vacuum drying, 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (58.4 g, 351.5 mmol, yield 39.6%) was obtained as a creamy, fluffy solid. 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 acidic): 1.04 min, m / z 167.0 [M+H]+(100%).

[0403] C. Synthesis of compounds A-1 and A-2 [ka]

[0404] Step 1: Potassium carbonate (832 mg, 6.02 mmol) was added at room temperature to a stirred solution of 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (250 mg, 1.5 mmol), P2 (see Step A, 292 mg, 1.5 mmol; 85% ee) and DMSO (2 mL). The reaction mixture was degassed, flushed three times with nitrogen, and stirred at 100°C for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and the resulting mixture was extracted with ELISA (20 mL). Next, a solution of citric acid (1156.3 mg, 6.02 mmol) in water (10 mL) was added to the aqueous layer to obtain a solid precipitate. This precipitate was filtered and vacuum-dried to obtain (S)- or (R)-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid (345 mg, 1.01 mmol, yield 67%) as a white solid. UPLC-MS (ES+, short acid): 1.29 min, m / z 341.1[M+H]+. 1H NMR(400 MHz, 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).

[0405] Step 2: Propylphosphonic anhydride (0.91 mL, 1.52 mmol) was added at room temperature to a stirred solution of (S)-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxylic acid (345 mg, 1.01 mmol), 2-amino-1-(4-fluorophenyl)ethanone 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 completed by LC-MS. Water (50 mL) and toluene (50 mL) were added, the organic layer was separated, and washed with saturated aqueous NaHCO3 solution (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 eluate of 0-5% MeOH in DCM to obtain (S)- or (R)-N-[2-(4-fluorophenyl)-2-oxo-ethyl]-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyrizin-4-yl)oxy]chroman-3-carboxamide (300 mg, 0.63 mmol, yield 62%) as a yellow solid. UPLC-MS (ES+, short acidity): 1.52 min, m / z 476.4[M+H]+. 1H 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 = 8.8Hz, 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 replaceable protons are observed.

[0406] Step 3: (S)- or (R)-N-[2-(4-fluorophenyl)-2-oxo-ethyl]-6-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridine-4-yl)oxy]chroman-3-carboxamide (300 mg, 0.63 mmol), ammonium acetate (1216 mg, 15.77 mmol), and acetic acid (5 mL) were combined in a sealable vial. The vial was sealed, the reaction mixture was stirred, and the mixture was heated at 130°C for 18 hours to allow it to react. The reaction was completed by LC-MS. The reaction mixture was cooled to room temperature, and AcOH was removed under vacuum. DCM (50 mL) was added to the residue, and saturated aqueous NaHCO3 (50 mL) was added. The organic layer was separated, washed with brine, dried over Na2SO4, and the solvent was removed under vacuum. The residue was purified by column chromatography using eluate of 0-10% MeOH in DCM to obtain (R)- or (S)-5-[3-[4-(4-fluorophenyl)-1H-imidazole-2-yl]chroman-6-yl]oxy-3,4-dihydro-1H-1,8-naphthirizin-2-one (141 mg, 0.31 mmol, yield 49%) as a yellow solid.

[0407] The chiral LC-MS of the product, along with the chiral LC-MS of compounds A-1 and A-2, indicates that the product is primarily compound A-1 and has an ee similar to that of the starting acid (85% ee) (Figure 7), however, overlapping peaks prevent accurate analysis. UPLC-MS (ES+, short acid): 1.36 min, m / z 457.2[M+H]+. 1 H NMR(400 MHz, 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).

[0408] Chiral LCMS:

[0409] Chiracel OZ-RH

[0410] 150mm x 4.6mm, 5um

[0411] Mobile phase A: 20 mM ammonium bicarbonate

[0412] Mobile phase B: Acetonitrile

[0413] Uniform concentration 1.2ml / min

[0414] 50% A; 50% B

[0415] Sample diluted with methanol (1 mg / ml)

[0416] The synthesis, primarily for preparing compound A-2, can be carried out using P1 instead of P2 (see Step A).

[0417] The enantiomers of the product can be separated using the following conditions:

[0418] Equipment: Thar 200 preparative SFC (SFC-7)

[0419] Column: ChiralPak AS, 300×50mm ID, 10μm

[0420] Mobile phase: A for CO2, B for ethanol

[0421] Gradient: B 50%

[0422] Flow rate: 200mL / min

[0423] Back pressure: 100 bar

[0424] Column temperature: 38℃

[0425] Wavelength: 220nm

[0426] Cycle time: Approximately 5 minutes

[0427] Example 4. Large-scale chiral synthesis of compounds A-1 and A-2

[0428] Liquid chromatography-mass spectrometry: Unless otherwise stated, the following ultra-high-performance LC-MS methods and parameters were used to characterize the products of each step described in this example. [Table 39]

[0429] A. Synthesis of P2 [ka]

[0430] Step 1: 2,5-Dihydroxybenzaldehyde (13.6 kg, 98.18 mol) was dried with 2 × 125–130 kg of THF up to 35°C using a 2 × azeotropic concentration and concentrated to 27–41 kg each time under vacuum. Then, the THF was removed with 4 × 179–187 kg of DCM up to 35°C using a 4 × azeotropic concentration and concentrated to 27–41 kg each time under vacuum. The concentrate was diluted with DCM (284 kg) and p-toluenesulfonate pyridine (PPTS; 1.25 kg, 4.97 mol) was added. 3,4-Dihydro-2H-pyran (10.4 kg, 123.63 mol) was slowly added at 25–35°C and the reaction was stirred at 30°C for 90 minutes. The mixture was added at -15°C to a solution of Na2CO3 (7.1 kg) in water (138 kg), heated to 25°C, and stirred for 6 hours. The mixture was filtered through Celite® (33 kg) and washed with DCM (92.5 kg). The filtrate was allowed to stand for 1 hour, then the organic phase was separated and concentrated to 27-41 kg. The DCM was then removed using a 3 × azeotropic concentration with 3 × 10⁵ kg of n-heptane up to 35°C, and concentrated to 27-41 kg each time under vacuum. The concentrate was diluted with n-heptane (210 kg), heated to 30-40°C, and stirred for 6 hours. The solution was then cooled to -5 to -15°C over 4 hours, stirred for 9 hours, filtered, and the filtered cake was washed with n-heptane (39.5 kg). The wet cake was vacuum-dried at 30-40°C for 24 hours to obtain 2-hydroxy-5-(oxan-2-yloxy)benzaldehyde (9.38 kg, 40.6%). An additional 8.00 kg (34.3%) of the product was recovered by dissolving the solid adhering to the reaction vessel walls with 42 kg of DCM, concentrating the resulting solution under vacuum, and obtaining a further 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]-.

[0431] Step 2: K2CO3 (21.4 kg, 154.83 mol) was added to a stirred solution of 2-hydroxy-5-(oxan-2-yloxy)benzaldehyde (16.95 kg, 76.27 mol) in diglym (113.4 kg), and the mixture was heated to 80-90°C. Tert-butylpropa-2-enoate (20.0 kg, 156.04 mol) was added, and the mixture was heated to 120-130°C and stirred for 18 hours. The mixture was cooled, filtered, and the filtered cake was washed with DCM (80.0 mL). The filtrate was diluted with ELISA (238.0 kg) and water (338.0 kg), stirred at 20-30°C for 1 hour, and then allowed to stand for 2 hours. The mixture was filtered through Celite® (40.0 kg), and the filtered cake was washed with ELISA (84.0 kg). The filtrate was allowed to stand for 2 hours, the aqueous layer was extracted with siRNA (312.0 kg), stirred at 0–30°C for 1 hour, and then allowed to stand for 2 hours. The organic layers were combined and washed with 2 × 345 kg of water, stirred at 20–30°C for 1 hour, and allowed to stand for 2 hours after each wash. The combined organic matter was then concentrated to 182.4 kg under vacuum, maintaining the temperature below 50°C. This yielded the product tert-butyl 6-(oxan-2-yloxy)-2H-chromene-3-carboxylate as a 9.3% solution in diglyme / siRNA (yield 66.9%), which was used in the next step without further isolation. LCMS (ES-): 20.26 min, m / z 247.12 [M-THP]-.

[0432] Step 3: Tert-butyl 6-(oxan-2-yloxy)-2H-chromene-3-carboxylate (16.9 kg, 50.84 mol) as a 181.8 kg solution in diglym / siRNA 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 stream of nitrogen and stirred for 8 hours. The mixture was then diluted with DCM (222.0 kg), cooled to -5 to -15°C, and stirred for 7 hours. The mixture was filtered, and the filtered cake was washed with DCM (67.0 mL). The wet cake was dried under vacuum at 30-40°C for 24 hours to obtain 6-hydroxy-2H-chromene-3-carboxylic acid (8.75 kg, yield 78.5%). LCMS (ES-): 0.85 min, m / z 191.11 [MH]-.

[0433] Step 4: To a solution of 6-hydroxy-2H-chromene-3-carboxylic acid (7.19 kg, 37.4 mol) in N2-degassed EtOH (60 kg), (R)-Phanephos (131 g, 0.227 mol), [RuCl2(p-cym)]2 (70 g, 0.114 mol), and Et3N (5.6 kg, 55.3 mol) were added. The reaction atmosphere was replaced three times with N2, then three times with H2, and the H2 pressure was adjusted to 0.5-0.6 MPa, and the mixture was stirred at 40°C for 18 hours. The atmosphere was then replaced three times with N2, then three times with H2, and the H2 pressure was again adjusted to 0.5-0.6 MPa, and the mixture was stirred for a further 18 hours.

[0434] The mixture was vacuum concentrated to obtain approximately 30 kg at a temperature below 40°C. The reaction product was diluted with MTBE (53 kg) and cooled to 15-25°C. 5% Na2CO3 (80 kg) was added dropwise, the mixture was stirred for 2 hours, and then allowed to stand at 15-25°C for 2 hours. The aqueous layer was collected, 5% Na2CO3 (48 kg) was added to the organic layer, and the mixture was then stirred at 15-25°C for 2 hours and filtered through Celite® (10.0 kg). The wet cake was washed with water (20 kg), and the combined aqueous filtrate and aqueous layer were diluted with IPAc (129.0 kg). 6N HCl (29 kg) was added dropwise at 15-25°C to adjust the pH of the mixture to 1-3, and the mixture was stirred for 2 hours. The mixture was filtered through Celite® (10 kg), the filtered cake was washed with IPAc (34 kg), and the filtrate was allowed to stand at 15-25°C for 2 hours. Next, the aqueous layer was extracted with IPAc (34 kg), and the combined organic layers were concentrated to approximately 35 kg under vacuum at 40°C or below. Me-cyclohexane (21 kg) was added dropwise at 15-25°C, and the mixture was concentrated to approximately 35 kg under vacuum at 40°C or below. Another 20 kg of Me-cyclohexane was added dropwise at 15-25°C and stirred for 3 hours. The mixture was then stirred at 40-50°C for 4 hours, cooled to 15-25°C over 3 hours, and then stirred for another 2 hours.

[0435] Next, the mixture was filtered, and the filtered cake was washed with 16.4 kg of IPAc / Me-cyclohexane (1 / 4, v / v). The wet cake was dried under vacuum at 35-45°C for 24 hours to obtain (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (5.2 kg, yield 68.6%, chiral purity 95.5%). Further products were isolated by rinsing the solid from the reaction vessel walls with EtOH (42 kg) and concentrating to dryness. The obtained solid was suspended in IPAc (875 mL) and Me-cyclohexane (2625 mL), stirred at 40°C for 5 hours, cooled to 20°C over 2 hours, stirred for 16 hours, and filtered. The filtered 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 filtered cake was dried at 45°C to obtain (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (1.27 kg, yield 17%, chiral purity 96.2%). LCMS (ES-): 1.74 min, m / z 193.03 [MH]-.

[0436] Chiral splitting to improve chiral purity:

[0437] (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 filtered through Celite® (12 kg) and washed with IPAc (25 kg). In a separate container, (S)-(+)-2-phenylglycinol (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 over 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 below 40°C. The concentrate was stirred at 15-25°C for 3 hours, filtered, and washed with IPAc (12 kg) (chiral purity = 96.2%).

[0438] The wet 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 minutes. The mixture was concentrated to approximately 42 kg under vacuum below 40°C and rediluted with IPAc (64 kg). This step was repeated two more times, followed by stirring at 40-50°C for 8 hours. The mixture was filtered and washed with IPAc (13 kg) (chiral purity = 97.7%). This recrystallization process was repeated two more times, for a total of three recrystallization rounds, to obtain a substance with a chiral purity of 98.9%.

[0439] Next, the wet cake (10.7 kg) was dissolved in 1N HCl (45.4 kg) and stirred at 20-30°C for 1 hour. The mixture was filtered through Celite® (11.5 kg) and washed with IPAc (28 kg). The aqueous layer was extracted with IPAc (28.8 kg), the combined organic layers were washed with water (30 kg), and then concentrated under vacuum at 40°C to obtain approximately 24 kg. Me-cyclohexane (19 kg) was added at 20°C, and the mixture was concentrated under vacuum at 40°C to obtain approximately 24 kg. This step was repeated two more times. The concentrate was diluted with Me-cyclohexane (29 kg) and stirred at 15-25°C for 1 hour. The mixture was filtered, and the wet cake was rinsed with Me-cyclohexane (59 kg). The wet cake was vacuum-dried at 35-45°C for 16 hours to obtain (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (3.02 kg, yield 50.2%).

[0440] The chiral purity of compound P2 was determined by supercritical fluid chromatography (SFC). [Table 40]

[0441] B. Synthesis of 5-fluoro-3,4-dihydro-1,8-naphthyridine-2(1H)-one [ka]

[0442] Step 1: To a stirred solution of 4-fluoro-2-pyridineamine (10.6 kg, 94.55 mol) in THF (104.0 kg), DMAP (0.59 kg, 4.82 mol) was added while maintaining the temperature at 8-12°C. In a separate reaction vessel, Boc2O (24.9 kg, 114.09 mol) was dissolved in THF (19 kg) while stirring, maintaining the temperature at 20-30°C and stirring for 30 minutes. This solution was then slowly transferred at 10°C to a vessel containing 4-fluoro-2-pyridineamine, and the mixture was stirred for 7 hours.

[0443] Next, N',N'-dimethylethane-1,2-diamine (10.05 kg, 114.01 mol) was slowly added to the reaction mixture at 10°C, and the resulting mixture was stirred and maintained at a temperature of 38-42°C for 22 hours. Then, water (42 kg) was added over 2 hours at 25°C, and the mixture was stirred at 20-30°C for 2 hours. Then, while maintaining the temperature at 25°C, water (202 kg) was added over 6 hours, and the mixture was stirred at 20-30°C for 1 hour. Next, the container was cooled to 10°C over 2 hours and stirred for 5 hours. The mixture was filtered at 10°C, and the wet cake was washed with 38.6 kg of water / THF 1 / 3 (v / v). The wet cake was dried at 45-55°C for 23 hours to obtain (4-fluoropyridine-2-yl)-carbamate tert-butyl ester (15.98 kg, yield 78.4%). LCMS (ES+): 16.59 min, m / z 156.97 [M-tBu]+.

[0444] Step 2: Prepare 111.4 mL of a solution of (4-fluoropyridine-2-yl)-carbamate tert-butyl ester (12.6 kg, 59.36 mol) and TMEDA (17.78 kg, 153.0 mol) in THF (130 kg, 12 volumes). -1 Then, 40 mL of n-BuLi (1.6 M in n-hexane) (45.25 kg, 168.8 mol) -1The solutions were then supplied to flow reactors at -40°C. The residence time in these flow reactors was 14 minutes before the solutions entered another flow reactor at -55 to -40°C. Simultaneously, 70 mL of I2 (26.7 kg, 95.3 mol) in THF (105.3 kg) was added. -1 This was then supplied to the flow reactor. The residence time for iodation was 14 minutes at -55 to -40°C, after which the temperature was adjusted to 0 to 10°C, rapidly cooled by supplying 5.0 equivalents of AcOH in water, and then transferred to a separation container.

[0445] The organic layer was separated and treated with 2.0 equivalents of Na2S2O3 (16.7% in water). The organic layer was separated again and diluted with RINKAN (88.2 L) and water (37.8 L). The organic matter was recovered, washed with water (3 × 38.2 kg), and vacuum concentrated to 50 L at less than 30°C. IPAc (58 kg) was added, and the resulting mixture was vacuum concentrated to approximately 4 volumes. This process was repeated to remove residual THF to less than 1%, and the resulting mixture was stirred at 10-25°C for 3 hours, filtered, and the filtered cake was washed with IPAc (37 kg). The wet cake was vacuum dried at 30-40°C to obtain the product (4-fluoro-3-iodopyridine-2-yl)-carbamate tert-butyl ester (15.1 kg, yield 75.2%). LCMS (Method A, ES+): 14.49 min, m / z 282.73 [M-tBu]+.

[0446] Step 3a: N,N-dimethylacetamide (132 kg) was mechanically stirred, and N2 was passed through the reaction vessel for 12 hours. Et3N (10.8 kg, 106.73 mol), butyl propaneo-2-enoate (10.4 kg, 81.149 mol), (4-fluoro-3-iodopyridine-2-yl)-carbamate tert-butyl ester (14.4 kg, 42.59 mol), and 10% wet Pd / C (1.45 kg) were added, the atmosphere of the reaction vessel was evacuated, and the mixture was replaced three times with N2. The mixture was heated to 95-105°C under N2 and stirred for 16 hours. The mixture was then cooled, filtered through Celite® (19.95 kg), and washed with RINKAN (63.6 kg).

[0447] The filtrate was diluted with RINKAN (33 kg) and water (106 kg), 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 × 65 kg of RINKAN, stirred for 1 hour after each extraction, and allowed to stand for 2 hours at 20-30°C. The combined organic matter was washed with 3 × 71 kg of water at 20-30°C, stirred for 1 hour after each wash, 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 to concentrate the solution to about 1 / 6 of its volume. This was repeated three more times to reduce the RINKAN content to about 1%. This yielded butyl(2E)-3-(2-amino-4-fluoropyridine-3-yl)prop-2-enoate as a solution in THF (total 50.4 kg, 8.52 kg, product yield 84%). LCMS (ES+): 17.69 min, m / z 239.08 [M+H]+.

[0448] Step 3b: Two identical reactions were carried out. 10% wet Pd / C (0.80 kg) was added to a stirred solution of butyl(2E)-3-(2-amino-4-fluoropyridine-3-yl)propane-2-enoate (4.19 kg, 17.58 mol) in THF (20.61 kg). The reaction atmosphere was evacuated, purged three times with argon, then evacuated again, and purged three times with H2. The H2 pressure was adjusted to 30-40 psi, and the reactants were heated to 35-45°C and stirred for 18 hours. The mixture was filtered through Celite® (8.2 kg) and washed with THF (21 kg) to obtain butyl 3-(2-amino-4-fluoropyridine-3-yl)propanoate as a solution in THF.

[0449] Step 3c: Two butyl 3-(2-amino-4-fluoropyridine-3-yl)propanoate solutions in THF were combined and concentrated to about one-fifth of the volume. EtOH (51 kg) was added, and the resulting solution was concentrated to about one-fifth of the volume. This process was repeated four more times to reduce the residual THF to about 0.5%. After adding EtOH (11 kg) and t-BuOK (0.20 kg, 1.8 mol), the mixture was stirred at 35°C for 8 hours. The mixture was neutralized with 1 M HCl (1.6 kg) at 25°C and diluted with water (42 kg). The mixture was cooled to 5-15°C and stirred for 3 hours. The precipitate was filtered, and the filtered cake was washed with 2 × 27 kg of 1 / 3 (v / v) EtOH / water. The wet cake was vacuum-dried at 40-50°C for 24 hours to obtain 5-fluoro-1,2,3,4-tetrahydro-1,8-naphthirizin-2-one (4.9 kg, 79% yield in 2 steps). LC-MS (ES+): 7.83 min, m / z 166.99 [M+H]+.

[0450] C. Synthesis of Compound A-1 [ka]

[0451] Step 1: To a stirred solution of (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (1.73 kg, 8.91 mol, chiral purity 98.9%) in N2-degassed NMP (54 kg), 5-fluoro-1,2,3,4-tetrahydro-1,8-naphthyridine-2-one (1.54 kg, 9.27 mol) and K3PO4 (7.7 kg, 36.27 mol) were added, and the reaction mixture was stirred at 95-105°C for 24 hours.

[0452] Next, the reaction mixture was cooled to 20-30°C, diluted with THF (15.8 kg), and then stirred at -15 to -5°C for 4 hours. The mixture was filtered, and the filtered cake was washed with DCM (19.8 mL). The wet cake was stirred in water (79 kg) at 15-25°C for 2 hours, and then pH was adjusted to 1 by adding 2N HCl (40 kg) dropwise. The resulting suspension was stirred at 15-25°C for 3 hours, filtered, and the filtered cake was washed with water (44 kg). The wet cake was dried under vacuum at 50-60°C for 36 hours, then further dried at 55-65°C for 30 hours to obtain (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (2.80 kg, yield 87.5%, chiral purity 99.2%). LCMS (ES+): 8.79 min, m / z 341.08 [M+H]+.

[0453] The chiral purity of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid was determined by SFC. [Table 41]

[0454] Step 2: To a stirred mixture of (3R)-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (2.758 kg, 8.10 mol, chiral purity 99.2%) in N2-degassed DCM (73 kg), 2-(4-fluorophenyl)-2-oxoethane-1-aminium chloride (2.32 kg, 12.24 mol) and T3P (8.50 kg, 13.36 mol) were added, and the reaction mixture was rinsed with DCM (10 kg). DIPEA (5.80 kg, 44.88 mol) was added dropwise over 3 hours, and the reaction mixture was stirred at 20-30°C for 8 hours.

[0455] Next, the reaction mixture was diluted with MTBE (42 kg) and concentrated to 38 L under vacuum at 40°C or below. The concentrate was diluted with MTBE (16 kg) and DCM (7.5 kg) and then re-concentrated to 41 L under vacuum at 40°C or below. The concentrate was stirred at 15-25°C for 1.5 hours, filtered, and the wet cake was washed with 12 kg of MTBE / DCM (2 / 1, v / v). The wet cake was resuspended in 38 kg of MTBE / DCM (2 / 1, v / v) and stirred at 15-25°C for 7 hours. The mixture was then filtered, and the filtered cake was washed with 13 kg of MTBE / DCM (2 / 1, v / v). Next, the wet cake was dried under vacuum at 55-65°C for 24 hours to obtain (3R)-N-[2-(4-fluorophenyl)-2-oxoethyl]-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxamide (3.40 kg, 87.1%, chiral purity 99.1%). LCMS (ES+): 15.01 min, m / z 476.01 [M+H]+.

[0456] The chiral purity of (3R)-N-[2-(4-fluorophenyl)-2-oxoethyl]-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxamide was determined by SFC. [Table 42]

[0457] Step 3: CF3SO2NH2 (1570 g, 25 equivalents) was added to the solution of AcOH (1900 g, 9.5 vol) over 30 minutes at 40°C under a nitrogen atmosphere. Next, NH4OAc (811 g, 25 equivalents) was added to the reaction vessel over 1 hour at 35-40°C under a nitrogen atmosphere. Then, P2O5 (106 g, 1.78 equivalents) was added to the reaction vessel over 30 minutes at 35-40°C under a nitrogen atmosphere, followed by the addition of AcOH (150 g, 0.75 vol). The mixture was then stirred at 35-40°C for 2 hours.

[0458] Next, P2O5 (13.5 g, 0.23 equivalents) was added to the mixture under a nitrogen atmosphere, followed by AcOH (50 g, 0.25 volume) under a nitrogen atmosphere. The mixture was then stirred at 35-40°C for 18 hours.

[0459] Next, (3R)-N-[2-(4-fluorophenyl)-2-oxoethyl]-6-[(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy]-3,4-dihydro-2H-1-benzopyran-3-carboxamide (200.05 g, 1 equivalent) was added to the reaction mixture over 30 minutes at 35-40°C under a nitrogen atmosphere. The reaction temperature was raised to 90-95°C and stirred for 24 hours under a nitrogen atmosphere, after which the temperature was 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.

[0460] The temperature was lowered again to 40-50°C. NH4OAc (486.5g, 15 equivalents) was added to the reaction mixture under a nitrogen atmosphere, and the reaction temperature was raised to 90-95°C, with stirring for 24 hours. After this, the temperature was lowered again to 40-50°C. NH4OAc (486.5g, 15 equivalents) was added to the reaction mixture under a nitrogen atmosphere, and the reaction temperature was raised to 90-95°C, with stirring for 24 hours.

[0461] Next, the reaction temperature was raised to 20-30°C, and a sodium hydroxide aqueous solution (50 vol, 5 wt%) was added to a separate reaction vessel. 0.7 g of 5-{[(3S)-3-[4-(4-fluorophenyl)-1H-imidazole-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl]oxy}-1,2,3,4-tetrahydro-1,8-naphthyridine-2-one was added to the cooled reaction mixture as a seed. The reaction mixture was then slowly transferred to a container containing NaOH solution, and the resulting mixture was stirred at 20-30°C for 12 hours. The reaction mixture was then filtered, and the filtered cake was washed with water (20 vol).

[0462] Next, the filtered cake was dissolved in TFA (0.25 vol), water (12.5 vol), MeCN (7.5 vol), and THF (2.5 vol), and the resulting solution was purified by preparative HPLC under the following conditions:

[0463] Column: YMC Triart 250×50mm, 7μm

[0464] Mobile phase: A is H2O (0.1% TFA), B is MeCN.

[0465] Flow rate: 80mL / min

[0466] Column temperature: Room temperature

[0467] Wavelength: 220nm, 254nm

[0468] Cycle time: Approximately 31 minutes

[0469] Injection: 40 mL per injection

[0470] When NH3.H2O was added to the combined fraction, the solid disintegrated. The resulting mixture was filtered, and the filtrate was concentrated under vacuum to obtain 5-{[(3S)-3-[4-(4-fluorophenyl)-1H-imidazole-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl]oxy}-1,2,3,4-tetrahydro-1,8-naphthyridine-2-one (146.4 g, yield 75%, chiral purity 98.6%) as an off-white solid. LCMS (ES+): 23.00 min, m / z 457.40 [M+H]+.

[0471] The chiral purity of 5-{[(3S)-3-[4-(4-fluorophenyl)-1H-imidazole-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl]oxy}-1,2,3,4-tetrahydro-1,8-naphthyridine-2-one was determined by SFC. [Table 43]

[0472] LC-MS method and parameters of 5-{[(3S)-3-[4-(4-fluorophenyl)-1H-imidazole-2-yl]-3,4-dihydro-2H-1-benzopyran-6-yl]oxy}-1,2,3,4-tetrahydro-1,8-naphthyrizin-2-one: [Table 44] [Table 45]

[0473] Example 5. Single crystal analysis of (3R)-6-hydroxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (P2) [ka]

[0474] Compound P2, with 90% ee, was used for single crystal growth. Single crystal growth experiments were conducted using various solvents via slow evaporation, vapor diffusion, and slow cooling. Slow evaporation in acetonitrile or tetrahydrofuran (THF) / water solvent systems yielded single crystals suitable for structural analysis. The crystal structures of single crystals obtained in both acetonitrile and tetrahydrofuran (THF) / water solvent systems were determined.

[0475] Slow evaporation in acetonitrile: Approximately 5-10 mg of compound P2 was added to a 40 mL glass vial with 10 mL of acetonitrile. After sonication for approximately 30 seconds, the vial was centrifuged, and the solvent was evaporated under ambient conditions.

[0476] Slow evaporation in a tetrahydrofuran (THF) / water (v:v=2:1) ​​solvent system: Approximately 5-10 mg of compound P2 was added to a 1 mL glass vial with 0.4 mL of THF / water (v:v=2:1) ​​solvent. After sonication for approximately 30 seconds, the resulting solution or suspension was filtered through a 0.45 μm membrane filter. The filtrate was transferred to a 1 mL glass vial. The vial was then covered with a plastic lid with a pinhole. The vial was placed in a ventilated hood and slowly evaporated under ambient conditions.

[0477] The single-crystal structure of compound P2 was determined at 170(2)K. The absolute configuration of the chiral C atom was determined to be "R" for single crystals obtained from both solvent systems. Crystals on bottle vials were collected along with the single crystals for chiral purity testing while slowly evaporating in acetonitrile. The chiral purity of the samples was 97%. Furthermore, the retention time of the main peak coincided with the retention time of the desired enantiomer. This indicates that the absolute configuration of the desired enantiomer of compound P2 is R.

[0478] [Table 46]

[0479] The crystalline form obtained from acetonitrile crystallizes in a monoclinic system, and the P21 space group is R int =3.4%, absolute structure parameter =0.05, and final R1 = [I>2σ(I)] = 3.6% at 170(2)K (Table 33A). The asymmetric unit does not contain solvent molecules. Figure 8A shows the Ortep image of the single crystal of compound P2 obtained from acetonitrile.

[0480] [Table 47]

[0481] The crystalline form obtained from the THF / water solvent system is monoclinic, and the P21 space group is R int=4.9%, absolute structure parameter = -0.04, and final R1 = [I>2σ(I)] = 3.9% at 170(2)K (Table 33B). The asymmetric unit does not contain solvent molecules. Figure 8B shows the Ortep image of the single crystal of compound P2 obtained from the THF / water solvent system.

[0482] [Table 48]

[0483] Example 6. Alternative synthesis of 5-fluoro-3,4-dihydro-1,8-naphthyridine-2(1H)-one [ka]

[0484] Step 1: Tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate (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 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (1.55 g, 1.9 mmol) was added to this mixture, and the reaction was heated overnight at 90°C. Deprotection of the initial 2-Boc position was observed first and proceeded cleanly. Subsequently, conversion of the Suzuki product became effective. The reaction mixture was evaporated to dryness, dissolved in DCM (150 mL), and treated with saturated NH4Cl aqueous solution (50 mL). Further extraction was performed with DCM (2 × 150 mL), washed with brine, dried (MgSO4), filtered, and then evaporated to dryness under vacuum. The residue was subjected to flash column chromatography (120 g silica) and eluted with ethyl in petroleum ether (25-75%). The required compound was cleanly eluted with approximately 60% ethyl in petroleum ether, yielding ethyl(E)-3-(2-amino-4-fluoro-3-pyridyl)propa-2-enoate (3.10 g, 14.8 mmol, yield 78%) as a waxy yellow solid. 1 H 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 acidic): 1.1 min, m / z 211.1 [M+H]+(100%).

[0485] Step 2: Ethyl-(E)-3-(2-amino-4-fluoro-3-pyridyl)prop-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 reactants were exposed to a hydrogen gas atmosphere and stirred overnight at room temperature. The reaction appeared to be mainly due to the reduction of side chains (approximately 90%) and the appearance of the required final cyclization hinge material (8%). The reaction mixture was filtered to remove the Pd catalyst, and evaporated to dryness to obtain a crude mixture containing the required products, ethyl-3-(2-amino-4-fluoro-3-pyridyl)propanoate (900 mg, 4.09 mmol, yield 86%) and 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (64 mg, 0.46 mmol, yield 10%). 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 7.79 (dd, J = 9.1, 5.6 Hz, 1H), 6.38 (dd, J = 9.2, 5.7 Hz, 1H), 6.11 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.73 (ddd, J = 8.1, 6.8, 1.3 Hz, 2H), 2.45 (dd, J = 8.4, 7.0 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H).

[0486] Step 3: Ethyl-3-(2-amino-4-fluoro-3-pyridyl)propanoate (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 minutes. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (2 mL), evaporated to dryness under vacuum, then dissolved in water and thoroughly sonicated. The precipitate was slurryed in water for 1 hour, the solid was filtered, washed with water, and dried in a vacuum oven to obtain 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (691 mg, 4.2 mmol, 93% yield) as a fluffy white solid product. 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 acidic): 1.07 min, m / z 166.9 [M+H]+(100%).

[0487] Example 7 Alternative synthesis of 5-fluoro-3,4-dihydro-1,8-naphthyridine-2(1H)-one [ka]

[0488] Step 1: Tert-butyl N-(4-fluoro-3-iodo-2-pyridyl)carbamate (150 g, 444 mmol) was suspended in 1,4-dioxane (1.25 L) with butyl acrylate (159 mL, 1109 mmol), and TFA (155 mL, 1109 mmol) was added. Palladium (10 wt% on carbon powder, 50% wet) (10.6 g, 99.8 mmol) was added, the reaction mixture was stirred, heated under reflux overnight, and then cooled. UPLC-MS showed 94% of the desired product. The reaction mixture was diluted with water (750 mL) and ethyl acetate (500 mL), and the catalyst was removed by filtration through Celite. Washed with ethyl acetate (500 mL). The layers were separated, and the aqueous layer was re-extracted with ethyl acetate (500 mL). The combined organic layers were washed with water (500 mL), dried, filtered, and reduced under vacuum to obtain butyl(E)-3-(2-amino-4-fluoro-3-pyridyl)prop-2-enoate (117.5 g, 439 mmol, yield 99%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 7.98 (dd, J = 8.9, 5.5 Hz, 1H), 7.56 (d, J = 16.1 Hz, 1H), 6.71 (s, 2H), 6.56 - 6.40 (m, 2H), 4.15 (t, J = 6.6 Hz, 2H), 1.63 (dq, J = 8.4, 6.7 Hz, 2H), 1.45 - 1.29 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). UPLC-MS(ES + , short acid): 1.47 min, m / z 239.3 [M+H] + (100%).

[0489] Step 2: Ethyl-(E)-3-(2-amino-4-fluoro-3-pyridyl)prop-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 reactants were exposed to a hydrogen gas atmosphere and stirred overnight at room temperature. The reaction appeared to be mainly due to the reduction of the side chain (approximately 90%) and the appearance of the desired final cyclized product (8%). The reaction mixture was filtered to remove the Pd catalyst, and evaporated to dryness to obtain a crude mixture containing the required products, ethyl-3-(2-amino-4-fluoro-3-pyridyl)propanoate (900 mg, 4.09 mmol, yield 86%) and 5-fluoro-3,4-dihydro-1H-1,8-naphthyrizin-2-one (64 mg, 0.46 mmol, yield 10%). 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 7.79 (dd, J = 9.1, 5.6 Hz, 1H), 6.38 (dd, J = 9.2, 5.7 Hz, 1H), 6.11 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.73 (ddd, J = 8.1, 6.8, 1.3 Hz, 2H), 2.45 (dd, J = 8.4, 7.0 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H).

[0490] Step 3. Step 3: Dissolve ethyl-3-(2-amino-4-fluoro-3-pyridyl)propanoate (950 mg, 4.5 mmol) in THF (10 mL), then KO t The mixture was treated with Bu (754 mg, 6.7 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (2 mL), evaporated to dryness under vacuum, then dissolved in water and thoroughly sonicated. The precipitate was slurryed in water for 1 hour, the solid was filtered, washed with water, and dried in a vacuum oven to obtain 5-fluoro-3,4-dihydro-1H-1,8-naphthyridine-2-one (691 mg, 4.2 mmol, 93% yield) as a fluffy white solid product. 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%).

[0491] Example 8. Biological assay

[0492] HCT-116 AlphaLISA SureFire pERK1 / 2 Cell Assay

[0493] Human HCT-116 colorectal cancer cell line (ATCC CCL-247) triggers constitutive activation of the MAP kinase pathway and phosphorylation of ERK in KRAS G13DThe mutation is endogenously expressed. To determine whether the compounds inhibit constitutive ERK phosphorylation in HCT-116 cells, they were tested using AlphaLISA® SureFire® technology (PerkinElmer p-ERK1 / 2p-T202 / Y204 assay kit ALSU-PERK-A10K). Assay readouts were performed 2 or 24 hours after compound administration. On day 1, HCT-116 cells were harvested, resuspended in growth medium (McCoys5A containing Glutamax (LifeTechnologies36600021) and 10% heat-inactivated fetal bovine serum (SigmaF9665)) and counted. Cells were seeded in each well of a 96-well culture dish (Sigma CLS3598) at a rate of 100 μl per well, up to a final cell density of 30,000 cells per well (2-hour reading) or 15,000 cells per well (24-hour reading), and incubated overnight at 37°C in 5% CO2. On day 2, the growth medium was replaced with administration medium (McCoys 5A (Life Technologies 36600021) containing Glutamax and 1% heat-inactivated fetal bovine serum (Sigma F9665)), and the cells were administered compounds that produced 10 dose-response points, with a peak concentration of 1 μM and subsequent concentrations at 1 / 3 dilution intervals. A corresponding DMSO control was included. The cells were then incubated at 37°C in 5% CO2 for 2 hours or 24 hours. After incubation, the medium was removed, and the cells were incubated at room temperature for 15 minutes with lysis buffer containing a phosphatase inhibitor. Cell lysates were transferred to a 1 / 2 area 96-well white Optiplate (trademark) (PerkinElmer 6005569) and incubated with anti-mouse IgG acceptor beads, an anti-ERK1 / 2 rabbit antibody that recognizes both phosphorylated and unphosphorylated ERK1 / 2, a mouse antibody that targets the Thr202 / Tyr204 epitope and recognizes only phosphorylated ERK protein, and streptavidin-coated donor beads. The biotinylated antibody bound to the streptavidin-coated donor beads, while the phopsho-ERK1 / 2 antibody bound to the acceptor beads.The plate was read with an EnVision reader (Perkin Elmer). Laser excitation of the beads at 680 nm induced the release of singlet oxygen molecules from the donor beads, which triggered energy transfer to the adjacent acceptor beads, generating a signal measurable at 570 nm. Both antibodies bound to phosphorylated ERK protein, and the donor and acceptor beads were brought into close proximity. All data were analyzed using the Dotmatics or GraphPadPrism software package. Inhibition of ERK phosphorylation is defined as the absolute IC50, which is the concentration of the compound required to reduce the level of phosphorylated ERK protein by 50% compared to the DMSO control. 50 The evaluation was based on the determination of a value.

[0494] WiDr AlphaLISA SureFire pERK1 / 2 Cell Assay

[0495] Human WiDr colorectal adenocarcinoma cell line (ATCC CCL-218) induces constitutive activation of the MAP kinase pathway and phosphorylation of ERK in BRAF V600EThe mutation is endogenously expressed. To determine whether the compounds inhibit constitutive ERK phosphorylation in WiDr cells, they were tested using AlphaLISA® SureFire® technology (PerkinElmer p-ERK1 / 2p-T202 / Y204 assay kit ALSU-PERK-A10K). The main procedure was basically the same as for HCT-116 cells (above), with the following adjustments: growth medium (Eagle's Minimal Essential Medium (SigmaM2279) containing 1×Glutamax (Life Technologies 35050038), 1×sodium pyruvate (SigmaS8636), and 10% heat-inactivated fetal bovine serum (SigmaF9665)); administration medium (Eagle's Minimal Essential Medium (SigmaM2279) containing 1×Glutamax (Life Technologies 35050038), 1×sodium pyruvate (SigmaS8636), and 1% heat-inactivated fetal bovine serum (SigmaF9665)); and seeding density (2 hours: 50,000 cells per well; 24 hours: 35,000 cells per well). In addition, the compound was administered at a maximum concentration of 10 μM at 1 / 2 log dilution intervals.

[0496] HCT-116 AlphaLISA SureFire pERK1 / 2 cell assay (dimer)

[0497] Human HCT-116 colorectal cancer cell line (ATCC CCL-247) triggers constitutive activation of the MAP kinase pathway and phosphorylation of ERK in KRAS G13DThe mutation is expressed endogenously. First-generation RAF inhibitors can promote RAF dimerization in KRAS-mutated tumors, resulting in paradoxical activation of the pathway. To determine whether compounds circumvent this problem and inhibit RAF dimerization in HCT-116 cells, they were tested using AlphaLISA® SureFire® technology (PerkinElmer p-ERK1 / 2p-T202 / Y204 assay kit ALSU-PERK-A10K). The main procedure was essentially the same as above, with the following modifications: cells were seeded at a seeding density of 30,000 cells per well. On day 2 (administration day), no medium change was performed, and cells were administered 1 μM encorafenib over 1 hour (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 compound of interest was administered to the cells to generate 10 dose-response points, with a peak concentration of 10 μM and subsequent concentrations at 1 / 2 dilution intervals. The cells were further incubated at 37°C in 5% CO2 for 1 hour before lysis and treatment with the pERK AlphaLISA® SureFire® kit as described above.

[0498] A375 AlphaLISA SureFire pERK1 / 2 Cell Assay (Monomer)

[0499] Human A375 melanoma cell line (ATCC CRL-1619) induces constitutive activation of the MAP kinase pathway and phosphorylation of ERK through BRAF V600E The mutation is expressed endogenously. BRAF V600EIn mutant tumors, BRAF signals ERK activation as a monomer. To determine whether compounds can inhibit the BRAF monomer in A375 cells, they were tested using AlphaLISA® SureFire® technology (PerkinElmer p-ERK1 / 2p-T202 / Y204 assay kit ALSU-PERK-A10K). The main procedure was essentially the same as described above for HCT-116 cells, with the following modifications: A375 cells were cultured and administered in Dulbecco's Modified Eagle Medium containing 4.5 g / L D-glucose (SigmaD6546), 10% heat-inactivated fetal bovine serum (SigmaF9665), and 1% sodium pyruvate (SigmaS8636), seeded at a seeding density of 30,000 cells per well. Ten dose-response points were generated, with the maximum concentration being 10 μM and subsequent concentrations at 1 / 2 dilution intervals, without changing the culture medium before administering the compound. Subsequently, the cells were incubated at 37°C in CO2 for 1 hour before lysis.

[0500] HCT-116 CellTiter-Glo 3D Cell Proliferation Assay

[0501] Human HCT-116 colorectal cancer cell line (ATCC CCL-247) promotes KRAS, which is responsible for signaling survival and proliferation. G13DThe mutation is endogenously expressed. To determine whether the compound inhibits the proliferation of HCT-116 cells, the CellTiter-Glo® 3D Cell Viability Assay Kit (PromegaG9683) was used for testing. On day 1, HCT-116 cells were harvested, resuspended in growth medium (McCoys5A (LifeTechnologies36600021) containing Glutamax, with 10% heat-inactivated fetal bovine serum (SigmaF9665)) and counted. Cells were seeded in each well of a Corning 7007 96-well clear round-bottom ultra-low adhesion plate (VWR444-1020) at a rate of 100 μl per well, up to a final density of 1000 cells per well. Cells were seeded for pre-treatment and post-treatment readings. Cells were then incubated at 37°C in 5% CO2 for 3 days (72 hours) to form spheroids. After 72 hours, the plates seeded for pre-treatment reading were removed from the incubator and allowed to equilibrate at room temperature for 30 minutes before adding the CellTitre-Glo® reagent to each well. The plates were incubated at room temperature for 5 minutes with shaking at 300 rpm, followed by 25 minutes of incubation on a benchtop, and then read with an Envision reader (Perkin Elmer) as described below. On the same day, the compound was administered to cells seeded for post-treatment reading, generating 9 dose-response points with a peak concentration of 15 μM and subsequent concentrations at 1 / 2 dilution intervals. These cells were then incubated for a further 4 days (96 hours) at 37°C in 5% CO2. After 4 days, the plates were removed from the incubator, allowed to equilibrate at room temperature for 30 minutes, and treated with the CellTitre-Glo® reagent as described above. This method allows for the quantification of ATP present in the wells, which is directly proportional to the amount of viable (and therefore metabolically active) cells in the 3D cell culture. CellTitle Glo® reagents lyse cells and contain luciferin and luciferase (Ultra-Glo® recombinant luciferase), which can generate bioluminescence from luciferin in the presence of ATP and oxygen.Therefore, plates were read with an EnVision reader (Perkin Elmer) and luminescence signals were recorded. Cell proliferation was determined on day 4 post-administration, compared to pre-treatment readings. All data were analyzed using the Dotmatics or GraphPadPrism software package. Proliferation inhibition was defined as the GI (Gross Index) of the compound required to reduce the level of cell proliferation by 50% compared to the DMSO control. 50 The evaluation was based on the determination of a value.

[0502] WiDr CellTiter-Glo 3D Cell Proliferation Assay

[0503] Human WiDr colorectal adenocarcinoma cell line (ATCC CCL-218) promotes BRAF, which facilitates signaling for survival and proliferation. V600E The mutation is expressed endogenously. To determine whether the compound inhibits the proliferation of WiDr cells, the growth medium was prepared and tested using the CellTiter-Glo® 3D Cell Viability Assay Kit (Promega G9683) as described for HCT-116 cells, with the following preparations: Eagle's Minimal Essential Medium (Sigma M2279) containing 1×Glutamax (Life Technologies 35050038), 1×Sodium Pyruvate (Sigma S8636), and 10% heat-inactivated fetal bovine serum (Sigma F9665).

[0504] [Table 49]

[0505] [Table 50]

[0506] Microsome Stability Assay

[0507] Stability studies were performed manually using a substrate depletion approach. The test compound was divided into 0.5 mg / mL units.-1 The reaction was incubated at 37°C with mouse or human liver microsomes (Corning) that had been cryopreserved at the protein concentration and a final substrate concentration of 1 μM. Aliquots were removed from the incubation at predetermined time points, and the reaction was terminated by adding ice-cold organic solvent. Compound concentrations were determined by LC-MS / MS analysis. The natural logarithm of the percentage of remaining compound was plotted against each time point, and the slope was determined. Half-life (t 1 / 2 ) and CL int These were calculated using equations 1 and 2, respectively. Data analysis was performed using Excel (Microsoft, USA).

[0508] t 1 / 2 (minutes) = 0.693 / - slope (1)

[0509] CL int (μL / min / mg) = (LN(2) / t 1 / 2 (min) * 1000 / microsomal protein (mg / mL) (2)

[0510] The results of the stability assays for HLM (human liver microsomes) and MLM (mouse liver microsomes) are shown in Table 34C.

[0511] Hepatocyte stability assay

[0512] Hepatocyte stability studies were performed manually using a substrate depletion approach. The compounds were tested on cryopreserved mouse (Bioreclamation) or human (Corning) hepatocytes at a rate of 0.5 × 10⁶. 6 The cells were incubated at 37°C at a cell density of cells / mL and a final compound concentration of 1 μM. Sampling was performed at predetermined time points, and the reaction was terminated by adding ice-cold organic solvent. Compound concentrations were determined by LC-MS / MS analysis. The natural logarithm of the percentage of residual compound was plotted against each time point, and the slope was determined. Half-life (t) 1 / 2 ) and CL intThese were calculated using equations 1 and 3, respectively. Data analysis was performed using Excel (Microsoft, USA).

[0513] CL int (μL / min / 10 6 cells)=(LN(2) / t 1 / 2 (min))*1000 / cell density(10 6 cells / mL) (3)

[0514] The results of the stability assays for HLH (human hepatocytes) and MLH (mouse hepatocytes) are shown in Table 34C.

[0515] [Table 51]

[0516] Plasma protein binding assay

[0517] Plasma protein binding was determined by equilibrium dialysis. Known concentrations (5 μM) of the compound in pre-frozen human or mouse plasma (Sera Labs) were dialyzed against phosphate buffer at 37°C for 4 hours using a RED device (Life Technologies). The concentrations of the compound on the protein-containing (PC) and protein-free (PF) sides of the dialysis membrane were determined by LC-MS / MS, and the percentage of the free compound was determined by Equation 4. Data analysis was performed using Excel (Microsoft, USA).

[0518] Free % = (1 - ((PC - PF) / PC)) × 100 (4)

[0519] The results for hPPB (human plasma protein binding) and mPPB (mouse plasma protein binding) are shown in Table 34D.

[0520] FeSSIF solubility assay

[0521] 1.0 mg of the compound was added to 1 mL of simulated feeding intestinal fluid (FeSSIF) prepared using FaSSIF / FeSSIF / FaSSGF powder (Biorelevant.com) and pH 5 acetate buffer, and then incubated for 24 hours (Bioshake iQ, 650 rpm, 37°C). Following filtration under positive pressure, the concentration of the compound in the solution was evaluated by LC-UV compared to the response of a calibration standard of known concentration (250 μM). The results of the FeSSIF solubility are shown in Table 34D.

[0522] [Table 52]

[0523] The publications discussed herein are provided only for disclosures prior to the filing date of this application. Nothing herein should be construed as an acknowledgment that the present invention has no prior rights to such publications for the sake of prior art.

[0524] While the present invention is described in relation to its proposed specific embodiments, it should be understood that the invention is subject to further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention, including any deviations from this disclosure in accordance with the appended claims, which may be included in known or practiced practices within the scope of the art to which the invention relates, in general, in accordance with the principles of the invention, and which may be applied to the essential features described above.

[0525] Numbered Embodiments

[0526] The compound of Embodiment 1(IIb), or a pharmaceutically acceptable salt or tautomer thereof, [ka]

[0527] (In the formula,

[0528] R3 is halogen, -OR A , -NR A R B , -SO2R C -SOR C ,-CN,C 1-4 Alkyl, C 1-4 Haloalkyl, or C 3-6 It is a cycloalkyl, alkyl is a haloalkyl, and cycloalkyl is -OR A -CN, -SOR C , or -NR A R B It is optionally replaced by 1 to 3 elements that are independently selected from it;

[0529] R A and R B These are H and C, respectively, independently. 1-4 Alkyl and C 1-4 Selected from haloalkyl;

[0530] R C C 1-4 Alkyl and C 1-4 Selected from haloalkyl;

[0531] (where n is 0, 1, 2, 3, or 4)

[0532] A method for synthesizing, wherein the method

[0533] a) Reacting 5-fluoro-3,4-dihydro-1,8-naphthyridine-2(1H)-one with (R)-6-hydroxychroman-3-carboxylic acid to provide (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid; [ka]

[0534] b) Reacting (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid with 2-amino-1-phenylethane-1-one or a salt thereof to provide a compound of formula 4B-(R).

[0535] (2-amino-1-phenylethane-1-one is R 3 (It is replaced by an optional choice.) [ka]

[0536] c) The method comprising cyclizing the compound of formula 4B-(R) of 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. [ka]

[0537] Embodiment 2. The method according to Embodiment 1, wherein (R)-6-hydroxychroman-3-carboxylic acid is prepared by chiral hydrogenation of 6-hydroxy-2H-chromen-3-carboxylic acid. [ka]

[0538] Embodiment 3. The method according to Embodiment 2, wherein the chiral hydrogenation is carried out in the presence of a Ru or Rh catalyst and a chiral ligand.

[0539] Embodiment 4. The method according to Embodiment 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.

[0540] Embodiment 5. The method according to Embodiment 3 or 4, wherein the Ru catalyst is selected from [RuCl2(p-cym)]2, Ru(COD)(Me-allyl)2, or Ru(COD)(TFA)2.

[0541] Embodiment 6. The method according to any one of Embodiments 3 to 5, wherein the chiral ligand is selected from (R)-PhanePhos or (R)-An-PhanePhos.

[0542] Embodiment 7. The method according to Embodiment 3, wherein the chiral hydrogenation is carried out in the presence of a chiral Ru complex or a chiral Rh complex.

[0543] Embodiment 8. The method according to Embodiment 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)].

[0544] Embodiment 9. The method according to any one of Embodiments 2 to 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.

[0545] Embodiment 10. The method according to any one of Embodiments 2 to 8, wherein the chiral hydrogenation is carried out with a substrate / catalyst loading in the range of about 200 / 1 to about 1,000 / 1.

[0546] Embodiment 11. The method according to any one of Embodiments 2 to 10, wherein the chiral hydrogenation is carried out in the presence of a base.

[0547] Embodiment 12. The method according to Embodiment 11, wherein the base is triethylamine, NaOMe, or Na2CO3.

[0548] Embodiment 13. The method according to Embodiment 11 or 12, wherein the base is used in an equivalent amount 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 relative to 6-hydroxy-2H-chromen-3-carboxylic acid.

[0549] Embodiment 14. The method according to any one of Embodiments 2 to 13, wherein the chiral hydrogenation is carried out at a temperature in the range of about 30°C to about 50°C.

[0550] Embodiment 15. The method according to any one of Embodiments 2 to 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.

[0551] Embodiment 16. The method according to any one of Embodiments 2 to 15, wherein the chiral hydrogenation is carried out at a hydrogen pressure in the range of about 2 bar to about 30 bar.

[0552] Embodiment 17. The method according to any one of Embodiments 2 to 15, wherein the chiral hydrogenation is carried out at a hydrogen pressure in the range of about 3 bar to about 10 bar.

[0553] Embodiment 18. The method according to any one of Embodiments 2 to 17, wherein the chiral hydrogenation is carried out in the presence of an alcohol solvent.

[0554] Embodiment 19. The method according to Embodiment 18, wherein the solvent is methanol, ethanol, or isopropanol.

[0555] Embodiment 20. The method according to any one of Embodiments 1 to 19, wherein (R)-6-hydroxychroman-3-carboxylic acid has an enantiomer excess of at least 90%.

[0556] Embodiment 21. The method according to any one of Embodiments 1 to 19, wherein (R)-6-hydroxychroman-3-carboxylic acid has an enantiomer excess of at least 95%.

[0557] Embodiment 22. The method according to any one of Embodiments 1 to 21, wherein (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid has an enantiomer excess of at least 90%.

[0558] Embodiment 23. The method according to any one of Embodiments 1 to 21, wherein (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid has an enantiomer excess of at least 95%.

[0559] Embodiment 24. The method according to any one of Embodiments 1 to 23, wherein the compound of formula 4B-(R) in step b) has an enantiomeric excess of at least 90%.

[0560] Embodiment 25. The method according to any one of Embodiments 1 to 23, wherein the compound of formula 4B-(R) in step b) has an enantiomeric excess of at least 95%.

[0561] Embodiment 26. The method according to any one of Embodiments 1 to 25, wherein the compound of formula (IIb), or a pharmaceutically acceptable salt or tautomer thereof, has an enantiomeric excess of at least 90%.

[0562] Embodiment 27. The method according to any one of Embodiments 1 to 25, wherein the compound of formula (IIb), or a pharmaceutically acceptable salt or tautomer thereof, has an enantiomeric excess of at least 95%.

[0563] Embodiment 28. The method according to any one of Embodiments 1 to 25, wherein the compound of formula (IIb), or a pharmaceutically acceptable salt or tautomer thereof, has an enantiomeric excess of at least 98%.

[0564] Embodiment 29. R 3 is halogen, C 1-4 Alkyl, -SO2(C 1-4 The method according to any one of Embodiments 1 to 28, wherein the alkyl is...

[0565] Embodiment 30. R 3 The method according to any one of Embodiments 1 to 28, wherein the element is F, Cl, Br, or I.

[0566] The method according to any one of embodiments 2 to 30, wherein embodiment 31.n is 0, 1, or 2.

[0567] Embodiment 32. The compound is [ka] The method according to any one of Embodiments 1 to 31, or selected from a pharmaceutically acceptable salt or tautomer thereof.

[0568] Embodiment 33. A compound of formula (IIb), or a pharmaceutically acceptable salt or tautomer thereof, prepared by the method described in any one of Embodiments 1 to 32.

[0569] Embodiment 34. A structure prepared by the method described in any one of Embodiments 1 to 32. [ka] A compound having, or a pharmaceutically acceptable salt or tautomer thereof.

[0570] Embodiment 35. The compound according to Embodiment 33 or 34, wherein the compound has an enantiomeric excess of at least 90%.

[0571] Embodiment 36. The compound according to any one of Embodiments 33 to 35, wherein the compound has an enantiomeric excess of at least 95%.

[0572] Embodiment 37. The compound according to any one of Embodiments 33 to 36, wherein the compound has an enantiomeric excess of at least 98%.

[0573] Embodiment 38. The compound according to any one of Embodiments 33 to 37, wherein the compound has a chemical purity of at least 85%.

[0574] Embodiment 39. The compound according to any one of Embodiments 33 to 38, wherein the compound has a chemical purity of at least 90%.

[0575] Embodiment 40. The compound according to any one of Embodiments 33 to 39, wherein the compound has a chemical purity of at least 95%.

[0576] Embodiment 41. A pharmaceutical composition comprising a compound described in any one of Embodiments 33 to 40 and a pharmaceutically acceptable excipient or carrier.

[0577] Embodiment 42. The pharmaceutical composition according to Embodiment 41, further comprising an additional therapeutic agent.

[0578] Embodiment 43. The pharmaceutical composition according to Embodiment 42, wherein the additional therapeutic agent is selected from antiproliferative agents or antineoplastic agents, cell proliferation inhibitors, anti-infiltration agents, growth factor function inhibitors, anti-angiogenic agents, steroids, targeted therapy agents, or immunotherapy agents.

[0579] Embodiment 44. A method for treating a condition regulated by RAF kinase, comprising administering an effective amount of any one of Embodiments 33 to 40 to a subject in need thereof.

[0580] Embodiment 45. The method according to Embodiment 44, wherein the condition is treatable by inhibition of one or more Raf kinases.

[0581] Embodiment 46. The method according to Embodiment 44 or 45, wherein the condition is selected from cancer, sarcoma, melanoma, skin cancer, hematological malignancy, lymphoma, carcinoma, or leukemia.

[0582] Embodiment 47. The method according to Embodiment 44 or 45, wherein the condition is selected from Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma; astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (metastases to the central nervous system from tumors originating outside the central nervous system); brain tumors; brain metastases; colorectal cancer; colon cancer; gastric cancer; head and neck cancers; 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.

[0583] Embodiment 48. A method for treating cancer, comprising administering an effective amount of a compound described in any one of Embodiments 33 to 40 to a subject in need thereof.

[0584] Embodiment 49. The method according to Embodiment 48, wherein the cancer comprises at least one mutation in BRAF kinase.

[0585] Embodiment 50. The cancer is BRAF V600E The method according to Embodiment 49, including a variation.

[0586] Embodiment 51. The method according to Embodiment 49, wherein the cancer is selected from melanoma, thyroid cancer, Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumors, glioblastoma, astrocytoma, ependymoma, colorectal cancer, colon cancer, gastric cancer, head and neck cancer, hematological cancer, leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, megakaryoblastic leukemia, multiple myeloma, hepatocellular carcinoma, lung cancer, ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, kidney cancer, sarcoma, uveal melanoma, or skin cancer.

[0587] Embodiment 52. The cancer is BRAF V600E Melanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid cancer, BRAF V600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAF V600E Hepatobiliary cancer, BRAF V600E hairy cell leukemia, BRAF V600E Non-small cell carcinoma, or BRAF V600E The method according to embodiment 50, wherein the tumor is a pilocytic astrocytoma.

[0588] Embodiment 53. The method according to any one of Embodiments 46 to 52, wherein the cancer is colorectal cancer.

Claims

1. Compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts or tautomers thereof, or mixtures of multiple compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts or tautomers thereof. 【Chemistry 1】 (In the formula, R １ C is a substitution or non-substitution. １－６ Alkyl, C １－６ Selected from haloalkyl, aryl, heterocyclyl, or heteroaryl; R ２ is H; X １ is N or CR ８ And; X ２ is N or CR ９ And; R ６ is hydrogen, halogen, alkyl, alkoxy, -NH ２ , -NR Ｆ C(O)R ５ , -NR Ｆ C(O)CH ２ R ５ , -NR Ｆ C(O)CH(CH ３ ), R ５ , or -NR Ｆ R ５ ; R ７ , R ８ , and R ９ Each of these is independently hydrogen, halogen, or alkyl; Alternatively, R ６ and R ８ together, or R ７ and R ９ Together, they form a five- or six-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, with the atoms to which they are bonded, and the ring is substituted or unsubstituted; R ５ is a substituted or unsubstituted group selected from alkyl, carbocykryl, aryl, heterocyclyl, or heteroaryl; R Ｆ is H or C １－３ (It is alkyl.) A method for synthesizing, wherein the method a) Reacting a compound of formula 1A with (R)-6-hydroxychroman-3-carboxylic acid or (S)-6-hydroxychroman-3-carboxylic acid or a mixture thereof to obtain a compound of formula 2A or a mixture of multiple compounds of formula 2A. (The compound of formula 2A has (R) or (S) stereochemistry at the carbon indicated by *); 【Chemistry 2】 b) Reacting the compound of formula 2A or a mixture of multiple compounds of formula 2A with the compound of formula 3A or a salt thereof to obtain the compound of formula 4A or a mixture of multiple compounds of formula 4A. (The compound of formula 4A has (R) or (S) stereochemistry at the carbon indicated by *); 【Transformation 3】 c) The method comprising cyclizing the compound of formula 4A or a mixture of multiple compounds of formula 4A in step b) in the presence of ammonia or an ammonium salt to provide a compound of formula (Ia) or (Ib), a pharmaceutically acceptable salt or tautomer thereof, or a mixture of multiple compounds of formula (Ia) or (Ib), or a pharmaceutically acceptable salt or tautomer thereof. 【Chemistry 4】

2. Compounds of formula (IIa) or (IIb), or pharmaceutically acceptable salts or tautomers thereof, or mixtures of multiple compounds of formula (IIa) or (IIb), or pharmaceutically acceptable salts or tautomers thereof. 【Transformation 5】 (In the formula, R ３ is halogen, -OR Ａ , -NR Ａ R Ｂ , -SO ２ R Ｃ , -SOR Ｃ ,-CN,C １－４ Alkyl, C １－４ Haloalkyl, or C ３－６ It is a cycloalkyl, alkyl is a haloalkyl, and cycloalkyl is -OR Ａ -CN, -SOR Ｃ , or -NR Ａ R Ｂ It is optionally replaced by 1 to 3 elements that are independently selected from; R Ａ and R Ｂ These are H and C, respectively, independently. １－４ Alkyl, or C １－４ It is a haloalkyl; R Ｃ C １－４ Alkyl or C １－４ It is a haloalkyl; n is 0, 1, 2, 3, or 4. A method for synthesizing, wherein the method a) Reacting 5-fluoro-3,4-dihydro-1,8-naphthyridine-2(1H)-one with (R)-6-hydroxychroman-3-carboxylic acid, (S)-6-hydroxychroman-3-carboxylic acid, or a mixture thereof, to provide (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid, (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid, or a mixture thereof; 【Transformation 6】 b) (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid, (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid, or a mixture thereof, reacted with 2-amino-1-phenylethane-1-one or a salt thereof to provide a compound of formula 4B or a mixture of multiple compounds of formula 4B. (2-amino-1-phenylethane-1-one is R ３ It is replaced by an optional choice; The compounds of formula 4B have (R) or (S) stereochemistry at the carbon indicated by *; 【Transformation 7】 c) The method comprising cyclizing the compound of formula 4B or a mixture of multiple compounds of formula 4B in step b) in the presence of ammonia or an ammonium salt to provide a compound of formula (IIa) or (IIb), a pharmaceutically acceptable salt or tautomer thereof, or a mixture of multiple compounds of formula (IIa) or (IIb), or pharmaceutically acceptable salts or tautomers thereof. 【Transformation 8】

3. The method according to claim 1 or 2, wherein (R)-6-hydroxychroman-3-carboxylic acid, (S)-6-hydroxychroman-3-carboxylic acid, or a mixture thereof is prepared by chiral hydrogenation of 6-hydroxy-2H-chromen-3-carboxylic acid. 【Chemistry 9】

4. The method according to claim 3, wherein the chiral hydrogenation is carried out in the presence of a Ru or Rh catalyst and a chiral ligand.

5. The Ru or Rh catalyst is Ru(OAc) ２ [RuCl ２ (p-cym) ２ , Ru(COD)(Me-allyl) ２ , Ru(COD)(TFA) ２ [Rh(COD) ２ ]OTf, or [Rh(COD) ２ ] BF ４ The method according to claim 4, selected from the following.

6. The Ru catalyst is [RuCl ２ (p-cym) ２ , Ru(COD)(Me-allyl) ２ , or Ru(COD)(TFA) ２ The method according to claim 4 or 5, selected from the above.

7. The chiral ligand is (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, (R,R)-BPPM, or Josiphos The method according to any one of claims 4 to 6, selected from SL-J002-1.

8. The method according to any one of claims 4 to 6, wherein the chiral ligand is selected from (S)- or (R)-PhanePhos or (S)- or (R)-An-PhanePhos.

9. The method according to claim 4, wherein the chiral hydrogenation is carried out in the presence of a chiral Ru complex or a chiral Rh complex.

10. The chiral Ru complex or the chiral Rh complex is [(R)-Phanephos-RuCl ２ (p-cym)], [(S)-Phanephos-RuCl ２ (p-cym)], [(R)-An-Phanephos-RuCl ２ (p-cym)], [(S)-An-Phanephos-RuCl ２ (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)]BF ４ , [(S)-Phanephos-Rh(COD)]BF ４ The method according to claim 9, selected from [(R)-Phanephos-Rh(COD)]OTf or [(S)-Phanephos-Rh(COD)]OTf.

11. The chiral Ru complex is [(R)-Phanephos-RuCl ２ (p-cym)], [(S)-Phanephos-RuCl ２ (p-cym)], [(R)-An-Phanephos-RuCl ２ (p-cym)], or [(S)-An-Phanephos-RuCl] ２ The method according to claim 9, selected from (p-cym).

12. The method according to any one of claims 3 to 11, wherein the chiral hydrogenation is carried out with a substrate / catalyst loading in the range of 25 / 1 to 1,000 / 1.

13. The method according to any one of claims 3 to 11, wherein the chiral hydrogenation is carried out with a substrate / catalyst loading in the range of 200 / 1 to 1,000 / 1.

14. The method according to any one of claims 3 to 13, wherein the chiral hydrogenation is carried out in the presence of a base.

15. The base is triethylamine, NaOMe, or Na ２ CO ３ The method according to claim 14.

16. The method according to claim 14 or 15, wherein the base is used in an equivalent amount of 2.0 or less relative to 6-hydroxy-2H-chromen-3-carboxylic acid.

17. The method according to any one of claims 3 to 16, wherein the chiral hydrogenation is carried out at a temperature in the range of 30°C to 50°C.

18. The method according to any one of claims 3 to 17, 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.

19. The method according to any one of claims 3 to 18, wherein the chiral hydrogenation is carried out at a hydrogen pressure in the range of 2 bar to 30 bar.

20. The method according to any one of claims 3 to 18, wherein the chiral hydrogenation is carried out at a hydrogen pressure in the range of 3 bar to 10 bar.

21. The method according to any one of claims 3 to 20, wherein the chiral hydrogenation is carried out in the presence of an alcohol solvent.

22. The method according to claim 21, wherein the solvent is methanol, ethanol, or isopropanol.

23. a) The mixture of (R)-6-hydroxychroman-3-carboxylic acid and (S)-6-hydroxychroman-3-carboxylic acid has an enantiomer excess of at least 90%, or b) The method according to any one of claims 1 to 22, wherein the mixture of (R)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid and (S)-6-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine-4-yl)oxy)chroman-3-carboxylic acid has an enantiomer excess of at least 90%.

24. a) The mixture of multiple compounds of formula 4B in step b) has an enantiomeric excess of at least 90%, or b) The method according to any one of claims 2 to 23, wherein the mixture of a plurality of compounds of formulas (IIa) and (IIb), or pharmaceutically acceptable salts or tautomers thereof, has an enantiomeric excess of at least 90%.

25. R ３ is halogen, C １－４ Alkyl, or -SO ２ (C １－４ The method according to any one of claims 2 to 24, wherein the alkyl group is...

26. R ３ The method according to any one of claims 2 to 25, wherein the is F, Cl, Br, or I.

27. The method according to any one of claims 2 to 26, wherein n is 0, 1, or 2.

28. The method according to claim 1, wherein the mixture of multiple compounds of formula 4A in step b) has an enantiomer excess of at least 90%.

29. R １ The method according to claim 1, wherein is a substituted or unsubstituted heteroaryl.

30. The compound or the mixture of multiple compounds 【Chemistry 10】 or a pharmaceutically acceptable salt or tautomer thereof, or multiple compounds 【Chemistry 11】 and 【Chemistry 12】 The method according to any one of claims 1 to 27, or selected from a pharmaceutically acceptable salt or tautomer thereof.

31. The method described above is: 【Chemistry 13】 or 【Chemistry 14】 The method according to any one of claims 1 to 27, or the method for synthesizing a pharmaceutically acceptable salt or tautomer thereof.

32. The compound or mixture of the compound is 【Chemistry 15】 or a pharmaceutically acceptable salt or tautomer thereof, or multiple compounds 【Chemistry 16】 and 【Chemistry 17】 The method according to claim 1, or selected from a pharmaceutically acceptable salt or tautomer thereof.

33. The method described above, [Chemistry 18] or 【Chemistry 19】 The method according to claim 1, or the method for synthesizing a pharmaceutically acceptable salt or tautomer thereof.

34. A compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt or tautomer thereof, 【Chemistry 20】 (In the formula, R1 is selected from substituted or unsubstituted C1-6 alkyl, C1-6 haloalkyl, aryl, heterocyclyl, or heteroaryl; R² is H; X1 is N or CR8; X2 is N or CR9; R 6 is hydrogen, halogen, alkyl, alkoxy, -NH 2, -NR F C(O)R 5, -NR F C(O)CH 2 R 5, -NR F C(O)CH(CH 3)R 5, or -NR F R 5; R7, R8, and R9 are each independently hydrogen, halogen, or alkyl; Alternatively, R6 and R8 together, or R7 and R9 together, together with the atom they bond to, may form a five- or six-membered partially unsaturated or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the ring may be substituted or unsubstituted; R5 is a substituted or unsubstituted group selected from alkyl, carbocyryl, aryl, heterocyclyl, or heteroaryl groups; (R F is H or C 1-3 alkyl) A method for synthesizing, wherein the method a) Reacting the compound of formula 1A with (R)-6-hydroxychroman-3-carboxylic acid or (S)-6-hydroxychroman-3-carboxylic acid to obtain the compound of formula 2A. (The compound of formula 2A has (R) or (S) stereochemistry at the carbon indicated by *); 【Chemistry 21】 b) Reacting the compound of formula 2A with the compound of formula 3A or a salt thereof to obtain the compound of formula 4A. (The compound of formula 4A has (R) or (S) stereochemistry at the carbon indicated by *); 【Chemistry 22】 c) The method comprising cyclizing the compound of formula 4A of 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. 【Chemistry 23】

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