Methods for making KRAS G12C inhibitors

Abstract

The present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof, processes and intermediates useful for preparing compounds of formula (I), pharmaceutical compositions containing compounds of formula (I), and methods of treating cancer using compounds of formula (I). [Formula 1] TIFF2025511697000118.tif33128

Description

[Technical field]

[0001] The present disclosure relates to compounds and pharma- ceutically acceptable salts thereof that can be used to treat cancer. [Background technology]

[0002] WO 2021 / 118877 and U.S. Patent Application Publication No. 2021 / 0179633(A1) (hereinafter, the "'877 and '633 references") disclose certain KRas G12C inhibitors or salts thereof that can be used to treat cancer. Methods of preparing these compounds are also disclosed. Compounds made using the methods disclosed in the '877 and '633 references may contain impurities. These impurities may include Michael addition impurities that can be difficult to remove. Summary of the Invention [Problem to be solved by the invention]

[0003] It would therefore be useful to develop new processes and intermediates that can be used to prepare compounds of formula I. Preferably, these new processes would provide final compounds that contain fewer impurities, such as Michael reaction-based impurities, and / or improved M:P atropisomer ratios. [Means for solving the problem]

[0004] Disclosed herein are compounds of formula I or pharma- ceutically acceptable salts thereof that can be obtained by using the newly developed intermediates and methods. Also disclosed herein are intermediates useful for preparing compounds of formula I or pharma- ceutically acceptable salts thereof. Also disclosed herein are methods for producing compounds of formula I or pharma- ceutically acceptable salts thereof.

[0005] In one embodiment, acryloyl chloride 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;

[0006] [ka] in a continuous stirred tank reactor, and having less than 1% Michael adduct impurity as determined by HPLC analysis,

[0007] [ka] Compounds of or a pharma- ceutically acceptable salt thereof is disclosed herein. In one embodiment, the compound of formula I or a pharma- ceutically acceptable salt thereof is The following intermediate can be obtained by reacting (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, N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate tert-butyl, potassium carbonate and a catalyst in a solvent:

[0008] [ka] or a pharma- ceutically acceptable salt thereof, The M:P atropisomer ratio is at least 4:1.

[0009] In another embodiment, the compound of formula I or a pharma- ceutically acceptable salt thereof is The following intermediates can be obtained by reacting (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, diacetate [(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II), N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-2-yl]carbamate tert-butyl, a base and 1,1,1-tris(hydroxymethyl)ethane:

[0010] [ka] or a pharma- ceutically acceptable salt thereof, The P atropisomer ratio of the intermediate is at least 4:1.

[0011] With regard to intermediates useful for preparing compounds of formula I or pharma- ceutically acceptable salts thereof, the compounds of formula Ii:

[0012] [ka] An intermediate compound of or a pharma- ceutically acceptable salt thereof is disclosed herein; During the ceremony, R is a protecting group.

[0013] In one embodiment disclosed herein, the intermediate compound of formula Ii is represented by formula Iia:

[0014] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0015] In one aspect, a compound of formula Iia: tert-butyl (3S)-3-(2-hydroxyethyl)piperazine-1-carboxylate, obtainable by combining phosphoric acid (1:1), a base, and 4-bromo-2,5-difluorobenzoic acid to provide (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate, [ka] Compounds of or a pharma- ceutically acceptable salt thereof is disclosed herein.

[0016] With regard to intermediates useful for preparing compounds of formula I or pharma- ceutically acceptable salts thereof, the compounds of formula IIi:

[0017] [ka] An intermediate compound of or a pharma- ceutically acceptable salt thereof is disclosed herein; During the ceremony, R is a protecting group.

[0018] In one embodiment disclosed herein, the intermediate compound of formula IIi is represented by formula IIia:

[0019] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0020] In one embodiment, the compound of formula IIia, obtainable by combining (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate with a cyclization base to give (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate,

[0021] [ka] An intermediate compound of or a pharma- ceutically acceptable salt thereof is disclosed herein.

[0022] In one embodiment, a compound of formula IIIia, obtainable by combining (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate with a chlorinating agent to give (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate,

[0023] [ka] An intermediate compound of or a pharma- ceutically acceptable salt thereof is disclosed herein.

[0024] The present disclosure relates to

[0025] [ka]

[0026] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0027] The present disclosure relates to

[0028] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0029] The present disclosure relates to

[0030] [ka] Also provided is a compound selected from the group consisting of:

[0031] The present disclosure relates to

[0032] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0033] The present disclosure relates to

[0034] [ka] The present invention provides a compound selected from the group consisting of:

[0035] The present disclosure relates to

[0036] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0037] The present disclosure relates to

[0038] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0039] The present disclosure relates to

[0040] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0041] The present disclosure relates to

[0042] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0043] The present disclosure relates to

[0044] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0045] The present disclosure relates to

[0046] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0047] The present disclosure relates to

[0048] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0049] The present disclosure relates to

[0050] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0051] The present disclosure relates to

[0052] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0053] The present disclosure relates to

[0054] [ka] A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

[0055] The present disclosure relates to

[0056] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0057] The present disclosure relates to

[0058] [ka] Compounds of or a pharma- ceutically acceptable salt thereof.

[0059] The present disclosure also provides a pharmaceutical composition comprising a compound according to any one of Examples 1 to 8 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier, diluent or excipient.

[0060] The present disclosure also provides a method of treating a cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of Examples 1-8 or a pharma- ceutically acceptable salt thereof. 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, bile duct cancer, or esophageal cancer. In preferred embodiments, the cancer is advanced non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In even more preferred embodiments, the cancer is non-small cell lung cancer.

[0061] In yet another aspect, the disclosure includes a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of Examples 1-8 or a pharma- ceutically acceptable salt thereof. 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 a mutated pancreatic cancer. In another embodiment, the disclosure includes a method of treating cancers of other origins that have a KRas G12C mutation.

[0062] The present disclosure also provides a method of treating a patient with a cancer having a KRAS G12C mutation, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of Examples 1-8 or a pharma- ceutically acceptable salt thereof.

[0063] The present disclosure also provides a method of modulating a mutant KRas G12C enzyme in a patient in need of such modulation by administering a compound or a pharma- ceutically acceptable salt thereof according to any one of Examples 1 to 8. Preferably, the method comprises inhibiting a human mutant KRas G12C enzyme.

[0064] The compounds of the present disclosure or salts thereof may be prepared by a variety of procedures, some of which are exemplified in the preparations and examples below, and by the preparations and examples in the '877 and '633 references. The compounds of the present disclosure may be prepared by methods well known and well understood in the art, according to the preparations and examples below, and by the preparations and examples in the '877 and '633 references. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitutions of solvents and co-reagents are within the skill of the art. Similarly, those skilled in the art will appreciate that synthetic intermediates may be isolated and / or purified by various well-known techniques as necessary or desired, and that in many cases, various intermediates may be used directly in subsequent synthetic steps with little or no purification. By way of example, the compounds of the preparations and examples may be isolated, for example, by silica gel purification, or may be isolated directly by filtration or crystallization. Furthermore, those skilled in the art will appreciate that under some circumstances, the order in which the moieties are introduced is not important. The particular order of steps required to produce the compounds of the present disclosure will depend on the particular compound being synthesized, the starting compound, and the relative disadvantages of the substituted moieties, as is well understood by the skilled chemist. All substituents are as previously defined unless otherwise indicated, and all reagents are well known and understood in the art.

[0065] The specific synthetic steps of each of the routes described can be combined in different ways or combined with steps of different routes to prepare the compounds or salts of the 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.

[0066] The compounds of the present disclosure can be prepared by several methods well known to those skilled in the art of organic synthesis.As an example, the compounds of the present disclosure can be synthesized using the following methods, together with synthetic methods known in the art of organic synthetic chemistry or variations thereof that are understood by those skilled in the art.Preferred methods include, but are not limited to, the methods described below.

[0067] definition Certain abbreviations are defined as follows: "APCI-MS" refers to atmospheric pressure chemical ionization mass spectrometry; "Boc" refers to tert-butoxycarbonyl; "CDI" refers to 1,1'-carbonyldiimidazole; "CDMT" refers to 2-chloro-4,6-dimethoxy-1,3,5-triazine; "DCC" refers to 1,3-dicyclohexylcarbodiimide; "DIC" refers to 1,3-diisopropylcarbodiimide; "DIPEA" refers to N,N-diisopropylethylamine; "DMAc" refers to dimethylacetamide or DMA; "DMAP" refers to 4-dimethylaminopyridine; and "DMF" refers to N,N-dimethylformamide (N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, "EtOH" refers to ethanol or ethyl alcohol, "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, and "HPLC" refers to high-performance liquid chromatography. "MeTHF" refers to 2-methyltetrahydrofuran, "MP(DSC)" refers to melting point by differential scanning calorimetry, "NCS" refers to N-chlorosuccinimide, "NMM" refers to N-methylmorpholine, "NMP" refers to N-methyl-2-pyrrolidone, "NMR" refers to nuclear magnetic resonance, "PG" refers to a protecting group, "PyBOP" refers to (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), "PyBrOP" refers to bromo(tripyrrolidinyl)phosphonium hexafluorophosphate, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, and "THF" refers to tetrahydrofuran.

[0068] 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 to 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, and "DIPEA" or "DIEA" refers to "DMAc" or "DMA" refers 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, and "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, and "MTBE" refers to methyl tert-butyl ether. ether), "NCS" refers to N-chlorosuccinimide, "NMM" refers to N-methylmorpholine, "NMP" refers to N-methyl-2-pyrrolidone, "NMR" refers to Nuclear Magnetic Resonance, "PG" refers to a protecting group, "PyBOP" refers to (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), "PyBrOP" refers to bromo(tripyrrolidinyl)phosphonium hexafluorophosphate, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, and "THF" refers to tetrahydrofuran.

[0069] A "base" is a molecule that is a proton acceptor or can neutralize an acid. Examples of bases include K 2 CO 3 These include, but are not limited to:

[0070] A "cyclizing base" is a base that aids in ring formation. Examples of "cyclizing bases" include sodium hydride, N,N-diisopropylethylamine (DIPEA or DIEA), triethylamine (TEA), cesium carbonate, diazabicycloundecene (DBU), sodium tert-butoxide, sodium tert-pentoxide, sodium tert-amylate, potassium tert-pentoxide, or potassium tert-butoxide.

[0071] A "cyclization solvent" is a solvent that supports the cyclization reaction. Examples of cyclization solvents include DMF, NMP, DMAc, DMSO, or THF.

[0072] A "chlorinating agent" is an agent that aids in the chlorination of a molecule. Examples of chlorinating agents include trichloroisocyanuric acid or NCS.

[0073] The terms "continuous manufacturing" (hereinafter "CM"), "flow", and "flow chemistry" include the continuous supply of input materials to a manufacturing process, such as a continuously stirred tank reactor, the transformation of in-process materials within the manufacturing process, and the simultaneous removal of output materials from the manufacturing process. These 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, e.g., FDA, "Q13 Continuous Manufacturing of Drug Substances and Drug Products, Guidance for Industry", March 2023).

[0074] The terms "batch," "batch manufacturing," and "batch chemistry" include a specific amount of material produced in a process or series of processes such that the material produced is expected to be homogeneous within specified limits. A batch size can be defined by a fixed amount or by the amount produced in a fixed time interval. (See, e.g., FDA, "Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, Guidance for Industry," September 2016).

[0075] A "catalyst" is a substance that increases the rate of a chemical reaction without itself undergoing any permanent chemical change.

[0076] The term "M:P atropisomer ratio" is the atropisomer ratio between the corresponding M atropisomer and the P atropisomer.

[0077] A "protecting group" is a reversibly formed derivative of an existing functional group in a molecule. Some classes of protecting groups include alcohol protecting groups, amine protecting groups, carbonyl protecting groups, carboxylic acid protecting groups, phosphate protecting groups, and terminal alkyne protecting groups. Carboxylic acid protecting groups include types of protecting groups such as tert-butyl esters.

[0078] As used herein, the terms "treating," "treat," or "treatment" include slowing, alleviating, or reversing the progression or severity of an existing symptom, disorder, or condition, which in particular can include slowing the growth of cancerous lesions or the progression of abnormal cell proliferation and / or cell division.

[0079] As used herein, the term "PD-1" refers to programmed death receptor 1. As used herein, the term "PD-L1" refers to programmed death ligand 1.

[0080] As used herein, the term "CDK4 / CDK6 inhibitor" refers to any chemical entity that inhibits the function of CDK4 / CDK6.

[0081] As used herein, the term "EGFR inhibitor" refers to any chemical entity that inhibits the function of EGFR.

[0082] The term "ERK" refers to extracellular signal-regulated kinase. As used herein, the term "ERK inhibitor" refers to any chemical entity that inhibits the function of ERK.

[0083] As used herein, the term "platinum agent" refers to any platinum-containing chemical that inhibits cancer.

[0084] As used herein, the term "antifolate" refers to any chemical that inhibits the function of folic acid. In one embodiment, the antifolate is pemetrexed.

[0085] As used herein, the term "Aurora A inhibitor" refers to any chemical entity that inhibits the function of Aurora A kinase.

[0086] As used herein, the term "SHP2 inhibitor" refers to any chemical entity that inhibits the function of SHP2.

[0087] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with a PD-1 or PD-L1 inhibitor simultaneously, separately, or sequentially for use in treating a KRAS G12C mutant cancer. In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with pembrolizumab simultaneously, separately, or sequentially for use in treating a KRAS G12C mutant advanced NSCLC. In another embodiment, the PD-1 or PD-L1 inhibitor is pembrolizumab, and the pembrolizumab is administered at 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 one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0088] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of treating KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with pembrolizumab, either simultaneously, separately, or sequentially, in the treatment of KRAS G12C mutant advanced NSCLC, wherein pembrolizumab is administered intravenously at 200 mg once every three weeks. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0089] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a compound of formula I or a pharma- ceutically acceptable salt thereof at a dose of about 50 mg to about 200 mg in combination with a CDK4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof at a dose of about 50 mg to about 200 mg in combination with abemaciclib at a dose of about 50 mg to about 200 mg in combination with abemaciclib at a dose of about 50 mg to about 200 mg in combination with a patient in need of treating a KRAS G12C mutant cancer in the treatment of KRAS G12C mutant advanced NSCLC. In another embodiment, the CDK4 / CDK6 inhibitor is abemaciclib, and the abemaciclib is administered at 150 mg BID. In another embodiment, the CDK4 / CDK6 inhibitor is palbociclib. In another embodiment, the CDK4 / CDK6 inhibitor is ribociclib. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice a day. In one 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.

[0090] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of treating KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with abemaciclib, either simultaneously, separately, or sequentially, in the treatment of KRAS G12C mutant advanced NSCLC. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0091] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a compound of formula I or a pharma- ceutically acceptable salt thereof at a dose of about 50 mg to about 200 mg in combination with an EGFR inhibitor or a pharma- ceutically acceptable salt thereof simultaneously, separately, or sequentially. In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a compound of formula I or a pharma- ceutically acceptable salt thereof at a dose of about 50 mg to about 200 mg in combination with erlotinib simultaneously, separately, or sequentially in treatment of KRAS G12C mutant advanced NSCLC. In another embodiment, the EGFR inhibitor is erlotinib, and erlotinib is administered at 150 mg once daily. In another embodiment, the EGFR inhibitor is afatinib. In another embodiment, the EGFR inhibitor is gefitinib. In another embodiment, the EGFR inhibitor is cetuximab. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0092] In another aspect, disclosed herein is a method for treating KRAS G12C mutant cancer, comprising administering to a patient in need of treating KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with erlotinib, either simultaneously, separately, or sequentially, in the treatment of KRAS G12C mutant advanced NSCLC. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0093] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with cetuximab, either simultaneously, separately, or sequentially, in the treatment of KRAS G12C mutant advanced CRC. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0094] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of treating KRAS G12C mutant cancer a compound of formula I or a pharma- ceutically acceptable salt thereof at a dose of about 50 mg to about 200 mg in combination with an ERK inhibitor or a pharma- ceutically acceptable salt thereof simultaneously, separately, or sequentially. In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of treating KRAS G12C mutant cancer a compound of formula I or a pharma- ceutically acceptable salt thereof at a dose of about 50 mg to about 200 mg in combination with LY3214996 simultaneously, separately, or sequentially in treatment of KRAS G12C mutant advanced NSCLC or CRC. In another embodiment, the ERK inhibitor is LY3214996, and LY3214996 is dosed at 400 mg twice daily. In another embodiment, the ERK inhibitor is LTT462. In another embodiment, the ERK inhibitor is KO-947. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0095] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with LY3214996, either simultaneously, separately, or sequentially, in the treatment of KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0096] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with a platinum agent, either simultaneously, separately, or sequentially. In another embodiment, the platinum agent is cisplatin. In another embodiment, the platinum agent is carboplatin. In another embodiment, the platinum agent is oxaliplatin. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0097] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering a dose of about 50 mg to about 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of treatment for a KRAS G12C mutant cancer, for use in combination with an antifolate simultaneously, separately, or sequentially for the treatment of the KRAS G12C mutant cancer. In another embodiment, the antifolate is pemetrexed. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice a day. In one 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.

[0098] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of Formula I, or a pharma- ceutical acceptable salt thereof, and an Aurora A inhibitor, or a pharma- ceutical acceptable salt thereof. In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of treatment for KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt. In another embodiment, the Aurora A inhibitor is an aminopyridine compound or a pharma- ceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is an Aurora A selective inhibitor, or a pharma- ceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is alisertib, as described in WO 2008 / 063525. In another embodiment, the Aurora A inhibitor is a pan-Aurora inhibitor, or a pharma- ceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is tozasertib, as described in WO 2004 / 000833. In another embodiment, the Aurora A inhibitor is danusertib, as described in WO 2005 / 005427. In another embodiment, the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:

[0099] [ka] or a pharma- ceutically acceptable salt thereof. In one embodiment, the pharma- ceutically acceptable salt is an amine salt. An example of an amine salt is NH 3 Another example of an amine salt is the 2-methylpropane-2-amine salt.

[0100] In another aspect, a method of treating a KRAS G12C mutant cancer is provided comprising administering to a patient in need of treatment a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutical acceptable salt thereof, comprising administering to said patient ...

[0101] [ka] and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt having the formula:

[0102] In another aspect, a method of treating a KRAS G12C mutant cancer is provided comprising administering to a patient in need of treatment a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutical acceptable salt thereof, comprising administering to said patient ...

[0103] [ka] and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt having the formula:

[0104] In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0105] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of treatment of KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in the treatment of KRAS G12C mutant advanced NSCLC, in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt simultaneously, separately, or sequentially. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0106] In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof and an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof. In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with TNO155, either simultaneously, separately, or sequentially, in the treatment of KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the SHP2 inhibitor is a type I SHP2 inhibitor or a type II SHP2 inhibitor. In another embodiment, the type I SHP2 inhibitor is PHPS1 or GS-493, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is NSC-87877 or NSC-117199, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is cefsulodin, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is JAB-3068 or JAB-3312, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RMC-4550 or RMC-4630, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is SHP099, SHP244, SHP389, SHP394, or TNO155, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RG-6433 or RLY-1971, or a pharma- ceutically acceptable salt thereof. In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutical acceptable salt thereof and RMC-4630.In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of Formula I or a pharma- ceutically acceptable salt thereof and JAB-3068. In another embodiment, the SHP2 inhibitor is BBP-398, IACS-15509, or IACS-13909, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is X37 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ERAS-601 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is SH3809 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is HBI-2376 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ETS-001 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is PCC0208023 or a pharma- ceutically acceptable salt thereof. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0107] In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of treating KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with TNO155, either simultaneously, separately, or sequentially, in the treatment of KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0108] In another aspect, disclosed herein is the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, in which a dose of about 50 mg to about 200 mg of a compound of formula I, or a pharma- ceutically acceptable salt thereof, is administered to a patient in need thereof in simultaneous, separate, or sequential combination with a second therapeutic agent.

[0109] In another aspect, disclosed herein is the use of a compound of Formula I or a pharma- ceutical acceptable salt thereof, in the manufacture of a medicament for treating a KRAS G12C mutant cancer, wherein the compound is administered at a dose of about 50 mg to 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 pharma- ceutical acceptable salt thereof, a PD-L1 inhibitor or a pharma- ceutical acceptable salt thereof, a CDK4 / CDK6 inhibitor or a pharma- ceutical acceptable salt thereof, an EGFR inhibitor or a pharma- ceutical acceptable salt thereof, an ERK inhibitor or a pharma- ceutical acceptable salt thereof, a platinum agent or a pharma- ceutical acceptable salt thereof, an antifolate or a pharma- ceutical acceptable salt thereof, an Aurora A inhibitor or a pharma- ceutical acceptable salt thereof, and an SHP2 inhibitor or a pharma- ceutical acceptable salt thereof.

[0110] In another aspect, disclosed herein is the use of a compound of Formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a KRAS G12C mutant cancer, comprising administering to a patient in need thereof a dose of about 50 mg to about 200 mg of a compound of Formula I or a pharma- ceutically acceptable salt thereof in simultaneous, separate, or sequential combination with a PD-1 or PD-L1 inhibitor. In another embodiment, the PD-1 or PD-L1 inhibitor is pembrolizumab, and the pembrolizumab is administered at 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 one embodiment, the dose of the compound of formula I, or a pharma- ceutically acceptable salt thereof, is administered once daily. In one embodiment, the dose of the compound of formula I, or a pharma- ceutically acceptable salt thereof, is administered twice daily. In one embodiment, the dose of the compound of formula I, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0111] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of KRAS G12C-mutated advanced NSCLC, comprising administering to a patient in need thereof a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with pembrolizumab, either simultaneously, separately, or sequentially, wherein pembrolizumab is administered intravenously at 200 mg once every three weeks. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0112] In another aspect, disclosed herein is the use of a compound of Formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament, comprising administering to a patient in need of the compound of Formula I or a pharma- ceutically acceptable salt thereof a dose of about 50 mg to about 200 mg of the compound of Formula I or a pharma- ceutically acceptable salt thereof in simultaneous, separate, or sequential combination with a CDK4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof. In another embodiment, the CDK4 / CDK6 inhibitor is abemaciclib, and the abemaciclib is administered at 150 mg BID. In another embodiment, the CDK4 / CDK6 inhibitor is palbociclib. In another embodiment, the CDK4 / CDK6 inhibitor is ribociclib. In one embodiment, the dose of the compound of Formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of Formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0113] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for administering a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with abemaciclib simultaneously, separately, or sequentially to a patient in need thereof in the treatment of KRAS G12C-mutated advanced NSCLC. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0114] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament, comprising administering to a patient in need of a compound of formula I or a pharma- ceutically acceptable salt thereof a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in simultaneous, separate, or sequential combination with an EGFR inhibitor or a pharma- ceutically acceptable salt thereof. In another embodiment, the EGFR inhibitor is erlotinib, and the erlotinib is administered at 150 mg once a day. In another embodiment, the EGFR inhibitor is afatinib. In another embodiment, the EGFR inhibitor is gefitinib. In another embodiment, the EGFR inhibitor is cetuximab. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0115] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of KRAS G12C-mutated advanced NSCLC, comprising administering to a patient in need thereof a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with erlotinib, either simultaneously, separately, or sequentially. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0116] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of KRAS G12C-mutated advanced CRC, comprising administering to a patient in need thereof a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with cetuximab, either simultaneously, separately, or sequentially. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0117] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament, comprising administering to a patient in need of a compound of formula I or a pharma- ceutically acceptable salt thereof a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in simultaneous, separate, or sequential combination with an ERK inhibitor or a pharma- ceutically acceptable salt thereof. In another embodiment, the ERK inhibitor is LY3214996, which is dosed at 400 mg twice daily. In another embodiment, the ERK inhibitor is LTT462. In another embodiment, the ERK inhibitor is KO-947. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once daily. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice daily. In one embodiment, the dose of the compound of formula I, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0118] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of KRAS G12C-mutated advanced NSCLC or CRC, comprising administering a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with LY3214996, either simultaneously, separately, or sequentially, to a patient in need thereof. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0119] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament, comprising administering to a patient in need of a compound of formula I or a pharma- ceutically acceptable salt thereof a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with a platinum agent, either simultaneously, separately, or sequentially. In another embodiment, the platinum agent is cisplatin. In another embodiment, the platinum agent is carboplatin. In another embodiment, the platinum agent is oxaliplatin. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0120] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament, comprising administering a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof to a patient in need of the compound of formula I or a pharma- ceutically acceptable salt thereof for use in combination with an antifolate simultaneously, separately, or sequentially for the treatment of KRAS G12C mutant cancer. In another embodiment, the antifolate is pemetrexed. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0121] In another aspect, disclosed herein is the use of a compound of Formula I, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament, comprising administering to a patient in need thereof a dose of about 50 mg to about 200 mg of the compound of Formula I, or a pharma- ceutically acceptable salt thereof, and an Aurora A inhibitor, or a pharma- ceutically acceptable salt thereof. In another aspect, disclosed herein is a method of treating KRAS G12C mutant cancer, comprising administering to a patient in need of treatment for KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt. In another embodiment, the Aurora A inhibitor is an aminopyridine compound or a pharma- ceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is an Aurora A selective inhibitor, or a pharma- ceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is alisertib, as described in WO 2008 / 063525. In another embodiment, the Aurora A inhibitor is a pan-Aurora inhibitor, or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is tozasertib, as described in WO 2004 / 000833. In another embodiment, the Aurora A inhibitor is danusertib, as described in WO 2005 / 005427. In another embodiment, the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treatment for a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0122] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of KRAS G12C mutated advanced NSCLC, comprising administering to a patient in need thereof a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1h-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I, or a pharma- ceutically acceptable salt thereof, is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0123] In another aspect, disclosed herein is the use of a compound of Formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament, comprising administering to a patient in need of a compound of Formula I or a pharma- ceutically acceptable salt thereof a dose of about 50 mg to about 200 mg, and an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof. In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of Formula I or a pharma- ceutically acceptable salt thereof in combination with TNO155, either simultaneously, separately, or sequentially, in the treatment of KRAS G12C mutant advanced NSCLC or CRC. In one embodiment, the SHP2 inhibitor is a type I SHP2 inhibitor or a type II SHP2 inhibitor. In another embodiment, the type I SHP2 inhibitor is PHPS1 or GS-493, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is NSC-87877 or NSC-117199, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type I SHP2 inhibitor is cefsulodin, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is JAB-3068 or JAB-3312, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RMC-4550 or RMC-4630, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is SHP099, SHP244, SHP389, SHP394, or TNO155, or a pharma- ceutically acceptable salt thereof. In another embodiment, the type II SHP2 inhibitor is RG-6433 or RLY-1971, or a pharma- ceutically acceptable salt thereof.In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of formula I, or a pharma- ceutically acceptable salt thereof, and RMC-4630.In another aspect, disclosed herein is a method of treating a KRAS G12C mutant cancer, comprising administering to a patient in need of treating a KRAS G12C mutant cancer a dose of about 50 mg to about 200 mg of a compound of Formula I or a pharma- ceutically acceptable salt thereof and JAB-3068. In another embodiment, the SHP2 inhibitor is BBP-398, IACS-15509, or IACS-13909, or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is X37 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ERAS-601 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is SH3809 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is HBI-2376 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is ETS-001 or a pharma- ceutically acceptable salt thereof. In another embodiment, the SHP2 inhibitor is PCC0208023 or a pharma- ceutically acceptable salt thereof. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0124] In another aspect, disclosed herein is the use of a compound of formula I or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of KRAS G12C-mutated advanced NSCLC or CRC, comprising administering a dose of about 50 mg to about 200 mg of a compound of formula I or a pharma- ceutically acceptable salt thereof in combination with TNO155, either simultaneously, separately, or sequentially, to a patient in need thereof. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered once a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is administered twice a day. In one embodiment, the dose of the compound of formula I or a pharma- ceutically acceptable salt thereof is selected from the group consisting of about 50 mg, about 100 mg, about 150 mg, and about 200 mg.

[0125] The compounds of the present disclosure can be synthesized in part according to the steps outlined in Schemes 1-1a below, which include different sequences of construction of intermediates or compounds. Starting materials are either commercially available or made by known procedures reported in the literature or as illustrated below.

[0126] [ka]

[0127] In step 1 of Scheme 1, the protected piperazine-2-ethanol, compound (1), is reacted with a coupling reagent, such as CDMT, in a solvent system, such as acetonitrile and water, and an organic base, such as NMM, and K 2 CO 3In the case of 4-bromo-2,5-difluoro-benzoic acid, compound (2) is coupled in an amide bond formation using an inorganic base such as 4-bromo-2,5-difluoro-benzoic acid. R is a protecting group developed for amino groups such as carbamates and amides. Protecting groups such as carbamate protecting groups including allyloxycarbonyl, fluorenylmethoxycarbonyl, or benzyloxycarbonyl are well known and recognized in the art. A common preferred protecting group can be Boc. Those skilled in the art will recognize that there are several methods and reagents for amide formation resulting from the reaction of a carboxylic acid with an amine. For example, the reaction of an amine compound with a suitable 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 carbonyldiimidazoles such as CDI. Amide coupling additives such as HOBt and HOAt can also be used to enhance the reaction. In addition, uronium or phosphonium salts of non-nucleophilic anions such as HBTU, HATU, PyBOP, and PyBrOP can be used in place of more traditional coupling reagents. Additives 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).

[0128] In step 2, the intramolecular cyclization of compound (3) is completed using a suitable base such as potassium tert-butoxide, sodium tert-amylate, sodium tert-butoxide, sodium tert-pentoxide, DIPEA, TEA, DBU, sodium hydride, etc. in a solvent such as DMF to give compound 4. Other possible solvents can be NMP, DMAc, DMSO, and THF. This intramolecular cyclization of compound (3) to compound (4) can be carried out by slowly adding a solution of compound (3) to an excess of base to minimize impurities from intermolecular reactions.

[0129] In step 3, compound (4) can be chlorinated under acidic conditions using an acid such as TFA together with a chlorinating agent such as trichloroisocyanuric acid or NCS in a solvent such as acetonitrile or DMF to give compound (5).

[0130] [ka]

[0131] Scheme 1a illustrates the chiral synthesis of compound (5a). Compound (1a) can be prepared as described in 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.

[0132] (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 tert-butyl is synthesized using a seven-step sequence starting from commercially available S-aspartic acid, the source of the stereocenter.

[0133] It is known that in the isolation of intermediates, significant impurity elimination can be achieved, including elimination of the R-enantiomer. (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 tert-butyl can be isolated by crystallization to significant impurity elimination. Steps and schemes are used to control process and reagent impurities.

[0134] The present disclosure provides compounds of formula IIa:

[0135] [ka] An intermediate compound of or a pharma- ceutically acceptable salt thereof, comprising the steps of: By using a cyclizing base, Formula I:

[0136] [ka] Or formula Ia:

[0137] [ka] or a pharma- ceutically acceptable salt thereof.

[0138] In one embodiment, the cyclizing base is selected from the group consisting of sodium hydride, N,N-diisopropylethylamine (DIPEA or DIEA), triethylamine (TEA), cesium carbonate, diazabicycloundecene (DBU), sodium tert-butoxide, sodium tert-pentoxide, sodium tert-amylate, potassium tert-pentoxide, and potassium tert-butoxide.

[0139] In another embodiment, the preparation method further comprises a cyclization solvent, hi one embodiment, the cyclization solvent is N,N-dimethylformamide (DMF).

[0140] A process for preparing the same, wherein the cyclization step is carried out at about 0°C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0141] The desired KRAS G12C inhibitor has the following structure:

[0142] [ka] The compound 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 having the formula:

[0143] This compound was disclosed as Example 35 in each of the '877 and '633 references. As disclosed therein, this compound exists as atropisomers. The atropisomers may be separated. See Preparations 167 and 168 of the '877 and '633 references. The desired diastereomer is taught in Preparation 167 of the '877 and '633 references.

[0144] The desired diastereomer corresponds to the M atropisomer. The second diastereomer is further processed to give the following structure:

[0145] [ka] 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 having the formula:

[0146] 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 each of the '877 and '633 references, may be further elaborated to Example 35, M atropisomer, in each of the '877 and '633 references.

[0147] Example 35, the M atropisomer has the following structure:

[0148] [ka] Formula I 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, having the formula:

[0149] The compound of formula I is currently undergoing clinical trials to evaluate its usefulness in treating patients with cancer treatable by inhibiting KRAS G12C (ClinicalTrials.gov Identifier: NCT04956640). The compound of formula I may be used 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, bile duct cancer, gastric cancer, or esophageal cancer.

[0150] Another example of a procedure of interest is Scheme 18 disclosed in each of the '877 and '633 references. As disclosed therein, Scheme 18 shows the coupling of compound 37 with compound 87, followed by cyclization to give compound 88.

[0151] Another example of a procedure of interest is step D of scheme 20 disclosed in each of the '877 and '633 references. As disclosed therein, step D shows the coupling between compound (97) and a partner to give a compound of formula I. The partner can be an acid chloride, a carboxylic acid, or cyanogen bromide. In the case of an acid chloride, a suitable base such as TEA or DIEA in a solvent such as DCM is used. The acid chloride can also be used with potassium carbonate as the base in a biphasic solvent system such as EtOAc, THF, and water. In the case of a carboxylic acid, the conditions include a suitable coupling reagent such as propylphosphonic anhydride with a suitable base such as DIEA in a solvent such as DMF. In the case of a cyanogen bromide partner, a suitable base such as aqueous NaOH in a solvent such as DCM is used.

[0152] The compounds of the present disclosure or their salts may be prepared by various procedures, some of which are illustrated in the following preparations and examples. The specific synthetic steps of each of the described routes can be combined in different ways or combined with steps of different routes to prepare the compounds or salts of the present disclosure. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.

[0153] The compounds of the present disclosure may be prepared according to the following preparations and examples by methods well known and understood in the art. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitutions of solvents and co-reagents are within the skill of the art. Similarly, it will be understood by those skilled in the art that synthetic intermediates may be isolated and / or purified by various well-known techniques as necessary or desired, and that in many cases various intermediates can be used directly in subsequent synthetic steps with little or no purification.

[0154] As an example, the compounds of the present disclosure can be synthesized using the following methods, together with synthetic methods known in the art of organic synthetic chemistry or variations thereof that are understood by those skilled in the art. By way of example, the compounds of the preparations and examples can be isolated, for example, by silica gel purification, or can be isolated directly by filtration or crystallization. Furthermore, those skilled in the art will understand that in some circumstances, the order in which moieties are introduced is not important. The specific order of steps required to produce the compounds of the present disclosure will depend on the particular compound being synthesized, the starting compound, and the relative disadvantages of the substituting moieties, as is well understood by a skilled chemist. All substituents are as previously defined unless otherwise indicated, and all reagents are well known and understood in the art.

[0155] (3S)-tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate:phosphoric acid (1:1), base, and 4-bromo-2,5-difluorobenzoic acid,

[0156] [ka] Also disclosed herein is a method for preparing an intermediate compound of formula Ia or a pharma- ceutically acceptable salt thereof, comprising combining (3S)-tert-butyl 4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate. In one embodiment, the combining step further comprises adding CDMT, acetonitrile, and NMM to 4-bromo-2,5-difluorobenzoic acid. In another embodiment, the combining step further comprises adding K 2 CO 3 and water to the (3S)-tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate:phosphoric acid (1:1).

[0157] Also disclosed herein is a method for preparing an intermediate compound of formula IIa or a pharma- ceutically acceptable salt thereof, comprising cyclizing an intermediate compound of formula Ii or a pharma- ceutically acceptable salt thereof, or an intermediate compound of formula Iia or a pharma- ceutically acceptable salt thereof, by using a cyclizing base. In one embodiment, the cyclizing base is selected from the group consisting of sodium hydride, N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), cesium carbonate, diazabicycloundecene (DBU), sodium tert-butoxide, sodium tert-pentoxide, sodium tert-amylate, potassium tert-pentoxide, and potassium tert-butoxide. In another embodiment, the method further comprises a cyclizing solvent. In yet another embodiment, the cyclizing solvent is N,N-dimethylformamide (DMF). In yet another embodiment, the method is a method in which the cyclizing step is carried out at about 0°C.

[0158] Also disclosed herein is a method for preparing a compound of formula I, comprising combining acryloyl chloride with 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 a continuous stirred tank reactor. In one embodiment, the combining step further comprises adding a feed A comprising a phosphate and water. In one embodiment, the phosphate comprises monopotassium phosphate and dipotassium phosphate. In yet another embodiment, the acryloyl chloride is included in feed B, and feed B comprises 2-methyltetrahydrofuran. In yet another embodiment, 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 included in Feed C, Feed C includes 2-methyltetrahydrofuran and water. In yet another embodiment, the combining step further includes pumping from the continuous stirred tank reactor to a second continuous stirred tank reactor. In yet another embodiment, the Michael adduct impurities are less than 1.5% as measured using HPLC analysis as described herein. In yet another embodiment, the Michael adduct impurities are less than 1% as measured using HPLC analysis as described herein. In yet another embodiment, the Michael adduct impurities are less than 0.75% as measured using HPLC analysis as described herein. In yet another embodiment, the Michael adduct impurities are less than 0.5% as measured using the HPLC analysis described herein. In yet another embodiment, the Michael adduct impurities are less than 0.4% as measured using the HPLC analysis described herein. In yet another embodiment, the Michael adduct impurities are less than 0.3% as measured using the HPLC analysis described herein.In yet another embodiment, the Michael adduct impurity is less than 0.25% as measured using the HPLC analysis described herein. In yet another embodiment, the method further comprises removing the Michael adduct impurity.

[0159] For clarity, in the following schemes, certain stereochemical centers are left unspecified and certain substituents are excluded, but are not intended to limit the teaching of these schemes in any way. It will be understood that all stereoisomers are included. 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 salts to non-salt forms, and isolating the enantiomers. The 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 the compounds of the present 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 EL Eliel and SH Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994).

[0160] Additionally, the intermediates depicted in the following schemes contain some nitrogen or oxygen protecting groups. The variable protecting groups may be the same or different from one occurrence to the next, depending on the specific reaction conditions and the specific transformation carried out. Protection and deprotection conditions are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis", Fourth Edition, by Peter GMWuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

[0161] One of ordinary skill in the art will also understand that the compounds of Formula I-IIa described herein, or pharma-ceutically acceptable salts thereof, can be deuterated (a hydrogen can be replaced by deuterium) and such molecules are considered to be included within the scope of the compounds disclosed herein.

[0162] Preparations and Examples Preparation 1 4-Amino-3-chloro-2,5-difluoro-benzoic acid methyl ester

[0163] [ka] The title compound was prepared similarly to the methods of the '877 and '633 references; Preparation 31. ES / MS m / z: 222 [M+H] + .

[0164] Preparation 2 3-Chloro-2,5-difluoro-4-iodobenzoic acid methyl ester

[0165] [ka] Cuprous iodide (22.7 g, 119 mmol), ACN (100 mL) and tert-butyl nitrite (17.7 mL, 149 mmol) were combined and stirred at room temperature for 45 minutes. 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 3 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 (17.8 g, 54%) as a white solid. 1 H NMR (CDCl 3 )δ 7.60(dd,J=5.6,7.6Hz,1H),3.98(s,3H).

[0166] Preparation 3 3-Chloro-2,5-difluoro-4-iodo-benzoic acid

[0167] [ka] MeOH (50 mL) was added to a solution of 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 the organic solvents. The remaining aqueous solution was cooled with ice chips and the pH was adjusted to about 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%). 1 H NMR δ(DMSO-d6)13.91(s,1H),7.68(dd,J=5.8,7.8Hz,1H).

[0168] Preparation 4 (3R)-tert-butyl 4-(3-chloro-2,5-difluoro-4-iodo-benzoyl)-3-(hydroxymethyl)piperazine-1-carboxylate

[0169] [ka] 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 1 h. A solution of (3R)-tert-butyl 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 h, at 60° C. for 3 h, and 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 and washed with brine. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (10-50% EtOAc / hexanes) to give the title compound (3.82 g, 82%) as a white solid. ES / MS m / z( 35 Cl / 37 Cl)461 / 463[M-tert-Butyl+H] + .

[0170] Preparation 5 (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 ester

[0171] [ka] The title compound was prepared similarly to the methods of the '877 and '633 references; Preparation 117. ES / MS m / z ( 79 Br / 81 Br)407 / 409[M-tert-Butyl+H] + .

[0172] Preparation 20 (3S)-tert-butyl 4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate

[0173] [ka] CDMT (802.8 g, 4.57 mol) was added to the reactor along with acetonitrile (20.0 L) and the mixture was cooled to 0° C. NMM (708.2 g, 7.00 mol) was added and the mixture was stirred at 0° C. for 30 minutes. 4-Bromo-2,5-difluorobenzoic acid (794.8 g, 3.35 mol),

[0174] [ka] was added and the mixture was stirred at 0° C. for 1 h. 2 CO 3 (842 g, 6.09 mol), water (5.0 L) and (3S)-tert-butyl 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 the internal temperature at 0° C. The mixture was stirred for 2.5 h at 0° C. The bottom layer was drained from the reactor. The reaction mixture was stirred at 0° C. for an additional 64 h and then concentrated to 2 L / kg. 2-MeTHF (10.0 L) and n-heptane (3.0 L) were added. 1M NaHCO 3 Aqueous solution (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. 1M NaHCO 3Aqueous solution (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. Aqueous 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 top 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 showed the following spectroscopic characteristics: APCI-MS found 471 and 473 (M+Na + ); 1 H NMR (500MHz, d 6 -DMSO+TFA, multiple rotamers exist) δ7.84(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).

[0175] Preparation 21 (13aS)-9-Bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate tert-butyl ester

[0176] [ka] Sodium tert-pentoxide (462 g, 4.20 mol) was added to the reactor along with DMF (9.1 L). The mixture was stirred to form a solution and cooled to 0° C. A solution of (3S)-tert-butyl 4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (4.03 kg, 31.2% assay, 2.80 mol) in DMF was added over 8 hours at 0° C. 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 the clean reactor. 1.30 kg of the product solution was added to the water over 3 hours at 25° C. The mixture was stirred for 64 hours at 25° C. The resulting solid was isolated by filtration and washed with a mixture of DMF (0.3 L) and water (0.3 L). The crude solid was added to a reactor along with EtOH (628 mL). The mixture was heated to 55° C. and stirred for 30 min. Water (314 mL) was added over 2 h and the mixture was held at 55° C. for an additional 30 min. The slurry was cooled to 20° C. over 2 h and then held at 20° C. for 2 h. The resulting solid was isolated by filtration and washed with a mixture of water (60 mL) and EtOH (60 mL). The product was dried under vacuum at 50° C. for 16 h to give the title compound (98.2 g, 73% yield). APCI-MS found 451 and 453 (M+Na +1 ); 1 H NMR (400MHz, d 6 -DMSO-)δ7.32(d,J=6.0Hz,1H),7.28(d,J=9.2Hz,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,2H),2.06(m,1H),1.76(m,1H),1.04(s,9H).

[0177] Alternative synthesis of preparation 5 (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 ester

[0178] [ka] (13aS)-tert-Butyl 9-bromo-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 the reactor along with acetonitrile (20 mL) and the mixture was cooled to 5° C. Trichloroisocyanuric acid (1.08 g, 4.66 mmol) was added and the mixture was stirred at 5° C. for 5 min. A solution of phosphoric acid (0.96 mL, 14.0 mmol; stock solution was 1.92 mL phosphoric acid in 4.0 mL acetonitrile) was added over 2 min and the mixture was stirred at 5° C. for 23 h. 2 CO 3 Aqueous solution (40%, 20 mL) was added and the mixture was stirred at 5° C. for 30 min, warmed to 20° C., and stirred at 20° C. for 2 h. Ethyl acetate (20 mL) and water (20 mL) were added and the mixture was stirred until the solids had dissolved. Solids reappeared after standing for 1 h. NaHSO 3 Aqueous solution (5%, 10 mL) was added and the mixture was stirred overnight. 2 CO 3 Aqueous solution (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° C. Water (4 volumes) was added over 1 hour and the mixture was stirred at 57° C. for 2 hours. The mixture was cooled and stirred at 20° C. overnight, filtered and washed with 1:2 isopropanol:water (3 volumes). The product was dried under vacuum at 50° C. for 3 hours to give the title compound (1.85 g, 86% yield).

[0179] Preparation 6 (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 ester

[0180] [ka] A solution of (3R)-tert-butyl 4-(3-chloro-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% by weight in paraffin oil) was added. After 4 h 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 (4 times). The combined organic extracts were washed with water (3 times) and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography (15-40% EtOAc / hexanes) to give the title compound (3.82 g, 82%) as a white solid. ES / MS m / z ( 35 Cl / 37 Cl)441 / 443[M-tert-Butyl+H] + .

[0181] Preparation 7 tert-Butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate

[0182] [ka] The title compound was prepared similarly to the methods of the '877 and '633 references; Preparation 14. ES / MS m / z ( 79 Br / 81 Br)315 / 317[M-tert-Butyl+H] + .

[0183] 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

[0184] [ka] A mixture of tert-butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate (3.10 g, 8.35 mmol), bis(pinacolato)diboron (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 min. 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 h. The reaction mixture was filtered through diatomaceous earth. The filtrate was diluted with water and extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (10-50% (20% acetone / DCM) / hexanes) to give the title compound (4.45 g, 87%). ES / MS m / z 363 [M-tert-butyl+H] + .

[0185] Preparation 9 tert-Butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-2-yl]carbamate

[0186] [ka] The title compound was prepared similarly to the methods of the '877 and '633 references; 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).

[0187] Preparations 10 and 11 (13aS)-tert-Butyl 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 and M atropisomer

[0188] [ka] The title compound was prepared similarly to the methods of the '877 and '633 references; Preparation 167. The mixture of atropisomers was separated by silica gel flash chromatography (0-30% acetone / hexanes). Preparation 10 (P atropisomer) was the first compound to elute from the column. Preparation 11 (M atropisomer) was the second compound to elute from the column. Both were analyzed by ES / MS m / z ( 35 Cl / 37 Cl)657 / 659[M+H] + .

[0189] Preparations 12 and 13 (13aS)-tert-Butyl 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 atropisomer and M atropisomer

[0190] [ka] (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 (10.0 g, 21.6 mmol), N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate tert-butyl (12.3 g, 30.4 mmol), A mixture of (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) (also known as "(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthylpalladium dichloride") (3.84 g, 4.42 mmol) was added to 1,4-dioxane (215 mL) that was flushed with nitrogen (direct sparge) for 30 min. The reaction flask was sealed and heated at 105 °C for 14 h. Additional tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-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.

[0191] 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 / hexanes). Preparation 12 (P atropisomer) eluted first, followed by Preparation 13 (M atropisomer). The impure fraction of the P atropisomer was further purified by silica gel flash chromatography. This afforded the two title compounds (P atropisomer, 0.35 g, 2%; M atropisomer, 5.6 g, 38%). Both had ES / MS m / z 619 [M-tert-butyl+H]. + .

[0192] Catalyst screening of preparations 12 and 13. (13aS)-tert-Butyl 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 atropisomer and M atropisomer

[0193] [ka] In a glove box, a mixture of (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate (0.025 g, 0.054 mmol), 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 progress and ratio of atropisomers:

[0194] [Table 1]

[0195] Alternative synthesis of preparation 13 (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 tert-butyl, M atropisomer

[0196] [ka] To a small flask in a glove box was added palladium(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 gave [(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) diacetate. The mixture was capped and stirred for 1 h. (13aS)-tert-butyl 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 solid was rinsed with toluene (25 mL), which was added to the original filtrate.

[0197] 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.

[0198] To a third flask was added tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-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 minutes.

[0199] 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 / hr). After a total of 10 hours of heating, HPLC analysis showed complete conversion of the bromide starting material to product with a 4.36:1 M:P atropisomer ratio.

[0200] After a total of 12 hours of heating, the mixture was cooled 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 (approximately 20%) of the organic layer (26.2 g) was distilled to approximately 10 mL, diluted with isopropyl acetate (20 mL), distilled to approximately 10 mL, diluted with isopropyl acetate (20 mL) and distilled to approximately 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.

[0201] Preparations 14 and 15 (4aR)-tert-Butyl 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 and M atropisomer

[0202] [ka] A solution of 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 (0.50 g, 1.01 mmol), tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (0.63 g, 1.51 mmol), and potassium phosphate (0.50 g, 2.36 mmol) in water (2 mL) and 1,4-dioxane (10 mL) was flushed with nitrogen (direct sparge) for 10 min. 1,1'-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.20 g, 0.30 mmol) was added, and the reaction flask was sealed and heated at 70° C. for 3 hours.

[0203] A solution of 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 (0.20 g, 0.40 mmol), tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (0.24 g, 0.57 mmol), and potassium phosphate (0.20 g, 0.96 mmol) in water (2.5 mL) and 1,4-dioxane (8 mL) was flushed with nitrogen (direct sparge) for 10 min. 1,1'-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.080 g, 0.12 mmol) was added, and the reaction flask was sealed and heated at 70° C. for 5 hours.

[0204] The two reaction mixtures were combined and filtered through diatomaceous earth, rinsing with EtOAc. The filtrate was diluted with MTBE and saturated aqueous sodium bicarbonate. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography (0-30% acetone in hexanes). Preparation 14 (P atropisomer) eluted first, followed by Preparation 15 (M atropisomer). The impure fraction of the P atropisomer was further purified by silica gel flash chromatography (0-100% EtOAc / hexanes). This afforded the two title compounds (P atropisomer, 0.17 g, 17%; M atropisomer, 0.21 g, 21%). Both were identified by ES / MS m / z ( 35 Cl / 37 Cl)605 / 607[M-tert-Butyl+H] + .

[0205] 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

[0206] [ka] TFA (4 mL) was added to a solution of (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 tert-butyl, P atropisomer (0.98 g, 1.5 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 3 h, 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 ( 35 Cl / 37Cl)457 / 459[M+H] + .

[0207] 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

[0208] [ka] The title compound was prepared similarly to the methods of the '877 and '633 references; Preparation 187. ES / MS m / z ( 35 Cl / 37 Cl)457 / 459[M+H] + .

[0209] 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

[0210] [ka] TFA (2 mL) was added to a solution of (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 tert-butyl, P atropisomer (0.018 g, 0.027 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 30 min, concentrated in vacuo, and purified by silica gel flash chromatography (0-10% MeOH in DCM, followed by 0-10% 7N ammoniated MeOH in DCM) to give the title compound (0.013 g, 100%). ES / MS m / z ( 35 Cl / 37 Cl)461 / 463[M+H] + .

[0211] 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

[0212] [ka] TFA (2.5 mL) was added to an ice-cold solution of (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 tert-butyl, M atropisomer (0.20 g, 0.31 mmol) in DCM (2.5 mL). The reaction mixture was stirred at room temperature for 2 h, 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 ( 35 Cl / 37Cl)461 / 463[M+H] + .

[0213] 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

[0214] [ka] (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 tert-butyl, M atropisomer (100.0 g, 148.1 mmol) was added to a reactor containing 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° C. for 20 h and then cooled to 0° C. with stirring. A mixture of KOH (118.8 g, 1.80 mol) in water (1.0 L) was added slowly with stirring. 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 approximately 200 mL. Acetonitrile (1.0 L) was added dropwise. The mixture was stirred and cooled to 0° C. for 1 h. The solid was collected by filtration, washed with acetonitrile (200 mL) and dried under vacuum to give the title compound as a white solid (66.4 g, 85% yield). APCI-MS 475 (M+H + ).

[0215] Examples 1 and 2 (13aS)-9-(2-amino-7-fluoro-1,3-benzothiazol-4-yl)-8,10-dichloro-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocin-6-one, P atropisomer and M atropisomer

[0216] [ka] The title compounds were prepared similarly to the methods in the '877 and '633 references; Example 1. The mixture of atropisomers was dissolved in 100 mL of 100 mL of 100% EtOH / CO 2 The separation was performed using a chromatograph at 5 mL / min and 225 nm. Example 1 (P atropisomer) was the first compound to elute from the column. Example 2 (M atropisomer) was the second compound to elute from the column. Both were analyzed by ES / MS m / z ( 35 Cl / 37 Cl)521 / 523[M+H] + .

[0217] Example 3 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-benzothiophene-3-carbonitrile, P atropisomer

[0218] [ka] 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-benzothiophene-3-carbonitrile, P atropisomer (0.115 g, 0.252 mmol) and DIEA (0.20 mL, 1.2 mmol) in DCM (2 mL) was cooled to -78 °C. Acryloyl chloride (0.02 mL, 0.2 mmol) was added. After 5 min, it was diluted with a small amount of 2-propanol and concentrated in vacuo. The crude was purified by silica gel flash chromatography (20-100% acetone / hexanes) to give the title compound (0.091 g, 71%). ES / MS m / z ( 35 Cl / 37 Cl)511 / 513[M+H] + .

[0219] Example 4 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-benzothiophene-3-carbonitrile, M atropisomer

[0220] [ka] The title compound was prepared similarly to the methods of the '877 and '633 references; Example 34. ES / MS m / z ( 35 Cl / 37 Cl)511 / 513[M+H] + .

[0221] Example 5 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, P atropisomer

[0222] [ka] TFA (1 mL) was added to a solution of (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 tert-butyl, P atropisomer (0.025 g, 0.037 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 30 min and then concentrated in vacuo to give the crude deprotected material.

[0223] The residue was dissolved in DCM (1 mL) and DIEA (0.013 mL, 0.074 mmol) was added. The solution was cooled to -78°C. A solution of acryloyl chloride (0.0030 mL) in DCM (1 mL) was added. After 30 min, it was concentrated in vacuo. The crude was purified by silica gel flash chromatography (20-80% acetone in hexanes) to give the title compound (0.012 g, 61%). ES / MS m / z ( 35 Cl / 37 Cl)529 / 531[M+H] + .

[0224] Example 6 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

[0225] [ka] HCl gas was bubbled through an ice-cold solution of (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 tert-butyl, M atropisomer (0.786 g, 1.17 mmol) in DCM (12 mL) and 2-propanol (12 mL) for 5 min. The reaction mixture was stirred at room temperature for 5 h and then cooled in an ice bath. HCl gas was bubbled through the reaction mixture for 5 min. The reaction mixture was stirred at room temperature for 14 h and then concentrated in vacuo. The residue was diluted twice with n-heptane and concentrated in vacuo. MTBE (50 mL) was added. The mixture was stirred at room temperature for 10 min and then filtered to give the deprotected material as the dihydrochloride salt.

[0226] 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 stirred vigorously while cooling in an ice bath. A solution of acryloyl chloride (0.10 mL, 1.28 mmol) in 2-methyltetrahydrofuran (5 mL) was added dropwise. After 5 min, it was diluted with brine and 2-methyltetrahydrofuran. The aqueous layer was extracted with 2-methyltetrahydrofuran (2 times). 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 ( 35 Cl / 37 Cl)529 / 531[M+H] + .

[0227] Alternative synthesis of Example 6: 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

[0228] [ka] A continuously stirred tank reactor (105 mL, 15 °C) was charged with Feed A [monopotassium phosphate (25.02 g), dipotassium phosphate (2.61 g), and water (to 600 mL volume); pH approx. 5.8; flow rate 4.73 g / min], Feed B [acryloyl chloride (13.15 g, 1.15 equiv.) and 2-methyltetrahydrofuran (6 volumes); flow rate 2.48 g / min], and Feed C [4-[(13aS)-10-chloro-2,4-dihydro-1,5 ... [0.126 mol]-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] were added. 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") were: 0.1% H using an Agilent 1260 chromatograph equipped with a UV detector. 3 PO 4Contains an Inertsil ODS-3V column (4.6 × 250 mm; 5 μm) eluted with 20%–95% ACN in aqueous solution. HPLC analysis showed 0.33% of the 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;

[0229] [ka] showed.

[0230] "MA impurity" shown in Table 2. This MA impurity is a Michael adduct in which 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, the M atropisomer, reacts with the compound of formula I, thereby forming a dimer. It is possible that trace amounts of the corresponding M,P atropisomer dimer may be present. The lower percentage of this impurity in the flow reaction compared to the higher percentage of this impurity in the comparative batch reaction was surprising and unexpected. The final mixture layers were separated. The aqueous layer was extracted with 2-methyltetrahydrofuran (5 volumes). The combined organic phase was washed twice with aqueous sodium bicarbonate (5% by weight, 10 vol) and once with aqueous sodium chloride (10%, 10 vol). The organic phase was concentrated to 10 vol, diluted with isopropanol (10 vol), concentrated to 10 vol, diluted with isopropanol (10 vol), stirred at 15° C. for 2 h, filtered, washed and dried to give the crude title compound (approximately 60 g).

[0231] The crude title compound (approximately 50 g) was dissolved in 4:1 THF:MeOH (11 vol) at 35° C., diluted with methylcyclohexane (0.58 vol), seeded (2.5 wt%) and stirred for 30 min. Methylcyclohexane (12.3 vol) was added slowly over 10-12 h. The mixture was stirred overnight at 35° C., filtered, washed with methylcyclohexane (2 vol) and dried to give the title compound (46.4 g, 84% corrected yield).

[0232] Alternative synthesis of Example 6: 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

[0233] [ka] A batch reaction (1 / 6 scale) was performed in which a solution of acryloyl chloride (2.19 g, 1.15 equiv.) in 2-methyltetrahydrofuran (6 volumes) was added dropwise 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.

[0234] [Table 2]

[0235] Example 7 4-[(4aR)-7-chloro-9-fluoro-11-oxo-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, P atropisomer

[0236] [ka]

[0237] Acryloyl chloride (0.0022 mL, 0.027 mmol) was added to an ice-cold mixture of 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 (0.013 g, 0.027 mmol) and potassium carbonate (0.011 g, 0.082 mmol) in EtOAc (0.27 mL) and water (0.27 mL). After 20 min, it was diluted with EtOAc and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash chromatography (20-100% acetone in hexanes) to give the title compound (0.011 g, 78%). ES / MS m / z( 35 Cl / 37 Cl)515 / 517[M+H] + .

[0238] Example 8 4-[(4aR)-7-chloro-9-fluoro-11-oxo-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer

[0239] [ka] Acryloyl chloride (0.25 M in DCM, 1.1 mL, 0.28 mmol) was added to an ice-cold mixture of 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 (0.128 g, 0.28 mmol) and potassium carbonate (0.12 g, 0.83 mmol) in EtOAc (3 mL) and water (3 mL). After 5 min, it was diluted with EtOAc and the layers were separated. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel flash chromatography (0-10% 7N ammoniated MeOH / DCM) to give the title compound (0.13 g, 87%). ES / MS m / z( 35 Cl / 37 Cl)515 / 517[M+H] + .

[0240] Biological assays The following assays demonstrate that the exemplified compounds are inhibitors of KRas G12C and inhibit the growth of certain tumors in vitro and / or in vivo.

[0241] KRas G12C probe occupancy TR-FRET assay The purpose of this assay is to measure the ability of inhibitors to compete with the probe for binding and covalently modifying KRas G12C at codon 12. Signal is generated by time-resolved transfer of fluorescence between europium on antibody bound to KRas G12C europium-labeled anti-histidine tag antibody LanthaScreen (Eu Anti-His antibody) and fluorescent tracer 647 (Alexa Fluor™) bound to KRas G12C ("KRas probe", see preparation 223) via streptavidin and biotinylated inhibitor.

[0242] Inhibitors are tested in a dose-response format from 10 mM stocks in 100% DMSO. Using a Labycyte Echo® 555, dilute and transfer 100 nL per well containing 10-point, 2.8-fold serial dilutions to the assay plate. After 5 and 60 minutes of incubation of inhibitors with KRas G12C, prepare two copies of the assay plate to measure potency. His-tagged KRas G12C (20 nM) is added to the plate in assay buffer (20 mM Tris-HCl, pH 7.5, 0.01% TX-100, 1 mM DTT). After 5 or 60 minutes of incubation, add 1 μM KRas probe and allow free KRas G12C to be covalently modified for 1 hour. This is diluted 4-fold in buffer containing Eu Anti-His antibody and streptavidin-coated tracer 647 (both from Life Technologies) to achieve KRas G12C (5 nM), Anti-His antibody (2 nM), KRas probe (300 nM), and streptavidin-coated tracer 647 (500 nM). After 30 minutes, the fluorescent signal is read on an Envision™ plate reader (excitation at 340 nM, tracer emission (em) at 665 nM, and antibody emission at 615 nM). Maximum control wells lack inhibitor, and minimum control wells lack both inhibitor and KRas G12C. The signal ratio (em at 665 / em at 615) is converted to percent inhibition using the following equation: % inhibition = 100 - [(test compound signal - minimum median signal) / (maximum median signal - minimum median signal) x 100]. IC 50 is determined by fitting the percent inhibition at each inhibitor concentration to a four parameter non-linear logistic equation using Genedata Screener®: y=(A+((BA) / (1+((C / x)^D)))) where y=% inhibition, A=minimum asymptote, B=maximum asymptote, C=relative IC 50or the inhibitor concentration that produces 50% inhibition within the range of fit of both asymptote, and D=Hill slope). Compounds within the scope of the present disclosure are evaluated in this assay substantially as described above. Exemplary compounds of the present disclosure that are evaluated in this assay exhibit KRas G12C inhibitor activity by competing with the probe for binding to KRas G12C and covalently modifying KRas G12C at codon 12, as shown in Table 3.

[0243] [Table 3]

[0244] As shown in Table 3, Examples 2, 4, 6 and 8 (designated M atropisomers) exhibit superior IC50 concentrations compared to Examples 1, 3, 5 and 7 (designated P atropisomers).

[0245] H358 Cell Phospho-ERK AlphaLISA® The purpose of this assay is to measure the ability of test compounds to inhibit phosphorylation of p-ERK1 / 2, a downstream effector of KRas, in human lung cancer cells H358 (ATCC CRL-5807). Briefly, the AlphaLISA® SureFire® Ultra™ p-ERK1 / 2 (Thr202 / Tyr204) Assay is a sandwich immunoassay for the quantitative detection of phospho-ERK1 / 2 (phosphorylated at Thr202 / Tyr204 of ERK1 or Thr185 / Tyr187 of ERK2) in cell lysates using Alpha Technology (Perkin Elmer Cat. No. ALSU-PERK-A50K).

[0246] Seed H358 cells at 40K cells per well in 100 μL medium (RPMI1640, GIBCO catalog number 22400-071) containing 10% FBS (GIBCO catalog number: 10082-147) in a 96-well plate (Costar #3596) and incubated at 37 °C and 5% CO. 2The next morning, add 10 μL of serially diluted (3x) test compounds (highest concentration of 50 μM) and 10 μL of control (maximum signal wells: 5% DMSO and minimum signal wells: 2 μM N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-D]pyrimidin-1(2H)-yl}phenyl)acetamide (trametinib as positive control) to the cell plates and incubate at 37 °C / 5% CO. 2 Incubate at 37 °C for 2 h in a humid tray. Prepare lysis buffer with protease and phosphatase inhibitor cocktail at ambient temperature. Remove culture medium by inverting cell plate in sink, shaking, then blotting with paper towel. Add lysis buffer to cell plate (50 μL per well) and incubate plate at ambient temperature for 10 min on shaker. For p-ERK detection, acceptor beads are diluted in suspension mixture with buffer. Using STARlet liquid handler, transfer 5 μL of acceptor beads and 2 μL of cell lysate as single step in-chip dilution to 384-well assay plate. Seal assay plate with foil and incubate at ambient temperature for 2 h. Dilute donor beads in suspension mixture with buffer. Using STARlet, add 5 μL of donor beads to assay plate, then seal it and wrap it in foil. Incubate plate in dark at ambient temperature for 2 h. The assay plate is then read on an EnVision™ plate reader (Perkin Elmer) using the luminescence program.

[0247] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test compound signal - Median minimum signal) / (Median maximum signal - Median minimum signal) x 100]. The maximum signal is the control well with no inhibitor. The minimum signal is the control well containing enough reference inhibitor to completely inhibit activity. IC 50is determined by fitting the percent inhibition at each inhibitor concentration to a four parameter non-linear logistic equation using Genedata Screener®: y=(A+((BA) / (1+((C / x)^D)))) where y=% inhibition, A=minimum asymptote, B=maximum asymptote, C=relative IC 50 or the inhibitor concentration that produces 50% inhibition within the fit range of both asymptote, and D = Hill slope).

[0248] Compounds within the scope of the present disclosure are evaluated in this assay substantially as described above.Example compounds show the ability to inhibit the phosphorylation of p-ERK1 / 2.The data in Table 4 show that example compounds show KRas G12C inhibitory activity in this cellular assay.

[0249] [Table 4]

[0250] H358 Cellular Activity RAS GTPase ELISA The purpose of this assay is to measure the ability of test compounds to inhibit the activity of constitutive RAS GTPase in human lung cancer cells H358 (ATCC CRL-5807). The RAS GTPase ELISA kit (Active Motif catalog number 52097) contains a 96-well plate pre-coated with glutathione to capture the GST-Raf-RBD protein supplied in the kit. Activated RAS (GTP bound) in the cell extract specifically binds to Raf-RBD. Bound RAS is detected with a primary antibody that recognizes human KRas. A secondary antibody conjugated to HRP recognizes the primary antibody, and a developing solution provides a chemiluminescent readout.

[0251] Seed H358 cells at 80,000 cells / well in 90 μL serum-free medium (RPMI1640, GIBCO) and incubate at 37 °C / 5% CO 2The next morning, add 10 μL of serially diluted (3x) test compounds (500 μM highest concentration) and 10 μL of control (maximum signal wells: 5% DMSO and minimum signal wells: 500 μM 1-[4-[6-chloro-8-fluoro-7-(3-hydroxy-1-naphthyl)quinazolin-4-yl]piperazin-1-yl]prop-2-en-1-one, WO2015054572, as inhibitor) to the cell plates and incubate at 37 °C / 5% CO. 2Incubate at 4°C for 2 hours. Prepare complete lysis / binding buffer containing protease inhibitor cocktail and GST-Raf-RBD and store on ice. One hour before the incubation of the cell plate is completed, dilute 50 μL of GST-Raf-RBD in lysis / binding buffer and add the buffer to the ELISA assay plate, which is incubated at 4°C for 1 hour with gentle rocking. After 2 hours, wash the cells with 100 μL of ice-cold PBS and lyse with 100 μL of lysis / binding buffer. Shake the cell plate for 10 minutes at ambient temperature. Then, centrifuge the cell plate at 1500 rpm for 10 minutes at ambient temperature. During this time, prepare 1x wash buffer at ambient temperature and then use to wash (3x100 μL) the GST-Raf-RBD coated assay plate. After washing, 50 μL of cell lysate is added to the GST-Raf-RBD coated assay plate and incubated for 1 hour at ambient temperature with gentle shaking. During this incubation period, 1x antibody binding buffer is prepared and brought to ambient temperature. The assay plate is washed 3x100 μL with 1x wash buffer, then 50 μL of primary antibody (diluted 1:500 in 1x antibody binding buffer) is added. The plate is incubated for 1 hour at ambient temperature. The assay plate is washed 3x100 μL with 1x wash buffer, then 50 μL of secondary antibody (diluted 1:5000 in 1x antibody binding buffer) is added and incubated for 1 hour at ambient temperature. The assay plate is washed 4x100 μL with 1x wash buffer, then 50 μL of chemiluminescence standard solution is added at ambient temperature. The assay plate is then read on an EnVision™ plate reader (Perkin Elmer) using the luminescence program.

[0252] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test compound signal - Median minimum signal) / (Median maximum signal - Median minimum signal) x 100]. The maximum signal is the control well with no inhibitor. The minimum signal is the control well containing enough reference inhibitor to completely inhibit activity. IC 50is determined by fitting the percent inhibition at each inhibitor concentration to a four parameter non-linear logistic equation using Genedata Screener®: y=(A+((BA) / (1+((C / x)^D)))) where y=% inhibition, A=minimum asymptote, B=maximum asymptote, C=relative IC 50 or the inhibitor concentration that produces 50% inhibition within the fit range of both asymptote, and D = Hill slope).

[0253] Compounds within the scope of the present disclosure are evaluated in this assay substantially as described above.Example compounds show the ability to inhibit constitutive RAS GTPase activity.The data in Table 5 show that example compounds show KRas-GTP inhibitory activity in this human lung cancer cell culture.

[0254] [Table 5]

[0255] Additional embodiments: Embodiment 1. A compound selected from the group consisting of:

[0256] [ka] or a pharma- ceutically acceptable salt thereof.

[0257] Embodiment 2. A compound according to embodiment 1, selected from the group consisting of:

[0258] [ka] or a pharma- ceutically acceptable salt thereof.

[0259] Embodiment 3. A compound according to embodiment 1, selected from the group consisting of:

[0260] [ka]

[0261] Embodiment 4. A compound according to embodiment 1, selected from the group consisting of:

[0262] [ka] or a pharma- ceutically acceptable salt thereof.

[0263] Embodiment 5. A compound according to embodiment 1, selected from the group consisting of:

[0264] [ka] Embodiment 6. A compound according to embodiment 1, selected from the group consisting of:

[0265] [ka] or a pharma- ceutically acceptable salt thereof.

[0266] Embodiment 7. The compound of embodiment 1 or 6, wherein the compound is

[0267] [ka] or a pharma- ceutically acceptable salt thereof.

[0268] Embodiment 8. The compound of embodiment 1 or 6, wherein the compound is

[0269] [ka] or a pharma- ceutically acceptable salt thereof.

[0270] Embodiment 9. A compound according to embodiment 1, selected from the group consisting of:

[0271] [ka] or a pharma- ceutically acceptable salt thereof.

[0272] Embodiment 10. The compound of embodiment 1 or 9, wherein the compound is

[0273] [ka] or a pharma- ceutically acceptable salt thereof.

[0274] Embodiment 11. The compound of embodiment 1 or 9, wherein the compound is

[0275] [ka] or a pharma- ceutically acceptable salt thereof.

[0276] Embodiment 12. A compound according to embodiment 1, selected from the group consisting of:

[0277] [ka] or a pharma- ceutically acceptable salt thereof.

[0278] Embodiment 13. The compound of embodiment 1 or 12, wherein the compound is

[0279] [ka] or a pharma- ceutically acceptable salt thereof.

[0280] Embodiment 14. The compound of embodiment 1 or 12, wherein the compound is

[0281] [ka] or a pharma- ceutically acceptable salt thereof.

[0282] Embodiment 15. A compound according to embodiment 1, selected from the group consisting of:

[0283] [ka] or a pharma- ceutically acceptable salt thereof.

[0284] Embodiment 16. The compound of embodiment 1 or 15, wherein the compound is

[0285] [ka] or a pharma- ceutically acceptable salt thereof.

[0286] Embodiment 17. The compound of embodiment 1 or 15, wherein the compound is

[0287] [ka] or a pharma- ceutically acceptable salt thereof.

[0288] Embodiment 18. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 17, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0289] Embodiment 19. A method of treating a patient with cancer, wherein one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need of treatment an effective amount of the pharmaceutical composition of embodiment 6, wherein the cancer is selected from lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

[0290] Embodiment 20. A method of treating a patient with cancer, wherein one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of embodiments 1 to 17 or a pharma- ceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

[0291] Embodiment 21 The method of embodiment 19, wherein the cancer is non-small cell lung cancer.

[0292] Embodiment 22 The method of embodiment 19 or 20, wherein the cancer is advanced non-small cell lung cancer.

[0293] Embodiment 23 The method of embodiment 19, wherein the cancer is colorectal cancer.

[0294] Embodiment 24 The method of embodiment 19, wherein the cancer is pancreatic cancer.

[0295] Embodiment 25. The method of embodiment 19, wherein the patient has a cancer determined to have one or more cells expressing a KRas G12C mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

[0296] Embodiment 26. A method of treating a patient with a cancer having a KRAS G12C mutation, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of embodiments 1 to 17, or a pharma- ceutically acceptable salt thereof.

[0297] Embodiment 27. The method of any one of embodiments 19-25, wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

[0298] Embodiment 28. The method of any one of embodiments 19 to 26, wherein the patient has not undergone prior treatment with a KRAS G12C inhibitor or a pharma- ceutically acceptable salt thereof.

[0299] Embodiment 29. The method of any one of embodiments 19-27, wherein the patient has not been pretreated with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

[0300] Embodiment 30. The method of any one of embodiments 19-27, wherein the patient has been pretreated with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

[0301] Embodiment 31. The method of any one of embodiments 19-26, wherein the patient has been pretreated with a KRAS G12C inhibitor or a pharma- ceutically acceptable salt thereof.

[0302] Embodiment 32. The method of any one of embodiments 19-26 or 30, wherein the patient has not been pretreated with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

[0303] Embodiment 33. The method of any one of embodiments 19-26 or 30, wherein the patient has been pretreated with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

[0304] Embodiment 34. A compound according to any one of embodiments 1 to 17, or a pharma- ceutically acceptable salt thereof, for use in therapy.

[0305] Embodiment 35. A compound according to any one of embodiments 1 to 17, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

[0306] Embodiment 36. The compound or a pharma- ceutically acceptable salt thereof for use according to embodiment 35, wherein the cancer is selected from lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

[0307] Embodiment 37. A compound according to any one of embodiments 1 to 17 or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer in simultaneous, separate or sequential combination with one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

[0308] 38. A process for preparing a compound according to embodiment 1 or 9, comprising separating the M and P atropisomers of 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 by silica gel flash chromatography.

[0309] Embodiment 39. The method of embodiment 38, further comprising using 0-30% acetone in hexane.

[0310] Embodiment 40. A method comprising the steps of: adding TFA to a solution of the P atropisomer of 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 in DCM, followed by Stirring at approximately room temperature for approximately 3 hours; concentrating in vacuum; 40. The method of embodiment 38 or 39, further comprising:

[0311] EMBODIMENT 41. 41. The method of any one of embodiments 38-40, further comprising purifying the P atropisomer 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-benzothiophene-3-carbonitrile by silica gel flash chromatography.

[0312] Embodiment 42. The method of embodiment 41, further comprising using 4-10% 7N ammoniated MeOH in DCM.

[0313] Embodiment 43. A method comprising the steps of: cooling a solution of the P atropisomer 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-benzothiophene-3-carbonitrile, atropisomer 1, and DIEA in DCM to about −78° C.; and adding acryloyl chloride; and after about 5 minutes, diluting with a small amount of 2-propanol; concentrating in vacuum; 43. The method of any one of embodiments 38 to 42, further comprising:

[0314] Embodiment 44. A method comprising the steps of: 44. The method of any one of embodiments 38-43, further comprising purifying the P atropisomer of 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-benzothiophene-3-carbonitrile by silica gel flash chromatography.

[0315] Embodiment 45. The method of any one of embodiments 38 to 44, further comprising using 20 to 100% acetone in hexane.

[0316] EMBODIMENT 46. 13. A process for preparing a compound according to embodiment 1 or 12, comprising reacting (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, N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate tert-butyl, potassium carbonate and dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) with 1,4-dioxane in a reaction flask.

[0317] Embodiment 47. The method of embodiment 46, wherein the 1,4-dioxane is flushed with nitrogen by direct sparging for 30 minutes.

[0318] Embodiment 48. A method comprising the steps of: sealing the reaction flask and heating at 105° C. for about 14 hours; and then adding additional tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate and dichloro[(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II); and then sealing the reaction flask and heating at 105° C. for about 14 hours to produce a reaction mixture. 48. The method of embodiment 46 or 47, further comprising:

[0319] Embodiment 49. A method comprising the steps of: filtering the reaction mixture through diatomaceous earth; rinsing with EtOAc to produce a filtrate; 49. The method of embodiment 48, further comprising:

[0320] Embodiment 50. A method comprising the steps of: concentrating the filtrate in vacuo; diluting with EtOAc, water and brine to form an aqueous layer; 50. The method of embodiment 49, further comprising:

[0321] Embodiment 51. A method comprising the steps of: extracting the aqueous layer with EtOAc to produce at least one organic extract; and drying the organic extract over magnesium sulfate, filtering and concentrating in vacuo; The method of any one of embodiments 46 to 50, further comprising:

[0322] Embodiment 52. A method comprising the steps of: 52. The method of any one of embodiments 46-51, further comprising purifying the M and P atropisomers 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 by silica gel flash chromatography.

[0323] Embodiment 53. The method of embodiment 52, further comprising using 10-40% acetone in hexane.

[0324] Embodiment 54. A method comprising the steps of: adding TFA to a solution of the P atropisomer 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 in DCM; stirring at room temperature for about 30 minutes; and then concentrating in vacuo to obtain a crude deprotected residue. 54. The method of any one of embodiments 46 to 53, further comprising:

[0325] Embodiment 55. A method comprising the steps of: dissolving the crude deprotected residue in DCM and DIEA and then cooling to -78°C; adding acryloyl chloride in DCM and after about 30 minutes concentrating in vacuo; 55. The method of embodiment 54, further comprising:

[0326] Embodiment 56. A method comprising the steps of: 56. The method of any one of embodiments 46-55, further comprising purifying the P atropisomer of 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 by silica gel flash chromatography.

[0327] Embodiment 57. The method of embodiment 56, further comprising using 20-80% acetone in hexane.

[0328] Embodiment 58. A method comprising the steps of: bubbling HCl gas through an ice-cold solution of the M atropisomer 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 in DCM and 2-propanol for about 5 minutes; stirring at about room temperature for about 5 hours; and thereafter cooling in an ice bath; and thereafter A step of passing HCl gas for about 5 minutes; and then stirring at about room temperature for about 14 hours; and thereafter concentrating in vacuo to produce a residue; Diluting the residue twice with n-heptane, and then concentrating in vacuum; and thereafter adding MTBE; stirring at about room temperature for about 10 minutes; and filtering to produce the dihydrochloride salt. The method of any one of embodiments 46 to 57, further comprising:

[0329] Embodiment 59. A method comprising the steps of: dissolving the dihydrochloride in water; and then adding an aqueous solution of 2-methyltetrahydrofuran and potassium carbonate; and then vigorously stirring while cooling in an ice bath; and then adding dropwise acryloyl chloride in 2-methyltetrahydrofuran and after about 5 minutes, diluting with brine and 2-methyltetrahydrofuran; extracting the aqueous layer twice with 2-methyltetrahydrofuran; and then washing the combined organic extracts with water; drying over magnesium sulfate, filtering and concentrating in vacuo; 59. The method of embodiment 58, further comprising:

[0330] Embodiment 60. A method comprising the steps of: 55. The method of any one of embodiments 37-54, further comprising purifying the M atropisomer of 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 by silica gel flash chromatography.

[0331] The method of embodiment 61., further comprising using 20-30% 4:1 EtOAc:MeOH in 3:1 EtOAc:hexane.

[0332] Embodiment 62. A method comprising the steps of: adding 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 N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate, and potassium phosphate in water and 1,4-dioxane to a first reaction flask; flushing the first reaction flask with nitrogen by direct sparging for about 10 minutes; adding 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride to a first reaction flask; sealing the first reaction flask and heating at about 70° C. for about 3 hours to produce a first reaction mixture; 16. A method for preparing a compound according to embodiment 1 or 15, comprising:

[0333] Embodiment 63. A method for preparing a compound according to any one of embodiments 1, 15 or 62, comprising: adding 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 N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate, and potassium phosphate in water and 1,4-dioxane to a second reaction flask; flushing the second reaction flask with nitrogen by direct sparging for about 10 minutes; adding 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride to a second reaction flask; sealing the second reaction flask and heating at about 70° C. for about 5 hours to produce a second reaction mixture; A method comprising:

[0334] Embodiment 64. A method comprising the steps of: combining the first and second reaction mixtures to form a combined reaction mixture; filtering the combined reaction mixture through diatomaceous earth; rinsing with EtOAc to produce a filtrate; The method of preparing the compound of embodiment 63, further comprising:

[0335] Embodiment 65. A method comprising the steps of: diluting the filtrate with MTBE and saturated aqueous sodium bicarbonate to produce an organic extract; and washing the organic extract with brine; drying over magnesium sulfate, filtering and concentrating in vacuo to yield a crude product. The method of preparing the compound of embodiment 64, further comprising:

[0336] Embodiment 66. A method comprising the steps of: 66. The process for preparing the compound of embodiment 65, further comprising purifying the M and P atropisomers 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 by silica gel flash chromatography.

[0337] Embodiment 67. The method of preparing a compound of embodiment 66, further comprising using 0-30% acetone in hexane.

[0338] Embodiment 68. A method comprising the steps of: 68. The process for preparing the compound of embodiment 66 or 67, further comprising the step of further purifying the P atropisomer 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 by silica gel flash chromatography.

[0339] Embodiment 69. A method for preparing a compound according to embodiment 68, further comprising using 0-100% EtOAc in hexane.

[0340] Embodiment 70. A method comprising the steps of: adding TFA to a solution of the P atropisomer 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 in DCM, followed by Stirring at room temperature for about 30 minutes; concentrating in vacuum; purifying the P atropisomer of 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 by silica gel flash chromatography; The method of preparing a compound according to any one of embodiments 66 to 69, further comprising:

[0341] Embodiment 71. A method of preparing a compound according to embodiment 70, further comprising using 0-10% MeOH in DCM followed by 0-10% 7N ammoniated MeOH in DCM.

[0342] Embodiment 72. A method comprising the steps of: adding acryloyl chloride to an ice-cooled mixture of the P atropisomer of 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 and potassium carbonate in EtOAc and water; and after about 20 minutes, diluting with EtOAc and brine; drying the resulting organic extract over sodium sulfate, filtering and concentrating in vacuo; The method of preparation of a compound according to any one of embodiments 66 to 71, further comprising:

[0343] EMBODIMENT 73. The process for preparing the compound of any one of embodiments 66-72 further comprising purifying the P atropisomer of 4-[(4aR)-7-chloro-9-fluoro-11-oxo-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile by silica gel flash chromatography.

[0344] Embodiment 74. The method of preparing a compound of embodiment 73, further comprising using 20-100% acetone in hexane.

[0345] Embodiment 75. A method comprising the steps of: adding TFA to an ice-cold solution of the M atropisomer 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 in DCM; Stirring at room temperature for about 2 hours; concentrating in vacuum; The method of preparation of a compound according to any one of embodiments 66 to 74, further comprising:

[0346] Embodiment 76. A method comprising the steps of: purifying the M atropisomer of 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 by silica gel flash chromatography. The method of preparing a compound according to any one of embodiments 66 to 75, further comprising:

[0347] Embodiment 77. A method of preparing a compound according to embodiment 76, further comprising using 0-10% 7N ammoniated MeOH in DCM.

[0348] Embodiment 78. A method comprising the steps of: adding acryloyl chloride to an ice-cooled mixture of the M atropisomer of 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 and potassium carbonate in EtOAc and water; and after about 5 minutes, diluting with EtOAc; separating the organic layer and the aqueous layer; drying the organic layer over magnesium sulfate, filtering and concentrating in vacuo; The method of preparing a compound according to any one of embodiments 66 to 77, further comprising:

[0349] Embodiment 79. A method comprising the steps of: The process for preparing the compound of any one of embodiments 66-78, further comprising purifying the M atropisomer of 4-[(4aR)-7-chloro-9-fluoro-11-oxo-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepin-8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile by silica gel flash chromatography.

[0350] Embodiment 80. A method of preparing a compound of embodiment 79, further comprising using 0-10% 7N ammoniated MeOH in DCM.

[0351] Embodiment 81. The formula:

[0352] [ka] Compounds of or a pharma- ceutically acceptable salt thereof, wherein: R is a protecting group.

[0353] Embodiment 82. A compound according to embodiment 81, wherein R is Boc.

[0354] Embodiment 83. A compound of the formula:

[0355] [ka] The compound of embodiment 81 or 82, wherein or a pharma- ceutically acceptable salt thereof.

[0356] Embodiment 84. A compound of the formula:

[0357] [ka] The compound of any one of embodiments 81-83, wherein

[0358] Embodiment 85. The formula:

[0359] [ka] Compounds of or a pharma- ceutically acceptable salt thereof, wherein: R is a protecting group.

[0360] Embodiment 86. A compound according to embodiment 85, wherein R is Boc.

[0361] Embodiment 87. The compound is

[0362] [ka] The compound according to embodiment 85 or 86, or a pharma- ceutically acceptable salt thereof.

[0363] Embodiment 88. The compound comprises:

[0364] [ka] The compound of any one of embodiments 85-87, wherein

[0365] 89. A method for preparing a compound according to any one of embodiments 81-88, comprising combining (3S)-tert-butyl 4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate with a cyclizing base to obtain tert-butyl (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate.

[0366] Embodiment 90. A method for preparing a compound according to embodiment 89, wherein the cyclizing base is selected from the group consisting of sodium hydride, N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), cesium carbonate, diazabicycloundecene (DBU), sodium tert-butoxide, sodium tert-pentoxide, sodium tert-amylate, potassium tert-pentoxide and potassium tert-butoxide.

[0367] Embodiment 91. A method for the preparation of a compound according to embodiment 89 or 90, wherein the cyclizing base is selected from the group consisting of potassium tert-butoxide, sodium tert-amylate, potassium tert-pentoxide, sodium tert-butoxide and sodium tert-pentoxide.

[0368] Embodiment 92. A method for the preparation of a compound according to any one of embodiments 89 to 91, further comprising the use of a cyclization solvent.

[0369] Embodiment 93. A method for the preparation of a compound according to embodiment 92, wherein the cyclization solvent is selected from the group consisting of DMF, NMP, DMAc, DMSO and THF.

[0370] Embodiment 94. A method for preparing a compound according to any one of embodiments 89 to 93, comprising: providing sodium tert-pentoxide to a polar aprotic solvent; agitating to form a reactor solution; and cooling the reactor solution to at least about 0° C.

[0371] Embodiment 95. A method for the preparation of a compound according to embodiment 94, wherein the polar aprotic solvent is selected from the group consisting of DMAc, NMP, DMSO and DMF.

[0372] Embodiment 96. A method for the preparation of a compound according to embodiment 94 or 95, wherein the polar aprotic solvent is DMF.

[0373] EMBODIMENT 97. The method of preparing the compound further comprises providing (3S)-tert-butyl 4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate to the reactor solution at about 0° C. for at least about 4 hours.

[0374] EMBODIMENT 98. adding a portion of the reactor solution comprising tert-butyl (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate to water within a range of about 10° C. to about 40° C. over a period of at least about 1 hour to form a prepared mixture; Stirring the prepared mixture at a temperature ranging from about 10° C. to about 40° C. for at least about 32 hours. The method of preparing a compound according to any one of embodiments 94 to 97, further comprising:

[0375] EMBODIMENT 99. isolating the solid from the prepared mixture by filtration; The solid from the preparation mixture was washed with a combination of DMF and water. The method of preparing the compound of embodiment 98, further comprising:

[0376] EMBODIMENT 100. 100. The process for preparing a compound according to embodiment 98 or 99, further comprising adding the solid from the preparation mixture to EtOH to form a preparation solution.

[0377] EMBODIMENT 101. The process for preparing a compound according to any one of embodiments 98-100, further comprising heating the prepared solution to at least about 30° C. and stirring for at least about 15 minutes.

[0378] EMBODIMENT 102. The method of preparing a compound according to any one of embodiments 98-101, further comprising adding water to the prepared solution for at least about 2 hours.

[0379] EMBODIMENT 103. The method of preparing a compound according to any one of embodiments 98-102, further comprising maintaining the prepared solution at about 30° C. for at least about 15 minutes.

[0380] EMBODIMENT 104. The process for preparing a compound according to any one of embodiments 98-103, further comprising cooling the prepared solution to at least about 20° C. for at least about 2 hours.

[0381] EMBODIMENT 105. The method of preparing a compound according to any one of embodiments 98-104, further comprising maintaining the prepared solution at about 20° C. for at least about 2 hours.

[0382] EMBODIMENT 106. The process for preparing a compound according to any one of embodiments 98 to 105, further comprising separating, washing and drying a solid comprising tert-butyl (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate from the prepared solution.

[0383] Embodiment 107. The method of preparing a compound according to embodiment 106, wherein the step of isolating the solid comprising tert-butyl (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate is by filtration.

[0384] Embodiment 108. A method for preparing a compound according to embodiment 106 or 107, wherein the step of washing the solid comprising tert-butyl (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate is with a combination of EtOH and water.

[0385] Embodiment 109. The method for preparing a compound according to any one of embodiments 106 to 108, wherein the step of drying the solid comprising tert-butyl (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate is under vacuum at about 50° C. for at least about 16 hours.

[0386] Embodiment 110. Before the step of claim 89, adding CDMT to the reactor together with acetonitrile and cooling the reactor to about 0° C.; and adding an organic base to the reactor and stirring at about 0° C. for at least 30 minutes; and 4-bromo-2,5-difluorobenzoic acid,

[0387] [ka] to the reactor and stirring at about 0° C. for at least 1 hour to form an acetonitrile coupling solution; The method of preparing a compound according to any one of embodiments 89 to 97, further comprising:

[0388] EMBODIMENT 111. adding an inorganic base and then water to a separate vessel; and then adding (3S)-tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate:phosphoric acid (1:1) and a base to a separate vessel to form an aqueous piperazine solution; The method of preparing the compound of embodiment 110, further comprising:

[0389] Embodiment 112. A method for preparing a compound according to embodiment 110, wherein the organic base is NMM.

[0390] Embodiment 113. The inorganic base is K 2 CO 3 112. A method of preparing a compound according to embodiment 111, wherein

[0391] EMBODIMENT 114. The process for preparing a compound according to any one of embodiments 110-113, further comprising adding the aqueous piperazine solution to the acetonitrile coupling solution of the reactor over a period of at least 5 minutes while maintaining an internal temperature of about 0° C.

[0392] EMBODIMENT 115. The process for preparing a compound according to any one of embodiments 110 to 114, further comprising stirring the solution at about 0° C. for at least 2.5 hours.

[0393] EMBODIMENT 116. removing a bottom layer of the solution from the reactor; The remaining solution is stirred at about 0° C. for at least 64 hours. The method of preparing a compound according to any one of embodiments 110 to 115, further comprising:

[0394] EMBODIMENT 117. The process for preparing a compound according to any one of embodiments 110-116, further comprising concentrating the remaining solution and adding 2-MeTHF together with n-heptane.

[0395] EMBODIMENT 118. Add 1M NaHCO to the remaining solution. 3 The process for preparing a compound according to any one of embodiments 110-117, further comprising adding an aqueous solution and stirring for at least 15 minutes.

[0396] EMBODIMENT 119. allowing the remaining solution layers to separate; and removing the bottom layer of remaining solution from the reactor; 1M NaHCO 3 Repeat the process of adding the aqueous solution, stirring, and removing the bottom layer. The method of preparing a compound according to any one of embodiments 110 to 118, further comprising:

[0397] EMBODIMENT 120. The process for preparing a compound according to any one of embodiments 110-119, further comprising adding 0.05 M aqueous HCl to the remaining solution and stirring for at least 15 minutes.

[0398] EMBODIMENT 121. allowing the remaining solution layers to separate; and removing the bottom layer of remaining solution from the reactor; The method of preparing a compound according to any one of embodiments 110 to 120, further comprising:

[0399] EMBODIMENT 122. The process for preparing a compound according to any one of embodiments 110-121, further comprising adding water to the remaining solution and stirring for at least 15 minutes.

[0400] EMBODIMENT 123. allowing the remaining solution layers to separate; and removing the bottom layer of remaining solution from the reactor; The method of preparation of a compound according to any one of embodiments 110 to 122, further comprising:

[0401] EMBODIMENT 124. The remaining solution is concentrated and 2-MeTHF is added; Repeat the steps of concentrating and adding 2-MeTHF. The method of preparation of a compound according to any one of embodiments 110 to 123, further comprising:

[0402] EMBODIMENT 125. The process for preparing the compound of any one of embodiments 110-124, further comprising concentrating the remaining solution and adding DMF to give tert-butyl (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate.

Claims

1. (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, N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate tert-butyl, potassium carbonate and a catalyst in 1,4-dioxane, having a M:P atropisomer ratio of at least 4:1, 【Chemistry 1】 Compounds of or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, further obtainable by adding additional tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate and said catalyst.

3. The catalyst is selected from the group consisting of diacetate[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II), dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II), dichloro[(R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II), dichloro1,1'-bis(diphenylphosphino)ferrocenepalladium(II)dichloromethane, dichloro(1,2-bis(diphenylphosphino)ethane)palladium(II), dichloro(1,3-bis(diphenylphosphino)propane)palladium(II), dichloro[1 ,4-bis(diphenylphosphino)butane]palladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]palladium(II), dibromo[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), [(1,2,3-η)-2-buten-1-yl]chloro[dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphine-κP]palladium, [(1,2,3-η)-2-butenyl]chloro(tricyclohexylphosphine)palladium or trans-dichlorobis(tricyclohexylphosphine)palladium(II).

4. 4. The compound according to any one of claims 1 to 3, wherein the catalyst is diacetate[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II) or dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II).

5. Acryloyl chloride 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; 【Chemistry 2】 and in a continuous stirred tank reactor, the 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; 【Chemistry 3】 is less than 1% as measured by HPLC analysis; formula, 【Chemistry 4】 Compounds of or a pharma- ceutically acceptable salt thereof.

6. formula, 【Chemistry 5】 Compounds of or a pharma- ceutically acceptable salt thereof.

7. The compound is 【Chemistry 6】 7. The compound of claim 6,

8. (3S)-tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate: obtainable by combining phosphoric acid (1:1), base, and 4-bromo-2,5-difluorobenzoic acid to give (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate of formula: 【Chemistry 7】 Compounds of or a pharma- ceutically acceptable salt thereof.

9. formula, 【Chemistry 8】 Compounds of or a pharma- ceutically acceptable salt thereof.

10. The compound is 【Chemistry 9】 10. The compound of claim 9,

11. tert-butyl (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate with a cyclizing base to give tert-butyl (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate of formula: 【Chemistry 10】 Compounds of or a pharma- ceutically acceptable salt thereof.

12. 12. The compound of claim 11, wherein the cyclizing base comprises sodium hydride, N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), cesium carbonate, diazabicycloundecene (DBU), sodium tert-butoxide, sodium tert-pentoxide, sodium tert-amylate, potassium tert-pentoxide, or potassium tert-butoxide.

13. 13. The compound of claim 11 or 12, wherein the cyclizing base comprises potassium tert-butoxide, sodium tert-amylate, potassium tert-pentoxide, sodium tert-butoxide or sodium tert-pentoxide.

14. A compound according to any one of claims 11 to 13, obtainable by further comprising a cyclization solvent.

15. 15. The compound of claim 14, wherein the cyclization solvent comprises DMF, NMP, DMAc, DMSO, or THF.

16. tert-butyl (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate with a chlorinating agent to give 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 of formula 【Chemistry 11】 Compounds of or a pharma- ceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent or excipient.

18. 20. A method of treating a patient with a cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need of treatment an effective amount of the pharmaceutical composition of claim 17, wherein the cancer is selected from lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

19. 19. A method of treating a patient with a cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

20. 20. The method of claim 19, wherein the cancer is non-small cell lung cancer.

21. 20. The method of claim 19, wherein the cancer is advanced non-small cell lung cancer.

22. 20. The method of claim 19, wherein the cancer is colorectal cancer.

23. 20. The method of claim 19, wherein the cancer is pancreatic cancer.

24. 20. The method of claim 19, wherein the patient has a cancer determined to have one or more cells that express the KRas G12C mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

25. 17. A method of treating a patient with a cancer harboring a KRAS G12C mutation, comprising administering to said patient in need of treatment an effective amount of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof.

26. 26. The method of any one of claims 18-25, wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

27. The method of any one of claims 18 to 26, wherein the patient has not been previously treated with a KRAS G12C inhibitor or a pharma- ceutically acceptable salt thereof.

28. 28. The method of any one of claims 18-27, wherein the patient has not been pretreated with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

29. 28. The method of any one of claims 18-27, wherein the patient has been pre-treated with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

30. The method of any one of claims 18 to 26, wherein the patient has been pre-treated with a KRAS G12C inhibitor or a pharma- ceutically acceptable salt thereof.

31. 31. The method of any one of claims 18-26 or 30, wherein the patient has not been pretreated with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

32. 31. The method of any one of claims 18-26 or 30, wherein the patient has been pre-treated with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutically acceptable salt thereof, an EGFR inhibitor or a pharma- ceutically acceptable salt thereof, an ERK inhibitor or a pharma- ceutically acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutically acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof.

33. 17. A compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, for use in therapy.

34. 17. The compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

35. 35. The compound or a pharma- ceutically acceptable salt thereof for use according to claim 34, wherein the cancer is selected from lung cancer, advanced non-small cell lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

36. 17. The compound or pharma- ceutical acceptable salt thereof according to any one of claims 1 to 16, for use in the treatment of cancer in simultaneous, separate or sequential combination with one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CD4 / CDK6 inhibitor or a pharma- ceutical acceptable salt thereof, an EGFR inhibitor or a pharma- ceutical acceptable salt thereof, an ERK inhibitor or a pharma- ceutical acceptable salt thereof, a platinum agent, pemetrexed, an Aurora A inhibitor or a pharma- ceutical acceptable salt thereof, an SHP2 inhibitor or a pharma- ceutical acceptable salt thereof.

37. 7. A method of preparing the compound of claim 6 comprising combining (3S)-tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate:phosphoric acid (1:1), base, and 4-bromo-2,5-difluorobenzoic acid to provide (3S)-4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate.

38. 10. A method of preparing the compound of claim 9 comprising combining (3S)-tert-butyl 4-(4-bromo-2,5-difluoro-benzoyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate with a cyclizing base to obtain tert-butyl (13aS)-9-bromo-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylate.

39. 39. The method of claim 38, wherein the cyclizing base comprises sodium hydride, N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), cesium carbonate, diazabicycloundecene (DBU), sodium tert-butoxide, sodium tert-pentoxide, sodium tert-amylate, potassium tert-pentoxide, or potassium tert-butoxide.

40. 40. The method of claim 38 or 39, wherein the cyclizing base comprises potassium tert-butoxide, sodium tert-amylate, potassium tert-pentoxide, sodium tert-butoxide, or sodium tert-pentoxide.

41. The method of any one of claims 38 to 40, wherein the method further comprises a cyclization solvent.

42. 42. The method of claim 41 , wherein the cyclization solvent comprises DMF, NMP, DMAc, DMSO, or THF.

43. 1. A method of producing a compound of formula (I) comprising reacting, in a solvent, (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 N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-2-yl]carbamate, potassium carbonate and dichloro[(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II), 【Chemistry 12】 Compounds of or a process for preparing a pharma- ceutically acceptable salt thereof.

44. 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, diacetate[(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium(II), N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-7-fluoro-benzothiophene-2-yl]carbamate tert-butyl, base, and 1,1,1-tris(hydroxymethyl)ethane of formula 【Chemistry 13】 Compounds of or a process for preparing a pharma- ceutically acceptable salt thereof.

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