Process for making a KRAS g12c inhibitor

Abstract

The present disclosure provides processes that can be used to prepare the compound of Formula I:, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compound of Formula I, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, and methods of treating cancer using the compound of Formula I and pharmaceutical compositions.

Description

[0001] PROCESS FOR MAKING A KRAS G12C INHIBITOR The present disclosure relates to processes that can be used to prepare the compound of Formula I, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compound of Formula I, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis. The compound of Formula I and pharmaceutical compositions can be used to treat cancer. WO 2021 / 118877 (hereinafter “the ‘877 reference”) discloses certain KRas G12C inhibitors, or salts thereof, that can be used to treat cancer. Methods of preparing these compounds are also disclosed. The methods disclosed in the ‘877 reference use a phosphate buffer. These methods result in greater quantities of impurities than desired. These impurities include, in greater quantities than desired, a Michael adduct impurity, 4-[(13aS)- 2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-10-chloro-8-fluoro-6- oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-2-yl]-3-oxo-propyl]- 10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-9- yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M,M atropisomer, , which can be difficult to remove. Accordingly, there is a need for an alternative process for the preparation of the compound of Formula I. It would be useful to develop new processes that can be used to prepare the compound of Formula I that contain less impurities, especially the Michael adduct impurity. SUMMARY Disclosed herein are methods of making the compound of Formula I, or pharmaceutically acceptable salts thereof. Also disclosed herein are the compound of Formula I, or pharmaceutically acceptable salts thereof, obtainable by using newly developed processes. In an aspect, disclosed herein is a method of preparing a compound of the formula, , or a pharmaceutically acceptable salt thereof, the method comprising: combining citrate buffer, an acryloyl group, and 4-[(13aS)-10-chloro-8-fluoro-6- oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7- fluoro-benzothiophene-3-carbonitrile, M atropisomer, . In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of the formula, , or a a Michael adduct impurity, 4-[(13aS)-2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-10-chloro-8- fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-2-yl]-3-oxo- propyl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M,M atropisomer, , an as Analysis, and a pharmaceutically acceptable carrier, diluent or excipient. In an aspect, disclosed herein is a compound of the formula, , or a obtainable by combining citrate buffer, an acryloyl group, and 4-[(13aS)-10-chloro- 8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2- amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer, , wherein the Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis.

[0002] The present disclosure also provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, obtainable by combining citrate buffer, an acryloyl group, and 4-[(13aS)-10-chloro-8-fluoro-6-oxo- 2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7- fluoro-benzothiophene-3-carbonitrile, M atropisomer, , wherein the an amount of less than 0.3% as measured by HPLC Analysis, and a pharmaceutically acceptable carrier, diluent, or excipient. A surprising result is that the use of a citrate buffer in a base catalyzed reaction lowers the Michael adduct impurity amount. The present disclosure also provides a method of treating cancer wherein one or more cells express Kras G12C mutant protein, comprising administering to a patient in need thereof, a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis. In various embodiments, the cancer is lung cancer, such as advanced non-small cell lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer. In preferred embodiments, the cancer is advanced non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In still more preferred embodiments, the cancer is non-small cell lung cancer. In still yet another form, the present disclosure comprises a method of treating cancer, comprising administering to a patient in need thereof, a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis. In another embodiment, the cancer is non-small cell lung carcinoma. In another embodiment, the cancer is colorectal carcinoma. In yet another embodiment, the cancer is mutant pancreatic cancer. In another embodiment, the present disclosure comprising a method of treating Kras G12C mutant bearing cancers of other origins. The present disclosure also provides a method of treating a patient with a cancer that has a KRAS G12C mutation comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis. The present disclosure also provides a method of modulating a mutant Kras G12C enzyme in a patient in need thereof, by administering a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis. Preferably the method comprises inhibiting a human mutant Kras G12C enzyme. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament for treating a KRAS G12C mutant cancer, wherein the compound is administered at a dose between about 50 mg and about 200 mg, in simultaneous, separate or sequential combination with a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of: one or more of a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, a PD-L1 inhibitor, or a pharmaceutically acceptable salt thereof, a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, or a pharmaceutically acceptable salt thereof, an antifolate, or a pharmaceutically acceptable salt thereof, an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, or pharmaceutically acceptable salts thereof. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose between about 50 mg and about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with a PD-1 or PD-L1 inhibitor, for treatment of a KRAS G12C mutant cancer. In another embodiment, the PD-1 or PD-L1 inhibitor is pembrolizumab, wherein pembrolizumab is dosed (or administered) 200 mg once every three weeks. In another embodiment, the PD-1 or PD-L1 inhibitor is nivolumab. In another embodiment, the PD- 1 or PD-L1 inhibitor is cimiplimab. In another embodiment, the PD-1 or PD-L1 inhibitor is sintilimab. In another embodiment, the PD-1 or PD-L1 inhibitor is atezolizumab. In another embodiment, the PD-1 or PD-L1 inhibitor is avelumab. In another embodiment, the PD-1 or PD-L1 inhibitor is durvalumab. In another embodiment, the PD-1 or PD-L1 inhibitor is lodapilimab. In an embodiment, the dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose between about 50 mg and about 200 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab in the treatment of KRAS G12C-mutant advanced NSCLC, wherein pembrolizumab is dosed intravenously at 200 mg once every three weeks. In an embodiment, the dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered once a day. In an embodiment, the dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered twice a day. In an embodiment, the dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 150 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. In an embodiment, the patient in need thereof has received at least one treatment, including prior KRAS G12C inhibitor. In yet another embodiment, the patient in need thereof has a tumor proportion score (TPS) status of 0% to 49%. In yet another embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of 0% to 49%. In an embodiment, the patient in need thereof has a tumor proportion score (TPS) status of 1% to 49%. In an embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of 1% to 49%. In an embodiment, the patient in need thereof has a tumor proportion score (TPS) status of greater than or equal to 50%. In an embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of greater than or equal to 50%. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. In an embodiment, the patient in need thereof has received at least one treatment, including prior KRAS G12C inhibitor. In yet another embodiment, the patient in need thereof has a tumor proportion score (TPS) status of 0% to 49%. In yet another embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of 0% to 49%. In an embodiment, the patient in need thereof has a tumor proportion score (TPS) status of 1% to 49%. In an embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of 1% to 49%. In an embodiment, the patient in need thereof has a tumor proportion score (TPS) status of greater than or equal to 50%. In an embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of greater than or equal to 50%. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 50 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. In an embodiment, the patient in need thereof has received at least one treatment, including prior KRAS G12C inhibitor. In yet another embodiment, the patient in need thereof has a tumor proportion score (TPS) status of 0% to 49%. In yet another embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of 0% to 49%. In an embodiment, the patient in need thereof has a tumor proportion score (TPS) status of 1% to 49%. In an embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of 1% to 49%. In an embodiment, the patient in need thereof has a tumor proportion score (TPS) status of greater than or equal to 50%. In an embodiment, the KRAS G12C-mutant advanced NSCLC has a tumor proportion score (TPS) status of greater than or equal to 50%. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 150 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and cisplatin in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is dosed (or administered) 200 mg once every three weeks. In an embodiment, pemetrexed is dosed (or administered) 500 mg / m2 once every three weeks. In an embodiment, cisplatin is dosed (or administered) 75 mg / m2 once every three weeks. In an embodiment, pemetrexed and cisplatin are administered on the same day. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, cisplatin is administered for up to four cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and cisplatin in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is dosed (or administered) 200 mg once every three weeks. In an embodiment, pemetrexed is dosed (or administered) 500 mg / m2 once every three weeks. In an embodiment, cisplatin is dosed (or administered) 75 mg / m2 once every three weeks. In an embodiment, pemetrexed and cisplatin are administered on the same day. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, cisplatin is administered for up to four cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 50 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and cisplatin in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is dosed (or administered) 200 mg once every three weeks. In an embodiment, pemetrexed is dosed (or administered) 500 mg / m2 once every three weeks. In an embodiment, cisplatin is dosed (or administered) 75 mg / m2 once every three weeks. In an embodiment, pemetrexed and cisplatin are administered on the same day. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, cisplatin is administered for up to four cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 150 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and carboplatin in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is dosed (or administered) 200 mg once every three weeks. In an embodiment, pemetrexed is dosed (or administered) 500 mg / m2 once every three weeks. In an embodiment, carboplatin is dosed (or administered) area under the curve (AUC) 5 mg / ml / minute once every three weeks for a maximum dose of 750 mg. In an embodiment, pemetrexed and carboplatin are administered on the same day. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, carboplatin is administered for up to four cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 100 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and carboplatin in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is dosed (or administered) 200 mg once every three weeks. In an embodiment, pemetrexed is dosed (or administered) 500 mg / m2 once every three weeks. In an embodiment, carboplatin is dosed (or administered) area under the curve (AUC) 5 mg / ml / minute once every three weeks for a maximum dose of 750 mg. In an embodiment, pemetrexed and carboplatin are administered on the same day. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, carboplatin is administered for up to four cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. In another aspect, disclosed herein is a use of a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity is present in an amount of less than 0.3% as measured by HPLC Analysis, in the manufacture of a medicament, administering to a patient in need thereof, a dose of about 50 mg of the compound of Formula I, or a pharmaceutically acceptable salt thereof, in simultaneous, separate or sequential combination with pembrolizumab, pemetrexed, and carboplatin in the treatment of KRAS G12C-mutant advanced NSCLC. In an embodiment, pembrolizumab is dosed (or administered) 200 mg once every three weeks. In an embodiment, pemetrexed is dosed (or administered) 500 mg / m2 once every three weeks. In an embodiment, carboplatin is dosed (or administered) area under the curve (AUC) 5 mg / ml / minute once every three weeks for a maximum dose of 750 mg. In an embodiment, pemetrexed and carboplatin are administered on the same day. In an embodiment, pembrolizumab is administered for up to thirty-five cycles. In an embodiment, carboplatin is administered for up to four cycles. In an embodiment, the patient in need thereof is treatment naïve to KRAS G12Ci, PD-1, or PD-L1 therapy. The starting materials and intermediates leading to the compounds of the present disclosure, or salts thereof, may be prepared by a variety of procedures, some of which are illustrated in the following Preparations and Examples and by Preparations and Examples in the ‘877 reference. The starting materials and intermediates leading to the compounds of the present disclosure may be prepared by methods well known and appreciated in the art according to the following Preparations and Examples and by Preparations and Examples of the ‘877 reference. Suitable reaction conditions for the steps of these Preparations and Example are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may be isolated and / or purified by various well-known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. As an illustration, the starting materials and intermediates leading to compounds of the preparations and examples can be isolated, for example, by silica gel purification, isolated directly by filtration, or crystallization. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of the present disclosure is dependent upon the particular compound being synthesized, the starting materials, and the relative liability of the substituted moieties, as is well appreciated by the skilled chemist. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different routes, to prepare compounds or salts of the present disclosure. The products of each step in the Preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Definitions Certain abbreviations are defined as follows: “ACN” refers to acetonitrile; “APCI- MS” refers to atmospheric pressure chemical ionization mass spectrometry; “Boc” refers to tert-butoxycarbonyl; “CDI” refers 1,1’-carbonyldiimidazole; “CDMT” refers to 2- chloro-4,6-dimethoxy-1,3,5-triazine; “DCC” refers to 1,3-dicyclohexylcarbodiimide; “DCM” refers to dichloromethane; “DIC” refers to 1,3-diisopropylcarbodiimide; “DIPEA” or “DIEA” refers to N,N-diisopropylethylamine; “DMAc” or “DMA” refer to dimethylacetamide; “DMAP” refers to 4-dimethylaminopyridine; “DMF” refers to N,N- dimethylformamide; “DMSO” refers to dimethylsulfoxide; “DMSO-d6” refers to deuterated dimethylsulfoxide; “EDCI” refers to 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride; “EtOAc” refers to ethyl acetate; “EtOH” refers to ethanol or ethyl alcohol; “H3PO4” refers to phosphoric acid; “HATU” refers to O-(7- Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; “HOAt” refers to 1-hydroxy-7-azobenzotriazole; “HBTU” refers to 3- [bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate; “HOBt” refers to 1-hydroxylbenzotriazole hydrate; “HPLC” refers to high-performance liquid chromatography; “MeOH” refers to methanol; “2-MeTHF” refers to 2- methyltetrahydrofuran; “MP (DSC)” refers to melting point by differential scanning calorimetry; “MTBE” refers to methyl tert-butyl ether; “NCS” refers to N- chlorosuccinimide; “NMM” refers to N-methylmorpholine; “NMP” refers to N-methyl-2- pyrrolidone; “NMR” refers to nuclear magnetic resonance; “PyBOP” refers to (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate); “PyBrOP” refers to bromo(tri-pyrrolidinyl)phosphoniumhexafluorophosphate; and “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran. An “acryloyl group” is any alpha,beta unsaturated carbonyl conjugated to a terminal alkene (CH2=CH-C(O)-), such as acryloyl chloride, acryloyl bromide, or acryloyl anhydride. A “base” is a molecule that is a proton acceptor, or a molecule that can neutralize an acid. Examples of bases include but are not limited to, K2CO3. A “citrate buffer” is any salt, ester, or polyatomic anion including a derivative of citric acid. A “citric acid buffer” is any buffer including citric acid. The terms "continuous manufacturing” (herein after “CM”), “flow”, and “flow chemistry” involve the continuous feeding of input materials into, the transformation of in- process materials within, and the concomitant removal of output materials from a manufacturing process, such as a continuous stirred-tank reactor. The terms are applicable to CM for new products (e.g., new drugs, generic drugs, biosimilars) and the conversion of batch manufacturing to CM for existing products. (See for example, FDA, "Q13 Continuous Manufacturing of Drug Substances and Drug Products, Guidance for Industry", March 2023). A continuous stirred-tank reactor is a vessel in which reactants are added and products are removed continuously and the reactor contents are stirred using internal agitation. The terms "batch”, “batch manufacturing” and “batch chemistry” involve a specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval. (See for example, FDA, "Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Guidance for Industry", September 2016). A “catalyst” is a substance that increases the rate of a chemical reaction without itself undergoing any permanent chemical change. As used herein, the terms “treating”, “to treat”, or “treatment”, includes slowing, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, which can include specifically slowing the growth of a cancerous lesion or progression of abnormal cell growth and / or cell division. The term “PD-1” as used herein refers to programmed death receptor 1. The term “PD-L1” as used herein refers to programmed death ligand 1. The term “CDK4 / CDK6 inhibitor” as used herein refers to any chemical that inhibits the function of CDK4 / CDK6. The term “EGFR inhibitor” as used herein refers to any chemical that inhibits the function of EGFR. The term “ERK” refers to extracellular signal-regulated kinases. The term “ERK inhibitor” as used herein refers to any chemical that inhibits the function of ERK. The term “platinum agent” as used herein refers to any platinum containing chemical that inhibits cancer. The term “antifolate” as used herein refers to any chemical that inhibits the function of folic acid. In an embodiment, the antifolate is pemetrexed. The term “Aurora A inhibitor” as used herein refers to any chemical that inhibits the function of Aurora A kinase. The term “SHP2 inhibitor” as used herein refers to any chemical that inhibits the function of SHP2. Pharmaceutical compositions containing the compounds of Formula I as described herein may be prepared using a pharmaceutically acceptable carrier, diluent, or excipient. Examples of pharmaceutical compositions and processes for their preparation can be found in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22ndEd., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include the following: saline, water, starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose, alginates, gelatin, and polyvinyl-pyrrolidone; kaolin and bentonite; and polyethyl glycols. Compounds of the present disclosure can be synthesized in part by following the steps outlined in the following Schemes 1 – 1a which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.

[0003] Scheme 1 with 4-bromo-2,5-difluoro-benzoic acid, compound (2), in an amide bond formation using a coupling reagent such as CDMT with an organic base such as NMM in a solvent system such as acetonitrile and water and an inorganic base such as K2CO3. R is a protecting group developed for the amino group, such as carbamates and amides. Such protecting groups are well known and appreciated in the art, such as carbamate protecting groups including allyloxycarbonyl, fluorenylmethoxycarbonyl, or benzyloxycarbonyl. A common and preferred protecting group can be Boc. One skilled in the art will recognize that there are a number of methods and reagents for amide formation resulting from the reaction of carboxylic acids and amines. For example, the reaction of the amine compound with an appropriate carboxylic acid in the presence of a coupling reagent with or without an organic base such as DIPEA or TEA can provide compound (3). Other coupling reagents include carbodiimides, such as DCC, DIC, EDCI or a carbonyldiimidazole such as CDI. Amide coupling additives, such as HOBt and HOAt can also be used to enhance the reaction. Additionally, uronium or phosphonium salts of non-nucleophilic anions, such as HBTU, HATU, PyBOP, and PyBrOP could be used in place of the more traditional coupling reagents. An additive such as DMAP may be used to enhance the reaction. Alternatively, the acid chloride of compound (2) can be used in the presence of a base, such as TEA or pyridine to give compound (3). In Step 2, the intramolecular cyclization of compound (3) is completed using an appropriate base such as potassium tert-butoxide, sodium tert-amylate, sodium tert- butoxide, sodium tert-pentoxide, DIPEA, TEA, DBU, sodium hydride in a solvent such as DMF to give compound 4. Other possible solvents could be NMP, DMAc, DMSO, and THF. This intramolecular cyclization of compound (3) to compound (4) may be conducted by slowly adding a solution of compound (3) to an excess of base so as to minimize intermolecular reaction derived impurities. In Step 3, compound (4) can be chlorinated with under acidic conditions using an acid such as TFA, H3PO4, with a chlorinating agent such as trichloroisocyanuric acid or NCS in a solvent such as acetonitrile or DMF to give compound (5). Scheme 1a a . can be prepared as described by Medicinal Chemistry route to 1, Development of an Alternative Route to the Bicyclic Piperazine, Retrosynthetic analysis of bicyclic piperazine core 2, and / or Coupling, cyclization, reduction, and Michael addition to afford Piperazine 24 in Org Proc Res Dev., 2011, 15(6). 1328-1335. Compounds (3a), (4a), and (5a) can be prepared as described in Scheme 1. Scheme 2 depicts the formation of products arising from reaction of amine (1) with acryloyl chloride (2). With a 1,2-addition, the compound of Formula I (3) is achieved. A 1,4-addition produces an amine impurity, acid chloride (4). Reaction of either acid chloride (4) or compound of Formula I (3) with an additional molecule of amine (1) results in Michael adduct impurity (6), while hydrolysis of acid chloride (4) with water results in acid impurity (5).

[0004] Scheme 2 tert-Butyl (S)-9-bromo-10-fluoro-12-oxo-1,2,4,4a,5,6-hexahydro-3H,12H- benzo[b]pyrazino[1,2-e][1,5]oxazocine-3-carboxylate is synthesized using a 7-step sequence beginning with commercially available S-aspartic acid, which is the source of the stereocenter. It is known that significant impurity rejection including rejection of the R- enantiomer can be achieved in the isolation of intermediates. tert-Butyl (S)-9-bromo-10- fluoro-12-oxo-1,2,4,4a,5,6-hexahydro-3H,12H-benzo[b]pyrazino[1,2-e][1,5]oxazocine-3- carboxylate can be isolated by crystallization with significant impurity rejection. Steps and Schemes are used to control process and reagent impurities. DETAILED DESCRIPTION A KRAS G12C inhibitor of interest is 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop- 2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7- fluoro-benzothiophene-3-carbonitrile, which has the following structure: . This compound was disclosed as Example 35 in the ‘877 reference. As disclosed therein, this compound exists as atropisomers. The atropisomers may be separated. See Preparations 167 and 168 of the ‘877 reference. The desired diastereomer is taught in Preparation 168 of the ‘877 reference. This desired diastereomer corresponds to an M atropisomer. The second diastereomer may be further processed to 4-[(13aS)-10-chloro-8-fluoro-6-oxo- 2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7- fluoro-benzothiophene-3-carbonitrile, M atropisomer, which has the following structure: . 4-[(13aS)-10- hexahydro-1H-pyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer in the ‘877 reference may be further processed to Example 35, M atropisomer in the ‘877 reference. Example 35, M atropisomer is 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2- enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7- fluoro-benzothiophene-3-carbonitrile, M atropisomer (hereinafter “Formula I”) having the following structure: (Formula I). The compound of Formula I is currently undergoing clinical testing (ClinicalTrials.gov Identifier: NCT04956640) to assess its utility in treating patients having cancer that is treatable by inhibiting KRAS G12C. The compound of Formula I may be used, either as a monotherapy, in combination with one or more other therapeutic agents, or as part of neoadjuvant, adjuvant, advanced, or metastatic therapy, to treat cancer. Such cancers include but are not limited to lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma or esophageal cancer. Compounds of the preparations and examples can be isolated, for example, by silica gel purification, isolated directly by filtration, or crystallization. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of the present disclosure is dependent upon the particular compound being synthesized, the starting compound, and the relative liability of the substituted moieties, as is well appreciated by the skilled chemist. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art. Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. It will be understood that all stereoisomers are encompassed. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enriched starting materials and / or reagents. Alternatively, enantiomers can be separated using methods known in the art, such as chiral chromatography or by converting the enantiomers to diastereomeric salts, separating the diastereomeric salts, converting the diastereomeric salt into a non-salt form and isolating the enantiomer. Individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the disclosure, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). Additionally, the intermediates described in the following schemes contain a number of nitrogen or oxygen protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example “Greene’s Protective Groups in Organic Synthesis”, Fourth Edition, by Peter G.M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc.2007). One of skill in the art will also appreciate that the compound of Formula I, described herein, or pharmaceutically acceptable salts thereof, can be deuterated (where a hydrogen can be replaced by a deuterium) and such molecules are within the scope of the compounds disclosed herein. Preparations and Examples Preparation 1 Methyl 4-amino-3-chloro-2,5-difluoro-benzoate The title compound was manner as the method of the ‘877 reference; Preparation 31. ES / MS m / z: 222 [M+H]+. Preparation 2 Methyl 3-chloro-2,5-difluoro-4-iodo-benzoate Cuprous iodide (22.7 g, 119 mmol), ACN (100 mL), and tert-butyl nitrite (17.7 mL, 149 mmol) were combined and stirred for 45 minutes at room temperature. A solution of methyl 4-amino-3-chloro-2,5-difluoro-benzoate (22.1 g, 100 mmol) in ACN (100 mL) was added. The reaction mixture was stirred at 40°C for three hours, allowed to cool to room temperature, filtered through diatomaceous earth, and rinsed with DCM. The filtrate was concentrated in vacuo and purified by silica gel flash chromatography (10% EtOAc in hexanes) to give the title compound as a white solid (17.8 g, 54%).1H NMR (CDCl3) δ 7.60 (dd, J=5.6,7.6 Hz, 1H), 3.98 (s, 3H). Preparation 3 3-Chloro-2,5-difluoro-4-iodo-benzoic acid MeOH (50 mL) was added methyl 3-chloro-2,5-difluoro-4-iodo- benzoate (16.8 g, 50.5 mmol) in THF (125 mL). The reaction mixture was cooled in an ice bath. 1N aqueous NaOH (150 mL, 150 mmol) was added in three portions. The reaction mixture was allowed to stir at room temperature for 30 minutes and concentrated in vacuo to remove organic solvents. The aqueous remainder was cooled with ice chips and the pH adjusted to ~2 with 5N aqueous HCl (25 mL). The aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (15.8 g, 98%).1H NMR δ (DMSO-d6) 13.91 (s, 1H), 7.68 (dd, J=5.8,7.8 Hz, 1H). Preparation 4 tert-Butyl (3R)-4-(3-chloro-2,5-difluoro-4-iodo-benzoyl)-3-(hydroxymethyl)piperazine-1- carboxylate HATU (3.31 g, 8.53 mmol) was added to a solution of 3-chloro-2,5-difluoro-4-iodo- benzoic acid (2.99 g, 9.39 mmol) and DIEA (6.7 mL, 38 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature for one hour. A solution of tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (1.92 g, 8.52 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 14 hours and 60°C for three hours, then diluted with EtOAc and water. The organic layer was washed with water, 1N aqueous NaOH, and brine. The aqueous layer was extracted with EtOAc, which was washed with brine. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography (10-50% EtOAc in hexanes) to give the title compound as a white solid (3.82 g, 82%). ES / MS m / z (35Cl / 37Cl) 461 / 463 [M-tert-Butyl+H]+. Preparation 5 tert-Butyl (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate The title compound was same manner as the method of the ‘877 reference; Preparation 117. ES / MS m / z (79Br / 81Br) 407 / 409 [M-tert-Butyl+H]+.

[0005] Preparation 20 tert-Butyl (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1- carboxylate CDMT (802.8 g, 4.57 along with acetonitrile (20.0 L) and the mixture was cooled to 0 ºC. NMM (708.2 g, 7.00 mol) was added and the mixture was stirred for 30 min at 0 ºC.4-bromo-2,5-difluorobenzoic acid (794.8 g, 3.35 mol), , was added and the mixture was stirred for 1 h at 0 ºC. In a separate vessel, K2CO3 (842 g, 6.09 mol), water (5.0 L), and tert-butyl (3S)-3-(2-hydroxyethyl)piperazine-1- carboxylate:phosphoric acid (1:1) (1000 g, 3.05 mol) were combined. The aqueous piperazine solution was added to the acetonitrile coupling solution over 5 min while maintaining an internal temperature of 0 ºC. The mixture was stirred for 2.5 h at 0 ºC. The bottom layer was drained from the reactor. The reaction mixture was stirred for an additional 64 h at 0 ºC, then concentrated to 2 L / kg.2-MeTHF (10.0 L) and n-heptane (3.0 L) were added. 1 M aq. NaHCO3 (10.0 L) was added and the mixture was stirred for 15 min. The layers were allowed to separate and the bottom layer was drained. 1 M aq. NaHCO3 (10.0 L) was added and the mixture was stirred for 15 min. The layers were allowed to separate and the bottom layer was drained. Aq. HCl (0.05 M, 5.0 L) was added and the mixture was stirred for 15 min. The layers were allowed to separate and the bottom layer was drained. Water (5.0 L) was added and the mixture was stirred for 15 min. The layers were allowed to separate and the bottom layer was drained. The upper layer was concentrated to 2 L / kg and 2-MeTHF (1.0 L) was added. The mixture was concentrated to 2 L / kg and 2-MeTHF (1.0 L) was added. The mixture was concentrated to 2 L / kg and DMF (2.7 L) was added to give the title compound as a DMF solution (4.03 kg, 31.2% assay, 2.80 mol, 92% yield), which was used without further manipulation. An analytical sample was prepared by chromatography and exhibited the following spectroscopic characteristics: APCI-MS found 471 and 473 (M+Na+);1H NMR (500 MHz, d6-DMSO + TFA, multiple rotamers present) δ 7.84 (m, 1H), 7.53 (br s, 1H), 4.71 (br s, 0.5H), 4.33 – 4.27 (m, 0.5H), 4.12 – 3.72 (m, 2H), 3.65 (br s, 0.5H), 3.47 (br, 1H), 3.38 – 3.11 (m, 2H), 3.11 – 2.56 (m, 2.5H), 1.68 (m, 2H), 1.39 (s 9H). Sodium tert-pentoxide (462 g, 4.20 mol) was added to a reactor along with DMF (9.1 L). The mixture was stirred to form a solution and cooled to 0 ºC. The DMF solution of tert-butyl (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1- carboxylate (4.03 kg, 31.2% assay, 2.80 mol) was added over 8 h at 0 ºC. The total mass of the product solution at this point is 12.95 kg. A portion of the solution (1.30 kg) was placed in a separate reactor. Water (2.6 kg) was added to a clean reactor. The 1.30 kg of product solution was added to the water over 3 h at 25 ºC. The mixture was stirred for 64 h at 25 ºC. The resulting solids were isolated by filtration and washed with a mixture of DMF (0.3 L) and water (0.3 L). The crude solids were added to a reactor along with EtOH (628 mL). The mixture was heated to 55 ºC and stirred for 30 min. Water (314 mL) was added over 2 h and the mixture was held at 55 ºC for an additional 30 min. The slurry was cooled to 20 ºC over 2 h, then held at 20 ºC for 2 h. The resulting solids were isolated by filtration and washed with a mixture of water (60 mL) and EtOH (60 mL). The product was dried under vacuum at 50 ºC for 16 h to give the title compound (98.2 g, 73% yield). APCI-MS found 451 and 453 (M+Na+1);1H NMR (400 MHz, d6-DMSO-) δ 7.32 (d, J = 6.0 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 4.24–4.18 (m, 2H), 4.05–3.91 (m, 2H), 3.87–3.76 (m, 2H), 3.06 (br, 1H), 2.95–2.80 (brm, , 2.06 (m, 1H), 1.76 (m, 1H), 1.04 (s, 9H). Alternative Synthesis of Preparation 5 tert-Butyl (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate tert-Butyl - 8-fluoro-6-oxo-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate (2.00 g, 4.66 mmol) was added to a reactor along with acetonitrile (20 mL) and the mixture was cooled to 5 ºC. Trichloroisocyanuric acid (1.08 g, 4.66 mmol) was added and the mixture was stirred at 5 ºC for 5 min. A solution of phosphoric acid (0.96 mL, 14.0 mmol; stock solution was 1.92 mL of phosphoric acid in 4.0 mL of acetonitrile) was added over 2 min and the mixture was stirred at 5 ºC for 23 h. Aq. K2CO3 (40%, 20 mL) was added and the mixture was stirred at 5 ºC for 30 min, warmed to 20 ºC, and stirred at 20 ºC for 2 h. Ethyl acetate (20 mL) and water (20 mL) were added and the mixture was stirred until solids dissolved. Solids reappeared after sitting for 1 h. Aq. NaHSO3(5%, 10 mL) was added and the mixture was stirred overnight. Aq. K2CO3 (40%, 4 mL) and di-tert-butyl dicarbonate (0.20 g, 0.93 mmol) were added and the mixture was stirred overnight. The mixture was concentrated to 2-3 volumes and isopropanol (4 volumes) was added. The mixture was concentrated to 2- 3 volumes and isopropanol (4 volumes) was added. The mixture was concentrated to 2-3 volumes and isopropanol (2 volumes) was added. The mixture was stirred at 57 ºC. Water (4 volumes) was added over 1 h and the mixture was stirred at 57 ºC for 2 h. The mixture was cooled and stirred overnight at 20°C, filtered, and washed with 1:2 isopropanol:water (3 volumes). The product was dried under vacuum at 50 ºC for 3 h to give the title compound (1.85 g, 86% yield). Preparation 6 tert-Butyl (4aR)-7-chloro-9-fluoro-8-iodo-11-oxo-2,4,4a,5-tetrahydro-1H-pyrazino[2,1- c][1,4]benzoxazepine-3-carboxylate tert-Butyl - 2,5-difluoro-4-iodo-benzoyl)-3- (hydroxymethyl)piperazine-1-carboxylate (4.59 g, 8.88 mmol) in DMF (150 mL) was cooled to 0°C. Sodium hydride (0.89 g, 22 mmol, 60 mass% in paraffin oil) was added. After four hours at 0°C, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with water and diethyl ether. The aqueous layer was extracted with diethyl ether (4x). The combined organic extracts were washed with water (3x) and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography (15-40% EtOAc in hexanes) to give the title compound as a white solid (3.82 g, 82%). ES / MS m / z (35Cl / 37Cl) 441 / 443 [M-tert-Butyl+H]+.

[0006] Preparation 7 tert-Butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate The title compound was manner as the method of the ‘877 reference; Preparation 14. ES / MS m / z (79Br / 81Br) 315 / 317 [M-tert-Butyl+H]+. Preparation 8 tert-Butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzothiophen-2-yl]carbamate 3-cyano-7-fluoro-benzothiophen-2- (21.0 g, 82.7 mmol), and potassium acetate (2.50 g, 25.5 mmol) in 1,4-dioxane (50 mL) was flushed with nitrogen (direct sparge) for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (1.0 g, 1.2 mmol) was added. The reaction flask was sealed and heated at 80-85°C for 3.5 hours. The reaction mixture was filtered through diatomaceous earth. The filtrate was diluted with water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography (10-50% (20% acetone in DCM) in hexanes) to give the title compound (4.45 g, 87%). ES / MS m / z 363 [M-tert-Butyl+H]+. Preparation 9 tert-Butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen- 2-yl]carbamate The title compound was as the method of the ‘877 reference; Preparation 15.1H NMR (DMSO-d6) δ 11.6 (s, 1H), 7.61 (m, 1H), 7.20 (m, 1H), 3.78 (s, 4H), 1.54 (s, 9H), 1.03 (s, 6H). Preparations 10 and 11 tert-Butyl (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-benzothiophen-4-yl]-10- chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2- carboxylate, P and M atropisomers P atropisomer M atropisomer The title as the method of the ‘877 reference; Preparation 167. The mixture of atropisomers were separated by silica gel flash chromatography (0-30% acetone in hexanes). Preparation 10 (P atropisomer) was the first compound to elute off the column. Preparation 11 (M atropisomer) was the second compound to elute off the column. For both, ES / MS m / z (35Cl / 37Cl) 657 / 659 [M+H]+.

[0007] Preparations 12 and 13 tert-Butyl (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4- yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocine-2-carboxylate, P and M atropisomers The title method of the ‘877 reference; Preparations 167 and 168: A mixture of tert-butyl (13aS)-9-bromo-10-chloro-8- fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2- carboxylate (10.0 g, 21.6 mmol), tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2- dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (12.3 g, 30.4 mmol), potassium carbonate (8.94 g, 64.7 mmol), and dichloro[(S)-(-)-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) (also known as “(S)-(-)-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl palladium dichloride”) (3.84 g, 4.42 mmol) was added to 1,4-dioxane (215 mL) that had been flushed with nitrogen (direct sparge) for 30 minutes. The reaction flask was sealed and heated at 105°C for 14 hours. Additional tert- butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2- yl]carbamate (3.54 g, 8.75 mmol) and dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'- binaphthyl]palladium(II) (0.97 g, 1.12 mmol) were added. The reaction flask was sealed and heated at 105°C for 14 hours. The reaction mixture was filtered through diatomaceous earth, and rinsed with EtOAc. The filtrate was concentrated in vacuo and diluted with EtOAc, water, and brine. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography (10-40% acetone in hexanes). Preparation 12 (P atropisomer) eluted first, followed by Preparation 13 (M atropisomer). Impure fractions of P atropisomer were further purified by silica gel flash chromatography. This gave the two title compounds (P atropisomer, 0.35 g, 2%; M atropisomer, 5.6 g, 38%). For both, ES / MS m / z 619 [M-tert-Butyl+H]+.

[0008] Catalyst Screen of Preparations 12 and 13 tert-Butyl (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4- yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocine-2-carboxylate, P and M atropisomers In a glove - 8-fluoro-6-oxo- 1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate (0.025 g, 0.054 mmol), tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro- benzothiophen-2-yl]carbamate (0.030 g, 0.074 mmol), potassium carbonate (0.022 g, 0.16 mmol), and catalyst (0.0081 mmol) was added to 1,4-dioxane (1 mL) in a vial. The vial was sealed and heated at 105°C for 19 hours, then cooled to room temperature. Reaction monitoring by LCMS showed the following reaction progression and ratio of atropisomers: Table 1: Ratio of Reaction Prep 12 : Prep [(1,2,3-η)-2-Buten-1-yl]chloro[dicyclohexyl(2',6'- dimethoxy[1,1'-biphenyl]-2-yl)phosphine- 28 1 : 4 Alternative Synthesis of Preparation 13 tert-Butyl (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4- yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocine-2-carboxylate, M atropisomer M atropisomer To a small a was (II) acetate (0.119 g, 0.528 mmol), (S)-(-)-2,2'-bis(diphenylphosphino)-1,1′-binaphthalene (0.364 g, 0.580 mmol) and toluene (25 mL), which would make diacetate[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'- binaphthyl]palladium(II). The mixture was capped and stirred for 1 hour. tert-Butyl (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocine-2-carboxylate (0.500 g, 1.06 mmol) and a solution of potassium carbonate in water (2 mL, made from 0.241 g potassium carbonate in 2 mL water) were added. The mixture was heated at 60°C for 6 hours. The organic and aqueous layers were separated. The organic layer was dried over magnesium sulfate and filtered. The solids were rinsed with toluene (25 mL), which was added to the original filtrate. To a second flask was added tert-butyl (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo- 1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate (9.51 g, 20.16 mmol) and cesium carbonate (31.1 g, 95.0 mmol). The flask was cycled through vacuum and nitrogen four times. To a third flask was added tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2- dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (10.9 g, 25.3 mmol), 1,1,1- tris(hydroxymethyl)ethane (1.69 g), and THF (50 mL). The mixture was stirred for 25 min. To the second flask was added the ligand-catalyst filtrate and THF (50 mL). The mixture was heated at 60°C under nitrogen. The contents of the third flask were added dropwise (6 mL / hour). After 10 total hours of heating, HPLC analysis showed complete conversion of bromide starting material to product in a 4.36:1 M:P atropisomer ratio. After 12 total hours of heating, the mixture was allowed to cool to room temperature. Water (100 mL) was added and the organic and aqueous layers were separated. 20% brine (50 mL) was added and the organic and aqueous layers were separated. A portion (~20%) of the organic layer (26.2 g) was distilled to ~10 mL, diluted with isopropyl acetate (20 mL), distilled to ~10 mL, diluted with isopropyl acetate (20 mL), and distilled to ~10 mL. The resulting suspension was filtered and dried under vacuum to give the title compound (1.85 g). HPLC analysis showed 98.23% M atropisomer and 0.76% P atropisomer.

[0009] Preparation 16 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-benzothiophene-3-carbonitrile, P atropisomer TFA (4 mL) tert-butyl (13aS)-9-[2-(tert- butoxycarbonylamino)-3-cyano-benzothiophen-4-yl]-10-chloro-8-fluoro-6-oxo- 1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate, P atropisomer (0.98 g, 1.5 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for three hours, concentrated in vacuo, and purified by silica gel flash chromatography (4-10% 7N ammoniated MeOH in DCM) to give the title compound (0.57 g, 84%). ES / MS m / z (35Cl / 37Cl) 457 / 459 [M+H]+. Preparation 17 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-benzothiophene-3-carbonitrile, M atropisomer The title compound was prepared in the same manner as the method of the ‘877 reference; Preparation 187. ES / MS m / z (35Cl / 37Cl) 457 / 459 [M+H]+. Preparation 18 4-[(4aR)-7-Chloro-9-fluoro-11-oxo-1,2,3,4,4a,5-hexahydropyrazino[2,1- c][1,4]benzoxazepin-8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, P atropisomer TFA (2 mL) of tert-butyl (4aR)-8-[2-(tert- butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-7-chloro-9-fluoro-11-oxo- 2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine-3-carboxylate, P atropisomer (0.018 g, 0.027 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 30 minutes, concentrated in vacuo, and purified by silica gel flash chromatography (0-10% MeOH in DCM, then 0-10% 7N ammoniated MeOH in DCM) to give the title compound (0.013 g, 100%). ES / MS m / z (35Cl / 37Cl) 461 / 463 [M+H]+.

[0010] Preparation 19 4-[(4aR)-7-Chloro-9-fluoro-11-oxo-1,2,3,4,4a,5-hexahydropyrazino[2,1- c][1,4]benzoxazepin-8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer TFA (2.5 mL) was of tert-butyl (4aR)-8-[2-(tert- butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-7-chloro-9-fluoro-11-oxo- 2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine-3-carboxylate, M atropisomer (0.20 g, 0.31 mmol) in DCM (2.5 mL). The reaction mixture was stirred at room temperature for two hours, concentrated in vacuo, and purified by silica gel flash chromatography (0-10% 7N ammoniated MeOH in DCM) to give the title compound (0.13 g, 89%). ES / MS m / z (35Cl / 37Cl) 461 / 463 [M+H]+. Preparation 22 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer tert-Butyl (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4- yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocine-2-carboxylate, M atropisomer (100.0 g, 148.1 mmol) was added to a reactor with EtOH (300 mL). A solution of HCl in EtOH (30%, 216 g, 1.78 mol) was added over 30 min with stirring. The mixture was heated to 40 ºC for 20 h, then cooled to 0 ºC with stirring. A mixture of KOH (118.8 g, 1.80 mol) in water (1.0 L) was gradually added with stirring. The EtOH was removed by distillation. The residue was extracted with 2- MeTHF (1.0 L) and again with 2-MeTHF (500 mL). The organic extracts were combined, washed with saturated aqueous NaCl (3 × 0.5 L), and concentrated to ~200 mL. Acetonitrile (1.0 L) was added in a dropwise manner. The mixture was stirred and cooled to 0 ºC for 1 h. The solids were collected by filtration, washed with acetonitrile (200 mL), and dried under vacuum to afford the title compound as a white solid (66.4 g, 85% yield). APCI-MS 475 (M+H+). Example 1 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer (Example 1) HCl gas was bubbled for five minutes into an ice-cooled solution of tert-butyl (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-10- chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2- carboxylate, M atropisomer (0.786 g, 1.17 mmol) in DCM (12 mL) and 2-propanol (12 mL). The reaction mixture was stirred at room temperature for five hours, then cooled in an ice bath. HCl gas was bubbled into the reaction mixture for five minutes. The reaction mixture was stirred at room temperature for 14 hours, then concentrated in vacuo. The residue was twice diluted with n-heptane and concentrated in vacuo. MTBE (50 mL) was added. The mixture was stirred at room temperature for ten minutes, then filtered to give the deprotected material as a dihydrochloride salt. The dihydrochloride salt was dissolved in water (12 mL). 2-Methyltetrahydrofuran (12 mL) was added. A solution of potassium carbonate (0.81 g, 5.82 mmol) in water (12 mL) was added. The mixture was vigorously stirred while being cooled in an ice bath. Acryloyl chloride (0.10 mL, 1.28 mmol) in 2-methyltetrahydrofuran (5 mL) was added dropwise. After five minutes, diluted with brine and 2-methyltetrahydrofuran. The aqueous layer was extracted with 2-methyltetrahydrofuran (2x). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography (20-30% B in A; A:3:1 EtOAc:hexanes; B: 4:1 EtOAc:MeOH) to give the title compound (0.409 g, 66%). ES / MS m / z (35Cl / 37Cl) 529 / 531 [M+H]+. Alternative Synthesis 1 of Example 1: Flow Chemistry 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer To a continuous stirred-tank reactor (105 mL, 15°C) was added material from feed A [monopotassium phosphate (25.02 g), dipotassium phosphate (2.61 g), and water (to 600 mL volume); pH ~ 5.8; flow rate 4.73 g / min], feed B [acryloyl chloride (13.15 g, 1.15 eq) and 2-methyltetrahydrofuran (6 volumes); flow rate 2.48 g / min], and feed C [4-[(13aS)-10- chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin- 9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer (60 g, 0.126 mol), 2-methyltetrahydrofuran (6 volumes), and water (0.2 volumes); flow rate 2.97 g / min]. The mixture in the reactor was pumped to a second continuous stirred-tank reactor (105 mL, 15°C) at a flow rate of 10.5 g / min, and then collected in a separate receiving bottle. HPLC analysis conditions (“HPLC analysis”) comprise an Inertsil ODS-3V column (4.6 x 250 mm; 5 mm) eluted with 20% to 95% ACN in 0.1% aqueous H3PO4using an Agilent 1260 chromatograph with UV detector. HPLC analysis showed 0.33% Michael adduct impurity, 4-[(13aS)-2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-10-chloro-8- fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-2-yl]-3-oxo- propyl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M,M atropisomer, , adduct wherein unreacted [4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H- pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer reacts with the compound of Formula I and thereby forms a dimer. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present. The final mixture layers were separated. The aqueous phase was extracted with 2- methyltetrahydrofuran (5 volumes). The combined organic phases were washed with aqueous sodium bicarbonate (5 wt%, 10 volumes) twice and aqueous sodium chloride (10%, 10 volumes) once. The organic phase was concentrated to 10 volumes, diluted with isopropanol (10 volumes), concentrated to 10 volumes, diluted with isopropanol (10 volumes), stirred at 15°C for 2 hours, filtered, washed, and dried to give crude title compound (~60 g). Crude title compound (~50 g) was dissolved in 4:1 THF:MeOH (11 volumes) at 35°C, diluted with methylcyclohexane (0.58 volumes), seeded (2.5 wt%), and stirred for 30 min. Methylcyclohexane (12.3 volumes) was added steadily over 10-12 hours. The mixture was stirred overnight at 35°C, filtered, washed with methylcyclohexane (2 volumes), and dried to give the title compound (46.4 g, 84% adjusted yield). Alternative Synthesis 2 of Example 1: Batch Chemistry 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer A batch reaction (one-sixth scale) was carried out, in which a solution of acryloyl chloride (2.19 g, 1.15 eq) in 2-methyltetrahydrofuran (6 volumes) was added in a dropwise manner over 30 min to a solution of 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a- hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro- benzothiophene-3-carbonitrile, M atropisomer (10 g, 21 mmol) in 2-methyltetrahydrofuran (6 volumes) and pH 5.8 buffer [monopotassium phosphate (4.17 g), dipotassium phosphate (0.435 g), and water (to 100 mL volume)]. HPLC analysis after 25 min showed 1.63% MA impurity as shown in Table 2. Alternative Synthesis 3 of Example 1: Flow Chemistry 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer To a continuous stirred-tank reactor (55 mL, 12°C-13°C, 300 rpm) was added material from feed A [monopotassium phosphate (25.02 g), dipotassium phosphate (2.61 g), and water (to 600 mL volume); pH ~ 5.8; flow rate 2.3 mL / min], feed B [acryloyl chloride ( 8.38 g, 1.25 eq) and 2-methyltetrahydrofuran (6 volumes); flow rate 1.6 mL / min], and feed C [4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H- pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer (36.01 g, 0.076 mol), 2-methyltetrahydrofuran (6 volumes), and water (0.4 volumes); flow rate 1.6 mL / min]. The mixture in the reactor was pumped to a receiving bottle at 15 mL / min. Material from feed A, B, and C was dispensed for 20 minutes at the flow rates specified above before pausing the system and taking a reactor sample of the organic for HPLC analysis. HPLC analysis conditions (“HPLC analysis”) comprise an Inertsil ODS-3V column (4.6 x 250 mm; 5 mm) eluted with 20% to 95% ACN in 0.1% aqueous H3PO4 using an Agilent 1260 chromatograph with UV detector. HPLC analysis showed 0.32% MA impurity as shown in Table 2. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present. Alternative Synthesis 4 of Example 1: Flow Chemistry 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer To a continuous stirred-tank reactor (55 mL, 12°C-13°C, 300 rpm) was added material from feed A [citric acid (29.30 g), sodium citrate dihydrate (3.10 g), and water (to 500 mL volume); heat to dissolve, pH ~ 3.0; flow rate 2.3 ml / min], feed B [acryloyl chloride (2.54 g, 1.25 eq) and 2-methyltetrahydrofuran (6 volumes); flow rate 1.6 mL / min], and feed C [4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer (8.05 g, 0.017 mol), 2-methyltetrahydrofuran (6 volumes), and water (0.4 volumes); flow rate 1.6 mL / min]. The mixture in the reactor was pumped to a receiving bottle at 15 mL / min. Material from feed A, B, and C was dispensed for 20 minutes at the flow rates specified above before pausing the system and taking a reactor sample of the organic for HPLC analysis. HPLC analysis conditions (“HPLC analysis”) comprise an Inertsil ODS-3V column (4.6 x 250 mm; 5 mm) eluted with 20% to 95% ACN in 0.1% aqueous H3PO4using an Agilent 1260 chromatograph with UV detector. HPLC analysis showed 0.14% MA impurity as shown in Table 2. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present. Alternative Synthesis 5 of Example 1: Flow Chemistry 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer To a continuous stirred-tank reactor (110 mL, 450 rpm) was added material from feed A [citric acid monohydrate (78.22 g), sodium citrate dihydrate (30.94 g), and water (to 1 L volume); heat to dissolve, pH ~ 3.0; flow rate 3.6 mL / min], feed B [acryloyl chloride (10.20 g, 1.25 eq) and 2-methyltetrahydrofuran (2 volumes); flow rate 0.8 mL / min], and feed C [4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer (21.96 g, 0.046 mol), 2-methyltetrahydrofuran (18 volumes), and water (0.6 volumes); flow rate 6.6 mL / min]. The mixture in the reactor was pumped to a receiving bottle at 20 mL / min. Material from feed A, B, and C was dispensed for 30 minutes at the flow rates specified above before pausing the system and taking a reactor sample of the organic for HPLC analysis. HPLC analysis conditions ("HPLC analysis") comprise an CSH Phenyl Hexyl column (3.0 x 100 mm, 2.5 mm) eluted with 20% to 95% ACN in 0.1% aqueous TFA using an Agilent 1260 chromatograph with UV detector. HPLC analysis showed 0.07% MA impurity as shown in Table 2. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present. A surprising result is that the use of a higher rpm, such as the range of approximately 300 rpm to approximately 800 rpm, the range of approximately 400 rpm to approximately 500 rpm, and specific examples, such as approximately 300 rpm, approximately 450 rpm, or approximately 600 rpm, in the continuous stirred-tank reactor lowers the Michael adduct impurity amount. Alternative Synthesis 6 of Example 1: Flow Chemistry 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer To a continuous stirred-tank reactor (110 mL, 10-11°C, 600 rpm) was added material from feed A [citric acid monohydrate (39.0 g), sodium citrate dihydrate (4.15 g), and water (to 0.5 L volume); heat to dissolve, pH ~ 3.0; flow rate 3.6 mL / min], feed B [acryloyl chloride (8.30 g, 1.25 eq) and 2-methyltetrahydrofuran (2 volumes); flow rate 0.8 mL / min], and feed C [4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H- pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer (21.96 g, 0.046 mol), 2-methyltetrahydrofuran (18 volumes), and water (0.6 volumes); flow rate 6.6 mL / min]. The mixture in the reactor was pumped to a receiving bottle at 20 mL / min. Material from feed A, B, and C was dispensed for 30 minutes at the flow rates specified above before pausing the system and taking a reactor sample of the organic for HPLC analysis. HPLC analysis conditions ("HPLC analysis") comprise an CSH Phenyl Hexyl column (3.0 x 100 mm, 2.5 mm) eluted with 20% to 95% ACN in 0.1% aqueous TFA using an Agilent 1260 chromatograph with UV detector. HPLC analysis showed 0.06% impurity, 4-[(13aS)-2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro- benzothiophen-4-yl)-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocin-2-yl]-3-oxo-propyl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M,M atropisomer, , “MA impurity” as shown in Table 2. This MA impurity is a Michael adduct wherein unreacted [4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H- pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer reacts with the compound of Formula I and thereby forms a dimer. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present. Alternative Synthesis 7 of Example 1: Semi-Batch Chemistry 4-[(13aS)-10-Chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M atropisomer added material from feed A [citric acid monohydrate (78.22 g), sodium citrate dihydrate (30.94 g), and water (to 1 L volume); heat to dissolve, pH ~ 3.0; 20 mL charged to flask] and feed C [4-[(13aS)-10- chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin- 9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer (2.0010 g, 0.046 mol), 2-methyltetrahydrofuran (18 volumes), and water (0.6 volumes)]. 4.2 mL of feed B [acryloyl chloride (0.625 mL, 1.25 eq) and 2-methyltetrahydrofuran (2 volumes); flow rate 4.42 mL / min] was added to the round bottom flask using a syringe pump and stirred for 10 minutes before sampling. HPLC analysis conditions ("HPLC analysis") comprise an CSH Phenyl Hexyl column (3.0 x 100 mm, 2.5 mm) eluted with 20% to 95% ACN in 0.1% aqueous TFA using an Agilent 1260 chromatograph with UV detector. HPLC analysis showed 0.16% impurity, 4-[(13aS)-2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro- benzothiophen-4-yl)-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocin-2-yl]-3-oxo-propyl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3- carbonitrile, M,M atropisomer, , Michael adduct wherein unreacted [4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H- pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer reacts with the compound of Formula I and thereby forms a dimer. It is possible for trace amounts of the corresponding M,P atropisomer dimer may be present. Table 2 Alternative Synthesis of Example 1 % MA impurity

Claims

What is Claimed is:

1. A method of preparing a compound of the formula, ,or a comprising: combining citrate buffer, an acryloyl group, and 4-[(13aS)-10-chloro-8-fluoro-6- oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7- fluoro-benzothiophene-3-carbonitrile, M atropisomer, .

2. The method of claim 1, wherein the step of preparing is in a continuous stirred-tank reactor.

3. The method of claims 1 or 2, wherein the acryloyl group is acryloyl chloride, acryloyl bromide, or acryloyl anhydride.

4. The method of any one of claims 1 to 3, wherein the acryloyl group is acryloyl chloride.

5. The method of any one of claims 1 to 4, wherein the acryloyl group is within the range of approximately 1.05 eq to approximately 1.35 eq relative to the 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin- 9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer.

6. The method of any one of claims 1 to 5, wherein the acryloyl group is approximately 1.25 eq relative to the 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a- hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro- benzothiophene-3-carbonitrile, M atropisomer.

7. The method of any one of claims 1 to 6, wherein the citrate buffer is within the range of approximately 2.0 pH to approximately 4.0 pH.

8. The method of any one of claims 1 to 7, wherein the citrate buffer is approximately 3.0 pH.

9. The method of any one of claims 2 to 8, wherein the continuous stirred-tank reactor is operated within the range of approximately 300 rpm to approximately 600 rpm.

10. The method of any one of claims 2 to 9, wherein the continuous stirred-tank reactor is operated at approximately 450 rpm.

11. The method of any one of claims 2 to 10, wherein the citrate buffer is added into the continuous stirred-tank reactor at a flow rate of approximately 3.6 mL / min.

12. The method of any one of claims 2 to 11, wherein the acryloyl group is added into the continuous stirred-tank reactor at a flow rate of approximately 0.8 mL / min.

13. The method of any one of claims 2 to 12, wherein the 4-[(13aS)-10-chloro- 8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2- amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer, ,is added into the continuous stirred-tank reactor at a flow rate of approximately 6.6 mL / min.

14. The method of any one of claims 1 to 13, wherein a Michael adduct impurity, 4-[(13aS)-2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-10- chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-2- yl]-3-oxo-propyl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M,M atropisomer, ,Analysis.

15. The method of claims 14 wherein the Michael adduct impurity is less than 0.15% as measured by HPLC Analysis.

16. A pharmaceutical composition comprising a compound of the formula, ,or a pharmaceutically acceptable salt thereof, wherein a Michael adduct impurity, 4-[(13aS)-2-[3-[(13aS)-9-(2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-2-yl]-3-oxo- propyl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M,M atropisomer, ,Analysis, and a pharmaceutically acceptable carrier, diluent or excipient.

17. The pharmaceutical composition of claim 16, wherein the Michael adduct impurity is present in an amount of less than 0.15% as measured by HPLC Analysis.

18. A method of treating a patient for cancer wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof, a pharmaceutical composition according to claims 16 or 17, wherein the cancer is selected from the group consisting of lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

19. A compound of the formula, ,or a obtainable by combining citrate buffer, an acryloyl group, and 4-[(13aS)-10-chloro- 8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2- amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer, ,wherein Michael adduct impurity, 4-[(13aS)-2-[3-[(13aS)-9-(2-amino-3-cyano-7- fluoro-benzothiophen-4-yl)-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a- hexahydropyrazino[2,1-d][1,5]benzoxazocin-2-yl]-3-oxo-propyl]-10-chloro-8-fluoro-6- oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7- fluoro-benzothiophene-3-carbonitrile, M,M atropisomer,,Analysis.

20. The compound of claim 19, wherein the step of combining is in a continuous stirred-tank reactor.

21. The compound of claims 19 or 20, wherein the acryloyl group is acryloyl chloride, acryloyl bromide, or acryloyl anhydride.

22. The compound of any one of claims 19 to 21, wherein the acryloyl group is acryloyl chloride.

23. The compound of any one of claims 19 to 22, wherein the acryloyl group is within the range of approximately 1.05 eq to approximately 1.35 eq relative to the 4- [(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1- d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer.

24. The compound of any one of claims 19 to 23, wherein the acryloyl group is approximately 1.25 eq relative to the 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a- hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro- benzothiophene-3-carbonitrile, M atropisomer.

25. The compound of any one of claims 19 to 24, wherein the citrate buffer is within the range of approximately 2.0 pH to approximately 4.0 pH.

26. The compound of any one of claims 19 to 25, wherein the citrate buffer is approximately 3.0 pH.

27. The compound of any one of claims 19 to 26, wherein the Michael adduct impurity is present in an amount of less than 0.15% as measured by HPLC Analysis.

28. The compound of any one of claims 20 to 27, wherein the continuous stirred-tank reactor is operated within the range of approximately 300 rpm to approximately 600 rpm.

29. The compound of any one of claims 20 to 28, wherein the continuous stirred-tank reactor is operated at approximately 450 rpm.

30. The compound of any one of claims 20 to 29, wherein the citrate buffer is added into the continuous stirred-tank reactor at a flow rate of approximately 3.6 mL / min.

31. The compound of any one of claims 20 to 30, wherein the acryloyl group is added into the continuous stirred-tank reactor at a flow rate of approximately 0.8 mL / min.

32. The compound of any one of claims 20 to 31, wherein the 4-[(13aS)-10- chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazocin- 9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer, ,is added into the continuous stirred-tank reactor at a flow rate of approximately 6.6 mL / min.

33. A method of treating a patient for cancer wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of claims 19 to 32, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervicalcancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

34. The method according to claims 18 or 33 wherein the cancer is non-small cell lung cancer.

35. The method according to claims 18 or 33, wherein the cancer is advanced non-small cell lung cancer.

36. The method according to claims 18 or 33, wherein the cancer is colorectal cancer.

37. The method according to claims 18 or 33, wherein the cancer is pancreatic cancer.

38. The method according to claims 18 or 33, wherein the patient has a cancer that was determined to have one or more cells expressing the KRas G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

39. A method of treating a patient with a cancer that has a KRAS G12C mutation comprising administering to the patient in need thereof a compound according to any one of claims 19 to 32, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claims 16 or 17.

40. The method according to claim 39, wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, a SHP2 inhibitor, or pharmaceutically acceptable salts thereof, or a pharmaceutically acceptable salt thereof.

41. The method according to claim 40, wherein the patient has not received prior therapy with a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof.

42. The method according to claim 40, wherein the patient has not received prior therapy with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, or a SHP2 inhibitor, or pharmaceutically acceptable salts thereof.

43. The method according to claim 40, wherein the patient received prior therapy with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, or a SHP2 inhibitor, or pharmaceutically acceptable salts thereof.

44. The method according to claim 40, wherein the patient received prior therapy with a KRAS G12C inhibitor, or a pharmaceutically acceptable salt thereof.

45. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 19 to 32, or a pharmaceutical composition according to claims 16 or 17, for use in therapy.

46. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 19 to 32, or a pharmaceutical composition according to any one of claims 16 or 17, for use in the treatment of cancer.

47. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 46, wherein the cancer is selected from the group consisting of lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

48. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 19 to 32, or a pharmaceutical composition according to any one of claims16 or 17, for use in simultaneous, separate or sequential combination with one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, or a SHP2 inhibitor, or pharmaceutically acceptable salts thereof, in the treatment of cancer.

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