Methods for synthesizing quinazoline compounds

Abstract

Provided herein are methods for synthesizing compounds useful for the treatment of cancer that contain a quinazolinyl core moiety and at least one stereoisomeric or atropisomeric moiety.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 307,529, filed February 7, 2022, which is incorporated by reference herein in its entirety for all purposes.

[0002] Provided herein are methods for synthesizing compounds useful for the treatment of cancer that contain a quinazolinyl core moiety and at least one stereoisomeric or atropisomer moiety. [Background technology]

[0003] The configuration of the biaryl axis often plays an important role in the pharmacological properties of biologically active compounds and is the fundamental basis for useful reagents and catalysts in asymmetric synthesis. Highly atroposelective cross-coupling, especially cross-coupling of heterocycles for the synthesis of biheteroaryls, remains a challenging and unsolved problem. Furthermore, scaling up such processes to commercial / industrial scale often introduces unforeseen and unexpected difficulties in the process and synthesis. The present disclosure provides an improved method for the nonselective synthesis of aminopyridinyl-quinazolinyl compounds via Negishi coupling utilizing chiral ligands such as chiraphites.

[0004] Thus, there is an urgent need for methods that allow efficient and effective scale-up for the synthesis of compounds such as those described herein. Summary of the Invention

[0005] Solutions to the above problems, as well as other problems in the art, are provided herein.

[0006] In a first aspect, there is provided herein a method for synthesizing a compound of formula (I) as described herein, the method comprising the steps of: (a) contacting a compound of formula (II) as described herein with an organomagnesium compound, thereby forming a compound of formula (IIa) as described herein; (b) transferring the compound of formula (IIa) of step (a) to a continuous stirred tank reactor (CSTR) containing a zinc compound, thereby synthesizing a compound of formula (IIb) as described herein; and contacting compound (IIb) of step (b) with a compound of formula (III) as described herein, a transition metal catalyst precursor as described herein, and a chiral ligand as described herein, thereby synthesizing a compound of formula (I).

[0007] In one embodiment, the compound of formula (II) is prepared according to method P2 described herein.

[0008] In one embodiment, the compound of formula (III) is prepared according to method P4 described herein.

[0009] In one embodiment of the methods described herein, formula (I) comprises a compound of formula (Ia), (Ib), (Ic), or (Id) as described herein.

[0010] In one embodiment of the methods described herein, formula (I) comprises a compound of formula (1) as described herein.

[0011] In another aspect, there is provided a method (P5) for synthesizing a compound of formula (2) as described herein, the method comprising the steps of: (a) contacting a compound of formula (4a) as described herein with i-PrMgCl, followed by contacting with hydroxylamine, thereby synthesizing a compound of formula (4c) as described herein; (b) contacting a compound of formula (4c) as described herein with TFAA and triethylamine in acetonitrile, followed by contacting with ammonia, thereby synthesizing a compound of formula (4e) as described herein; contacting a compound of (4e) as described herein with a chlorinating agent, thereby synthesizing a compound of formula (4) as described herein; and (c) reacting a compound of formula (4) as described herein with CO in the presence of DBU, thereby synthesizing a compound of formula (4c) as described herein. 2 contacting a compound of formula (5) described herein with POCl, thereby synthesizing a compound of formula (5); 3 and DIPEA, followed by contacting with tert-butyl (S)-3-methylpiperazine-1-carboxylate in DIPEA, thereby synthesizing a compound of formula (5b); contacting a compound of (5b) as described herein with KF, DABCO and MsOH, thereby forming a compound of formula (2) as described herein.

[0012] In another aspect, there is provided a method (P7) for synthesizing a compound of formula (G) as described herein, or a tautomer, stereoisomer, atropisomer or pharma- ceutically acceptable salt thereof, comprising reacting a compound of formula (I), or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, with a base as described herein and an activating agent as described herein, at X, as described herein. A and optionally contacting a compound of formula (G1) with a moiety comprising a PG group and optionally R 1and contacting the compound of step (b) with a compound of formula (VII) as described herein in the presence of an activating agent as described herein, followed by contacting with a base as described herein, thereby producing a compound of formula (G), or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof.

[0013] Further disclosed is a method (P8) for synthesizing a compound of formula (1) as described herein, or a pharma- ceutically acceptable salt thereof, comprising the steps of contacting a pre-cooled solution comprising a compound of formula (2) as described herein, or a salt thereof, with a pre-cooled solution comprising i-PrMgCl·LiCl using a flow rate that provides a residence time for Mg-Br exchange of about 15 to 150 seconds, thereby synthesizing a compound of formula (2a) as described herein; 2 or Zn(OPiv) 2 transferring the compound of formula (2a) of step (a) to a continuous stirred tank reactor (CSTR) containing a solution of the formula (2a) and maintaining a constant residence time of about 3 to 7 minutes at about -20°C to 20°C, thereby synthesizing a compound of formula (2b) as described herein; contacting the compound of formula (2b) with NaTFA and a compound of formula (3) as described herein; contacting the mixture of step (c) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand, thereby synthesizing a compound of formula (11) as described herein, or a solvate or salt thereof; A (In the formula, X A is the formula TIFF2025505192000001.tif13170) and a base as described herein, thereby synthesizing a compound of formula (1b) as described herein, or a solvate or pharma- ceutically acceptable salt thereof; contacting a compound of formula (1b) with MsOH in an acid, thereby synthesizing a compound of formula (1a) as described herein, or a solvate or pharma- ceutically acceptable salt thereof; and Provided herein is a method for synthesizing a compound of formula (1) as described herein, or a pharma- ceutically acceptable salt thereof, comprising contacting TIFF2025505192000002.tif18170 in the presence of an activating agent, and subsequently contacting with a base, thereby producing a compound of formula (1), or a pharma- ceutically acceptable salt thereof.

[0014] The present embodiments can be more fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows an exemplary hardware setup for the continuous flow reaction described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.See, for example, Singleton et al. DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J.Wiley&Sons (New York, NY 1994); Sambrook et al. MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989).In carrying out the present invention, any method, device and material similar or equivalent to those described herein can be used.

[0017] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0018] As used herein, unless otherwise specified, the terms "about" and "approximately," when referring to a dose, amount, or weight percent of a component of a composition or dosage form, means a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. The equivalent dose, amount, or weight percent can be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percent.

[0019] The term "residence time" refers to the residence time distribution (RTD) of a continuous flow system, which is a probability distribution function that represents the amount of time a molecule or compound can spend within a reactor setup.

[0020] The terms "halogen" and "halo" are used interchangeably herein and refer to F, Cl, Br, or I.

[0021] The term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon group. In one example, an alkyl group is one to eighteen carbon atoms (C 1-18 In another example, the alkyl group is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , or C 1-3 Examples of alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-Butyl (n-Bu, n-Butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-Butyl (s-Bu, s-Butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), 1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 , 1-heptyl, and 1-octyl.

[0022] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by halogens. Examples of haloalkyls include trifluoromethyl, difluoromethyl, and fluoromethyl. "Fluoroalkyl" refers to an alkyl chain in which one or more hydrogens have been replaced by F.

[0023] The term "amino" means -NH 2 means...

[0024] The terms "cyano" and "nitrile" are used interchangeably herein and refer to --C.ident.N or --CN.

[0025] The term "cyanoalkyl" means an alkyl substituted with one cyano substituent.

[0026] The term "hydroxy" means --OH.

[0027] "Fused" means any cyclic structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with an existing cyclic structure in the compounds of the invention.

[0028] As used herein, "halogenating agent" refers to any reagent that adds one or more halogens to a compound described herein. As used herein, "chlorinating agent" refers to any reagent that adds one or more chlorine (Cl) atoms to a compound described herein. In one embodiment, the chlorinating agent is NCS or DCH as described herein. As used herein, "brominating" or "iodinating" agent refers to any reagent that adds one or more bromine (Br) or iodine (I) atoms, respectively, to a compound described herein.

[0029] As used herein, a "haloalkylating agent" refers to a group containing one or more haloalkyl groups (e.g., CF 3 "Fluoroalkylating agent" refers to any reagent that adds one or more fluoroalkyl groups to a compound described herein.

[0030] An "organomagnesium compound" is an organometallic compound in which the metal is magnesium.

[0031] The compounds of the present invention may contain one or more chiral carbon atoms. Thus, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may use racemates, diastereomers, or enantiomers as starting materials or intermediates. A mixture of specific diastereomeric compounds may be separated or enriched into one or more specific diastereomers by chromatographic or crystallization techniques. Similarly, enantiomeric mixtures may be separated or enantiomerically enriched using the same techniques or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration, and both of these configurations are within the scope of the present invention.

[0032] In the structures depicted herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included as compounds of the present invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, that stereoisomer is so specified and defined. Unless otherwise indicated, when a solid wedge or dashed line is used, relative stereochemistry is intended.

[0033] The term "stereoisomers" means compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, atropisomers, conformers, and the like.

[0034] The term "chiral" refers to molecules that have the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0035] The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activity. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0036] The term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0037] "Atropisomers" are stereoisomers resulting from sterically hindered rotation about a single bond or axis, where the energy difference due to steric strain or other factors creates a barrier to rotation high enough to permit isolation of individual conformers.

[0038] Stereochemical definitions and conventions used herein are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0039] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0040] As used herein, the term "amino protecting group" refers to a derivative of a group commonly used to block or protect an amino group, while the reaction is carried out at another functional group of the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many N-heteroatom derivatives that can be removed to regenerate the desired amine group. Particular amino protecting groups are PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), Cbz (carbobenzyloxy), Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, or DMB (dimethoxybenzyl). In some embodiments, the amino protecting group may be a group used to block or protect an amino group that results from the cyclization of a group attached to the amino group, but that can be subsequently removed or replaced. Such examples include 1,3,5-dioxazinane, 2,4-dimethyl-1,3,5-dioxazinane, 2,2,5,5-tetramethyl-1,2,5-azadisilolidine, and isoindoline-1,3-dione. Further exemplary amino protecting groups are described in TW Greene and PGM Wuts, "Protecting Groups in Organic Synthesis, Vol. 3. 版 , John Wiley & Sons, Inc., 1999. The term "protected amino" means an amino group substituted with one of the amino-protecting groups described above.

[0041] The term "leaving group" refers to a portion of a first reactant in a chemical reaction that is displaced from that first reactant. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy, and sulfonyloxy groups. Exemplary sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (e.g., methylsulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)), and arylsulfonyloxy groups (e.g., p-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylate group)).

[0042] The terms "inhibit" and "reduce / diminish" or any variation of these terms include any measurable reduction / diminishment or complete inhibition to achieve a desired result. For example, there may be a decrease in activity compared to normal, of about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any of these range variables.

[0043] The terms "antagonist" and "inhibitor" are used interchangeably to refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of a protein such as K-Ras, H-Ras, or N-Ras G12C. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of a target protein by interacting with other elements of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are associated with tumor progression, growth, or spread.

[0044] As used herein, the term "agonist" refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. While the preferred agonists herein specifically interact with the target (e.g., bind to the target), compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other elements of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0045] The terms "cancer" and "cancerous," "neoplasm," and "tumor," as well as related terms, refer to or describe a physiological condition in a mammal that is typically characterized by unregulated growth of cells. A "tumor" comprises one or more cancer cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinoma), and lung cancers (such as small cell lung carcinoma, non-small cell lung carcinoma ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin cancer, keratoacanthoma, follicular carcinoma, hairy cell leukemia, oral cavity cancer, pharyngeal (mouth) cancer, lip cancer, tongue cancer, mouth cancer, salivary gland cancer, esophageal cancer, laryngeal cancer, hepatocellular carcinoma, gastric cancer, stomach cancer, gastrointestinal cancer, small intestine cancer, large intestine cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, liver cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, genitourinary cancer, biliary tract cancer, thyroid cancer, papillary cancer, hepatoma, uterine cancer, uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, testicular cancer, vulvar cancer, peritoneal cancer, anal cancer, penile cancer, bone cancer, multiple myeloma, B cell lymphoma, diffuse large B cell lymphoma (DLBCL), central nervous system, brain cancer, head and neck cancer, Hodgkin's disease, and associated metastases. Examples of neoplastic disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocytosis, myelofibrosis such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0046] A "chemotherapeutic agent" is an agent that is useful for treating a given disorder, such as cancer or inflammatory disorder. Examples of chemotherapeutic agents are known in the art, and include, for example, those disclosed in U.S. Patent Application Publication No. 2010 / 0048557, which is incorporated herein by reference. In addition, chemotherapeutic agents include any pharma- ceutically acceptable salt, acid, or derivative of chemotherapeutic agents, and combinations of two or more of these.

[0047] The term "treatment" refers to a clinical intervention designed to change the natural course of the patient or cells being treated during the course of clinical pathology. The desired effects of treatment include reducing the rate of disease progression, reversing or alleviating the disease state, and remission or improvement of prognosis. For example, a patient is "treated" successfully if one or more symptoms associated with breast cancer as described herein are alleviated or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancer cells, reducing symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drugs required to treat the disease, and / or prolonging the patient's survival.

[0048] The term "delaying progression" of disease refers to postponing, preventing, delaying, retarding, stabilizing, and / or postponing the development of breast cancer as described herein. This delay can be of varying lengths of time depending on the history of cancer and / or the patient being treated. As will be appreciated by those skilled in the art, a sufficient or significant delay can essentially encompass prevention, in that the patient does not develop cancer.

[0049] An "effective amount" is at least the minimum amount required to effect a measurable improvement or prevention of breast cancer as described herein. The effective amount herein may vary depending on factors such as the disease state, age, sex, and weight of the patient, and the ability of the agent to induce a desired response in the patient. An effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. Beneficial or desired results include results such as eliminating or reducing risk, reducing severity, delaying the onset of the disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the development of the disease), reducing one or more symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug, such as by targeting, delaying the progression of the disease, and / or prolonging survival. In some embodiments, an effective amount of a drug may have an effect in reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or stopping) cancer cell invasion into peripheral organs; inhibiting (i.e., slowing or stopping) tumor metastasis; inhibiting (i.e., slowing or stopping) tumor growth; and / or alleviating one or more symptoms associated with a disorder. An effective amount may be administered in one or more administrations. An effective amount of a drug, compound, pharmaceutical composition or combination therapy described herein may be an amount sufficient to directly or indirectly achieve a therapeutic treatment. As clinically understood, an effective amount of a drug, compound or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition or combination therapy. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount when a desired result is obtained or achieved in combination with one or more other agents.

[0050] It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may also apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or utilize any compound or composition of the invention.

[0051] Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to measure the value.

[0052] Formula (I): Provided herein are methods for synthesizing a compound of TIFF2025505192000003.tif52170, or a solvate, tautomer, stereoisomer, atropisomer, or salt thereof.

[0053] In one embodiment, a compound of formula (I): TIFF2025505192000004.tif52170(in the formula, 1 and X 3 are each independently hydrogen or halogen; R 1 is hydrogen or PG 1 and; Each R 2 are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl, or unsubstituted C 1-6 is haloalkyl; R 3 is hydrogen, halogen, R 3A -Substituted or unsubstituted C 1-3 Alkyl, R 3A -Substituted or unsubstituted C 1-3 Haloalkyl, or R 3A -substituted or unsubstituted cyclopropyl; R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; R 4 is R 4A -Substituted or unsubstituted C 1-3 is haloalkyl; R 4A is unsubstituted C 1-3 is alkyl; n is 1 or 2; each PG is independently an amino protecting group; PG 1 is an amino protecting group), or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, comprising the steps of: This method, (a) Formula (II) TIFF2025505192000005.tif43170(in the formula, 2 is a halogen) with an organomagnesium compound, thereby forming a compound of formula (IIa): forming a compound of formula (IIa); (b) transferring the compound of formula (IIa) from step (a) to a continuous stirred tank reactor (CSTR) containing a zinc compound, thereby producing a compound of formula (IIb) TIFF2025505192000007.tif45170, where m is 0, 1, or 2; p is 1, 2 or 3; X 2 is a halogen or OPiv; (c) reacting compound (IIb) of step (b) with a compound of formula (III) TIFF2025505192000008.tif27170(in the formula, 4 is a halogen, There is provided a process (P1) for synthesizing a compound of formula (I), or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, comprising the step of contacting a transition metal catalyst precursor, and a chiral ligand, thereby synthesizing the compound of formula (I).

[0054] In one embodiment, X1 is a halogen. In one such embodiment, X 1 is F or Cl. In one embodiment, X 3 is a halogen. In one such embodiment, X 3 is F or Cl. In another embodiment, X 1 and X 3 are each independently a halogen. In one such embodiment, X 1 is F and X 3 is a halogen. In one such embodiment, X 3 is Cl, and X 1 is a halogen. In one such embodiment, X 1 is F and X 3 is Cl.

[0055] In one embodiment, the compound of formula (IIb) is: TIFF2025505192000009.tif48170(in the formula, 1 , X 2 , X 3 , R 1 , R 2 and n is as defined herein.

[0056] In one embodiment, X 2 is Cl, Br or OPiv. In one embodiment, X 2 is Cl or Br. In one embodiment, X 2 is Br. In one embodiment, X 2 is Cl.

[0057] In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1 or 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1 or 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1 or 2, and p is 3.

[0058] In one embodiment of the compound of formula (IIb), X2 is Cl, m is 0 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 0, and p is 3.

[0059] In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1 and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1, and p is 3.

[0060] In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 2 and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 2 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 2, and p is 3.

[0061] In one embodiment of the compound of formula (IIb), X 2 is Br, m is 1 or 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 1 or 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 1 or 2, and p is 3.

[0062] In one embodiment of the compound of formula (IIb), X 2 is Br, m is 0 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 0, and p is 3.

[0063] In one embodiment of the compound of formula (IIb), X 2 is Br, m is 1 and p is 1. In one embodiment of the compound of formula (IIb), X 2is Br, m is 1 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Cl, m is 1, and p is 3.

[0064] In one embodiment of the compound of formula (IIb), X 2 is Br, m is 2 and p is 1. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 2 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is Br, m is 2, and p is 3.

[0065] In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1 or 2, and p is 1. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1 or 2, and p is 2. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1 or 2, and p is 3.

[0066] In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 0 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 0, and p is 3.

[0067] In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1 and p is 1. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 1, and p is 3.

[0068] In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 2 and p is 1. In one embodiment of the compound of formula (IIb), X 2is OPiv, m is 2 and p is 2. In one embodiment of the compound of formula (IIb), X 2 is OPiv, m is 2, and p is 3.

[0069] In another embodiment, the compound of formula (IIb) has the formula: TIFF2025505192000010.tif43170, where p and m are as described herein. In one embodiment, when the zinc compound contains Cl, X 2 is Cl. In one embodiment, when the zinc compound comprises OPiv, X 2 is OPiv. In one embodiment, compound 2b is 2 , m and p are different. In one embodiment, compound 2b comprises at least two or three different species. In one such embodiment, such species can be interconverted.

[0070] In one embodiment, R 1 is PG 1 and P.G. 1 is as described herein. In one such embodiment, PG 1 is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy). 1 is an acid labile amino protecting group. In one embodiment, PG 1 is tert-butyloxycarbonyl (Boc).

[0071] In one embodiment, each R 2 is independently halogen or cyano. In another such embodiment, each R 2 are independently unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl, or unsubstituted C 1-6haloalkyl. In one embodiment, each R 2 are independently unsubstituted C 1-3 In one such embodiment, each R 2 is independently methyl or ethyl. In one embodiment, each R 2 is independently methyl. In one such embodiment, R 2 is methyl and n is 1. In one such embodiment, each R 2 is independently methyl or ethyl, and n is 1. In another embodiment, each R 2 are independently unsubstituted C 1-3 Cyanoalkyl or unsubstituted C 1-3 In one such embodiment, the unsubstituted C 1-6 Cyanoalkyl, or unsubstituted C 1-6 HaloalkylCH 2 F, CHF 2 , C.F. 3 , C.H. 2 CH 2 F, C.H. 2 CHF 2 , C.H. 2 CF 3 , C.H. 2 CN, or CH 2 CH 2 In one such embodiment, the unsubstituted C 1-6 Cyanoalkyl or unsubstituted C 1-6 HaloalkylCH 2 F, CHF 2 , C.F. 3 , C.H. 2 CH 2 F, C.H. 2 CHF 2 , C.H. 2 CF 3 , C.H. 2 CN, or CH 2 CH 2 CN, and n is 1. In one embodiment, R 2 is unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 It is a cyanoalkyl.

[0072] In one embodiment, R 3is hydrogen, halogen, or R 3A -Substituted or unsubstituted C 1-3 In one embodiment, R 3 is R 3A -Substituted or unsubstituted C 1-3 Haloalkyl, or R 3A In one embodiment, R 3 is hydrogen or R 3A Substituted or unsubstituted C 1-3 In one embodiment, R 3 is hydrogen or methyl. In one embodiment, R 3 is methyl. In one embodiment, R 3 is hydrogen, and R 4 CF 3 In another embodiment, R 3 is methyl, R 4 CF 3 It is.

[0073] In one embodiment, R 4 CF 3 , CHF 2 or CH 2 It's F.

[0074] In one embodiment, each PG is independently a protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy). In one embodiment, each PG is the same. When each PG is the same, in such an embodiment, each PG is PMB.

[0075] The organomagnesium compound may be, for example, a Grignard reagent. In one embodiment, the organomagnesium compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate). In one embodiment, the organomagnesium compound of the method described herein is i-PrMgCl·LiCl.

[0076] In the methods described herein, the Zn compound is ZnCl, including LiCl or LiTFA salt. 2 , ZnBr 2 , ZnI 2 , Zn(TFA) 2 , Zn(OAc) 2 , and Zn(OPiv) 2 In one embodiment, the Zn compound is selected from the group consisting of ZnCl 2 , ZnBr 2 , or ZnI 2 In one embodiment, the Zn compound is ZnCl 2 , ZnBr 2 , or Zn(OPiv) 2 In one embodiment, the Zn compound is ZnCl 2 or Zn(OPiv) 2 In one embodiment, the Zn compound is ZnCl 2 In one embodiment, the Zn compound is ZnCl 2 In one embodiment, the Zn compound is Zn(OPiv). 2 In one embodiment, the Zn compound is a salt, Zn(OPiv). 2 -LiCl.

[0077] In one embodiment, the transition metal catalyst precursor is a Pd or Ni catalyst precursor. In one embodiment, the transition metal catalyst precursor is a Pd or Ni catalyst precursor, and Pd(OAc) 2 , PdCl2 , PdCl 2 (MeCN) 2 , Pd(benzonitrile) 2 Cl 2、 Pd(dba) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , Pd(PCy 3 ) 2 , Pd(PtBu 3 ) 2 , Pd(TFA) 2 , [Pd(allyl)Cl] 2 [Pd(cinnamyl)Cl] 2 [PdCl(crotyl)] 2 , PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl 2 , NiBr 2 , Ni(OAc) 2 and nickel(II) acetylacetonate.

[0078] In one such embodiment of the method (P1) described herein, the Pd or Ni catalyst precursor is a Pd catalyst precursor. In one embodiment, the Pd catalyst precursor is Pd(OAc) 2 , PdCl 2 , PdCl 2 (MeCN) 2 , Pd(dba) 2 , Pd 2 (dba) 3 , Pd(TFA) 2 [Pd(allyl)Cl] 2 [Pd(cinnamyl)Cl] 2 [PdCl(crotyl)] 2 , PdCl(η-cyclopentadienyl), or [(η-allyl)(η-cyclopentadienyl)palladium(II)]. In another embodiment of the method (P1) described herein, the Pd catalyst precursor is Pd(OAc) 2or PdCl 2 In another embodiment of the method (P1) described herein, the Pd catalyst precursor is [PdCl(crotyl)] 2 , PdCl(η5-cyclopentadienyl), PdCl 2 (MeCN) 2 , Pd(dba) 2 , Pd 2 (dba) 3 , or Pd(TFA) 2 In another embodiment of the method (P1) described herein, the Pd catalyst precursor is [Pd(allyl)Cl] 2 [Pd(cinnamyl)Cl] 2 or (η-allyl)(η-cyclopentadienyl)palladium(II). In one embodiment, the Pd catalyst precursor is [Pd(allyl)Cl] 2 or [Pd(cinnamyl)Cl] 2 In one embodiment, the Pd catalyst precursor is [Pd(cinnamyl)Cl] 2 It is.

[0079] In another embodiment of the method (P1) described herein, the Pd or Ni catalyst precursor is a Ni catalyst precursor. In one embodiment, the Ni catalyst precursor is NiCp(allyl), bis(1,5-cyclooctadiene)nickel(0), NiCl 2 , NiBr 2 , Ni(OAc) 2 or nickel(II) acetylacetonate. In one embodiment, the Ni catalyst precursor is NiCl 2 , NiBr 2 , or Ni(OAc) 2 In another embodiment, the Ni catalyst precursor is NiCp(allyl), bis(1,5-cyclooctadiene)nickel(0), or nickel(II) acetylacetonate.

[0080] In one embodiment of the method (P1) described herein, a Pd precursor as described herein and a chiral ligand as described herein are contacted to form a Pd-ligand complex in situ. In another embodiment, a Pd precursor as described herein is treated with a chiral ligand as described herein to form a Pd-ligand complex, which may be isolated prior to use in the method described herein. In one embodiment, the Pd catalyst precursor is [Pd(cinnamyl)Cl] 2 and the zinc compound is ZnCl 2 or Zn(OPiv) 2 It is.

[0081] In one embodiment, the chiral ligand has the formula: TIFF2025505192000011.tif47170 (in the formula, Y is O or NR 7 and; R 7 and R 8 are independently unsubstituted C 1-6 It is a compound of the formula (I) (alkyl).

[0082] In one embodiment of the compound of formula L1, R 7 and R 8 In one such embodiment, R 7 and R 8 are each independently methyl, ethyl, or phenyl. 7 and R 8 are each methyl (e.g., (R,R)-chiraphite). In one embodiment, R 7 and R 8 Each is ethyl. In one embodiment of the method described herein, the chiral ligand is (R,R)-chiraphite.

[0083] In one embodiment of the method (P1) described herein, step (a) is carried out using a pre-cooled solution comprising a compound of formula (II) described herein and an organomagnesium compound described herein, respectively. In one such embodiment, the pre-cooling temperature is about -30°C to about 20°C; -30°C to about 15°C; -30°C to about 10°C; -30°C to about 5°C; -30°C to about 0°C; -25°C to about 20°C; -25°C to about 15°C; -25°C to about 10°C; -25°C to about 5°C; -25°C to about 0°C; -20°C to about 20°C; -20°C to about 15°C; -20°C to about 10°C; -20°C to about 5°C; or -20°C to about 0°C. In one embodiment, the compound of formula (IIb) is isolated (and optionally stored) prior to step (b). In one such embodiment, the compound of formula (IIa) is stable for at least 1, 2, 3, 4, 5 or 6 weeks.

[0084] In one embodiment, the organomagnesium compound described herein is present in an amount of about 0.9 to 1.50; 0.9 to 1.45; 0.9 to 1.40; 0.9 to 1.35; 0.9 to 1.30; 0.9 to 1.25; 0.9 to 1.20; 0.9 to 1.15; 0.9 to 1.10; 0.9 to 1.05; 0.9 to 1.02; 0.9 to 1.00; 0.95 to 1.50; 0.95 to 1.45; 0.95 to 1.40; 0.95 to 1.35; 0.95 to 1.30; 0.9 5-1.25;0.95-1.20;0.95-1.15;0.95-1.10;0.95-1.08;0.95-1.05;0.95-1.03;0.95-1.02;0.95-1.01;0.95-1.00;1.00-1.15;1.00-1.12;1.00-1.11;1.00-1.10;1.00-1.09;1.00-1.08;1.00-1.07;1.00-1.06;1.00-1.05;1.00-1.03;or 1.00-1.02 molar equivalents.

[0085] In one embodiment of the method (P1) described herein, step (b) is carried out at about -30°C to about 20°C; -30°C to about 15°C; -30°C to about 10°C; -30°C to about 5°C; -30°C to about 0°C; -25°C to about 20°C; -25°C to about 15°C; -25°C to about 10°C; -25°C to about 5°C; -25°C to about 0°C; -20°C to about 20°C; -20°C to about 15°C; -20°C to about 10°C; -20°C to about 5°C; or -20°C to about 0°C. In one embodiment of the method (P1) described herein, step (b) is carried out at about -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, or 10°C. In one such embodiment, step (b) is carried out at a temperature of about -5°C, 0°C or 5°C.

[0086] In one embodiment, the Zn compound described herein is present in an amount of about 0.3-1.50, 0.3-1.45, 0.3-1.40, 0.3-1.35; 0.3-1.30; 0.3-1.25; 0.3-1.20; 0.3-1.15; 0.3-1.10; 0.3-1.05; 0.3-1.02; 0.3-1.00; 0.3-0.95, 0.3-0.90, 0.3-0.8, 0.3-0.75, or 0.3-0.6 molar equivalents relative to the compound of formula (IIa) in step (a) of method (P1). In one embodiment, the Zn compound described herein is present in an amount of about 0.4-1.50, 0.4-1.45, 0.4-1.40, 0.4-1.35; 0.4-1.30; 0.4-1.25; 0.4-1.20; 0.4-1.15; 0.4-1.10; 0.4-1.05; 0.4-1.02; 0.4-1.00; 0.4-0.95, or 0.4-0.90 molar equivalents relative to the compound of Formula (IIa) in step (a) of method (P1).

[0087] In one embodiment, the Zn compound described herein is present in an amount of about 0.6-1.75, 0.6-1.70, 0.6-1.65, 0.6-1.60, 0.6-1.55, 0.6-1.50, 0.6-1.45, 0.6-1.40, 0.6-1.35; 0.6-1.30; 0.6-1.25; 0.6-1.20; 0.6-1.15; 0.6-1.10; 0.6-1.05; 0.6-1.02; 0.6-1.00; 0.6-0.95, or 0.6-0.90 molar equivalents relative to the compound of formula (IIa) in step (a) of method (P1). In one embodiment, the Zn compound described herein is present in an amount of about 0.3-0.6, 0.6-0.9, or 0.9-1.5 molar equivalents relative to the compound of formula (IIa) in step (a) of method (P1). In one embodiment, the Zn compound described herein is present in an amount of about 0.3-0.6 or 0.6-0.9 molar equivalents relative to the compound of formula (IIa) in step (a) of method (P1).

[0088] In one embodiment, the Zn compound as described herein is present in an amount of 0.95-1.50; 0.95-1.45; 0.95-1.40; 0.95-1.35; 0.95-1.30; 0.95-1.25; 0.95-1.20; 0.95-1.15; 0.95-1.10; 0.95-1.08; 0.95-1.05; 0. present in molar equivalents of .95 to 1.03; 0.95 to 1.02; 0.95 to 1.01; 0.95 to 1.00; 1.00 to 1.15; 1.00 to 1.12; 1.00 to 1.11; 1.00 to 1.10; 1.00 to 1.09; 1.00 to 1.08; 1.00 to 1.07; 1.00 to 1.06; 1.00 to 1.05; 1.00 to 1.03; or 1.00 to 1.02.

[0089] In one embodiment, the Zn compound as described herein is present in an amount of about 0.9-1.75, 0.9-1.70, 0.9-1.65, 0.9-1.60, 0.9-1.55, 0.9-1.50, 0.9-1.45, 0.9-1.40, 0.9-1.35; 0.9-1.30; 0.9-1.25; 0.9-1.20; 0.9-1.15; 0.9-1.10; 0.9-1.05; 0.9-1.02; 0.9-1.00; 0.95-1.50; 0.95-1.45; 0.95-1.40; 0.95 ~1.35;0.95-1.30;0.95-1.25;0.95-1.20;0.95-1.15;0.95-1.10;0.95-1.08;0.95-1.05;0.95-1.03;0.95-1.02;0.95-1.01;0.95-1.00;1.00-1.15;1.00-1.12;1.00-1.11;1.00-1.10;1.00-1.09;1.00-1.08;1.00-1.07;1.00-1.06;1.00-1.05;1.00-1.03;or 1.00-1.02 molar equivalents. In one embodiment, the compound of formula (IIb) is stable in solution under inert conditions for at least 1, 2, 3, 4, 5, or 6 weeks.

[0090] In one embodiment, the compound of formula (III) as described herein is present in an amount of about 0.9 to 1.50; 0.9 to 1.45; 0.9 to 1.40; 0.9 to 1.35; 0.9 to 1.30; 0.9 to 1.25; 0.9 to 1.20; 0.9 to 1.15; 0.9 to 1.10; 0.9 to 1.05; 0.9 to 1.02; 0.9 to 1.00; 0.95 to 1.50; 0.95 to 1.45; 0.95 to 1.40; 0.95 to 1.35; 0.95 to 1.30; 0.95 In one embodiment, the compound is present in an amount of from about 1.25; 0.95 to about 1.20; 0.95 to about 1.15; 0.95 to about 1.10; 0.95 to about 1.08; 0.95 to about 1.05; 0.95 to about 1.03; 0.95 to about 1.02; 0.95 to about 1.01; 0.95 to about 1.00; 1.00 to about 1.15; 1.00 to about 1.12; 1.00 to about 1.11; 1.00 to about 1.10; 1.00 to about 1.09; 1.00 to about 1.08; 1.00 to about 1.07; 1.00 to about 1.06; 1.00 to about 1.05; 1.00 to about 1.03; or 1.00 to about 1.02 molar equivalents.

[0091] In one embodiment, the compound of formula (II) is (a) In the presence of a base, CO 2 Formula (IV) below Compound (V) of TIFF2025505192000012.tif22170 cyclization to compound TIFF2025505192000013.tif23170; (b) contacting the compound of formula (V) with a chlorinating agent, thereby producing a compound of formula (Va) To synthesize compound TIFF2025505192000014.tif24170; (c) reacting the compound of step (b) with the compound of formula TIFF2025505192000015.tif24170, thereby contacting a piperazinyl moiety having formula (Vb) synthesizing the compound of TIFF2025505192000016.tif42170; and (d) contacting the compound of step (c) with a fluorinating agent in the presence of a base, thereby synthesizing a compound of formula (II). It is prepared by a method (P2) comprising:

[0092] In one embodiment of method (P2), the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In another embodiment, the base is DBN (1,5-diazabicyclo[4.3.0]non-5-ene), MTBD (7-methyl-1,5,7 triazabicyclo(4.4.0)dec-5-ene) or TBD (1,5,7 triazabicyclo(4.4.0)dec-5-ene). In another embodiment, the base is a carbonate base, e.g., Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 The solvent for the reaction is water, and it also acts in water as a solvent.

[0093] In one embodiment of the method (P2), the chlorinating agent in step (b) is POCl 3 , PCl 3 , PCl 5 , or SOCl 2 In one such embodiment, the chlorinating agent in step (b) is POCl 3 It is.

[0094] In one embodiment of method (P2), the base in step (c) is N-ethylmorpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), N-methylimidazole (NMI), DBU, tri(n-butyl)amine, pyridine, 2,6-lutidine, or 2,4,6-collidine. In one embodiment, the base in step (c) is DIPEA. In one embodiment, the base in step (c) is N-ethylmorpholine (NEM), triethylamine (TEA), or tri(n-propyl)amine (TPA). In one embodiment, the base in step (c) is N-methylmorpholine (NMM), N-methylimidazole (NMI), DBU, or tri(n-butyl)amine. In one embodiment, the base in step (c) is pyridine, 2,6-lutidine, or 2,4,6-collidine.

[0095] In another embodiment of method (P2), the fluorinating agent in step (d) is KF. In another embodiment of method (P2), the fluorinating agent in step (d) is CsF or NaF. In another embodiment of method (P2), the base is DABCO (1,4-diazabicyclo[2.2.2]octane). In one such embodiment, DABCO is present in a catalytic amount. In another such embodiment, step (d) of method (P2) further comprises MsOH as an additive.

[0096] Compound (IV) of process (P2) may be synthesized according to process (P3) described herein, the compound of formula (IV) being (a) Formula (IVa) contacting the compound of formula (IVb) with i-PrMgCl To synthesize compound TIFF2025505192000018.tif19170; (b) Reacting the compound of step (a) with hydroxylamine (NH 2 OH), thereby forming a compound of formula (IVc) To synthesize compound TIFF2025505192000019.tif27170; (c) contacting the compound of step (b) with a base and a dehydrating agent as described herein in acetonitrile, thereby obtaining a compound of formula (IVd): synthesizing the compound of TIFF2025505192000020.tif19170; (d) contacting the compound of step (c) with ammonia, thereby forming a compound of formula (IVe) synthesizing the compound of TIFF2025505192000021.tif19170; and (e) contacting the compound of step (d) with a halogenating agent, thereby synthesizing a compound of formula (IV). In one embodiment, the halogenating agent is a chlorinating agent, and X 3 is Cl.

[0097] In one embodiment of method (P3), the base in step (c) is a tertiary amine. In one embodiment, the base in step (c) is N-ethylmorpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), N-methylimidazole (NMI), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or tri(n-butyl)amine. In one such embodiment, the base is triethylamine. In another embodiment of method (P3), the base in step (c) is pyridine or DBU. In another embodiment of method (P3), the base in step (c) is an inorganic base, for example, K 2 CO 3 , NaOAc, NaOH or KOH could potentially also be used.

[0098] In one embodiment of method (P3), the dehydrating agent in step (c) is selected from the group consisting of trifluoroacetic anhydride (TFAA), acetic anhydride (AcO), methanesulfonic anhydride (MsO), p-toluenesulfonic anhydride (TsO), trifluoromethanesulfonic anhydride (TfO), propanephosphonic anhydride (T3P), methanesulfonyl chloride (MsCl), toluenesulfonyl chloride (TsCl), SOCl 2 , POCl 3 , or carbonyldiimidazole (CDI). In one such embodiment, the dehydrating agent is trifluoroacetic anhydride (TFAA) or acetic anhydride (Ac2O). In one such embodiment, the dehydrating agent in step (c) is trifluoroacetic anhydride (TFAA), acetic anhydride (Ac2O), methanesulfonic anhydride (Ms2O), p-toluenesulfonic anhydride (Ts2O), trifluoromethanesulfonic anhydride (Tf2O), or propanephosphonic anhydride (T3P). In another such embodiment, the dehydrating agent in step (c) is trifluoroacetic anhydride (TFAA), acetic anhydride (Ac2O), or trifluoromethanesulfonic anhydride (Tf2O). In another such embodiment, the dehydrating agent is trifluoroacetic anhydride (TFAA).

[0099] In one embodiment of method (P3), the halogenating agent in step (e) is 1,3-dichloro-5,5-dimethylhydantoin (DCDMH or DCH), SO 2 Cl 2 , TCCA (trichloroisocyanuric acid), N-chlorosaccharin or N-chlorosuccinimide (NCS). In one such embodiment, the halogenating agent is NCS. In one embodiment of method (P3), step (e) further comprises a substoichiometric amount of an acid. In one such embodiment, the acid is HCl.

[0100] In one embodiment of the method (P1), the compound of formula (III) is (a)X 6 Formula (VIa) in which TIFF2025505192000022.tif22170 is contacted with a halogenating agent to form a compound of formula (VIb) forming compounds of TIFF2025505192000023.tif22170; (b) brominating a compound of formula (VIb) to give a compound of formula (VI) forming a compound of formula TIFF2025505192000024.tif19170; and (c) reacting a compound of formula (VI) with a compound of formula NH(PG) 2 with a compound having the formula (III) It is prepared by a method (P4) comprising:

[0101] In one embodiment of the method (P4), each X 6 are the same. In one embodiment of the method (P4), each X 6 In one embodiment of method (P4), the halogenating agent in step (a) is SF in HF. 4 It is.

[0102] In one embodiment of method (P4), the bromination in step (b) is carried out using HBr in an acid. In one such embodiment, the acid is acetic acid. In another such embodiment, the acid is trifluoroacetic acid.

[0103] In one embodiment of the methods described herein, the compound of formula (III) has the formula: I have TIFF2025505192000025.tif25170.

[0104] In one such embodiment, the compound of formula (III) has the formula: Compound (3) may be synthesized according to the methods described herein (e.g., method (P4)).

[0105] In one such embodiment of method (P1), the compound of formula (III) has the formula (3): (a)Equation (6a) Compound TIFF2025505192000027.tif19170 in SF 4and HF, thereby forming a compound of formula (6b) To synthesize compound TIFF2025505192000028.tif19170; (b) contacting a compound of formula (6b) with HBr in AcOH to obtain a compound of formula (6): To form compounds of TIFF2025505192000029.tif18170; (c) Reacting the compound of formula (6) with NH(PMB) 2 with triethylamine and N-butylpyrrolidinone (NBP), thereby synthesizing a compound of formula (3). The compound is synthesized by the method (P6),

[0106] In one embodiment, the compound of formula (I) has the formula: I have TIFF2025505192000030.tif99170.

[0107] In one embodiment of the compounds of formula (Ia), (Ib), (Ic) and (Id), R 2 In one embodiment of the compounds of formula (Ia), (Ib), (Ic) and (Id), X 3 In one such embodiment, X is halo. 3 is Cl.

[0108] In one embodiment, the compound of formula (I) has the formula: TIFF2025505192000031.tif47170(Ie) (where X 3 is a halo).

[0109] In one embodiment, the compound of formula (I) has the formula: TIFF2025505192000032.tif47170(11).

[0110] Furthermore, equation (2): Methods for synthesizing the compound of TIFF2025505192000033.tif38170(2) are provided herein.

[0111] In one embodiment, there is provided a method (P5) for synthesizing a compound of formula (2), comprising: (a) Equation (4a) The compound in TIFF2025505192000034.tif18170 was contacted with i-PrMgCl, followed by hydroxylamine (NH 2 OH), thereby forming a compound of formula (4c) synthesizing the compound of TIFF2025505192000035.tif27170; (b) contacting a compound of formula (4c) with TFAA and triethylamine in acetonitrile, followed by contact with ammonia, thereby producing a compound of formula (4e) synthesizing the compound of TIFF2025505192000036.tif19170; (c) contacting the compound of (4e) with a chlorinating agent, thereby forming a compound of formula (4) synthesizing the compound of TIFF2025505192000037.tif19170; (d) Compound (4) is reacted with CO in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). 2 and thereby reacting with the compound of formula (5) synthesizing the compound of TIFF2025505192000038.tif23170; (e) The compound of formula (5) is reacted with POCl 3 and DIPEA, followed by contact with tert-butyl (S)-3-methylpiperazine-1-carboxylate, thereby forming a compound of formula (5b) synthesizing the compound of formula (I); and (f) contacting the compound of (5b) with KF, 1,4-diazabicyclo[2.2.2]octane (DABCO) and MsOH, thereby forming a compound of formula (2).

[0112] In one embodiment, step (a) of process (P5) is carried out in DMF as solvent.

[0113] In another embodiment, the method (P1) comprises the step of reacting a compound of formula (G) according to method (P7): TIFF2025505192000040.tif52170(in formula:X A teeth, TIFF2025505192000041.tif233170), or a tautomer, solvate, or pharma- ceutically acceptable salt thereof; This method is (a) reacting a compound of formula (I) synthesized as described herein, or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, with X in the presence of a base and an activating agent. A with a moiety comprising, thereby synthesizing a compound of formula (G1); TIFF2025505192000042.tif53170(b) A compound of formula (G1) from which a PG group and optionally R 1 and (c) reacting the compound of step (b) with R 5 is unsubstituted C 1-6 Formula (VII) which is alkyl or phenyl TIFF2025505192000043.tif17170, followed by contacting with a base, thereby producing a compound of formula (G), or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof. 5 is phenyl. In one embodiment, R 5 is methyl, ethyl, propyl or t-butyl.

[0114] In one embodiment, the compound of formula (VII) has the formula TIFF2025505192000044.tif18170(7).

[0115] In one embodiment, X A teeth, The file is TIFF2025505192000045.tif131170.

[0116] In one embodiment, X A teeth, The file is TIFF2025505192000046.tif97170.

[0117] In one embodiment, X A teeth TIFF2025505192000047.tif14170. In one such embodiment, X A teeth The file is TIFF2025505192000048.tif13170.

[0118] Formula (1): TIFF2025505192000049.tif52170, or a pharma- ceutically acceptable salt thereof (P8), comprising: (a) Equation (2) A pre-cooled solution containing the compound of formula (2a) or a salt thereof is contacted with a pre-cooled solution containing i-PrMgCl·LiCl using a flow rate that provides a residence time of about 15-150 seconds for Mg-Br exchange, thereby forming the compound of formula (2a); synthesizing the compound of TIFF2025505192000051.tif43170(2a); (b) ZnCl 2 or Zn(OPiv) 2 and maintaining a constant residence time of about 3 to 7 minutes at about -20°C to 20°C, thereby obtaining a compound of formula (2b); synthesizing the compound of TIFF2025505192000052.tif42170(2b); (c) reacting a compound of formula (2b) with NaTFA and a compound of formula (3) contacting the compound of formula (I) with a compound of formula (I); (d) contacting the mixture of step (c) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand, thereby forming a chiral ligand of formula (11): synthesizing a compound of formula (I) of TIFF2025505192000054.tif48170, or a solvate or salt thereof; (e) reacting a compound of formula (11) or a solvate or salt thereof with a compound of formula HO-X A (In the formula, X A is the formula TIFF2025505192000055.tif13170) and a base, thereby forming a compound of formula (1b); synthesizing a compound of formula (I) of TIFF2025505192000056.tif43170, or a solvate or a pharma- ceutically acceptable salt thereof; (f) contacting a compound of formula (1b) with MsOH in an acid, thereby producing a compound of formula (1a); TIFF2025505192000057.tif39170, or a solvate or a pharma- ceutically acceptable salt thereof; and (g) reacting a compound of formula (1a) or a solvate or a pharma- ceutically acceptable salt thereof in the presence of an activating agent. TIFF2025505192000058.tif18170, followed by contacting with a base, thereby producing a compound of formula (1), or a pharma- ceutically acceptable salt thereof. Further provided herein is a method (P8), comprising:

[0119] In one embodiment, the residence time of step (a) of method (P8) is about: 15-45 seconds, 15-60 seconds, 15-90 seconds, 15-100 seconds, or 15-120 seconds. In one embodiment, the residence time of step (a) of method (P8) is about: 30-45 seconds, 30-60 seconds, 30-90 seconds, 30-120 seconds, or 30-150 seconds. In yet another embodiment, the residence time of step (a) of method (P8) is about: 15-45 seconds or 60-90 seconds. In one embodiment, the residence time of step (a) of method (P8) is about 15-45 seconds. In one embodiment, the residence time of step (a) of method (P8) is about 60-90 seconds. In one embodiment, the residence time of step (a) of method (P8) is about 60-150 seconds. In one embodiment, the residence time in step (a) of method (P8) is about 90 to 150 seconds.

[0120] In one embodiment of the process of (P8), ZnCl 2 or Zn(OPiv) 2 In one such embodiment, the pre-cooled solution further comprises LiCl. 2 Contains LiCl.

[0121] In one embodiment of method (P8), compound 2b is as described herein. In one such embodiment, p is 1, m is 1, and X 2 is halogen (e.g., Cl or Br). In another such embodiment, compound 2b is 2 , m and p are different mixtures. In one embodiment, compound 2b contains at least two or three different species. In one such embodiment, the number of species depends on the number of equivalents of zinc compound used. In one such embodiment, more equivalents of zinc compound compared to compound 2a results in more species. In one such embodiment, the species may interconvert without affecting the kinetics of the following reaction. In one embodiment, the species is X as Br only when m is 1. 2 Includes.

[0122] In one embodiment, the compound of formula (2) is prepared according to method (P5) as described herein. In one embodiment, the compound of formula (3) is prepared according to method (P6).

[0123] Formula (1): TIFF2025505192000059.tif52170, or a pharma- ceutically acceptable salt thereof (P8), comprising: (a) Equation (2) contacting a pre-cooled solution containing the compound of formula (I) or a salt thereof with a pre-cooled solution containing i-PrMgCl·LiCl using a flow rate that provides a residence time for Mg-Br exchange of about 15 to 150 seconds; (b) ZnCl 2 or Zn(OPiv) 2 transferring the mixture of step (a) to a continuous stirred tank reactor (CSTR) containing a pre-cooled solution of the above and maintaining a constant residence time of about 3 to 7 minutes at about -20°C to 20°C; (c) reacting the mixture of step (b) with NaTFA and a compound represented by formula (3) contacting the compound of formula (I) with a compound of formula (I); (d) contacting the mixture of step (c) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand, thereby forming a chiral ligand of formula (11): synthesizing a compound of formula (I) of TIFF2025505192000062.tif48170, or a solvate or salt thereof; (e) reacting a compound of formula (11) or a solvate or salt thereof with a compound of formula HO-X A (In the formula, X A is the formula TIFF2025505192000063.tif13170) and a base, thereby forming a compound of formula (1b); synthesizing a compound of formula (I) of TIFF2025505192000064.tif43170, or a solvate or a pharma- ceutically acceptable salt thereof; (f) contacting a compound of formula (1b) with MsOH in an acid, thereby producing a compound of formula (1a); TIFF2025505192000065.tif39170, or a solvate or a pharma- ceutically acceptable salt thereof; and (g) reacting a compound of formula (1a) or a solvate or a pharma- ceutically acceptable salt thereof in the presence of an activating agent. Further provided herein is a method (P9) comprising contacting the compound of formula (1) with TIFF2025505192000066.tif18170, followed by contacting with a base, thereby producing a compound of formula (1), or a pharma- ceutically acceptable salt thereof.

[0124] In one embodiment, the residence time of step (a) of method (P9) is about: 15-45 seconds, 15-60 seconds, 15-90 seconds, 15-100 seconds, or 15-120 seconds. In one embodiment, the residence time of step (a) of method (P9) is about: 30-45 seconds, 30-60 seconds, 30-90 seconds, 30-120 seconds, or 30-150 seconds. In yet another embodiment, the residence time of step (a) of method (P9) is about: 15-45 seconds or 60-90 seconds. In one embodiment, the residence time of step (a) of method (P9) is about 15-45 seconds. In one embodiment, the residence time of step (a) of method (P9) is about 60-90 seconds. In one embodiment, the residence time of step (a) of method (P9) is about 60-150 seconds. In one embodiment, the residence time in step (a) of method (P9) is about 90 to 150 seconds.

[0125] In one embodiment of the method of (P9), ZnCl 2 or Zn(OPiv) 2 In one such embodiment, the pre-cooled solution further comprises LiCl. 2 In one such embodiment, the pre-cooled solution contains Zn(OPiv). 2 LiCl, and the residence time in step (a) of the method (P9) is about 60 to 90 seconds or about 60 to 150 seconds.

[0126] In one embodiment, the compound of formula (2) is prepared according to method (P5) as described herein. In one embodiment, the compound of formula (3) is prepared according to method (P6).

[0127] As used herein, "continuous flow" refers to chemical reactions that are conducted in a continuous flowing stream rather than batch production. In such cases, pumps move fluids into a flow system where the fluids contact each other and reactions occur. In some embodiments, microreactors are used. In some embodiments, tubular or plug flow reactors (PFRs) are used. In some other embodiments, continuous stirred tank reactors (CSTRs) are used. In such embodiments, the reactors may be cooled prior to the movement of agents or reactants therein. The continuous flow reactions described herein eliminate the need for low temperatures (e.g., -78°C) typically used for such reactions. Eliminating the need for such low temperatures increases reaction efficiency and allows for more robust scale-up to commercial product quantities. Additionally, the continuous flow reactions described herein improve the process robustness and control of reaction conditions. The methods described herein result in better purity of the synthesized intermediates and compounds and reduce the time required for reaction and production of compound (1).

[0128] Methods for Treating Cancer Compound 1, or a pharma- ceutically acceptable salt thereof, inhibits KRas G12C It can be administered to a patient in an effective amount (e.g., the amount described herein) to treat mutation-mediated cancer.In one such embodiment, the cancer is a solid tumor (e.g., lung cancer, CRC, or pancreatic cancer).It should be understood that the methods described herein also include treatment with a pharmaceutical composition as described herein, comprising compound 1 as described herein or a pharmaceutically acceptable salt thereof.

[0129] In one embodiment, KRas G12CA method of treating mutation-mediated lung cancer in a patient having such cancer, comprising administering to the patient having the cancer an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof.

[0130] In such embodiments, the lung cancer is a KRas G12C In another embodiment, the lung cancer is a non-small cell lung cancer (NSCLC) that includes a mutation. In another embodiment, the lung cancer is an adenocarcinoma, a squamous cell lung cancer, or a large cell lung cancer. In one such embodiment, the cancer is a lung adenocarcinoma. In another such embodiment, the lung cancer is a small cell lung cancer. In another embodiment, the lung cancer is a small cell lung carcinoma. In yet another embodiment, the lung cancer is an adenocarcinoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer can be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0131] Further provided herein is the use of Compound 1, or a pharma- ceutically acceptable salt thereof (UL1), for the treatment of lung cancer as described herein.

[0132] KRas G12C Also provided herein is a method of treating mutation-mediated colorectal cancer in a patient having such cancer, comprising administering to the patient having cancer an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof.

[0133] Further provided herein is the use of compound 1, as described herein, or a pharma- ceutically acceptable salt thereof (UC1), for treating colorectal cancer as described herein.

[0134] KRas G12C Further provided herein is a method of treating mutation-mediated pancreatic cancer in a patient having such cancer, comprising administering to the patient having the cancer an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, as described herein.

[0135] Further provided herein is the use of compound 1, or a pharma- ceutically acceptable salt thereof, as described herein (UP1), for the treatment of pancreatic cancer as described herein.

[0136] KRas G12C Further provided herein is a method of treating a tumor-independent cancer comprising a mutation in a patient having such a cancer. In one such embodiment, the method comprises treating a patient having a tumor-independent cancer comprising a mutation in KRas G12C 1. A method of treating a tumor-independent cancer comprising: (a) KRas in samples taken from patients diagnosed with suspected cancer G12C Determining the absence or presence of a mutation; and (b) treating tumor-independent cancer in a patient having such cancer by administering to the patient an effective amount of Compound 1, or a pharma- ceutically acceptable salt thereof, as described herein.

[0137] Further provided herein is the use of compound 1, or a pharma- ceutically acceptable salt thereof, as described herein (UA1), for treating a tumor-independent cancer as described herein.

[0138] In one embodiment of the methods and uses described herein, Compound 1 or a pharma- ceutically acceptable salt thereof is administered as a fixed dose QD. In one embodiment, administration is oral (PO) and Compound 1 or a pharma- ceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, Compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 600 mg, 25 mg to 500 mg, 25 mg to 400 mg, 25 mg to 5 ... In another embodiment, Compound 1 or a pharmacologic acceptable salt thereof is administered QD in an amount of about 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 25 mg, 25 mg, 300 mg, 400 mg, or 500 mg.

[0139] Embodiments: Several exemplary embodiments of the present invention are provided below.

[0140] Embodiment 1. Formula (I); TIFF2025505192000067.tif52170(in the formula, 1 and X 3 are each independently hydrogen or halogen; R 1 is hydrogen or PG 1 and; Each R 2 are independently halogen, cyano, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Cyanoalkyl, or unsubstituted C 1-6 is haloalkyl; R 3 is hydrogen, halogen, R3A -Substituted or unsubstituted C 1-3 Alkyl, R 3A -Substituted or unsubstituted C 1-3 Haloalkyl, or R 3A -substituted or unsubstituted cyclopropyl; R 3A is halogen, OH, CN, unsubstituted C 1-3 Alkyl or unsubstituted C 1-3 is haloalkyl; R 4 is R 4A -Substituted or unsubstituted C 1-3 is haloalkyl; R 4A is unsubstituted C 1-3 is alkyl; n is 1 or 2; each PG is independently an amino protecting group; PG 1 is an amino protecting group), or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, comprising the steps of: This method, (a) Formula (II) TIFF2025505192000068.tif43170(in the formula, 2 is a halogen) with an organomagnesium compound, thereby forming a compound of formula (IIa): forming a compound of formula (IIa); (b) transferring the compound of formula (IIa) from step (a) to a continuous stirred tank reactor (CSTR) containing a zinc compound, thereby producing a compound of formula (IIb) TIFF2025505192000070.tif45170, where m is 0, 1, or 2; p is 1, 2 or 3; X 2 is a halogen or OPiv; (c) reacting compound (IIb) of step (b) with a compound of formula (III) TIFF2025505192000071.tif26170(in the formula, 4 is a halogen, 1. A method for synthesizing a compound of formula (I), or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, comprising the step of contacting a transition metal catalyst precursor, and a chiral ligand, thereby synthesizing the compound of formula (I).

[0141] Embodiment 2.X 2 2. The method of embodiment 1, wherein is Br, Cl or OPiv.

[0142] Embodiment 3. A compound of formula (II) comprising: (a) In the presence of a base, CO 2 Formula (IV) below Compound (V) of TIFF2025505192000072.tif22170 cyclization to compound TIFF2025505192000073.tif24170; (b) contacting the compound of formula (V) with a chlorinating agent, thereby producing a compound of formula (Va) To synthesize compound TIFF2025505192000074.tif24170; (c) reacting the compound of step (b) with the compound of formula TIFF2025505192000075.tif24170, thereby contacting a piperazinyl moiety having formula (Vb) synthesizing the compound of TIFF2025505192000076.tif42170; and (d) contacting the compound of step (c) with a fluorinating agent in the presence of a base, thereby synthesizing a compound of formula (II). 3. The method according to claim 1 or 2, wherein the compound is prepared by a method (P2) comprising:

[0143] Embodiment 4. The method of embodiment 3, wherein the base in step (a) is DBU.

[0144] Embodiment 5. The chlorinating agent in step (b) is POCl 34. The method of embodiment 3, wherein

[0145] Embodiment 6. The method of embodiment 3, wherein the base in step (c) is DIPEA.

[0146] Embodiment 7. The method of embodiment 3, wherein the fluorinating agent in step (d) is KF.

[0147] Embodiment 8. A compound of formula (IV) is: (a) Formula (IVa) contacting the compound of formula (IVb) with i-PrMgCl To synthesize compound TIFF2025505192000078.tif19170; (b) contacting the compound of step (a) with hydroxylamine, thereby forming a compound of formula (IVc) To synthesize compound TIFF2025505192000079.tif27170; (c) contacting the compound of step (b) with a base and a dehydrating agent in acetonitrile, thereby obtaining a compound of formula (IVd) To synthesize compound TIFF2025505192000080.tif19170; (d) contacting the compound of step (c) with ammonia, thereby forming a compound of formula (IVe) synthesizing the compound of TIFF2025505192000081.tif19170; and (e) contacting the compound of step (d) with a chlorinating agent, thereby synthesizing a compound of formula (IV). The method according to any one of embodiments 3 to 7, wherein the compound is prepared by a method (P3) comprising:

[0148] Embodiment 9. A compound of formula (III): (a) (where X 6 is Cl or I) TIFF2025505192000082.tif22170 is contacted with a halogenating agent to form a compound of formula (VIb) forming compounds of TIFF2025505192000083.tif22170; (b) brominating a compound of formula (VIb) to give a compound of formula (VI) forming a compound of formula TIFF2025505192000084.tif22170; and (c) reacting a compound of formula (VI) with a compound of formula NH(PG) 2 with a compound having the formula (III) 2. The method of embodiment 1, wherein the compound is prepared by a method (P4) comprising:

[0149] Embodiment 10.X 6 10. The method of embodiment 9, wherein is Cl.

[0150] Embodiment 11. The halogenating agent is SF in HF 4 10. The method of embodiment 9, wherein

[0151] Embodiment 12. The method of embodiment 9, wherein the bromination is carried out using HBr in acid.

[0152] Embodiment 13. A compound of formula (III) comprising: The method of any one of embodiments 9 to 12, having TIFF2025505192000085.tif24170.

[0153] Embodiment 14.X 1 The method of any one of the preceding embodiments, wherein is a halogen.

[0154] Embodiment 15.X 1 The method of any one of the preceding embodiments, wherein is F or Cl.

[0155] Embodiment 16.X 3 The method of any one of the preceding embodiments, wherein is a halogen.

[0156] Embodiment 17.X 3The method of any one of the preceding embodiments, wherein is F or Cl.

[0157] Embodiment 18.R 1 PG 1 The method according to any one of embodiments 1 to 17, wherein

[0158] Embodiment 19. PG 1 The method of any one of embodiments 1-18, wherein is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy).

[0159] Embodiment 20.R 1 The method of any one of the preceding embodiments, wherein is Boc (tert-butyloxycarbonyl).

[0160] Embodiment 21.R 2 is unsubstituted C 1-6 Alkyl or unsubstituted C 1-6 The method of any one of the preceding embodiments, wherein the alkyl group is cyanoalkyl.

[0161] Embodiment 22.R 2 The method of any one of the preceding embodiments, wherein is methyl.

[0162] Embodiment 23.R 3 is hydrogen or R 3A -Substituted or unsubstituted C 1-3 The method of any one of the preceding embodiments, wherein the alkyl group is alkyl.

[0163] Embodiment 24.R 3 The method of any one of the preceding embodiments, wherein is methyl.

[0164] Embodiment 25.R 4 But CF3 , CHF 2 , or C.H. 2 The method of any one of embodiments 1-24, wherein

[0165] Embodiment 26.R 3 is methyl and R 4 CF 3 The method of any one of embodiments 1 to 25, wherein

[0166] Embodiment 27. The method of any one of embodiments 1 to 26, wherein each PG is independently a protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy).

[0167] Embodiment 28. The method of embodiment 27, wherein each PG is p-methoxybenzyl.

[0168] Embodiment 29. The method of any one of embodiments 1 to 28, wherein the organomagnesium compound is selected from the group consisting of isopropylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium iodide, isopropylmagnesium chloride lithium chloride complex, sec-butylmagnesium chloride, lithium tri-n-butylmagnesiate, lithium triisopropylmagnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate.

[0169] Embodiment 30. The method of embodiment 29, wherein the organomagnesium compound is i-PrMgCl·LiCl.

[0170] Embodiment 31. The zinc compound is ZnCl 2 , ZnBr 2 , ZnI 2, Zn(TFA) 2 , Zn(OAc) 2 , and Zn(OPiv) 2 31. The method of any one of the preceding embodiments, selected from the group consisting of:

[0171] Embodiment 32. The zinc compound is Zn(OPiv). 2 The method of embodiment 31, wherein said first and second electrodes are LiCl.

[0172] Embodiment 33. The transition metal catalyst precursor is a Pd or Ni catalyst precursor, and Pd(OAc) 2 , PdCl 2 , PdCl 2 (MeCN) 2 , Pd(benzonitrile) 2 Cl 2、 Pd(dba) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , Pd(PCy 3 ) 2 , Pd(PtBu 3 ) 2 , Pd(TFA) 2 , [Pd(allyl)Cl] 2 [Pd(cinnamyl)Cl] 2 [PdCl(crotyl)] 2 , PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl 2 , NiBr 2 , Ni(OAc) 2 32. The method of any one of the preceding embodiments, wherein the compound is selected from the group consisting of:

[0173] Embodiment 34. The chiral ligand is TIFF2025505192000086.tif46170 (in the formula, Y is O or NR 7 and; R 7 and R 8 are independently unsubstituted C 1-6 The method of any one of the preceding embodiments, wherein R is an alkyl group.

[0174] Embodiment 35.R 7 and R 8 34. The method of embodiment 33, wherein:

[0175] Embodiment 36.R 7 and R 8 is each independently methyl, ethyl or phenyl.

[0176] Embodiment 37. The method of any one of embodiments 1 to 33, wherein the chiral ligand is an (R,R)-chiraphite ligand.

[0177] Embodiment 38. The zinc compound is Zn(OPiv). 2 LiCl and the Pd catalyst precursor is [Pd(cinnamyl)Cl] 2 and the chiral ligand is a (R,R)-chiraphite ligand.

[0178] Embodiment 39. The compound of formula (I) has the formula: 2. The method of embodiment 1, having TIFF2025505192000087.tif100170.

[0179] Embodiment 40. The compound of formula (I) has the formula: TIFF2025505192000088.tif48170(in the formula, 3 2. The method of embodiment 1, wherein

[0180] Embodiment 41. The compound of formula (I) has the formula: 2. The method of embodiment 1, having TIFF2025505192000089.tif46170(11).

[0181] Embodiment 42. Formula (2) A method (P5) for synthesizing a compound of TIFF2025505192000090.tif38170(2), comprising: This method, (a) Equation (4a) The compound of formula (4c) is then contacted with i-PrMgCl and subsequently with hydroxylamine to obtain the compound of formula (4c) synthesizing the compound of TIFF2025505192000092.tif27170; (b) contacting a compound of formula (4c) with TFAA and triethylamine in acetonitrile, followed by contact with ammonia, thereby producing a compound of formula (4e) synthesizing the compound of TIFF2025505192000093.tif19170; (c) contacting the compound of (4e) with a chlorinating agent, thereby forming a compound of formula (4) synthesizing the compound of TIFF2025505192000094.tif19170; (d) Compound (4) was reacted with CO in the presence of DBU. 2 and thereby reacting with the compound of formula (5) synthesizing the compound of TIFF2025505192000095.tif23170; (e) The compound of formula (5) is reacted with POCl 3 and DIPEA, followed by contacting with tert-butyl (S)-3-methylpiperazine-1-carboxylate in DIPEA, thereby producing a compound of formula (5b): synthesizing the compound of TIFF2025505192000096.tif38170; and (f) contacting the compound of (5b) with KF, DABCO and MsOH, thereby forming a compound of formula (2).

[0182] Embodiment 43. The compound of formula (III) has the formula: has TIFF2025505192000097.tif19170(3); The compound of formula (3) (a)Equation (6a) Compound TIFF2025505192000098.tif19170 in SF 4 and HF, thereby forming a compound of formula (6b) To synthesize compound TIFF2025505192000099.tif19170; (b) contacting a compound of formula (6b) with HBr in AcOH to obtain a compound of formula (6): forming compounds of TIFF2025505192000100.tif19170; (c) reacting the compound of formula (6) with (PMB) 2 NH, triethylamine and NBP, thereby synthesizing a compound of formula (III). 2. The method of embodiment 1, wherein the compound is synthesized by method (P6), comprising:

[0183] Embodiment 44. A compound represented by formula (G) according to the method (P7) TIFF2025505192000101.tif52170(in formula:X A teeth, TIFF2025505192000102.tif234170), or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof, comprising: This method is (a) reacting a compound of formula (I) or a solvate, tautomer, stereoisomer, atropisomer or salt thereof with X in the presence of a base and an activating agent. A with a moiety comprising, thereby synthesizing a compound of formula (G1); TIFF2025505192000103.tif53170(b) A compound of formula (G1) from which a PG group and optionally R 1 and (c) reacting the compound of step (b) with the compound of formula (VII) in the presence of an activating agent and subsequently contacting with a base, thereby producing a compound of formula (G), or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof. A method comprising:

[0184] Embodiment 45. Formula: (1) TIFF2025505192000105.tif52170, or a pharma- ceutically acceptable salt thereof (P8), comprising: (a) Equation (2) contacting a pre-cooled solution containing the compound of formula (I) or a salt thereof with a pre-cooled solution containing i-PrMgCl·LiCl using a flow rate that provides a residence time for Mg-Br exchange of about 15 to 150 seconds; (b) ZnCl 2 or Zn(OPiv) 2 transferring the mixture of step (a) to a continuous stirred tank reactor (CSTR) containing a pre-cooled solution of the above and maintaining a constant residence time of about 3 to 7 minutes at about -20°C to 20°C; (c) reacting the mixture of step (b) with NaTFA and a compound represented by formula (3) contacting the compound of formula (I) with a compound of formula (I); (d) contacting the mixture of step (c) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand, thereby forming a chiral ligand of formula (11): synthesizing a compound of formula (I) TIFF2025505192000108.tif48170, or a solvate or salt thereof; (e) reacting a compound of formula (11) or a solvate or salt thereof with a compound of formula HO-X A (In the formula, X A is the formula TIFF2025505192000109.tif13170) and a base, thereby forming a compound of formula (1b); synthesizing a compound of formula (I) of TIFF2025505192000110.tif43170, or a solvate or a pharma- ceutically acceptable salt thereof; (f) contacting a compound of formula (1b) with MsOH in an acid, thereby producing a compound of formula (1a); TIFF2025505192000111.tif39170, or a solvate or a pharma- ceutically acceptable salt thereof; and (g) reacting a compound of formula (1a) or a solvate or a pharma- ceutically acceptable salt thereof in the presence of an activating agent. TIFF2025505192000112.tif18170, and subsequently contacting with a base, thereby producing a compound of formula (1), or a pharma- ceutically acceptable salt thereof (P9).

[0185] Embodiment 46. The method of embodiment 45, wherein the acid in step (f) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid, or trifluoromethanesulfonic acid.

[0186] Embodiment 47. The method according to embodiment 45, wherein compound (2) is synthesized according to the method of embodiment 42.

[0187] Embodiment 48. The pre-cooled solution of step (b) is Zn(OPiv). 2 The method of embodiment 45, comprising LiCl.

[0188] Working Example: The following examples are offered by way of illustration and not by way of limitation.

[0189] Example 1: Compound 2: tert-butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate TIFF2025505192000113.tif111170

[0190] Process 1

[0191] To a solution of 1,4-dibromo-2,3-difluorobenzene (100 g) in THF (200 mL) was added isopropylmagnesium bromide (1.1 eq., 2M in THF) at 0° C. over at least 2 h. After stirring for 30 min, DMF (2.0 eq.) was added over at least 3 h. After aging for 1 h (IPC conversion >97.5%-a / a), the mixture was added in one portion to a cooled solution (0° C.) of citric acid (1.2 eq.) in water (1 Veq.). The mixture was warmed to 45° C. and the aqueous phase was separated.

[0192] Process 2

[0193] To the organic phase containing 4b, hydroxylamine (1.05 equiv., 50% wt in water) was added at 45° C. over at least 1 h. After stirring for 30 min (IPC conversion >98.8%-a / a), brine (100 mL) was added at the same temperature. The aqueous phase was separated and the organic phase was concentrated to a total volume of 200 mL by vacuum distillation. The vacuum distillation was then proceeded at constant volume by feeding acetic acid (200 mL). After adjusting the solution to 70° C., water (100 mL) was added over at least 30 min and seeded. The resulting suspension was cooled to 20° C., followed by the addition of water (100 mL). The precipitate was filtered, the filter cake was washed with ACN / water (1:2) and the wet product was dried under reduced pressure to give 77.6 g of 4c (89% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=11.89(s,1H),8.19(s,1H),7.56-7.46(m,2H).

[0194] Step 3 and Step 4

[0195] To a suspension of 4c (100 g) in ACN (200 mL) was added triethylamine (2.2 equiv.) at 20° C. To the resulting solution was added TFAA (1.1 equiv.) over at least 2.5 h. After the addition was complete, the reaction mixture was stirred for 30 min (IPC conversion >99.8%-a / a). The solution containing 4d was placed in an autoclave and ammonia (6.8 equiv., 25% wt. in water) was added in one portion. The vessel was sealed and heated at 120° C. for at least 6 h (IPC conversion >99.0%-a / a). The mixture was adjusted to 90° C. and then cooled to 50° C. over at least 3 h, after which water (220 mL) was added over at least 1 h. The suspension was then further cooled to 20° C. and aged for 1 h. The precipitate was filtered and the filter cake was washed with ACN / water (1:2). The wet product was dried under vacuum to give 75.6 g of 4e (83% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=7.23(br d,J=8.4 Hz,1H),6.86(dd,J=8.4,6.1 Hz,1H),6.49(bs,2H).

[0196] Step 5:

[0197] To a solution of 4e (100 g) in DMF (500 mL) was added HCl in dioxane (4.0 M, 0.25 equiv.) at 0° C. The solution was cooled to −5° C. and NCS (1.15 equiv.) was added in small portions while maintaining the temperature below 2° C. (target −5° C.). After the addition was complete, the reaction mixture was stirred at −5° C. for 1.5 h (IPC). n-PrOH (100 mL) was then added at 0° C. to initiate precipitation of the product (visual IPC for suspension). After stirring for at least 30 min, water (250 mL) was added at 0-5° C. over at least 1.5 h. The suspension was filtered and the filter cake was washed twice with ACN / water (1:2) (100 mL). The wet product was dried in a vacuum oven at 60° C. to give 102.8 g of 4 (89% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=7.67(d,J=2.1 Hz,1H),6.49(bs,2H).

[0198] Another step 5: TIFF2025505192000114.tif35170

[0199] To a solution of 4e (100 g) in DMF (700 mL) was added HCl in dioxane (4.0 M, 0.25 equiv.) at 40 °C. The solution was cooled to -5 °C and 1,3-dichloro-5,5-dimethylhydantoin (DCH) (0.60 equiv.) was added in portions. After the addition was complete, the reaction temperature was adjusted to -10 to 0 °C and stirred for an additional 1.5 h. Then, n-PrOH (140 mL) and water (350 mL) were added at -5 to 5 °C to initiate precipitation of the product (visual IPC of the suspension). After stirring for at least 30 min at -5 to 5 °C, the suspension was filtered and the filter cake was washed twice with ACN / water (1:2) (2 × 100 mL). The wet product was dried in a vacuum oven at 60 °C to give 97.5 g of 4 (84% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=7.67(d,J=2.1 Hz,1H),6.49(bs,2H).

[0200] Step 6:

[0201] A suspension of 4 (50 g) in DMSO (150 mL) was dissolved in CO 2After stirring at 25° C. for 15 min under ambient conditions, DBU (33.6 g) was added. After stirring at 25° C. for 1 h, the reaction was heated to 70° C. and stirred for an additional 6 h (IPC: 4<1.0%-a / a). Acetic acid (14.4 g) was then added over at least 1 h. The mixture was stirred at 70° C. for at least 1 h, after which water (50 mL) was added over at least 2 h. The resulting suspension was aged at 70° C. for 3 h, then cooled to 25° C. over at least 3 h and stirred at that temperature for an additional 1 h. The suspension was filtered and washed with DMSO / water (3:1, 50 mL) and IPA / water (1:1, 50 mL). The filter cake was suspended in IPA / water (1:2, 200 mL), stirred for at least 30 min, filtered, washed with IPA / water (1:1, 20 mL), and dried in a vacuum oven at 60 °C to give 55.0 g of 5 (93.5% o.th.). 1 H NMR(400 MHz,DMSO-d6)δ [ppm]=11.64(s,1H),11.60(s,1H),7.84(d,J=1.8 Hz,1H).

[0202] Step 7:

[0203] A suspension of 5 (50 g) in toluene (300 ml) was added to POCl 3 (130.6 g) was added at 25° C. The mixture was stirred for 30 min, then DIPEA (49.5 g) was added over at least 2 h. The reaction mixture was warmed to 35° C. and stirred for 30 min. Water (0.77 g) was added in one portion to the resulting solution. The reaction mixture was heated to 70° C. and stirred for at least 2 h, then cooled to 25° C. (IPC: 5a>97.0%-a / a). The reaction mixture was added to water (400 mL) over at least 1 h at 25° C. After the addition was complete, the biphasic mixture was stirred for at least 30 min, then filtered through Harborlite 800 (10.3 g). The filter cake was rinsed with toluene (25 mL) and the phases were separated. The organic phase was washed with brine (20%-w / w in water, 100 mL) and reduced to 160 mL by distillation under reduced pressure.

[0204] Step 8:

[0205] The solution from step 7 was then telescoped and cooled to 25° C. and (S)-1-Boc-3-methylpiperazine (34.1 g) was added in 5 portions over at least 1 h. After stirring for 30 min, DIPEA (24.2 g) was added within 1 h and the resulting suspension was stirred for 30 min (IPC: 5a<0.4%-a / a). The mixture was heated to 40° C. and stirred for 1 h before heptane was added over at least 1 h. After stirring at 40° C. for an additional 1 h, the suspension was cooled to 25° C. over at least 1 h and aged for at least 2 h. The suspension was filtered and washed with heptane / toluene (2:1, 50 mL). The filter cake was suspended in IPA / water (2:1, 200 mL), stirred for at least 30 min, filtered, washed twice with IPA / water (2:1, 100 mL), and dried in a vacuum oven at 45° C. to give 74.1 g of 5b (88% o.th.). 1 H NMR (400 MHz, chloroform-d) δ [ppm] = 7.69 (d, J = 2.0 Hz, 1H), 4.74-4.65 (m, 1H), 4.30-3.85 (m, 3H), 3.68-3.56 (m, 1H), 3.33-2.97 (m, 2H), 1.48 (s, 9H), 1.45 (d, J = 6.7 Hz, 3H).

[0206] Step 9:

[0207] To a stirred suspension of 5b (20 g) in DMSO (100 mL) were added potassium fluoride (3.1 g, 1.3 equiv.), DABCO (0.18 g, 0.04 equiv.) and methanesulfonic acid (0.11 ml, 0.04 equiv.) at room temperature. The mixture was heated to 65° C. and stirred for at least 3 h. After complete conversion (IPC: 5b < 0.1%-a / a), the mixture was cooled to 50° C. and stirred at the same temperature for at least 1 h (precipitation of the product occurs). The suspension was then cooled to 20° C. over at least 3 h, after which 40 mL of ACN / water (1:2) was added over at least 1 h. After stirring for 30 min, the precipitate was filtered and washed with 20 mL of ACN / water (1:1). The filter cake was suspended in 60 mL of ACN / water (1:2), stirred for at least 30 min, filtered, washed with 20 mL of ACN / water (1:2), and dried in a vacuum oven at 60 °C to give 17.9 g of 2 (95% o.th.). 1 H NMR(400 MHz,chloroform-d)δ [ppm]=7.76(d,J=1.9 Hz,1H),4.77-4.70(m,1H),4.28-4.22(m,1H),4.18-3.85(m,2H),3.66(dd,J=13.0,3.1 Hz,1H),3.34-3.00(m,2H),1.51(s,9H),1.49(d,J=6.9 Hz,3H).

[0208] Example 2: Continuous flow processing of compound (2b) TIFF2025505192000115.tif71170

[0209] Feed preparation

[0210] Feed 1: 273 g of 2 was dissolved in 1166 g of THF to give 1500 mL of solution (0.38 M) with a density of 0.96. Feed 2: i-PrMgCl LiCl was used as a 1.20 M solution in THF (assay corrected based on CoA). ZnCl 2 was used as a 2.00 M (25.8 wt %) solution in 2-MeTHF (assay corrected based on CoA).

[0211] The setup of the system described above is shown in FIG.

[0212] All pumps and transfer lines were purged with the corresponding feeds. Feed 1 containing compound 2 (1.00 equiv.) and feed 2 containing i-PrMgCl LiCl (1.05 equiv.) were pre-cooled and continuously charged into a suitable flow-through reactor at a jacket temperature (JT) of -20 to 0 °C. The flow rates of the two feeds were adjusted to give a residence time of approximately 30 s for the Mg-Br exchange.

[0213] The outflowing reaction mixture (compound 2a) was directed to a continuous stirred tank reactor (CSTR) where ZnCl 2 were added simultaneously (1.15 equiv.) while maintaining a constant residence time of about 5 min. The temperature was kept constant at -10° C. internal temperature (IT).

[0214] Compound 2b was collected in a receiving tank at IT of 0–25° C. Compound 2b was found to be stable at −20–25° C. for several weeks.

[0215] Example 2a: TIFF2025505192000116.tif64170

[0216] Feed preparation

[0217] Feed 1: 117 g of 2 was dissolved in 783 g of THF to give 959.5 mL of a solution (0.25 M) with a density of 0.94. Feed 2: i-PrMgCl·LiCl was used as a 1.20 M solution in THF (assay corrected based on CoA). Zn(OPiv) 2 ·LiCl was used as a 0.67 M (20.0 wt %) solution in 2-MeTHF (assay corrected based on CoA).

[0218] The setup of the system described above is shown in FIG.

[0219] All pumps and transfer lines were purged with the corresponding feeds. Feed 1 containing compound 2 (1.00 equiv.) and feed 2 containing i-PrMgCl LiCl (1.15 equiv.) were pre-cooled and continuously charged into a suitable flow reactor at a jacket temperature (JT) of -20 to 0 °C. The flow rates of the two feeds were adjusted to give a residence time of approximately 45 s for the Mg-Br exchange.

[0220] The outflowing reaction mixture (compound 2a) was introduced into a continuous stirred tank reactor (CSTR) and Zn(OPiv) 2 A solution of LiCl was added simultaneously (0.75 equiv.) while maintaining a constant residence time of about 5 min. The temperature was kept constant at -5 to 5 °C internal temperature (IT).

[0221] Compound 2b was collected in a receiving tank at IT between 0 and 30° C. Compound 2b was found to be stable at −20 to 30° C. for several weeks.

[0222] ZnCl 2 Five different experiments were carried out in which the equivalents of compound 2a were varied from 0.33, 0.50, 0.75, and 1.00 to 1.50. 19 In the F NMR, the ZnCl 2 The presence of three different species / compounds was observed at different levels depending on the equivalent amount of . 2D NOESY showed that these species could be interconverted without significant effect on the resulting kinetics of Nesigi.

[0223] The Des-bromo-compound 2a is found as a separate compound present in the spectrum and originates from a proton quenching reaction due to residual moisture in the NMR solvent.

[0224] Example 3: TIFF2025505192000117.tif72170

[0225] Compound 2b was charged in a suspension (32 mmol, 1.1 equiv.) in a first reactor under argon atmosphere with a jacket temperature (TJ) of 10° C. NaTFA (11.8 g, 86.8 mmol, 3.00 equiv.) was added in three portions over 30 min. The resulting suspension was heated (1° C. / min.) to an internal temperature (IT) of 50° C. over 40 min. In a second reactor under argon atmosphere, compound 3 (14.4 g, 29.0 mmol, 1.00 equiv.) was added and the reactor was purged with argon for 10 min. Degassed THF (26 mL) was added and after stirring for 10 min, a solution was obtained as a result. The solution was transferred to the first reactor over 5 min via a pump. A solution of palladium (π-cinnamyl) chloride dimer (75.1 mg, 0.005 equiv.) and (R,R)-chiraphite (279.8 mg, 0.011 equiv.) in THF (8.0 mL) was then transferred via syringe to the first reactor. The resulting solution was stirred at IT of 50° C. until complete conversion was obtained (typically 15 h). The reaction mixture was cooled to room temperature (rt).

[0226] A tribasic aqueous sodium citrate solution (20% w / w, 110 g) and toluene (72 mL) were added to the third reactor under an argon atmosphere at TJ of 20° C. The reaction mixture in the second reactor was then transferred to the third reactor over 10 minutes. The biphasic mixture was stirred for 15 minutes and then the lower aqueous layer was drained from the third reactor. A tribasic aqueous sodium citrate solution (20% w / w, 110 g) was then added to the third reactor. The biphasic mixture was stirred for 15 minutes and then the lower aqueous layer was drained from the third reactor. Aqueous sodium chloride solution (10% w / w, 36.5 g) was then added to the third reactor. The biphasic mixture was stirred for 15 minutes and then the lower aqueous layer was drained from the third reactor. The organic layer was concentrated under reduced pressure at TJ of 50° C. to a volume of about 140 mL. The toluene layer was then distilled under reduced pressure to a constant volume (typically exchanging 64 g of toluene). The resulting solution was pumped over a heated charcoal filter over 45-60 min into the fourth reactor under an argon atmosphere. The third reactor and filter were rinsed with toluene (50 mL) and added to the fourth reactor. The resulting solution was concentrated under reduced pressure at TJ50 °C to a volume of about 75 mL.

[0227] The solution was cooled to IT 20°C and n-heptane (14 mL) was added over 10 min to seed. The suspension was aged for 1 h and n-heptane (160 mL) was added over 2 h. The suspension was stirred for an additional night. The crystals were filtered off, washed with a toluene / n-heptane solution (1:1 v / v) and dried under reduced pressure for 1 h to give the crude product (24.0 g) as a solid. The crude product (24.0 g) was suspended in toluene (100 mL). The suspension was stirred at TJ 50°C until a solution was obtained. The solution was concentrated under reduced pressure to a volume of about 70 mL. The solution was cooled to IT 20°C and n-heptane (9 mL) was added over 10 min to seed. The suspension was aged for 1 h and n-heptane (94 mL) was added over 2 h. The suspension was stirred for an additional night. The crystals were filtered off, washed with a toluene / n-heptane solution (1:1 v / v) and dried under reduced pressure to constant weight. The title compound was isolated as crystals in 57% yield (15.2 g).

[0228] Example 3a: TIFF2025505192000118.tif67170

[0229] In a first reactor under argon atmosphere with a jacket temperature (TJ) of 20° C., NaTFA (15.5 g, 114.3 mmol, 3.00 equiv.) was charged. A solution of compound 2b in THF and 2-Me-THF (41.9 mmol, 1.10 equiv., 230 g) was added. The resulting suspension was heated to an internal temperature (IT) of 50° C. over 40 min (1° C. / min). In a second reactor under argon atmosphere, compound 3 (18.9 g, 38.1 mmol, 1.00 equiv.) was added and the reactor was purged with argon for 10 min. Degassed THF (30.5 g) was added and after stirring for 10 min, a solution was obtained as a result. The solution was transferred to the first reactor via pump over 5 min. THF (8.9 g) was used to rinse the lines. A solution of palladium (π-cinnamyl) chloride dimer (148 mg, 0.0075 equiv.) and (R,R)-chiraphite (551, 0.0165 equiv.) in THF (11.6 g) was then transferred via syringe to the first reactor. The resulting solution was stirred at IT of 50° C. until complete conversion was obtained (typically 10 h). The reaction mixture was cooled to room temperature (rt).

[0230] A tribasic aqueous sodium citrate solution (20% w / w, 150 g) and toluene (82.4 g) were added to the third reactor under an argon atmosphere at TJ of 20° C. The reaction mixture in the second reactor was then transferred to the third reactor over 10 minutes. The biphasic mixture was stirred for 15 minutes and then the lower aqueous layer was drained from the third reactor. Aqueous tribasic sodium citrate and sodium carbonate solutions (20% and 5% w / w, respectively, 150 g) were then added to the third reactor. The biphasic mixture was stirred for 15 minutes and then the lower aqueous layer was drained from the third reactor. Aqueous sodium chloride solution (10% w / w, 50.1 g) was then added to the third reactor. The biphasic mixture was stirred for 15 minutes and then the lower aqueous layer was drained from the third reactor. The organic layer was concentrated under reduced pressure at TJ of 50° C. to a volume of about 140 mL. The toluene layer was then vacuum distilled at constant volume (typically exchanging 120 g of toluene) until the desired solvent composition was obtained. The resulting solution was pumped into the fourth reactor under argon atmosphere over a heated charcoal filter for 45-60 min. The third reactor and filter were rinsed with toluene (32.7 g) and added to the fourth reactor. The resulting solution was concentrated under reduced pressure at TJ50°C to a volume of approximately 140 mL.

[0231] The solution was cooled to IT 20°C and n-heptane (12.9 g) was added over 10 min to seed. The suspension was aged for 2 h and n-heptane (81 g) was added over 2 h. The suspension was cooled to 0°C over 2 h and further stirred overnight. The crystals were filtered off, washed with a toluene / n-heptane solution (1:1 v / v) and dried under reduced pressure to constant weight. The title compound was isolated as crystals in 81.4% yield (28.7 g, 88% assay).

[0232] Example 4: Compound 3: 2,6-dichloro-4-methyl-5-(trifluoromethyl)pyridine

[0233] Step 1: TIFF2025505192000119.tif22170

[0234] 2,6-Dichloro-4-methyl-pyridine-3-carboxylic acid (1.0 equiv., 22 kg) was charged to the autoclave at ambient temperature. The autoclave was cooled to -20°C and charged with HF (1.37 rel. wt.), then further cooled to -78°C and SF 4 (2.5 equiv.) was charged. The autoclave was sealed and the reaction mixture was allowed to warm to ambient temperature and then slowly heated to 70-80° C. and stirred at the same temperature.

[0235] After completion, the volatiles were evacuated by nitrogen sparging through a scrubber and then MTBE (5 rel vol) was added. The reaction mass was slowly added to ice cold demineralized water (DM) (5 rel vol) and then basified (pH 8-9) by adding 25% aqueous potassium carbonate (about 8 rel vol) below 10°C. The reaction mass was filtered through a celite pad, washed with MTBE (2.5 rel vol) and the layers separated. The aqueous layer was extracted with MTBE (2.5 rel vol). The combined organic layers were washed with DM water (2 x 2.5 rel vol) and concentrated below 30°C. The organic layers were concentrated under reduced pressure below 30°C and then methanol (1.0 rel vol) was charged and again distilled to a thick slurry.

[0236] Methanol (4.0 rel vol) followed by activated carbon Norit CG1 (10% w / w) was added to the slurry at 20-30°C and stirred for 60 min at the same temperature. The reaction mass was filtered through a celite bed and washed with methanol (1.5 rel vol).

[0237] The product was purified as follows: DM water (1.3 rel vol) was added to the product in MeOH solution at 20-30°C for 60 min (about 4.5 ml / min) and then stirred at the same temperature for 20 min. The pure product was seeded into the above solution and stirred at 20-30°C for 20 min. Slowly cooled to -4-2°C in 4 h. 0.7+0.5+0.5 rel vol (i.e. total 1.7 rel vol) of DM water was added at -4-2°C for 30 min (about 6 ml / min) (after addition of each lot of aqueous supernatant samples were checked for solid precipitation) and stirred at the same temperature for 3 h. The resulting solid was filtered and washed with chilled DM water.

[0238] Step 2: 2,6-Dibromo-4-methyl-3-(trifluoromethyl)pyridine TIFF2025505192000120.tif36170

[0239] 2,6-Dichloro-4-methyl-5-(trifluoromethyl)pyridine (5.00 kg, 1.00×, 1.00 equiv.) and hydrobromic acid in acetic acid (21.0 kg) were added to a 3000 L-GL reactor. The reactor was adjusted to 110-120°C and hydrobromic acid in acetic acid (56.8 kg) was added to the reactor in portions over 20 hours. The mixture was adjusted to 35-45°C. The mixture was stirred and nitrogen was bubbled through at 35-45°C for 1-2 hours. The reactor temperature was adjusted to 110-120°C and hydrobromic acid in acetic acid (7.0 kg) was added to the reactor. The mixture was adjusted to 35-45°C. Process water (72 kg) and MTBE (43 kg) were added to the reactor at 15-25°C and stirred for 0.5-1.5 hours. The organic layer was collected by separation and the aqueous layer was extracted with MTBE (12 kg). All the organic layers were combined and adjusted to 0-10°C, then the organic layer was washed with 30% NaOH solution (68 kg) and the pH of the mixture was adjusted to 7-8. Water (10 kg) was added. The organic layer was obtained by separation and washed with 2% NaHCO 3 The organic layer was recirculated with molecular sieves (6 kg) through F909 for 3-5 h to remove water, and after drying, the molecular sieves were washed with MTBE (20 kg). The organic solution was concentrated 2-3 times under reduced pressure below 50 °C and NBP (33 kg) was added. The mixture was concentrated under reduced pressure below 50 °C to remove MTBE (<0.2%, sepc.: <2.0%). 6.16 kg (purity 99.0 A%) product as NBP solution was obtained in 90.1% yield.

[0240] Step 3: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine

[0241] 2,6-Dibromo-4-methyl-3-(trifluoromethyl)pyridine NBP solution (6.16 kg, 1.00x, 1.0 equiv.) (assay corrected) was added to the reactor. (PMB) 2 NH (7.7 kg, 1.5 equiv.) and TEA (4.0 kg, 2.0 equiv.) were added to the reactor by pump addition. The reactor was adjusted to 70-75°C, stirred for 24 h, then adjusted to 45-55°C. The reactor was adjusted to 70-75°C, stirred for 8 h, then adjusted to 45-55°C. The mixture was adjusted to 45-55°C and 20% aqueous citric acid (68.0 kg) was added to the reactor over 2-3 h. The mixture was adjusted to 15-25°C for 1-2 h and the wet cake was isolated by centrifugation and rinsed with process water (30 kg) and methanol (11 kg) to obtain 7.15 kg of wet cake. After drying under vacuum at 20-30°C for 20 h, 7.15 kg of crude product was obtained.

[0242] Step 4: TIFF2025505192000121.tif23170

[0243] Crude 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine from step 2 (7.15 kg, 1.00x) and THF (31.15 kg) were added to the reactor. The mixture was decolorized with CUNO at 15-25 °C until pale yellow. The mixture was concentrated under reduced pressure at less than 40 °C to about 8.6 L. Methanol (6.79 kg) was added to the reactor. The reactor was adjusted to 45-55 °C, then methanol (23.70 kg) and crystal seeds (71.5 g) were added to the reactor and stirred for 1 h. Methanol (11.30 kg) was added to the reactor over 4 h and stirred for 0.5 h. The reactor was adjusted to 0° C. over 2 hours, stirred for 18 hours, and the wet cake was isolated by filter and rinsed successively with methanol (11.30 kg) and heptane (4.86 kg). After drying under reduced pressure at 45° C. for 18 hours, 6.75 kg of dry crude product was obtained.

[0244] 6.75 kg of the above dried crude product and heptane (20.4 kg) were added to the reactor. The suspension was adjusted to 50°C and stirred at 50°C for 2 hours, then cooled to 0°C over 1 hour and stirred at 0°C for 16 hours. The suspension was filtered and rinsed with heptane (9.18 kg) to obtain a wet cake. The wet cake was dried in a single cone under reduced pressure at 50-55°C for 26 hours to obtain 6.2 kg of pure product.

[0245] Example 5: TIFF2025505192000122.tif42170

[0246] A solution of tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-2,8-difluoro-quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (50.0 g, 53.7 mmol, 1.00 eq., 87.3% assay) and [(2S)-1-methylpyrrolidin-2-yl]methanol (7.44 g, 64.6 mmol, 1.20 eq.) in 2-Me-THF (320 g) was concentrated under reduced pressure (235 mbar) to a solution of 250 mL. The solution was cooled to -10°C. Sodium tert-pentoxide (NaOt-Am) (24.8 g, 64.6 mmol, 1.30 equiv, 31% w / w) as a solution in toluene was then charged over 10-60 min. The reaction mixture was stirred at 0 °C until complete conversion was achieved (typically 1 h). The reaction mixture was then quenched with a stirred biphasic mixture of potassium carbonate (200 g, 10% w / w solution), N-acetyl-L-cysteine ​​(24 g, 16% w / w aqueous solution) and 2-Me-THF (107 g), maintaining the internal temperature at 15-30 °C. The biphasic mixture was stirred at 25 °C for 1-2 h and the layers separated. The organic layer was further washed with potassium carbonate (100 g, 10% w / w aqueous solution) and then the organic layer was concentrated under reduced pressure (235 mbar) to 250 mL of solution, cooled to 20-40 °C and polish filtered. The filtrate was further concentrated under reduced pressure (235 mbar) to a 175 mL solution. 1-PrOH (100 g) was added and continuous exchange of 2-Me-THF to 1-PrOH was performed under reduced pressure (150-60 mbar). Water (100 g) was then added at 50 °C and the solution was seeded at this temperature. The resulting mixture was further stirred at this temperature for at least 2 h and water (100 g) was added over at least 2 h. The crystal slurry was cooled to 20 °C over at least 3 h and further stirred at this temperature for at least 5 h. The crystals were filtered off, washed with a solution of 1-PrOH / water and dried under reduced pressure until constant weight. The title compound is isolated as crystals in 96% yield (47.5 g). 11H NMR (600 MHz, DMSO-d6) δ ppm 7.82 (s, 1 H), 7.16 (d, J = 8.7 Hz, 4 H), 6.87 (br d, J = 8.3 Hz, 4 H), 6.82 (s, 1 H), 4.62 - 4.89 (m, 3 H), 4.56 (br d, J = 15.6 Hz, 2 H), 4.39 (dd, J = 10.7, 4.7 Hz, 1 H), 4.12 - 4.25 (m, 1 H), 4.05 (br d, J = 13.4 Hz, 1 H), 3.89 - 4.00 (m, 1 H), 3.76 - 3.84 (m, 1 H), 3.51 - 3.67 (m, 1 H), 2.88 - 3.18 (m, 2 H), 2.55 - 2.84 (m, 1 H), 2.27 - 2.43 (m, 5 H), 2.07 - 2.31 (m, 1 H), 1.85 - 2.00 (m, 1 H), 1.68 (br dd, J = 13.3, 7.9 Hz, 3 H), 1.42 (s, 9 H), 1.28 (br d, J = 6.6 Hz, 3 H) ppm. HR-MS (ESI): Calculated value C47H54ClF4N7O5 907.3811; Measured value: 907.3808.

[0247] Example 6: TIFF2025505192000123.tif44170

[0248] To a mixture of acetic acid (46.2 g), methanesulfonic acid (52.9 g) and toluene (34.7 g) at 40° C., a solution of tert-butyl (3S)-4-[7-[6-[bis[(4-methoxyphenyl)methyl]amino]-4-methyl-3-(trifluoromethyl)-2-pyridyl]-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3-methyl-piperazine-1-carboxylate (20.0 g, 22.0 mmol) in toluene (86.7 g) was added over at least 15 minutes. The reaction mixture was then heated to 52° C. until complete conversion was achieved (typically 2 hours). The reaction mixture was then cooled to 25° C. and the layers were separated. The acidic layer was quenched slowly (typically over 1 h) at 40-55 °C with a mixture of aqueous sodium hydroxide (211.5 g, 28% w / w), water (80.0 g) and toluene (121.4 g). Once the quench was complete, acetic acid (10.0 g) was added to rinse the lines. The biphasic mixture was warmed to 50 °C and the layers were separated. The organic layer was washed twice with aqueous sodium hydroxide (2 × 90.0 g, 0.1 N solution). The toluene layer was then vacuum distilled at constant volume (90 mbar; typically, 69 g of toluene is exchanged). After polish filtration, the resulting toluene solution was concentrated under reduced pressure (90 mbar) to a 94 mL solution, which was then warmed to 60 °C. n-heptane (34.6 g) was then added over at least 30 min and the solution was seeded at this temperature. The resulting mixture was further stirred at this temperature for at least 1 hour, and the crystal slurry was cooled to 0° C. over at least 4 hours and further stirred at this temperature for at least 1 hour. The crystals were filtered off, washed with a toluene / n-heptane solution (1:1 v / v) and dried under reduced pressure to constant weight. The title compound was isolated as crystals in 89% yield (11.7 g). 11H NMR (600 MHz, DMSO-d6) δ ppm 7.74 (d, J = 0.9 Hz, 1 H), 6.84 (s, 2 H), 6.49 (s, 1 H), 4.54 - 4.65 (m, 1 H), 4.38 (dd, J = 10.8, 4.6 Hz, 1 H), 4.14 (dd, J = 10.7, 6.5 Hz, 1 H), 3.96 (br d, J = 13.1 Hz, 1 H), 3.47 - 3.57 (m, 1 H), 2.89 - 3.00 (m, 3 H), 2.73 - 2.82 (m, 2 H), 2.55 - 2.60 (m, 1 H), 2.32 - 2.40 (m, 7 H), 2.12 - 2.20 (m, 1 H), 1.94 (dd, J = 11.9, 7.6 Hz, 1 H), 1.67 (br d, J = 8.3 Hz, 3 H), 1.40 (d, J = 6.9 Hz, 3 H) ppm. HR-MS (ESI): Calculated for C26H30ClF4N7O 567.2136; Found: 567.2141.

[0249] Example 7: TIFF2025505192000124.tif105170

[0250] A solution of 3-(phenylsulfonyl)propionic acid (22.9 g, 106 mmol, 1.33 eq.), N-methylmorpholine (13.4 g, 133 mmol, 1.65 eq.) in acetonitrile (180.7 g) was cooled to -10°C. Pivaloyl chloride (11.8 g, 97.9 mmol, 1.22 eq.) was dosed over 30 min. The reaction mixture was further stirred at this temperature for 1 h. Then, a solution of compound 1e (50.0 g, 80.4 mmol, 1.00 eq.) in acetonitrile (176.9 g) was added to the cold reaction mixture over 1 h and further stirred at -10°C until complete conversion to the sulfone intermediate was achieved (typically 1 h). The reaction mixture was warmed to 15° C. and quenched by the addition of water (50.4 g) followed by aqueous sodium hydroxide (68.9 g, 483 mmol, 6.0 equiv., 28% w / w solution). Stirring was continued until complete conversion was obtained (typically 15 h), the mixture was seeded and then water (900 g) was added over at least 2 h. The crystal slurry was further stirred at this temperature for at least 42 h and the crystals were filtered off, washed with a solution of acetonitrile / water (3:7 v / v), washed with water and then dried under reduced pressure to constant weight. The title compound was isolated as crystals in 91% yield (45.6 g). 1H NMR(600 MHz,DMSO-d6)δ 7.82(s,1 H),6.73-6.98(m,3 H),6.50(s,1 H),6.10-6.28(m,1 H),5.68-5.81(m,1 H),4.66-4.85(m,1 H),4.32-4.46(m,1 H),4.25(br d,J=13.5 Hz,1 H),4.06-4.21(m,2 H),3.98(br d,J=13.4 Hz,1 H),3.38-3.76(m,2 H),2.91-3.27(m,2 H),2.53-2.68(m,1 H),2.37(br d,J=1.4 Hz,6 H), 2.11-2.26(m, 1 H), 1.87-2.00(m, 1 H), 1.56-1.79(m, 3 H), 1.27(br dd, J=11.7, 6.7 Hz, 3 H) ppm. HR-MS(ESI): calcd for C29H32ClF4N7O2 621.2242; found: 621.2257.

[0251] Example 7a TIFF2025505192000125.tif166170

[0252] N-methylmorpholine (10.67 g, 1.65 equiv.) was added to a solution of 3-(phenylsulfonyl)propionic acid (18.91 g, 1.38 equiv.) in 2-Me-THF (136.6 g) at 20° C. Pivaloyl chloride (9.56 g, 1.24 equiv.) was dosed over 30 min while maintaining the internal temperature at −20 to 0° C. The reaction mixture was further stirred at this temperature for 1 h. Then, a solution of compound 1a (40.0 g, 1.00 equiv., 90.8% assay) and N-methylmorpholine (6.47 g, 1.00 equiv.) in 2-Me-THF (136.6 g) was added to the cold reaction mixture over 1 h and further stirred at −10° C. until complete conversion to the sulfone intermediate was achieved (typically 1 h). The reaction mixture was filtered and quenched by the addition of aqueous sodium hydroxide (31.2 g, 3.40 equiv., 28% w / w solution), followed by tetrabutylammonium chloride hydrate (3.55 g, 0.19 equiv.) and water (17.2 g) at 0-25 °C. The reaction mixture was stirred at 20-30 °C until complete conversion to compound 1 was achieved (typically 2.5 h), and aqueous sodium chloride (46.0 g, 20% w / w solution) was added. The layers were separated. The organic layer was washed successively with aqueous sodium bicarbonate (82.4 g, 5% w / w) and sodium chloride (82.4, 5% w / w). The organic layer was then concentrated under reduced pressure to a volume of 200 mL, and 2-Me-THF was exchanged until the desired water content was achieved, then cooled to 20 °C. After polish filtration, the resulting 2-Me-THF solution was concentrated under reduced pressure to a 100 mL solution. 2-BuOH (307.9 g) was added at 35-45 °C and adipic acid (10.28 g, 1.10 equiv.) was added at this temperature to give a solution. The solution was seeded at 30-40 °C and aged at this temperature for an additional 1.5 h. n-Heptane (161.4 g) was added to the crystal slurry at 30-40 °C over 30 min. The crystallization mixture was aged at this temperature for at least 2 h and cooled to 0 °C over at least 6 h. After aging at least 6 h at 0 °C, the crystals were filtered off, washed with 2-BuOH / n-heptane solution (1:1 v / v) and dried under reduced pressure to constant weight. The title compound was isolated as crystals in 93% yield (45.2 g). 11H NMR (600 MHz, DMSO-d 6 ) δ 7.77 (s, 1H), 6.81 (s, 2H), 6.76 (dd, J = 16.8, 10.6 Hz, 1H), 6.45 (s, 1H), 6.18 - 6.10 (m, 1H), 5.70 (dd, J = 10.4, 2.3 Hz, 1H), 4.75 - 4.66 (m, 1H), 4.38 - 4.30 (m, 2H), 4.25 - 3.89 (m, 4H), 3.61 (dq, J = 21.3, 12.4, 10.9 Hz, 2H), 3.20 (dd, J = 13.4, 3.8 Hz, 1H), 3.00 (td, J = 12.6, 3.7 Hz, 1H), 2.91 (ddd, J = 9.0, 6.0, 2.8 Hz, 1H), 2.59 - 2.51 (m, 1H), 2.32 (d, J = 6.2 Hz, 6H), 2.15 (td, J = 8.6, 7.7, 4.7 Hz, 5H), 1.94 - 1.85 (m, 1H), 1.61 (dddd, J = 20.8, 12.3, 8.0, 4.1 Hz, 3H), 1.45 (h, J = 3.4 Hz, 4H), 1.22 (dd, J = 12.4, 6.6 Hz, 3H); 13 13C{ 1 1H, 19 19F} NMR (151 MHz, DMSO-d 6 ) δ 174.9, 165.5, 164.8, 162.2, 161.4, 153.2, 148.8, 147.7, 143.0, 131.1, 128.5, 128.4, 128.3, 128.2, 125.6, 125.3, 121.0, 114.7, 112.2, 110.5, 69.8, 63.9, 57.4, 52.5, 52.4, 49.4, 45.9, 45.2, 44.9, 44.3, 42.0, 41.7, 40.6, 34.0, 29.1, 24.6, 23.1, 20.3, 15.9, 15.3; 19 19F NMR (565 MHz, DMSO-d 6 ) δ -53.5, -125.9.

[0253] Example 7b: TIFF2025505192000126.tif166170

[0254] Pivaloyl chloride (9.56 g, 1.24 equiv.) was added to a solution of 3-(phenylsulfonyl)propionic acid (18.91 g, 1.38 equiv.) in 2-Me-THF (136.6 g) at -20 to 0 °C. N-methylmorpholine (10.67 g, 1.65 equiv.) was added slowly while maintaining the internal temperature at -20 to 0 °C. The reaction mixture was further stirred at this temperature for 1 h. Then, a solution of compound 1a (40.0 g, 1.00 equiv., 90.8% assay) and N-methylmorpholine (6.47 g, 1.00 equiv.) in 2-Me-THF (136.6 g) was added to the cold reaction mixture over 1 h and further stirred at -10 °C until complete conversion to the sulfone intermediate was achieved (typically 1 h). The reaction mixture was filtered and quenched by the addition of aqueous sodium hydroxide (31.2 g, 3.40 equiv., 28% w / w solution), followed by tetrabutylammonium chloride hydrate (18.2 g, 0.94 equiv.) and water (17.2 g) at 0-25 °C. The reaction mixture was stirred at 20-30 °C until complete conversion to compound 1 was achieved (typically 1 h), and aqueous sodium chloride (46.0 g, 20% w / w solution) was added. The layers were separated. The organic layer was washed successively with aqueous sodium bicarbonate (82.4 g, 5% w / w) and sodium chloride (82.4, 5% w / w). The organic layer was then concentrated under reduced pressure to a volume of 200 mL, and 2-Me-THF was exchanged until the desired water content was achieved, then cooled to 20 °C. After polish filtration, the resulting 2-Me-THF solution was concentrated under reduced pressure to a 100 mL solution. 2-BuOH (307.9 g) was added at 35-45 °C and adipic acid (10.28 g, 1.10 equiv.) was added at this temperature to give a solution. The solution was seeded at 30-40 °C and aged at this temperature for an additional 1.5 h. n-Heptane (161.4 g) was added to the crystal slurry at 30-40 °C over 30 min. The crystallization mixture was aged at this temperature for at least 2 h and cooled to 0 °C over at least 6 h. After aging at least 6 h at 0 °C, the crystals were filtered off, washed with 2-BuOH / n-heptane solution (1:1 v / v) and dried under reduced pressure to constant weight. The title compound was isolated as crystals in 85% yield (42.7 g). 11H NMR (600 MHz, DMSO-d 6 ) δ 7.77 (s, 1H), 6.81 (s, 2H), 6.76 (dd, J = 16.8, 10.6 Hz, 1H), 6.45 (s, 1H), 6.18 - 6.10 (m, 1H), 5.70 (dd, J = 10.4, 2.3 Hz, 1H), 4.75 - 4.66 (m, 1H), 4.38 - 4.30 (m, 2H), 4.25 - 3.89 (m, 4H), 3.61 (dq, J = 21.3, 12.4, 10.9 Hz, 2H), 3.20 (dd, J = 13.4, 3.8 Hz, 1H), 3.00 (td, J = 12.6, 3.7 Hz, 1H), 2.91 (ddd, J = 9.0, 6.0, 2.8 Hz, 1H), 2.59 - 2.51 (m, 1H), 2.32 (d, J = 6.2 Hz, 6H), 2.15 (td, J = 8.6, 7.7, 4.7 Hz, 5H), 1.94 - 1.85 (m, 1H), 1.61 (dddd, J = 20.8, 12.3, 8.0, 4.1 Hz, 3H), 1.45 (h, J = 3.4 Hz, 4H), 1.22 (dd, J = 12.4, 6.6 Hz, 3H); 13 13C{ 1 1H, 19 19F} NMR (151 MHz, DMSO-d 6 ) δ 174.9, 165.5, 164.8, 162.2, 161.4, 153.2, 148.8, 147.7, 143.0, 131.1, 128.5, 128.4, 128.3, 128.2, 125.6, 125.3, 121.0, 114.7, 112.2, 110.5, 69.8, 63.9, 57.4, 52.5, 52.4, 49.4, 45.9, 45.2, 44.9, 44.3, 42.0, 41.7, 40.6, 34.0, 29.1, 24.6, 23.1, 20.3, 15.9, 15.3; 19 19F NMR (565 MHz, DMSO-d 6 ) δ -53.5, -125.9.

[0255] Example 8: TIFF2025505192000127.tif50170

[0256] Compound 1 (2.32 kg, 3.53 mol) and ground filtered 2-butanone (17.42 L, 7.5 L / kg) were combined in a 25 L reactor equipped with an active nitrogen line, overhead stirring, and temperature probe. Adipic acid (0.46 kg, 3.17 mol, 0.9 equiv.) and ground filtered 2-butanone (1.16 L, 0.5 L / kg) were charged to a separate 5 L vial. The reactor was then heated to 50° C.±10° C., and once the desired internal temperature target of >45° C. was reached, the adipic acid slurry in 2-butanone was charged to the reactor by pulling a vacuum. Compound B seed (0.02 kg, 1 wt%) was charged to the 5 L vial, followed by ground filtered butanone (2.32 L, 1.0 L / kg). Again, the slurry was charged to the reactor by pulling a vacuum. Finally, the 5 L glass bottle was rinsed with ground filtered 2-butanone (1.16 L, 0.5 L / kg) and then charged to the reactor by vacuum. The reactor contents were aged for a minimum of 1 hour, cooled to 0° C. for a minimum of 2 hours, and then aged at 0° C. overnight (15 hours). The contents were transferred to a pre-cooled filter dryer at 0° C. In parallel, ground filtered 2-butanone (9.29 L, 4.0 L / kg) was charged to the reactor at 0° C. and then stirred for 30 minutes. The material in the filter dryer was then filtered and the resulting cake was washed with chilled 2-butanone. After drying for a minimum of 8 hours using vacuum and nitrogen sweep, the filter dryer contents were discharged to give compound 1 adipate (2.137 kg, 77%) as a solid. 1 H NMR (600 MHz, DMSO-d 6)δ 7.77(s,1H),6.81(s,2H),6.76(dd,J=16.8,10.6 Hz,1H),6.45(s,1H),6.18 - 6.10(m,1H),5.70(dd,J=10.4,2.3 Hz,1H),4.75 - 4.66(m,1H),4.38 - 4.30(m,2H),4.25 - 3.89(m,4H),3.61(dq,J=21.3,12.4,10.9 Hz,2H),3.20(dd,J=13.4,3.8 Hz,1H),3.00(td,J=12.6,3.7 Hz,1H),2.91(ddd,J=9.0,6.0,2.8 Hz,1H),2.59 - 2.51(m,1H),2.32(d,J=6.2 Hz,6H),2.15(td,J=8.6,7.7,4.7 Hz,5H),1.94 - 1.85(m,1H),1.61(dddd,J=20.8,12.3,8.0,4.1 Hz,3H),1.45(h,J=3.4 Hz,4H),1.22(dd,J=12.4,6.6 Hz,3H); 13 C{ 1 H, 19 F} NMR(151 MHz,DMSO - d 6 )δ 174.9,165.5,164.8,162.2,161.4,153.2,148.8,147.7,143.0,131.1,128.5,128.4,128.3,128.2,125.6,125.3,121.0,114.7,112.2,110.5,69.8,63.9,57.4,52.5,52.4,49.4,45.9,45.2,44.9,44.3,42.0,41.7,40.6,34.0,29.1,24.6,23.1,20.3,15.9,15.3; 19 F NMR(565 MHz,DMSO - d 6 )δ - 53.5,-125.9.

[0257] Example 9: TIFF2025505192000128.tif54170

[0258] Compound 1 (1 molar equivalent) and adipic acid (1 molar equivalent) were suspended in 2-butanol and 2-methyltetrahydrofuran and dissolved by heating to about 70 °C. The polished filtered solution was cooled to about 25 °C. Jet milled compound B material was used for seeding. Seeding material compound 1 adipate was suspended in 2-butanol / n-heptane. This suspension was used to seed the solution at about 25 °C. The seeding equipment was rinsed with n-heptane, which was then added to the seed suspension. n-heptane was added within 15-30 min at about 25 °C. The suspension was stirred at about 25 °C for about 3 h. The suspension was cooled to about 0 °C and stirred for at least 5 h. The solid was isolated by solid / liquid separation and rinsed with a mixture of 2-butanol / n-heptane followed by n-heptane. The solid was dried under reduced pressure at about 40 °C to obtain a powder in 88-95% yield.

[0259] In another procedure, compound 1 (1 molar equivalent) and adipic acid (1 molar equivalent or excess) were suspended in 2-butanol and 2-methyltetrahydrofuran and dissolved by heating to about 70 °C. The polished filtered solution was cooled to the seeding temperature (about 25 °C). For seeding, the adipate salt of compound 1 was used without pretreatment or after impact milling, jet milling or wet milling. The seeding material, compound 1 adipic acid, was suspended in a solvent (n-heptane, or a 2-butanol / n-heptane mixture, or 2-butanol). This suspension was used for seeding at the seeding temperature. The seeding equipment was rinsed with a solvent (n-heptane, or a 2-butanol / n-heptane mixture, or 2-butanol), which was then added to the seeding suspension. n-heptane was added at the seeding temperature or lower (typically at about 25 °C) for about 15 to 30 minutes. The suspension was stirred at the n-heptane addition temperature for at least 3 h. The suspension was cooled to approximately 0 °C and stirred for at least 5 h. The solid was isolated by solid / liquid separation and rinsed with a mixture of 2-butanol / n-heptane followed by n-heptane. The solid was dried under reduced pressure at approximately 40 °C to give a powder in 88-95% yield.

[0260] Example 10:

[0261] The adipate salt of compound 1 was dissolved in 2-butanol and 2-methyltetrahydrofuran by heating to about 67 ° C. The polished filtered solution was cooled to the seeding temperature (about 45 ° C). For seeding, wet-ground adipic acid compound 1 was used. The adipate salt of compound 1 was wet-ground in a solvent (n-heptane, or a 2-butanol / n-heptane mixture). This suspension was used for seeding at the seeding temperature. The seeding equipment was rinsed with a solvent (n-heptane, or a 2-butanol / n-heptane mixture, respectively), which was then added to the seeding suspension. Pre-cooled n-heptane (about 0 ° C) was added over a period of about 15 to 30 minutes. The thus-cooled suspension was stirred at a temperature of about 25 ° C for at least 3 hours. The suspension was cooled to about 0 ° C and stirred for at least 2 hours. The solids were isolated by solid / liquid separation and rinsed with n-heptane or a mixture of 2-butanol / n-heptane, followed by n-heptane. The solids were dried under reduced pressure at about 40 °C, with yields ranging from 85 to 95%.

[0262] All technical and scientific terms used herein have the same meaning. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0263] Throughout this specification and the claims, the words "comprise," "comprises," and "comprising" are used in their non-exclusive sense, unless the context otherwise requires. It is understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0264] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is to be understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of the range and any other stated or intervening value in that stated range is included herein. The upper and lower limits of these smaller ranges that may be independently included in the smaller ranges are also included herein, subject to any specifically excluded limit in the stated range. Where one or both of the limits are included in the stated range, ranges excluding either or both of those included limits are also included herein.

[0265] Many modifications and other embodiments of the inventions described herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. Formula (I); (In the formula, X １ and X ３ are each independently hydrogen or halogen; R １ is hydrogen or PG １ and Each R ２ are independently halogen, cyano, unsubstituted C １－６ Alkyl, unsubstituted C １－６ Cyanoalkyl, or unsubstituted C １－６ haloalkyl; R ３ is hydrogen, halogen, R ３Ａ - substituted or unsubstituted C １－３ Alkyl, R ３Ａ - substituted or unsubstituted C １－３ Haloalkyl, or R ３Ａ - substituted or unsubstituted cyclopropyl; R ３Ａ is halogen, OH, CN, unsubstituted C １－３ Alkyl or unsubstituted C １－３ haloalkyl; R ４ is R ４Ａ - substituted or unsubstituted C １－３ haloalkyl; R ４Ａ is unsubstituted C １－３ is alkyl; n is 1 or 2; each PG is independently an amino protecting group; P.G. １ is an amino protecting group), or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, comprising: The method further comprising: (a) a compound represented by formula (II) (In the formula, X ２ is a halogen), with an organomagnesium compound, thereby forming a compound of formula (IIa): forming a compound of formula (IIa); (b) transferring said compound of formula (IIa) of step (a) to a continuous stirred tank reactor (CSTR) containing a zinc compound, thereby producing a compound of formula (IIb): wherein m is 0, 1 or 2; p is 1, 2 or 3; X ２ is halogen or OPiv; and (c) reacting said compound (IIb) of step (b) with a compound of formula (III) (In the formula, X ４ is a halogen, 2. A method comprising the step of contacting a transition metal catalyst precursor with a chiral ligand, thereby synthesizing a compound of formula (I).

2. X ２ The method of claim 1 , wherein is Br, Cl, or OPiv.

3. The compound of formula (II) (a) In the presence of a base, CO ２ Formula (IV) The compound of formula (V) cyclizing to a compound of formula (I); (b) contacting said compound of formula (V) with a chlorinating agent, thereby producing a compound of formula (Va): synthesizing a compound of formula (I); (c) reacting the compound of step (b) with a compound of the formula and contacting a piperazinyl moiety having the formula (Vb) synthesizing a compound of formula (I); and (d) contacting the compound of step (c) with a fluorinating agent in the presence of a base, thereby synthesizing a compound of formula (II).

3. The method according to claim 1 or 2, wherein the compound is prepared by a process (P2) comprising:

4. 4. The process of claim 3, wherein the base in step (a) is DBU.

5. The chlorinating agent in step (b) is POCl ３ The method according to claim 3, wherein

6. 4. The method of claim 3, wherein the base in step (c) is DIPEA.

7. 4. The method of claim 3, wherein the fluorinating agent in step (d) is KF.

8. The compound of formula (IV) (a) Formula (IVa) contacting a compound of formula (IVb) with i-PrMgCl, synthesizing a compound of formula (I); (b) contacting the compound of step (a) with hydroxylamine, thereby producing a compound of formula (IVc) synthesizing a compound of formula (I); (c) contacting the compound of step (b) with a base and a dehydrating agent in acetonitrile, thereby producing a compound of formula (IVd): synthesizing a compound of formula (I); (d) contacting the compound of step (c) with ammonia, thereby producing a compound of formula (IVe) synthesizing a compound of formula (I); and (e) contacting the compound of step (d) with a chlorinating agent, thereby synthesizing a compound of formula (IV). The method according to any one of claims 3 to 7, wherein the compound is prepared by a process (P3) comprising:

9. The compound of formula (III) (a) (wherein, X ６ is Cl or I, with a halogenating agent to obtain a compound of formula (VIb) forming a compound of (b) brominating said compound of formula (VIb) to give a compound of formula (VI): forming a compound of the formula: (c) reacting said compound of formula (VI) with a compound of formula NH(PG) ２ with a compound having the formula (III) 2. The method according to claim 1, wherein the compound is prepared by a process (P4) comprising:

10. X ６ The method of claim 9 , wherein is Cl.

11. The halogenating agent is SF in HF. ４ The method according to claim 9, wherein

12. 10. The method of claim 9, wherein the bromination is carried out using HBr in acid.

13. The compound of formula (III) has the formula: The method according to any one of claims 9 to 12, comprising:

14. X １ The method of any one of claims 1 to 13, wherein is a halogen.

15. X １ The method according to any one of claims 1 to 13, wherein is F or Cl.

16. X ３ The method of any one of claims 1 to 13, wherein is a halogen.

17. X ３ The method according to any one of claims 1 to 13, wherein is F or Cl.

18. R １ P.G. １ The method according to any one of claims 1 to 17, wherein

19. P.G. １ The method of any one of claims 1 to 18, wherein is Ac (acetyl), trifluoroacetyl, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl) or Cbz (carbobenzyloxy).

20. R １ The method according to any one of claims 1 to 19, wherein is Boc (tert-butyloxycarbonyl).

21. R ２ is unsubstituted C １－６ Alkyl or unsubstituted C １－６ The method of any one of claims 1 to 20, wherein the alkyl group is a cyanoalkyl group.

22. R ２ The method of any one of claims 1 to 21, wherein is methyl.

23. R ３ is hydrogen or R ３Ａ - substituted or unsubstituted C １－３ The method of any one of claims 1 to 22, wherein the alkyl group is an alkyl group.

24. R ３ The method of any one of claims 1 to 23, wherein is methyl.

25. R ４ But, CF ３ , C.H.F. ２ , or C.H. ２ The method according to any one of claims 1 to 24, wherein F is

26. R ３ is methyl, R ４ is CF ３ The method according to any one of claims 1 to 25, wherein

27. 27. The method of any one of claims 1-26, wherein each PG is independently a protecting group selected from the group consisting of Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (triphenylmethyl or trityl), benzylidenyl, p-toluenesulfonyl, DMB (dimethoxybenzyl), PMB (p-methoxybenzyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethyloxycarbonyl), or Cbz (carbobenzyloxy).

28. 28. The method of claim 27, wherein each PG is p-methoxybenzyl.

29. 29. The method of any one of claims 1 to 28, wherein the organomagnesium compound is selected from the group consisting of isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium iodide, isopropyl magnesium chloride lithium chloride complex, sec-butyl magnesium chloride, lithium tri-n-butyl magnesiate, lithium triisopropyl magnesiate, and lithium (isopropyl)(di-n-butyl)magnesiate.

30. 30. The method of claim 29, wherein the organomagnesium compound is i-PrMgCl.LiCl.

31. The zinc compound is ZnCl ２ , ZnBr ２ , ZnI ２ , Zn(TFA) ２ , Zn(OAc) ２ , and Zn(OPiv) ２ The method according to any one of claims 1 to 30, selected from the group consisting of:

32. The zinc compound is Zn(OPiv). ２ The method of claim 31, wherein LiCl.

33. The transition metal catalyst precursor is a Pd or Ni catalyst precursor, and Pd(OAc) ２ , PdCl ２ , PdCl ２ (MeCN) ２ , Pd(benzonitrile) ２ C ２ , Pd(dba) ２ , Pd ２ (dba) ３ , Pd(PPh ３ ) ４ , Pd(PCy ３ ) ２ , Pd(PtBu ３ ) ２ , Pd(TFA) ２ , [Pd(allyl)Cl] ２ [Pd(cinnamyl)Cl] ２ , [PdCl(crotyl)] ２ , PdCl(η5-cyclopentadienyl), [(η3-allyl)(η5-cyclopentadienyl)palladium(II)], [Ni(η5-cyclopentadienyl)(allyl)], [bis(1,5-cyclooctadiene)nickel(0)], NiCl ２ , NiBr ２ , Ni(OAc) ２ 32. The method of any one of claims 1 to 31, wherein the cation is selected from the group consisting of:

34. The chiral ligand is (In the formula, Y is O or NR ７ and R ７ and R ８ is independently an unsubstituted C １－６ The method of any one of claims 1 to 32, wherein the aryl group is alkyl.

35. R ７ and R ８ The method of claim 34, wherein

36. R ７ and R ８ 35. The method of claim 34, wherein each is independently methyl, ethyl, or phenyl.

37. The method according to any one of claims 1 to 34, wherein the chiral ligand is an (R,R)-chiraphite ligand.

38. The zinc compound is Zn(OPiv). ２ LiCl, and the Pd catalyst precursor is [Pd(cinnamyl)Cl] ２ and the chiral ligand is an (R,R)-chiraphite ligand.

39. The compound of formula (I) has the formula:

2. The method of claim 1, comprising:

40. The compound of formula (I) has the formula: (Ie) (wherein X ３ is halo.

41. The compound of formula (I) has the formula: The method of claim 1, further comprising the steps of:

42. Formula (2) A process (P5) for synthesizing the compound of (2), comprising the steps of: The method further comprising: (a) Formula (4a) is contacted with i-PrMgCl and subsequently with hydroxylamine, thereby forming a compound of formula (4c) synthesizing a compound of formula (I); (b) contacting the compound of formula (4c) with TFAA and triethylamine in acetonitrile, followed by contacting with ammonia, thereby producing the compound of formula (4e): synthesizing a compound of formula (I); (c) contacting said compound of (4e) with a chlorinating agent, thereby forming a compound of formula (4): synthesizing a compound of formula (I); (d) reacting the compound of (4) with CO in the presence of DBU. ２ and thereby contacting the compound of formula (5) synthesizing a compound of formula (I); (e) reacting the compound of formula (5) with POCl ３ and DIPEA, followed by contact with tert-butyl (S)-3-methylpiperazine-1-carboxylate in DIPEA, thereby producing a compound of formula (5b): and synthesizing a compound of formula (I); (f) contacting the compound of (5b) with KF, DABCO and MsOH, thereby forming a compound of formula (2). The method (P5) includes:

43. The compound of formula (III) has the formula: (3) The compound of formula (3) (a) Formula (6a) The compound of SF ４ and HF, thereby forming a compound of formula (6b) synthesizing a compound of formula (I); (b) contacting the compound of formula (6b) with HBr in AcOH to produce a compound of formula (6): forming a compound of (c) reacting the compound of formula (6) with (PMB) ２ NH, triethylamine and NBP, thereby synthesizing a compound of formula (III). The method according to claim 1 , wherein the compound is synthesized by the method (P6),

44. The compound represented by formula (G) can be obtained by the method (P7). (In the formula, X Ａ teeth, 10. The method of claim 1, further comprising synthesizing a compound of formula (I) selected from the group consisting of: The method comprises: (a) reacting the compound of formula (I), or a solvate, tautomer, stereoisomer, atropisomer or salt thereof, with X in the presence of a base and an activating agent. Ａ with a moiety comprising, thereby synthesizing a compound of formula (G1); (b) removing the PG group and optionally the R １ and (c) reacting the compound of step (b) with the compound of formula (VII) in the presence of an activating agent and subsequently contacting with a base, thereby producing a compound of formula (G) or a tautomer, stereoisomer, atropisomer, or pharma- ceutically acceptable salt thereof. A method comprising:

45. Formula: (1) or a pharma- ceutically acceptable salt thereof (P9), said process comprising: (a) Formula (2) or a salt thereof, with a pre-cooled solution containing i-PrMgCl.LiCl using a flow rate that provides a residence time for the Mg—Br exchange of about 15 to 150 seconds; (b) ZnCl ２ or Zn(OPiv) ２ and maintaining a constant residence time of about 3 to 7 minutes at about −20° C. to 20° C.; (c) reacting the mixture of step (b) with NaTFA and a compound represented by the formula (3) with a compound of formula (I); (d) contacting the mixture of step (c) or a salt thereof with a Pd or Ni catalyst precursor and a chiral ligand, thereby forming a compound of formula (11): or a solvate or salt thereof; (e) reacting the compound of formula (11), or a solvate or salt thereof, with a compound of formula HO-X Ａ (In the formula, X Ａ is the formula and a base, thereby forming a compound of formula (1b); or a solvate or a pharma- ceutically acceptable salt thereof; (f) contacting said compound of formula (1b) with MsOH in an acid, thereby producing a compound of formula (1a); or a solvate or a pharma- ceutically acceptable salt thereof; and (g) reacting the compound of formula (1a) or a solvate or a pharma- ceutically acceptable salt thereof in the presence of an activating agent, and subsequently contacting with a base, thereby producing a compound of formula (1), or a pharma- ceutically acceptable salt thereof (P9).

46. 46. ​​The method of claim 45, wherein the acid in step (f) is AcOH, trifluoroacetic acid, chlorosulfonic acid, sulfuric acid, HCl, HBr, p-toluenesulfonic acid, or trifluoromethanesulfonic acid.

47. The method of claim 45, wherein compound (2) is synthesized according to the method of claim 42.

48. The pre-cooled solution of step (b) is Zn(OPiv) ２ The method of claim 45, comprising LiCl.

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