Method of treatment including kras g12c inhibitors and aurora a inhibitors

Abstract

To provide a method of treating a patient for cancer that expresses KRas G12C mutant protein.SOLUTION: A method comprises administering a compound of the following formula or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Detailed description of the invention

[0001] This disclosure relates to a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need an effective amount of a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof together with an Aurora A kinase inhibitor or a pharmaceutically acceptable salt thereof, to treat cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer.

[0002] Oncogenic KRas mutations have been identified in approximately 30% of human cancers and have been shown to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, they remain a challenging therapeutic target. (Cox, ADDrugging the Undruggable RAS: Mission Possible? Nat. Rev. Drug Disc. 2014, 13, 828-851; Pylayeva-Gupta, y et al. RAS Oncogenes: Weaving a Tumorigenic Web. Nat. Rev. Cancer 2011, 11, 761-774).

[0003] WO2015 / 054572 and WO2016 / 164675 disclose certain quinazoline derivatives that can bind to KRAS G12C. WO2016 / 044772 also discloses methods using such quinazoline derivatives. WO2020 / 0081282 and WO2021 / 118877 disclose KRAS G12C inhibitors. WO2018 / 206539 and WO2020 / 178282 disclose certain heteroaryl compounds that can bind to the KRAS G12C oncoprotein.

[0004] Aurora kinase consists of three highly conserved serine / threonine isoforms, Aurora A, B, and C, which regulate mitosis and meiosis and play a clear role in cell cycle progression. Inhibition of Aurora A kinase activity severely impairs mitotic progression through activation of the mitotic checkpoint, resulting in defects in mitotic spindle formation and prometaphase arrest, followed by cell death via apoptotic pathways. Amplification or overexpression of the oncogenic Aurora A gene, AURKA, has been observed in a wide range of cancers.

[0005] Aurora A inhibitors are also known in the art. WO2008 / 026768, EP2062887, and WO2009 / 104802 disclose certain aminopyridine compounds having selective inhibitory activity against Aurora A. WO2013 / 129443 discloses certain piperidine compounds having selective inhibitory activity against Aurora A. WO2016 / 077161 and WO2020 / 112514 disclose certain aminopyridine compounds that inhibit Aurora A.

[0006] The (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt is as follows: [ka]

[0007] Aurora A inhibitors are potent selective inhibitors of Aurora A.

[0008] As described in WO2016 / 077161 and WO2020 / 112514, after administration of (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt to mice transplanted with xenografts and to PDX models, tumor growth arrest or regression was observed in several tumor types.

[0009] In vitro studies of combined inhibition of KRAS G12C with Aurora A using commercially available inhibitors have demonstrated synergistic antiproliferative and antitumor effects. See Lito et al., Rapid non-uniform adaptation to conformation-specific KRAS G12C inhibition, Nature. 2020 January;577(7790):421-425.

[0010] There remains a need to provide small molecule combinations of KRAS G12C inhibitors and Aurora A inhibitors. Specifically, there is a need to provide more potent, orally deliverable KRAS G12C inhibitors and Aurora A inhibitors useful for cancer treatment. More specifically, there is a need to provide small molecule inhibitor combinations that specifically inhibit KRas GTP activity and Aurora A activity. There is also a need to provide small molecule KRAS G12C inhibitor and Aurora A inhibitor combinations that exhibit synergistic antiproliferative and antitumor effects. Furthermore, there is a desire to provide KRAS G12C inhibitor and Aurora A inhibitor combinations that overcome avoidance of KRAS inhibitor therapy. There is also a need to provide KRAS G12C inhibitor and Aurora A inhibitor combinations that exhibit increased efficacy with reduced or minimized adverse or undesirable effects. This disclosure addresses one or more of these needs by providing KRAS G12C inhibitor and Aurora A inhibitor combinations, as well as methods and uses of such combinations.

[0011] The present disclosure relates to a method of treating a patient for cancer in which one or more cells express a KRas G12C mutant protein, the method comprising administering to a patient in need thereof an effective amount of a compound of the following formula, [Chemical formula] wherein, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-; B is -CH2- or -C(O)-; Y is -C(CN)- or -N-; R1 is -CN, -C(O)C≡CR8, or a group of the following formula, [Chemical formula] R2 is H, methyl, or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 alkyl-cyclopropyl, -C 10 alkyl optionally substituted 1 to 3 times with R 1-6 alkyl, or -O-C 10 alkyl optionally substituted 1 to 3 times with R 1-6 alkyl; R4 is H, halogen, or -C 10 alkyl optionally substituted 1 to 3 times with R 1-6 alkyl; R6 is H or -C 10 alkyl optionally substituted 1 to 3 times with R 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 , -CH2NR 11 R 12 , R 10 or R 13 alkyl optionally substituted 1 to 3 times with -C 1-6 alkyl, -C 0-3 alkyl-cyclopropyl, or -O-C 10 or R 13 alkyl optionally substituted 1 to 3 times with -C1-6 It is alkyl, R8 is H, R 10 -C is optionally replaced 1 to 3 times. 1-4 Alkyl, or R 10 -C is optionally replaced 1 to 3 times. 3-6 It is a cycloalkyl, R9 is H, Halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R 10 Each of these independently comprises halogen, oxygen, hydroxyl, and -C. 1-4 Alkyl, or -OC 1-4 It is alkyl, R 11 and R 12 Each of these is independent of H and -C 1-4 Alkyl, or -C 1-4 It is heteroalkyl, R 11 and R 12 They may bond to form a heterocycloalkyl group. R 13 Each of them independently, -N(CH3)2 or [ka] is a compound, or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an effective amount of an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof.

[0012] As used herein, the term halogen means fluoro(F), chloro(Cl), bromo(Br), or iodine(I). As used herein, the term alkyl means a saturated linear or branched monovalent hydrocarbon group having 1 to 6 carbon atoms, e.g., "-C1-6 alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, pentyl, and hexyl. As used herein, the term heteroalkyl means a saturated linear or branched monovalent hydrocarbon group having 2 to 5 carbon atoms and at least 1 heteroatom, e.g., "-C1-4 heteroalkyl". As used herein, the term cycloalkyl means a saturated monovalent cyclic molecule having 3 to 6 carbon atoms, e.g., "-C 3-6 This term means "cycloalkyl." Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. As used herein, the term cycloheteroalkyl refers to a saturated monovalent cyclic molecule having 2 to 5 carbon atoms and at least 1 heteroatom, e.g., "-C 3-6 This means "cycloheteroalkyl." Examples of cycloheteroalkyl groups include, but are not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, and piperazine.

[0013] If zero is shown, for example, -C0-3alkyl-C 3-6 In the case of cycloalkyl groups, the alkyl component of this substituent can be absent, and therefore, if R9 in formula I is a cyclopropyl group without alkyl at the beginning, this substituent is described for R9 -C 0-3 It will likely be represented by an alkyl-cyclopropyl substituent (i.e., this substituent will be -C0-cyclopropyl).

[0014] R 11 and R 12In cases where the formation of a heterocycloalkyl group is possible by chemistry, these two groups may be bonded to the nitrogen atom to which they are attached. Examples of such heterocycloalkyl groups include, but are not limited to, piperidine, piperazine, and morpholine.

[0015] In one embodiment, the Disclosure provides compounds according to any one of Formulas I or II-VI (see below) or pharmaceutically acceptable salts thereof for therapeutic use in combination with, separately from, or sequentially with Aurora A inhibitors or pharmaceutically acceptable salts thereof. The Disclosure also provides compounds according to any one of Formulas I or II-VI or pharmaceutically acceptable salts thereof for therapeutic use in combination with, separately from, or sequentially with Aurora A inhibitors or pharmaceutically acceptable salts thereof. The Disclosure also provides the use of compounds according to any one of Formulas I or II-VI or pharmaceutically acceptable salts thereof in the manufacture of agents for the therapeutic use of cancer in combination with, separately from, or sequentially with Aurora A kinase inhibitors or pharmaceutically acceptable salts thereof.

[0016] In one embodiment, the present disclosure is a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, wherein the patient is given an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula Ia. [ka] The present invention provides a method comprising administering a compound, or a pharmaceutically acceptable salt thereof, in which R1, R2, R3, R4, R5, A, B, and Y are as defined above, and an effective amount of an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-. In a further embodiment, in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-. In yet another embodiment, in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-.

[0018] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, B is -C(O)-.

[0019] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, Y is -C(CN)-.

[0020] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, Y is -N-.

[0021] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R1 is -CN, -C(O)C≡CR8. In yet another embodiment, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R1 is a group of the following formula: [ka]

[0022] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R2 is H or methyl. In yet another embodiment, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R2 is H.

[0023] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R3 is H, halogen, methyl, methoxy, ethyl, isopropyl, or cyclopropyl. In yet another embodiment, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R3 is halogen (preferably F or Cl).

[0024] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R4 is H or a halogen. In yet another embodiment, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R4 is H, F, or Cl.

[0025] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R5 is a halogen (preferably Cl).

[0026] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R6 is H or CH3.

[0027] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH. In yet another embodiment, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R9 is H.

[0028] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, or -CH2-morpholine. In yet another embodiment, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R7 is H.

[0029] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R9 is H, and R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, or -CH2-morpholine.

[0030] In further embodiments, in compounds of formula I or formula Ia, R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH, and in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R7 is H.

[0031] In a further embodiment, in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, both R7 and R9 are H.

[0032] In further embodiments, in a compound of formula I or formula Ia, R1 is -CN or -C(O)C≡CR8, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R8 is H, methyl, -CH2F, or -CH2OH.

[0033] In a further embodiment, in a compound of formula I or formula Ia, R1 is a group of the following formula: [ka] In compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, both R7 and R9 are H.

[0034] In a further embodiment, in a compound of formula I or formula Ia, R1 is a group of the following formula: [ka] In compounds of formula I or formula Ia, R7 is tert-butyl, and in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R9 is -CN.

[0035] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0036] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2- or -OCH2CH2-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0037] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2CH2-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0038] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, or -N(R6)CH2CH2-, in a compound of formula I or formula Ia, B is C(O), and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R2 is H or -CH3.

[0039] In further embodiments, A is -OCH2- or -OCH2CH2- in a compound of formula I or formula Ia, B is -C(O)- in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, and R2 is H or methyl.

[0040] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2CH2-, in a compound of formula I or formula Ia, B is -C(O)-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0041] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, in a compound of formula I or formula Ia, B is -C(O)-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0042] In a further embodiment, in a compound of formula I or formula Ia, A is -OCH2- or -OCH2CH2-, B is -C(O)- in a compound of formula I or formula Ia, and R2 is H in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof.

[0043] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2CH2-, in a compound of formula I or formula Ia, B is -C(O)-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0044] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2CH2-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0045] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2CH2-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0046] In further embodiments, in a compound of formula I or formula Ia, B is -C(O)-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0047] In a further embodiment, in a compound of formula I or formula Ia, B is -C(O)-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0048] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R3 and R5 are each independently selected from H, halogen, or methyl.

[0049] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R3 or R5 is a halogen.

[0050] In a further embodiment, in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are halogens.

[0051] In further embodiments, in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R3 and R5 are each independently selected from F or Cl.

[0052] In further embodiments, in a compound of formula I or formula Ia, Y is -C(CN)-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R4 is H or a halogen (preferably F or Cl).

[0053] In further embodiments, in a compound of formula I or formula Ia, Y is -N-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R4 is H or a halogen (preferably F or Cl).

[0054] In further embodiments, in a compound of formula I or formula Ia, Y is -C(CN)-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from methyl or halogen.

[0055] In further embodiments, in a compound of formula I or formula Ia, Y is -C(CN)-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each halogen (preferably F or Cl).

[0056] In further embodiments, in a compound of formula I or formula Ia, Y is -N-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from methyl or halogen.

[0057] In a further embodiment, in a compound of formula I or formula Ia, Y is -N-, and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each halogen (preferably F or Cl).

[0058] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2, in a compound of formula I or formula Ia, B is -CH2- or -C(O)-, in a compound of formula I or formula Ia, Y is -C(CN)- or -N-, and in a compound of formula I or formula Ia, R1 is -CN, -C(O)C≡CR8, or a group of the following formulas: [ka] In compounds of formula I or formula Ia, R2 is H or methyl; in compounds of formula I or formula Ia, R3 and R5 are H, F, Cl, or methyl, respectively; R4 is H or F; in compounds of formula I or formula Ia, R6 is H or methyl; in compounds of formula I or formula Ia, R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, -CH2-morpholine, or tert-butyl; in compounds of formula I or formula Ia, R8 is methyl, -CH2F, or -CH2OH; and in compounds of formula I or formula Ia, or pharmaceutically acceptable salts thereof, R9 is H, F, Cl, -CH2F, -CF3, -CH2OH, or CN.

[0059] In further embodiments, in a compound of formula I or formula Ia, A is -OCH2- or -OCH2CH2-; in a compound of formula I or formula Ia, B is -CH2- or -C(O)-; in a compound of formula I or formula Ia, Y is -C(CN)- or -N-; in a compound of formula I or formula Ia, R2, R7, and R8 are each H; in a compound of formula I or formula Ia, R4 is H or a halogen; and in a compound of formula I or formula Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each halogen.

[0060] This disclosure relates to a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, wherein the patient is given an effective amount of a compound of the following formula: [ka] In the formula, R is [ka] And, X is either Cl or F, A compound in which m is 1 or 2. or a pharmaceutically acceptable salt thereof, The present invention further provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0061] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound of formula IIa, [ka] In the formula, R is [ka] And, X is either Cl or F, A compound in which m is 1 or 2. or a pharmaceutically acceptable salt thereof, The present invention also provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0062] This disclosure relates to a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, wherein the patient is provided with an effective amount of a compound of formula I, where the compound of formula I is formula Ib. [ka] During the ceremony, A is -OCH2- or -OCH2CH2-, Y is -C(CN)- or -N-, R3 is either Cl or F. If Y is C(CN), then R4 is either H or F. If Y is N, then R4 is F in the compound. The present invention also provides a method comprising administering an effective amount of an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0063] Another way to describe the compound of formula IIa is by formula Ib, where A is as follows: [ka]

[0064] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound of formula I or Ia, selected from any one of the following formulas III to VI. [ka] or a pharmaceutically acceptable salt thereof, The present invention also provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0065] In another embodiment, the present disclosure is a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein an effective amount of the following compound of formula III is given to the patient in need. [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0066] In another embodiment, the present disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound of formula IV: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0067] In another embodiment, the present disclosure is a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound of formula V: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment, the present disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein an effective amount of the following compound of formula VI is given to the patient in need. [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0069] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound selected from the group consisting of the following: [ka] [ka] or a pharmaceutically acceptable salt thereof, The present invention also provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0070] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound selected from the group consisting of the following: [ka] or a pharmaceutically acceptable salt thereof, The present invention also provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0071] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound selected from the group consisting of the following: [ka] The present invention also provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0072] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound selected from the group consisting of the following: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0073] This disclosure relates to a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, comprising, to the patient in need, an effective amount of a compound selected from the group consisting of the following: [ka] The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0074] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound selected from the group consisting of the following: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0075] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0076] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0077] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound selected from the group consisting of the following: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0078] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0079] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0080] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound selected from the group consisting of the following: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0081] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0082] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0083] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound selected from the group consisting of the following: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0084] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0085] This disclosure relates to a method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of the following compound: [ka] or a pharmaceutically acceptable salt thereof, The present invention provides a method comprising administering an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0086] In another embodiment, a method for treating a patient for cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to the patient in need an effective amount of a compound according to any one of formulas I-VI or Examples 1-8, also comprising the fact that the Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, is an aminopyridine compound, or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is an Aurora A selective inhibitor, or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is aricertib as described in WO2008 / 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 tozacertib as described in WO2004 / 000833. In another embodiment, the Aurora A inhibitor is danurtive as described in WO2005 / 005427. In another embodiment, the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, [ka] or a pharmaceutically acceptable salt thereof.

[0087] In another embodiment, the present disclosure provides a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to the patient in need an effective amount of a compound according to any one of formulas I to VI or Examples 1 to 8, or a pharmaceutically acceptable salt thereof, together with (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0088] In another embodiment, the present disclosure provides a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need an effective amount of a compound according to any one of formulas I to VI or Examples 1 to 8, or a pharmaceutically acceptable salt thereof, together with a (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt. [ka]

[0089] In another embodiment, the present disclosure provides a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need an effective amount of a compound according to any one of formulas I to VI or Examples 1 to 8, or a pharmaceutically acceptable salt thereof, together with (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt. [ka]

[0090] The disclosure also provides a method for treating a patient with cancer in which one or more cells express a KRas G12C mutant protein, comprising administering to the patient in need an effective amount of a compound according to any one of formulas I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, together with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof.

[0091] In various embodiments, the cancer is 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 non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In even more preferred embodiments, the cancer is non-small cell lung cancer.

[0092] The Disclosure also provides a method for treating a patient having cancer, comprising administering to the patient in need an effective amount of a compound according to any one of Formulas I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, together with an Aurora A kinase inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a variant KRas G12C protein with or without Aurora A dysregulation or overexpression. The Disclosure also provides a method for treating cancer, comprising administering to the patient in need an effective amount of a compound according to any one of Formulas I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and an Aurora A kinase inhibitor compound, or a pharmaceutically acceptable salt thereof, wherein the cancer is non-small cell lung cancer, and one or more cells expressing a variant KRas G12C protein with or without Aurora A dysregulation or overexpression. The disclosure also provides a method for treating cancer, comprising administering to a patient in need an effective amount of a compound according to any one of formulas I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and an Aurora A kinase inhibitor compound, or a pharmaceutically acceptable salt thereof, wherein the cancer is colorectal cancer and one or more cells with or without Aurora A dysregulation or overexpression express the KRas G12C mutant protein. The disclosure also provides a method for treating cancer, comprising administering to a patient in need an effective amount of a compound according to any one of formulas I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and an Aurora A kinase inhibitor compound, or a pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer and one or more cells with or without Aurora A dysregulation or overexpression express the KRas G12C mutant protein.

[0093] This disclosure also provides a method for treating cancer in a patient requiring cancer treatment, wherein the patient has cancer that is determined to express a KRas G12C mutant protein and is accompanied by Aurora A dysregulation or overexpression.

[0094] In another embodiment, the cancer is non-small cell lung cancer, and the cancer has one or more cells expressing and / or having Aurora A dysregulation or overexpression. In yet another embodiment, the cancer is colorectal cancer, and the cancer has one or more cells expressing and / or having Aurora A dysregulation or overexpression. In yet another embodiment, the cancer is mutant pancreatic cancer, and the cancer has one or more cells expressing and / or having Aurora A dysregulation or overexpression. In yet another embodiment, the disclosure includes a method for treating cancer having KRas G12C mutants and / or Aurora A dysregulation or overexpression of other origins.

[0095] In yet another embodiment, the Disclosure provides a method for treating cancer, comprising administering to a patient in need an effective amount of a compound according to any one of formulas I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, together with an Aurora A kinase inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a variant KRas G12C protein or having Aurora A dysregulation or overexpression. In some embodiments, the patient has cancer that has been determined to have one or more cells expressing a KRas G12C variant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof, or the Aurora A inhibitor, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has cancer with a KRAS G12C mutation.

[0096] In yet another embodiment, the present disclosure provides a method for treating cancer, comprising administering to a patient in need an effective amount of a compound according to any one of Formulas I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, together with an Aurora A kinase inhibitor, or a pharmaceutically acceptable salt thereof, wherein the compound according to any one of Formulas I-VI or Examples 1-8 and the Aurora A inhibitor are administered to the patient in need simultaneously or sequentially. In some embodiments, the compound according to any one of Formulas I-VI or Examples 1-8 and the Aurora A inhibitor are administered to the patient in need simultaneously. In some embodiments, the compound according to any one of Formulas I-VI or Examples 1-8 and the Aurora A inhibitor are administered to the patient in need sequentially. In some embodiments, the compound according to any one of Formulas I-VI or Examples 1-8 is administered to the patient in need, followed by the administration of the Aurora A inhibitor to the patient in need. In some embodiments, after an Aurora A inhibitor is administered to a patient in need, a compound according to any one of formulas I-VI or examples 1-8 is administered to the patient in need.

[0097] Preferably, the cancer is lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. In a preferred embodiment, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In a more preferred embodiment, the cancer is non-small cell lung cancer. In other embodiments, the cancer has one or more cancer cells expressing and / or having Aurora A dysregulation or overexpression. Preferably, the cancer is selected from KRas G12C mutant non-small cell lung cancer, KRas G12C mutant colorectal cancer, and KRas G12C mutant pancreatic cancer.

[0098] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that is considered acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use,” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011, and in SMBerge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 1977, 66(1), 1–19.

[0099] The pharmaceutical compositions of this disclosure may be prepared using pharmaceutically acceptable additives. As used herein with respect to pharmaceutical compositions, the term “pharmaceutically acceptable additive” refers to one or more carriers, diluents, and excipients that are compatible with other additives in the composition or formulation and are not harmful to the patient. Examples of pharmaceutical compositions and processes for preparing them can be found in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22 nd This can be found in Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include saline, water, starch, sugar, mannitol, and silica derivatives, binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone, kaolin, and bentonite, as well as polyethyl glycol.

[0100] As used herein, the term “effective dose” refers to a quantity effective in treating cancerous lesions or disorders or diseases such as abnormal cell proliferation and / or progression of cell division. A physician skilled in the art can easily determine the effective dose by using the prior art and observing the results obtained under similar circumstances.

[0101] As used herein, the term “dose” refers to the total amount of drug administered at one time. Examples of drugs include compounds of formula I or their pharmaceutically acceptable salts. Other examples of drugs include Aurora A kinase inhibitor compounds or their pharmaceutically acceptable salts.

[0102] As used herein, the terms “dosage” or “dosage frequency” refer to a dose administered at a specific frequency.

[0103] The daily therapeutic dose of the compound of formula I is typically within the range of approximately 1 mg per day or twice per day to 1000 mg per day or twice per day, more preferably within the range of 100 mg per day or twice per day to 900 mg per day or twice per day.

[0104] The daily therapeutic dose of an Aurora A inhibitor, an aminopyridine compound, or a pharmaceutically acceptable salt thereof, or (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt, and (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt, or a pharmaceutically acceptable salt thereof, is usually in the range of approximately 0.1 to approximately 100 mg. In some cases, dose levels below the lower limit of this range may be more than sufficient, while in other cases, higher doses of Aurora A inhibitors, aminopyridine compounds, or pharmaceutically acceptable salts thereof, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt, or (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt, or pharmaceutically acceptable salts thereof may be used.The preferred dose of an Aurora A inhibitor, an aminopyridine compound, or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt, or (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt, or a pharmaceutically acceptable salt thereof, is within the range of 1 to 80 mg, more preferably 1 to 50 mg, even more preferably 1 to 30 mg, and still more preferably 1 to 25 mg. These doses can be administered once, twice, three times, or more times a day. In one embodiment, an Aurora A inhibitor, an aminopyridine compound, or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt, or (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt, or a pharmaceutically acceptable salt thereof may be administered in doses of 15 mg or 25 mg per dose administered orally twice daily (BID). Factors to be considered when determining the effective amount or dose of a compound include, if the compound or its salt is administered or used, concurrent administration of other drugs, the species of the patient being treated, the patient's size, age, sex, and general health status, the degree of involvement or stage and / or severity of the disorder, the individual patient's response, the method of administration, the bioavailability characteristics of the administered preparation, the chosen dosing regimen, and the use of other concomitant drugs.

[0105] A treating physician, veterinarian, or other healthcare professional may determine an effective dose of the compound for a patient requiring treatment. Preferred pharmaceutical compositions can be formulated as oral tablets or capsules, oral solutions, or injectable solutions. The tablets, capsules, or solutions may contain the compound of the Disclosure in an effective amount for treating a patient requiring treatment for cancer in which one or more cells express the KRas G12C mutant protein.

[0106] As used herein, the terms “to treat,” “to cure,” or “to treat” include slowing, reducing, or reversing the progression or severity of an existing symptom, disorder, or condition, which in particular may include slowing the growth of a cancerous lesion or abnormal cell proliferation and / or cell division.

[0107] As used herein, the term “patient” refers to a mammal in need of treatment. Preferably, the patient is a human being in need of treatment for cancer in which one or more cells express the KRas G12C mutant protein, for example, cancer having the KRas G12C mutant.

[0108] Individual isomers, enantiomers, diastereomers, and atropisomers can be separated or divided at any convenient point in the synthesis of the compounds listed below 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 ELEliel and SHWilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). This disclosure includes certain compounds that are atropisomers and may exist in different conformations or as different rotational isomers. Atropisomers are compounds that exist in different conformations resulting from restricted rotations around a single bond. Atropisomers can be separated as distinct chemical species if the energy barrier to rotation around a single bond is sufficiently high and the interconversion rate is sufficiently slow to separate the individual rotational isomers from each other. This disclosure intends to describe all isomers, enantiomers, diastereomers, and atropisomers disclosed herein or that can be prepared using the compounds disclosed herein.

[0109] Compounds conforming to any one of formulas I-VI or Examples 1-8 are readily convertible to pharmaceutically acceptable salts and can be isolated as pharmaceutically acceptable salts. Salt formation can occur upon addition of a pharmaceutically acceptable acid to form an acid addition salt. Salts can also be formed simultaneously upon deprotection of nitrogen or oxygen, i.e., upon removal of a protecting group. Examples, reactions, and conditions for salt formation can be found in Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19 (1977).

[0110] The compounds or salts thereof of this disclosure may be prepared by a variety of procedures, some of which are described in the preparations and examples of WO2021 / 118877, WO2016 / 077161, and WO2020 / 112514. The compounds or salts thereof of this disclosure may be prepared by combining specific synthesis steps of each described pathway in different ways, or by combining steps of different pathways. The products of each step in the following preparations may be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization.

[0111] The appropriate reaction conditions for these preparation and example steps are well known in the art, and suitable substitutions of solvents and co-reagents are within the scope of the art. Similarly, those skilled in the art will understand that synthetic intermediates can be isolated and / or purified by various well known techniques as needed or desired, and in many cases, various intermediates can be used directly in subsequent synthetic steps with little or no purification. For example, the compounds of the preparations and examples can be isolated, for example, by silica gel purification, by direct filtration, or by crystallization. Furthermore, those skilled in the art will recognize that, under certain circumstances, the order in which the moieties are introduced is not important. The specific order of steps required to produce the compounds of this disclosure depends on the relative disadvantages of the particular compound being synthesized, the starting compound, and the substituted moieties, as is well understood by skilled chemists. All substituents are as previously defined unless otherwise indicated, and all reagents are well known and understood in the art.

[0112] The compounds or salts of this disclosure can be prepared by combining specific synthesis steps of each described pathway in different ways, or by combining them with steps of different pathways. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization.

[0113] The compounds of this disclosure can be prepared by several methods well known to those skilled in the art of organic synthesis. For example, the compounds of this disclosure can be synthesized using the following methods, along with synthetic methods known in the field of organic synthesis chemistry as understood by those skilled in the art, or variations thereof. Preferred methods include, but are not limited to, the methods described below.

[0114] The compounds of this disclosure can be synthesized according to the steps outlined in the following schemes 1 to 1a, which include partially intermediates or different construction sequences of the compounds. The starting materials are either commercially available or prepared by known procedures in reported literature or by the procedures described below. [ka]

[0115] In step 1 of scheme 1, protected piperazine-2-ethanol, compound (1), is coupled with 4-bromo-2,5-difluorobenzoic acid, compound (2), in amide bond formation using a coupling reagent such as CDMT together with an organic base such as NMM and an inorganic base such as K2CO3 in a solvent system such as acetonitrile and water. 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 generally 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 carboxylic acids and amines. For example, compound (3) can be obtained by 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. Other coupling reagents include carbodiimides, such as DCC, DIC, EDCI, or carbonyldiimidazoles, such as CDI. The reaction can also be enhanced using amide coupling additives such as HOBt and HOAt. In addition, uronium or phosphonium salts of non-nucleophilic anions such as HBTU, HATU, PyBOP, and PyBrOP can be used instead of more traditional coupling reagents. The reaction can be enhanced using additives such as DMAP. Alternatively, compound (3) can be obtained by using an acid chloride of compound (2) in the presence of a base such as TEA or pyridine.

[0116] In step 2, the intramolecular cyclization of compound (3) is completed using a suitable base such as potassium tert-butoxide, sodium tert-amilate, sodium tert-butoxide, sodium tert-pentoxide, DIPEA, TEA, DBU, or sodium hydride in a solvent such as DMF to obtain compound 4. Other possible solvents may be NMP, DMAc, DMSO, and THF. This intramolecular cyclization from compound (3) to compound (4) can be carried out by slowly adding a solution of compound (3) to an excess of both bases to minimize impurities from intermolecular reactions.

[0117] In step 3, compound (4) is 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 obtain compound (5). [ka]

[0118] Scheme 1a describes 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.

[0119] (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-carboxylic acid tert-butyl is synthesized using a 7-step sequence starting from commercially available S-aspartic acid, which is a source of the stereocenter.

[0120] In the isolation of the intermediate, it is known that significant impurity elimination, including the elimination of the R-enantiomer, can be achieved. (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-carboxylic acid tert-butyl can be separated by crystallization to significantly eliminate impurities. Steps and schemes are used to control process and reagent impurities.

[0121] The present disclosure provides a method for preparing an intermediate compound of formula IIIa,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0122] 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.

[0123] In another embodiment, the preparation method further includes a cyclization solvent. In one embodiment, the cyclization solvent is N,N-dimethylformamide (DMF).

[0124] A preparation method in which the cyclization step is carried out at about 0 °C.

[0125] For clarity, in the following schemes, certain stereochemical centers remain unspecified and certain substituents are excluded, but are not intended to limit the teachings 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 by 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 the non-salt form, and isolating the enantiomers. Individual isomers, enantiomers, and diastereomers can 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 E. L. Eliel and S. H. Wilen, ''Stereochemistry of Organic Compounds'', Wiley-Interscience, 1994).

[0126] 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 N,N-diisopropylethyl "DMAc" or "DMA" refers to dimethylacetamide, "DMAP" refers to 4-dimethylaminopyridine, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "DMSO-d6" refers to deuterated dimethyl sulfoxide, "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, "Â" refers to ethyl acetate, "EtOH" refers to ethanol or ethyl alcohol, and "HATU" refers to O-(7-azabenzotriazole-1-yl)-N,N,N',"HOAt" refers to N'-tetramethyluronium hexafluorophosphate, "HBTU" refers to 1-hydroxy-7-azobenzotriazole, "HBTU" refers to 3-[bis(dimethylamino)methylumyl]-3H-benzotriazole-1-oxidehexafluorophosphate, "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 the melting point by differential scanning calorimetry, and "MTBE" refers to methyl tetrahydrofuran. "ert" refers to butyl ether, "NCS" refers to N-chlorosuccinimide, "NMM" refers to N-methylmorpholine, "NMP" refers to N-methyl-2-pyrrolidone, "NMR" refers to nuclear magnetic resonance, "PG" refers to a protecting group, "PyBOP" refers to (benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), "PyBrOP" refers to bromo(tri-pyrrolidinyl)phosphonium hexafluorophosphate, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, and "THF" refers to tetrahydrofuran.

[0127] The "cyclized 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-amilate, potassium tert-pentoxide, and potassium tert-butoxide.

[0128] Preparations and Examples Preparation 1 4-amino-3-chloro-2,5-difluorobenzoate methyl [ka] The title compound was prepared using the same method as preparation 31 in WO2021 / 118877. ES / MS m / z: 222 [M+H] + .

[0129] Preparation 2 3-Chloro-2,5-difluoro-4-iodobenzoate methyl [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 4-amino-3-chloro-2,5-difluorobenzoate methyl (22.1 g, 100 mmol) in ACN (100 mL) was added. The reaction mixture was stirred at 40 °C for 3 hours, cooled to room temperature, filtered through diatomaceous earth, and rinsed with DCM. The filtrate was concentrated under vacuum and purified by silica gel flash chromatography (10% siRNA / hexane) to obtain the title compound (17.8 g, 54%) as a white solid. 1 H NMR(CDCl3)δ 7.60(dd,J=5.6,7.6Hz,1H),3.98(s,3H).

[0130] Preparation 3 3-Chloro-2,5-difluoro-4-iodobenzoic acid [ka] 50 mL of MeOH was added to a solution of methyl 3-chloro-2,5-difluoro-4-iodobenzoate (16.8 g, 50.5 mmol) in THF (125 mL). The reaction mixture was cooled in an ice bath. 150 mL of 1 N NaOH aqueous solution (150 mmol) was added in three portions. The reaction mixture was stirred at room temperature for 30 minutes and concentrated under vacuum to remove the organic solvent. The remaining aqueous solution was cooled with ice and the pH was adjusted to approximately 2 with 25 mL of 5 N HCl aqueous solution. Extraction was performed with ELISA (three times). The combined organic extract was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain 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).

[0131] Preparation 4 (3R)-4-(3-chloro-2,5-difluoro-4-iodobenzoyl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl [ka] HATU (3.31 g, 8.53 mmol) was added to a solution of 3-chloro-2,5-difluoro-4-iodobenzoic 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 hour. A solution of (3R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (1.92 g, 8.52 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 14 hours, then stirred at 60°C for 3 hours, and then diluted with toluene and water. The organic layer was washed with water, 1N NaOH aqueous solution, and brine. The aqueous layer was extracted with toluene and washed with brine. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude compound was purified by silica gel flash chromatography (10-50% Âxane) to obtain 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] + .

[0132] Preparation 5 (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazosin-2-carboxylate tert-butyl [ka] The title compound was prepared using the same method as preparation 117 in WO2021 / 118877. ES / MS m / z( 79 Br / 81 Br)407 / 409[M-tert-butyl+H] + .

[0133] Modulation 6 (4aR)-7-chloro-9-fluoro-8-iodo-11-oxo-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine-3-carboxylic acid tert-butyl

Chemical formula

[0134] Modulation 7 tert-Butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate

Chemical formula

[0135] Modulation 8 N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl] tert-butyl carbamate [ka] A mixture of tert-butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate (3.10 g, 8.35 mmol), bis(pinacolate)diborone (21.0 g, 82.7 mmol), and potassium acetate (2.50 g, 25.5 mmol) in 1,4-dioxane (50 mL) was subjected to a direct sparge of nitrogen for 10 minutes. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (1.0 g, 1.2 mmol) was added. The reaction flask was sealed and heated at 80-85°C for 3.5 hours. The reaction mixture was filtered through diatomaceous earth. The filtrate was diluted with water and extracted with ethyl acetate (twice). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude compound was purified by silica gel flash chromatography (10-50% (20% acetone / DCM) / hexane) to obtain the title compound (4.45 g, 87%). ES / MS m / z 363 [M-tert-butyl+H] + .

[0136] Preparation 9 N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzothiophen-2-yl]carbamate tert-butyl [ka] The title compound was prepared using the method of WO2021 / 118877, in the same format as preparation 15. 1 H 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).

[0137] Preparation 10 and Preparation 11 (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]benzoxazosin-2-carboxylate tert-butyl, P-atropisomer and M-atropisomer [ka] The title compound was prepared using the same method as preparation 167 in WO2021 / 118877. The mixture of atropisomers was separated by silica gel flash chromatography (0-30% acetone / hexane). 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 using ES / MS m / z ( 35 Cl / 37 Cl)657 / 659[M+H] + .

[0138] Preparation 12 and 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]benzoxazosin-2-carboxylate tert-butyl, P-atropisomer and M-atropisomer [ka] (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazosin-2-carboxylate tert-butyl (10.0g, 21.6mmol), N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen- A mixture of tert-butyl 2-yl]carbamate (12.3 g, 30.4 mmol), potassium carbonate (8.94 g, 64.7 mmol), and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthylpalladium dichloride (3.84 g, 4.42 mmol) was added to 1,4-dioxane (215 mL) that had been subjected to nitrogen (direct sparge) for 30 minutes. The reaction flask was sealed and heated at 105°C for 14 hours. Additional tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (3.54 g, 8.75 mmol) and (S)-(-)-2,2'-bis(diphenylphosphin)-1,1'-binaphthylpalladium dichloride (0.97 g, 1.12 mmol) were added. The reaction flask was sealed and heated at 105°C for 14 hours.

[0139] The reaction mixture was filtered through diatomaceous earth and rinsed with RINKAN. The filtrate was concentrated under vacuum and diluted with RINKAN, water, and brine. The aqueous layer was extracted with RINKAN. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude was purified by silica gel flash chromatography (10-40% acetone / hexane). 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 yielded two title compounds (P-atropisomer, 0.35 g, 2%, M-atropisomer, 5.6 g, 38%). Both had ES / MS m / z values ​​of 619 [M-tert-butyl+H]. + .

[0140] Preparation 14 and Preparation 15 (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 and M-atropisomer [ka] (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 (0.50 g, 1.01 mmol), N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate tert-butyl (0.63 g, 1.51 mmol), and potassium phosphate (0.50 g, 2.36 mmol) were mixed in water (2 mL) and 1,4-dioxane (10 mL), and nitrogen (direct sparge) was passed over them for 10 minutes. 1,1'-Bis(di-tert-butylphosphin)ferrocene palladium dichloride (0.20 g, 0.30 mmol) was added. The reaction flask was sealed and heated at 70°C for 3 hours.

[0141] (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 (0.20 g, 0.40 mmol), N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate tert-butyl (0.24 g, 0.57 mmol), and potassium phosphate (0.20 g, 0.96 mmol) were mixed in water (2.5 mL) and 1,4-dioxane (8 mL), and nitrogen (direct sparge) was passed over them for 10 minutes. 1,1'-Bis(di-tert-butylphosphin)ferrocene palladium dichloride (0.080 g, 0.12 mmol) was added. The reaction flask was sealed and heated at 70°C for 5 hours.

[0142] The two reaction mixtures were combined, filtered through diatomaceous earth, and rinsed with RINKAN. The filtrate was diluted with MTBE and saturated sodium bicarbonate aqueous solution. The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude was purified by silica gel flash chromatography (0-30% acetone / hexane). 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% RINKAN / hexane). This yielded two title compounds (P-atropisomer, 0.17 g, 17%, M-atropisomer, 0.21 g, 21%). Both were analyzed using ES / MS m / z( 35 Cl / 37 Cl)605 / 607[M-tert-butyl+H] + .

[0143] Preparation 16 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazosin-9-yl]-2-amino-benzothiophene-3-carbonitrile, P-atrop isomer [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]benzoxazosin-2-carboxylic acid tert-butyl, P-atrop isomer (0.98 g, 1.5 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 3 hours, concentrated under vacuum, and purified by silica gel flash chromatography (4-10% 7N ammonia-treated MeOH / DCM) to obtain the title compound (0.57 g, 84%). ES / MS m / z( 35 Cl / 37 Cl)457 / 459[M+H] + .

[0144] Preparation 17 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazosin-9-yl]-2-amino-benzothiophene-3-carbonitrile, M atrop isomer [ka] The title compound was prepared using the same method as preparation 187 in WO2021 / 118877. ES / MS m / z( 35 Cl / 37 Cl)457 / 459[M+H] + .

[0145] Preparation 18 4-[(4aR)-7-chloro-9-fluoro-11-oxo-1,2,3,4,4a,5-hexahydropyrazino[2,1-c][1,4]benzoxazepine-8-yl]-2-amino-7-fluoro-benzothiophen-3-carbonitrile, P-atrop isomer [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-carboxylic acid tert-butyl, P-atrop isomer (0.018 g, 0.027 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 30 minutes, concentrated under vacuum, and purified by silica gel flash chromatography (0-10% MeOH / DCM, followed by 0-10% 7N ammonia-treated MeOH / DCM) to obtain the title compound (0.013 g, 100%). ES / MS m / z( 35 Cl / 37 Cl)461 / 463[M+H] + .

[0146] Preparation 19 4-[(4aR)-7-chloro-9-fluoro-11-oxo-1,2,3,4,4a,5-hexahydropyrazino[2,1-c][1,4]benzoxazepine-8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atrop isomer [ka] TFA (2.5 mL) was added to a 2.5 mL 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 atrop isomer (0.20 g, 0.31 mmol) in DCM (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated under vacuum, and purified by silica gel flash chromatography (0-10% 7N ammonia-treated MeOH / DCM) to obtain the title compound (0.13 g, 89%). ES / MS m / z( 35 Cl / 37 Cl)461 / 463[M+H] + .

[0147] Examples 1 and 2 (13aS)-9-(2-amino-7-fluoro-1,3-benzothiazole-4-yl)-8,10-dichloro-2-propa-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazosin-6-one, P-atropisomer and M-atropisomer [ka] The title compound was prepared using the method of WO2021 / 118877, in the same manner as in Example 1. The mixture of atrop isomers was separated using Chiralpak® IC, 4.6 × 150 mm, 40% EtOH / CO2, 5 mL / min, 225 nm. Example 1 (P atrop isomer) was the first compound to elute from the column. Example 2 (M atrop isomer) was the second compound to elute from the column. Both were analyzed using ES / MS m / z( 35 Cl / 37 Cl)521 / 523[M+H] + .

[0148] Example 3 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-propa-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazosin-9-yl]-2-amino-benzothiophene-3-carbonitrile, P-atrop isomer [ka] 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) were cooled to -78 °C. Acryloyl chloride (0.02 mL, 0.2 mmol) was added. After 5 minutes, it was diluted with a small amount of 2-propanol and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (20 - 100% acetone / hexane) to give the title compound (0.091 g, 71%). ES / MS m / z( 35 Cl / 37 Cl) 511 / 513 [M+H] + .

[0149] 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 [Chemical formula] The title compound was prepared in the same manner as in Example 34 of the method of WO2021 / 118877. ES / MS m / z( 35 Cl / 37 Cl) 511 / 513 [M+H] + .

[0150] 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 [Chemical formula] <​TFA (1 mL) was added to a solution of (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluorobenzothiophen-4-yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazosin-2-carboxylic acid tert-butyl, P-atrop isomer (0.025 g, 0.037 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under vacuum to obtain the deprotected crude product.

[0151] 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 minutes, the solution was concentrated under vacuum. The crude product was purified by silica gel flash chromatography (20-80% acetone / hexane) to obtain the title compound (0.012 g, 61%). ES / MS m / z( 35 Cl / 37 Cl)529 / 531[M+H] + .

[0152] Example 6 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-propa-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazosin-9-yl]-2-amino-7-fluorobenzothiophene-3-carbonitrile, M-atrop isomer ("KRAS G12C inhibitor") [ka] HCl gas was passed through a solution of (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluorobenzothiophen-4-yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazosin-2-carboxylic acid tert-butyl, M atrop isomer (0.786 g, 1.17 mmol) in DCM (12 mL) and 2-propanol (12 mL) ice-cold solution for 5 minutes. The reaction mixture was stirred at room temperature for 5 hours, then cooled in an ice bath. HCl gas was passed through the reaction mixture for 5 minutes. The reaction mixture was stirred at room temperature for 14 hours, then concentrated under vacuum. The residue was diluted twice with n-heptane and concentrated under vacuum. MTBE (50 mL) was added. The mixture was stirred at room temperature for 10 minutes, then filtered to obtain the deprotective substance as a dihydrochloride salt.

[0153] The dihydrochloride salt was dissolved in water (12 mL). 2-methyltetrahydrofuran (12 mL) was added. A solution of potassium carbonate (0.81 g, 5.82 mmol) in water (12 mL) was added. The mixture was vigorously stirred while 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 minutes, the mixture was diluted with brine and 2-methyltetrahydrofuran. The aqueous layer was extracted with 2-methyltetrahydrofuran (twice). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (20-30% B / A, A:3:1 Â:hexane, B:4:1 Â:MeOH) to obtain the title compound (0.409 g, 66%). ES / MS m / z( 35 Cl / 37 Cl)529 / 531[M+H] + .

[0154] 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

Chem.

[0155] 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

Chem.

[0156] Biological assays The following assays demonstrate that the compound combination described herein is a KRas G12C inhibitor and inhibits the growth of certain tumors in vitro and / or in vivo.

[0157] Example 1: Protocol for KRAS G12C inhibitor combined with Aurora A inhibitor The objective of these studies was to evaluate the antitumor growth activity of KRAS G12C inhibitors in combination with Aurora A inhibitors in human NSCLC tumor xenograft or PDX models carrying KRAS G12C mutations. In cell proliferation assays, synergistic or additive effects were observed with KRAS G12C inhibitors in combination with Aurora A inhibitors. In animal models, KRAS G12C inhibitors showed dose-dependent and time-dependent inhibition of KRAS activity and downstream signaling, resulting in significant tumor growth inhibition / regression in a panel of KRAS G12C mutant NSCLC, CRC, and PDAC xenograft and PDX models. In addition, KRAS G12C inhibitors showed an additive effect in KRAS G12C mutants in in vivo models when combined with Aurora A inhibitors.

[0158] KRAS G12C inhibitors also showed varying degrees of antitumor activity in KRAS G12C mutant animal models. Combining KRAS G12C inhibitors with other therapies yielded superior clinical activity, achieving more sustained responses in a wider range of tumors. KRAS G12C inhibitor combinations were evaluated in multiple KRAS G12C mutant in vivo models, including two lung cancer xenograft models (H358 and H1373), one lung cancer PDX model (EL3187), and one CRC xenograft model (SW837). Suboptimal doses of KRAS G12C inhibitors alone and Aurora A inhibitor monotherapy showed varying levels of antitumor activity in these models. The combination of KRAS G12C inhibitors and Aurora A inhibitors resulted in improved antitumor activity based on tumor growth inhibition and tumor regression. This combination demonstrated higher efficacy than monotherapy and did not adversely impact body weight.

[0159] For the growth of H358 and H1373 xenograft tumors, use 0.2 mL of Hanks equilibrium salt solution (HBSS): 5 × 10 in Matrigel (Corning, catalog number 354234) (1:1). 6Cells were subcutaneously transplanted into the right flank of each animal. H358 cells were transplanted into NOD SCID gamma mice (20-22g, The Jackson Laboratory, Bar Harbor, Maine), and H1373 cells were transplanted into female athymic nude mice (20-22g, Envigo RMS, Inc., Mount Comfort, Indiana). Tumor volume was measured twice a week using calipers. Tumor volume was 200-300 mm². 3 Once this point was reached, mice were randomized based on tumor measurements and body weight using a multitasking block randomization tool (n=5 or 6 / group). Treatment was initiated with 28 days of oral administration (enteral nutrition) of either 0.2 mL of vehicle (PEG 400 solution of 10% N-methyl-2-pyrrolidone "NMP" / 90% 15% w / v polyvinylpyrrolidone vinyl acetate "PVP-VA"), a KRAS G12C inhibitor (PEG 400 solution of 10% NMP / 90% 15% w / v PVP-VA) (10 mg / kg once daily), an Aurora A inhibitor (sterile aqueous solution of 20% w / v 2-hydroxypropyl-β-cyclodextrin "HPBCD") (57 mg / kg twice daily), or a combination of a KRAS G12C inhibitor (10 mg / kg once daily) and an Aurora A inhibitor (57 mg / kg twice daily). In the H1373 model, the dosage of the Aurora A inhibitor was changed to 57 mg / kg once daily from day 4. Statistical analysis results were compiled on day 28 of the H358 xenotransplant study and on day 24 of the H1373 xenotransplant study.

[0160] In the EL3187 PDX model, tumor fragments were subcutaneously transplanted into the right posterior flank of female athymic nude Foxn1nu feeder mice (20-22g, Envigo RMS, Inc., Mount Comfort, Indiana). The tumor volume was 800-1000 mm². 3 Upon reaching this stage, the animals were slaughtered and the tumors were harvested using a sterile method. Fresh tumors that had been passaged four times were collected at 10-15 mm intervals. 3The tumor was cut into fragments, placed in cold Gibco Hibernate Medium, and then the pooled tumor fragments were subcutaneously transplanted into animals using a 10g trocar needle. The tumor volume was 200-300 mm². 3 At this point, mice were randomized (n=5 / group). Treatment was initiated with 22 days of oral administration (enteral nutrition) of either 0.2 mL of vehicle (PEG 400 solution of 10% NMP / 90% 15% w / v PVP-VA), KRAS G12C inhibitor (PEG 400 solution of 10% NMP / 90% 15% w / v PVP-VA) (10 mg / kg once daily), Aurora A inhibitor (sterile aqueous solution of 20% w / v HPBCD) (57 mg / kg twice daily), or a combination of KRAS G12C inhibitor (3 mg / kg once daily) and Aurora A inhibitor (57 mg / kg twice daily). Statistical analysis results were compiled on day 22 of treatment. [Table 1]

[0161] Table 1 shows data from an H358 NSCLC xenograft model comparing monotherapy with a KRAS G12C inhibitor and monotherapy with an Aurora A inhibitor, compared with a combination of both. Treatment with a KRAS G12C inhibitor combined with an Aurora A inhibitor demonstrated in vivo efficacy compared to either monotherapy in the H358 NSCLC xenograft model, resulting in a 55.3% tumor regression rate. [Table 2]

[0162] Table 2 shows data from an H1373 NSCLC xenograft model comparing monotherapy with a KRAS G12C inhibitor and monotherapy with an Aurora A inhibitor, compared with a combination of both. Treatment with a KRAS G12C inhibitor combined with an Aurora A inhibitor demonstrated in vivo efficacy compared to either monotherapy in the H1373 NSCLC xenograft model, resulting in a 25.3% tumor regression rate. [Table 3]

[0163] Table 3 shows data from the EL3187 NSCLC PDX model comparing monotherapy with a KRAS G12C inhibitor and monotherapy with an Aurora A inhibitor in combination with a KRAS G12C inhibitor and an Aurora A inhibitor. Treatment with a KRAS G12C inhibitor in combination with an Aurora A inhibitor showed significant in vivo efficacy compared to either monotherapy in the EL3187 NSCLC PDX model, resulting in an 88.6% tumor regression rate.

[0164] The delta T / C% is calculated when the endpoint tumor volume in the treatment group becomes equal to or greater than the baseline tumor volume. The formula is 100 × (T - T0) / (C - C0), where T and C are the mean endpoint tumor volume in the treatment group or control group, respectively. T0 and C0 are the mean baseline tumor volumes in these groups.

[0165] The tumor regression percentage is calculated when the endpoint tumor volume in the treatment group falls below the baseline tumor volume. The formula is 100 × (T - T0) / T0, where T0 is the mean baseline tumor volume of the treatment group.

[0166] Additional embodiments: Embodiment 1. A method for treating a patient with cancer in which one or more cells express the KRas G12C mutant protein, wherein the patient is given an effective amount of a compound of the following formula: [ka] During the ceremony, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-, B is -CH2- or -C(O)-, Y is -C(CN)- or -N-, R1 is -CN, -C(O)C≡CR8, or the base of the following formula: [ka] R2 is H, methyl, or -CH2CN. R3 and R5 are independently H, halogen, and -C. 0-3 Alkyl-cyclopropyl, R 10 -C is optionally replaced 1 to 3 times. 1-6 Alkyl, or R 10 -OC is optionally replaced 1 to 3 times. 1-6 It is alkyl, R4 is H, halogen, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R6 is H or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R7 is H, halogen, -NR 11 R 12 -CH2NR 11 R 12 , R 10 Or R 13 -C is optionally replaced 1 to 3 times. 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or R 10 Or R 13 -OC is optionally replaced 1 to 3 times. 1-6 It is alkyl, R8 is H, R 10 -C is optionally replaced 1 to 3 times. 1-4 Alkyl, or R 10 -C is optionally replaced 1 to 3 times. 3-6 It is a cycloalkyl, R9 is H, Halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R10 Each of these independently comprises halogen, oxygen, hydroxyl, and -C. 1-4 Alkyl, or -OC 1-4 It is alkyl, R 11 and R 12 Each of these is independent of H and -C 1-4 Alkyl, or -C 1-4 It is heteroalkyl, R 11 and R 12 They may bond to form a heterocycloalkyl group. R 13 Each of them independently, -N(CH3)2 or [ka] is a compound, or a pharmaceutically acceptable salt thereof, A method comprising administering an effective amount of an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof.

[0167] Embodiment 2. A compound of the following formula, for use in combination with, separately from, or sequentially with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof during treatment, [ka] During the ceremony, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-, B is -CH2- or -C(O)-, Y is -C(CN)- or -N-, R1 is -CN, -C(O)C≡CR8, or the base of the following formula: [ka] R2 is H, methyl, or -CH2CN. R3 and R5 are independently H, halogen, and -C. 0-3 Alkyl-cyclopropyl, R 10-C is optionally replaced 1 to 3 times. 1-6 Alkyl, or R 10 -OC is optionally replaced 1 to 3 times. 1-6 It is alkyl, R4 is H, halogen, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R6 is H or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R7 is H, halogen, -NR 11 R 12 -CH2NR 11 R 12 , R 10 Or R 13 -C is optionally replaced 1 to 3 times. 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or R 10 Or R 13 -OC is optionally replaced 1 to 3 times. 1-6 It is alkyl, R8 is H, R 10 -C is optionally replaced 1 to 3 times. 1-4 Alkyl, or R 10 -C is optionally replaced 1 to 3 times. 3-6 It is a cycloalkyl, R9 is H, Halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R 10 Each of these independently comprises halogen, oxygen, hydroxyl, and -C. 1-4 Alkyl, or -OC 1-4 It is alkyl, R 11 and R 12 Each of these is independent of H and -C 1-4 Alkyl, or -C 1-4 It is heteroalkyl, R 11 and R 12They may bond to form a heterocycloalkyl group. R 13 Each of them independently, -N(CH3)2 or [ka] is a compound, or a pharmaceutically acceptable salt thereof.

[0168] Embodiment 3. A compound of the following formula, for use in combination with, separately from, or sequentially with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof in the treatment of cancer, [ka] During the ceremony, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-, B is -CH2- or -C(O)-, Y is -C(CN)- or -N-, R1 is -CN, -C(O)C≡CR8, or the base of the following formula: [ka] R2 is H, methyl, or -CH2CN. R3 and R5 are independently H, halogen, and -C. 0-3 Alkyl-cyclopropyl, R 10 -C is optionally replaced 1 to 3 times. 1-6 Alkyl, or R 10 -OC is optionally replaced 1 to 3 times. 1-6 It is alkyl, R4 is H, halogen, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R6 is H or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R7 is H, halogen, -NR 11 R 12 -CH2NR 11 R 12 , R 10 Or R 13 -C is optionally replaced 1 to 3 times. 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or R 10 Or R 13 -OC is optionally replaced 1 to 3 times. 1-6 It is alkyl, R8 is H, R 10 -C is optionally replaced 1 to 3 times. 1-4 Alkyl, or R 10 -C is optionally replaced 1 to 3 times. 3-6 It is a cycloalkyl, R9 is H, Halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R 10 Each of these independently comprises halogen, oxygen, hydroxyl, and -C. 1-4 Alkyl, or -OC 1-4 It is alkyl, R 11 and R 12 Each of these is independent of H and -C 1-4 Alkyl, or -C 1-4 It is heteroalkyl, R 11 and R 12 They may bond to form a heterocycloalkyl group. R 13 Each of them independently, -N(CH3)2 or [ka] is a compound, or a pharmaceutically acceptable salt thereof.

[0169] Embodiment 4. Compounds of the following formula, used in the manufacture of a drug for the treatment of cancer, which are used simultaneously, separately, or sequentially with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2-, or -CH2N(R6)CH2-, B is -CH2- or -C(O)-, Y is -C(CN)- or -N-, R1 is -CN, -C(O)C≡CR8, or the base of the following formula: [ka] R2 is H, methyl, or -CH2CN. R3 and R5 are independently H, halogen, and -C. 0-3 Alkyl-cyclopropyl, R 10 -C is optionally replaced 1 to 3 times. 1-6 Alkyl, or R 10 -OC is optionally replaced 1 to 3 times. 1-6 It is alkyl, R4 is H, halogen, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R6 is H or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R7 is H, halogen, -NR 11 R 12 -CH2NR 11 R 12 , R 10 Or R 13 -C is optionally replaced 1 to 3 times. 1-6 Alkyl, -C 0-3 Alkylcyclopropyl, or R 10 Or R 13-OC is optionally replaced 1 to 3 times. 1-6 It is alkyl, R8 is H, R 10 -C is optionally replaced 1 to 3 times. 1-4 Alkyl, or R 10 -C is optionally replaced 1 to 3 times. 3-6 It is a cycloalkyl, R9 is H, Halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl, or R 10 -C is optionally replaced 1 to 3 times. 1-6 It is alkyl, R 10 Each of these independently comprises halogen, oxygen, hydroxyl, and -C. 1-4 Alkyl, or -OC 1-4 It is alkyl, R 11 and R 12 Each of these is independent of H and -C 1-4 Alkyl, or -C 1-4 It is heteroalkyl, R 11 and R 12 They may bond to form a heterocycloalkyl group. R 13 Each of them independently, -N(CH3)2 or [ka] is a compound, Or the use of a pharmaceutically acceptable salt thereof.

[0170] Embodiment 5.A method, compound, or use thereof according to any one of Embodiments 1 to 4, wherein A is -OCH2CH2-.

[0171] Embodiment 6. A method, compound, or use thereof according to any one of Embodiments 1 to 5, wherein B is -C(O)-.

[0172] Embodiment 7. A method, compound, or use according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is -C(CN)-.

[0173] Embodiment 8. A method, compound, or use according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is -N-.

[0174] Embodiment 9.R1 is the basis of the following formula, [ka] A method, compound, or use thereof according to any one of Embodiments 1 to 8, wherein R7 is H, F, Cl, methyl, ethoxy, ethyl, isopropyl, or cyclopropyl.

[0175] Embodiment 10.R1 is based on the following formula: [ka] A method, compound, or use thereof according to any one of Embodiments 1 to 9, wherein R9 is H, F, Cl, -CHF2, -CF3, or -CH2OH.

[0176] Embodiment 11. A method, compound, or use thereof according to any one of Embodiments 1 to 8, wherein R1 is -CN or -C(O)C≡CR8, or a pharmaceutically acceptable salt thereof.

[0177] Embodiment 12. A method, compound, or use thereof according to any one of Embodiments 1 to 11, wherein R2 is H or methyl.

[0178] Embodiment 13. The method, compound, or use thereof according to any one of Embodiments 1 to 12, wherein R3 is H, F, Cl, methyl, methoxy, ethyl, isopropyl, or cyclopropyl.

[0179] Embodiment 14. A method, compound, or use thereof according to any one of Embodiments 1 to 13, wherein R4 is H, F, or Cl.

[0180] Embodiment 15. A method, compound, or use thereof according to any one of Embodiments 1 to 14, wherein R5 is H, -CHF2, -CH2F, -CH2OH, or -CH2OCH3.

[0181] Embodiment 16. The compound has the following formula: [ka] A method, compound, or use thereof as described in any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt thereof.

[0182] Embodiment 17. The compound has the following formula: [ka] In the formula, R is [ka] And, X is either Cl or F, m is 1 or 2. A method, compound, or use thereof according to any one of Embodiments 1-4, 6, 9, 10, 12-16, or a pharmaceutically acceptable salt thereof.

[0183] Embodiment 18. The compound has the following formula: [ka] In the formula, R is [ka] And, X is either Cl or F, m is 1 or 2. A method, compound, or use thereof according to any one of Embodiments 1-4, 6, 9, 10, 12-17, or a pharmaceutically acceptable salt thereof.

[0184] Embodiment 19. The compound has the following formula: [ka] During the ceremony, A is -OCH2- or -OCH2CH2-, Y is either C(CN) or N, R3 is either Cl or F. If Y is C(CN), then R4 is either H or F. If Y is N, then R4 is F. A method, compound, or use thereof according to any one of Embodiments 1-4, 6, 9, 10, 12-16, or a pharmaceutically acceptable salt thereof.

[0185] Embodiment 20.A is, [ka] The method, compound, or use described in any one of Embodiments 1-4 or 6-19.

[0186] Embodiment 21. The compound is [ka] That is, A method, compound, or use thereof according to any one of Embodiments 1-4, 6, 9, 10, or 12-20, or a pharmaceutically acceptable salt thereof.

[0187] Embodiment 22. The compound is [ka] The method, compound, or use according to any one of Embodiments 1-4, 6, 9, 10, 12-21.

[0188] Embodiment 23. The compound is [ka] That is, A method, compound, or use thereof according to any one of Embodiments 1-4, 6, 9, 10, 12-22, or a pharmaceutically acceptable salt thereof.

[0189] Embodiment 24. [ka] Selected from the group consisting of, The method, compound, or use thereof as described in Embodiment 23, or a pharmaceutically acceptable salt thereof.

[0190] Embodiment 25. [ka] A method, compound, or use according to Embodiment 23 or 24, selected from the group consisting of the following.

[0191] Embodiment 26. [ka] Selected from the group consisting of, The method, compound, or use thereof as described in Embodiment 23, or a pharmaceutically acceptable salt thereof.

[0192] Embodiment 27. [ka] A method, compound, or use according to Embodiment 23 or 26, selected from the group consisting of the following.

[0193] Embodiment 28. [ka] Selected from the group consisting of, The method, compound, or use thereof as described in Embodiment 23, or a pharmaceutically acceptable salt thereof.

[0194] Embodiment 29. The compound is as follows: [ka] A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 28, or a pharmaceutically acceptable salt thereof.

[0195] Embodiment 30. The compound is as follows: [ka] A method, compound, or use thereof according to any one of Embodiments 23, 26, 27, or 28, or a pharmaceutically acceptable salt thereof.

[0196] Embodiment 31. [ka] Selected from the group consisting of, The method, compound, or use thereof as described in Embodiment 23, or a pharmaceutically acceptable salt thereof.

[0197] Embodiment 32. The compound is as follows: [ka] A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 31, or a pharmaceutically acceptable salt thereof.

[0198] Embodiment 33. The compound is as follows: [ka] A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 31, or a pharmaceutically acceptable salt thereof.

[0199] Embodiment 34. [ka] Selected from the group consisting of, A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 31, or a pharmaceutically acceptable salt thereof.

[0200] Embodiment 35. The compound is as follows: [ka] A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 31, or a pharmaceutically acceptable salt thereof.

[0201] Embodiment 36. The compound is as follows: [ka] A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 31, or a pharmaceutically acceptable salt thereof.

[0202] Embodiment 37. [ka] Selected from the group consisting of, A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 31, or a pharmaceutically acceptable salt thereof.

[0203] Embodiment 38. The compound is as follows: [ka] A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 31, or a pharmaceutically acceptable salt thereof.

[0204] Embodiment 39. The compound is as follows: [ka] A method, compound, or use thereof according to any one of Embodiments 23, 24, 25, or 31, or a pharmaceutically acceptable salt thereof.

[0205] Embodiment 40. The Aurora A inhibitor is an Aurora A selective inhibitor or a pharmaceutically acceptable salt thereof, aricertib, a pan-aurora inhibitor or a pharmaceutically acceptable salt thereof, tozacertib, danucertib, an aminopyridine compound or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methylpiperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl A method, compound, or use according to any one of Embodiments 1 to 0, selected from the group consisting of (nyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methylpiperidine-4-carboxylic acid:2-methylpropane-2-amine (1:1) salt and (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methylpiperidine-4-carboxylic acid:amine (1:1) salt.

[0206] Embodiment 41. The method, compound, or use according to any one of Embodiments 1 to 40, wherein the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0207] Embodiment 42. The Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methylpiperidine-4-carboxylic acid, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl] A method, compound, or use according to any one of Embodiments 1 to 41, selected from the group consisting of methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt and (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt.

[0208] Embodiment 43. The method, compound, or use according to any one of Embodiments 1 to 42, wherein the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt.

[0209] Embodiment 44. The method, compound, or use according to any one of Embodiments 1 to 43, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

[0210] Embodiment 45. The method, compound, or use according to any one of Embodiments 1 to 44, wherein the cancer is non-small cell lung cancer and one or more cells with or without Aurora A dysregulation or overexpression express the KRas G12C mutant protein.

[0211] Embodiment 46. The method, compound, or use according to any one of Embodiments 1 to 44, wherein the cancer is colorectal cancer and one or more cells with or without Aurora A dysregulation or overexpression express the KRas G12C mutant protein.

[0212] Embodiment 47. The method, compound, or use according to any one of Embodiments 1 to 44, wherein the cancer is pancreatic cancer and one or more cells with or without Aurora A dysregulation or overexpression express the KRas G12C mutant protein.

[0213] Embodiment 48. The method, compound, or use according to any one of Embodiments 1 to 44, wherein the patient has cancer with a KRAS G12C mutation.

[0214] Embodiment 49. The method, compound, or use according to any one of Embodiments 1 to 48, wherein the patient has cancer that has been determined to have one or more cells expressing the KRas G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof, or the Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0215] Embodiment 50. The method, compound, or use according to any one of Embodiments 1 to 49, wherein the compound and the Aurora A inhibitor are administered simultaneously or sequentially to the patient in need thereof.

[0216] Embodiment 51. The method, compound, or use according to any one of Embodiments 1 to 50, wherein the compound of the formula or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered simultaneously in combination to a patient in need thereof.

[0217] Embodiment 52. The method, compound, or use according to any one of Embodiments 1 to 50, wherein the compound of the formula or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered sequentially in combination to the patient in need.

[0218] Embodiment 53. The method, compound, or use according to any one of Embodiments 1 to 52, wherein the compound of the formula or a pharmaceutically acceptable salt thereof is administered to the patient in need, and then the Aurora A inhibitor or a pharmaceutically acceptable salt thereof is administered to the patient in need.

[0219] Embodiment 54. The method, compound, or use according to any one of Embodiments 1 to 52, wherein the Aurora A inhibitor or a pharmaceutically acceptable salt thereof is administered to the patient in need, and then the compound of the formula or a pharmaceutically acceptable salt thereof is administered to the patient in need.

Claims

1. The following compound of formula I, 【Chemistry 1】 During the ceremony, A, -OCH ２ -、-N(R ６ )CH ２ -、-OCH ２ CH ２ -、-N(R ６ )CH ２ CH ２ -、-CH ２ OCH ２ - CH ２ N(R) ６ )CH ２ - B is -CH ２ - or -C(O)-, Y is -C(CN)- or -N-, R １ is -CN, -C(O)C≡CR ８ , or the basis of the following formula, 【Chemistry 2】 R ２ However, H, methyl, or -CH ２ It is CN, R ３ and R ５ Each of these independently represents H, halogen, and -C. ０－３ Alkyl-cyclopropyl, R １０ -C is optionally substituted 1 to 3 times. １－６ Alkyl, or R １０ -O-C is optionally substituted 1 to 3 times. １－６ It is alkyl, R ４ However, H, halogen, or R １０ -C is optionally substituted 1 to 3 times. １－６ It is alkyl, R ６ However, H or R １０ -C is optionally substituted 1 to 3 times. １－６ It is alkyl, R ７ However, H, halogen, -NR １１ R １２ ien-CH ２ NR １１ R １２ , R １０ Or R １３ -C is optionally substituted 1 to 3 times. １－６ Alkyl, -C ０－３ Alkylcyclopropyl, or R １０ Or R １３ -O-C is optionally substituted 1 to 3 times. １－６ It is alkyl, R ８ However, H, R １０ -C is optionally substituted 1 to 3 times. １－４ Alkyl, or R １０ -C is optionally substituted 1 to 3 times. ３－６ It is a cycloalkyl, R ９ However, H, halogen, -CN, -C ０－３ Alkyl-C ３－６ Cycloalkyl, or R １０ -C is optionally substituted 1 to 3 times. １－６ It is alkyl, R １０ Each of these independently comprises halogen, oxygen, hydroxyl, and -C. １－４ Alkyl, or -O-C １－４ It is alkyl, R １１ and R １２ These are H and -C, respectively, independently. １－４ Alkyl, or -C １－４ It is a heteroalkyl, R １１ and R １２ They may bond to form a heterocycloalkyl group. R １３ Each of them operates independently, -N(CH ３ ) ２ or 【Transformation 3】 is a compound, A therapeutic agent for treating patients with cancer in which one or more cells express the KRas G12C mutant protein, comprising a pharmaceutically acceptable salt thereof, A therapeutic agent characterized by being used in combination with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

2. The therapeutic agent according to claim 1, for use in combination with, separately from, or sequentially with the Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

3. Compounds of the following formula I, used in the manufacture of drugs for the treatment of cancer patients, which are used simultaneously, separately, or sequentially with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 During the ceremony, A, -OCH ２ -、-N(R ６ )CH ２ -、-OCH ２ CH ２ -、-N(R ６ )CH ２ CH ２ -、-CH ２ OCH ２ - CH ２ N(R) ６ )CH ２ - B is -CH ２ - or -C(O)-, Y is -C(CN)- or -N-, R １ is -CN, -C(O)C≡CR ８ , or the basis of the following formula, 【Transformation 5】 R ２ However, H, methyl, or -CH ２ It is CN, R ３ and R ５ are each independently H, halogen, -C ０－３ alkyl-cyclopropyl, R １０ which is optionally substituted 1 to 3 times with -C １－６ alkyl, or R １０ which is optionally substituted 1 to 3 times with -O-C １－６ alkyl, and R ４ However, H, halogen, or R １０ -C is optionally substituted 1 to 3 times. １－６ It is alkyl, R ６ is H or R １０ is optionally substituted 1 to 3 times with -C １－６ alkyl and R ７ However, H, halogen, -NR １１ R １２ ien-CH ２ NR １１ R １２ , R １０ Or R １３ -C is optionally substituted 1 to 3 times. １－６ Alkyl, -C ０－３ Alkylcyclopropyl, or R １０ Or R １３ -O-C is optionally substituted 1 to 3 times. １－６ It is alkyl, R ８ However, H, R １０ -C is optionally substituted 1 to 3 times. １－４ Alkyl, or R １０ -C is optionally substituted 1 to 3 times. ３－６ It is a cycloalkyl, R ９ However, H, halogen, -CN, -C ０－３ Alkyl-C ３－６ Cycloalkyl, or R １０ -C is optionally substituted 1 to 3 times. １－６ It is alkyl, R １０ Each of these independently comprises halogen, oxygen, hydroxyl, and -C. １－４ Alkyl, or -O-C １－４ It is alkyl, R １１ and R １２ These are H and -C, respectively, independently. １－４ Alkyl, or -C １－４ It is a heteroalkyl, R １１ and R １２ They may bond to form a heterocycloalkyl group. R １３ Each of them operates independently, -N(CH ３ ) ２ or 【Transformation 6】 is a compound, Or the use of a pharmaceutically acceptable salt thereof.

4. A is -OCH ２ CH ２ - The therapeutic agent or use according to claim 1 or 3.

5. The therapeutic agent or use according to claim 1 or 3, wherein B is -C(O)-.

6. The therapeutic agent or use according to claim 1 or 3, wherein Y is -C(CN)-.

7. The therapeutic agent or use according to claim 1 or 3, wherein Y is -N-.

8. R １ However, this is the basis of the following equation, 【Transformation 7】 In the formula, R ７ The therapeutic agent or use according to claim 1 or 3, wherein the active ingredient is H, F, Cl, methyl, ethoxy, ethyl, isopropyl, or cyclopropyl.

9. R １ However, this is the basis of the following equation, 【Transformation 8】 In the formula, R ９ However, H, F, Cl, -CHF ２ , -CF ３ , or -CH ２ The therapeutic agent or use according to claim 1 or 3, wherein it is OH.

10. R １ However, -CN or -C(O)C≡CR ８ The therapeutic agent or use according to claim 1 or 3.

11. R ２ The therapeutic agent or use according to claim 1 or 3, wherein the agent is H or methyl.

12. R ３ The therapeutic agent or use according to claim 1 or 3, wherein the active ingredient is H, F, Cl, methyl, methoxy, ethyl, isopropyl, or cyclopropyl.

13. R ４ The therapeutic agent or use according to claim 1 or 3, wherein the active ingredient is H, F, or Cl.

14. R ５ However, H, -CHF ２ ien-CH ２ F, -CH ２ OH, or -CH ２ OCH ３ The therapeutic agent or use according to claim 1 or 3.

15. The aforementioned compound is given by the following formula: 【Chemistry 9】 The therapeutic agent or use according to claim 1 or 3, which is a compound of or a pharmaceutically acceptable salt thereof.

16. The aforementioned compound is given by the following formula: 【Chemistry 10】 In the formula, R is 【Chemistry 11】 And, X is either Cl or F, m is 1 or 2. The therapeutic agent or use according to claim 1 or 3, which is a compound of or a pharmaceutically acceptable salt thereof.

17. The aforementioned compound is given by the following formula: 【Chemistry 12】 In the formula, R is 【Chemistry 13】 And, X is either Cl or F, m is 1 or 2. The therapeutic agent or use according to claim 1 or 3, which is a compound of or a pharmaceutically acceptable salt thereof.

18. The aforementioned compound is given by the following formula: 【Chemistry 14】 During the ceremony, A is -OCH ２ - or - OCH ２ CH ２ - and Y is C (CN) or N, R ３ However, it is either Cl or F, If Y is C (CN), then R ４ However, it is H or F, If Y is N, then R ４ However, F is The therapeutic agent or use according to claim 1 or 3, which is a compound of or a pharmaceutically acceptable salt thereof.

19. A, 【Chemistry 15】 The therapeutic agent or use according to claim 1 or 3.

20. The aforementioned compound, 【Chemistry 16】 or a pharmaceutically acceptable salt thereof The therapeutic agent or use according to claim 1 or 3.

21. The aforementioned compound, 【Chemistry 17】 The therapeutic agent or use according to claim 1 or 3.

22. The aforementioned compound, [Chemistry 18] or a pharmaceutically acceptable salt thereof The therapeutic agent or use according to claim 1 or 3.

23. The aforementioned compound is as follows: 【Chemistry 19】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, The therapeutic agent or use according to claim 22.

24. The aforementioned compound is the following compound: 【Chemistry 20】 A therapeutic agent or use according to claim 22, selected from the group consisting of the following.

25. The aforementioned compound is as follows: 【Chemistry 21】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, The therapeutic agent or use according to claim 22.

26. The aforementioned compound is the following compound: 【Chemistry 22】 A therapeutic agent or use according to claim 22, selected from the group consisting of the following.

27. The aforementioned compound is as follows: 【Chemistry 23】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, The therapeutic agent or use according to claim 22.

28. The aforementioned compound is as follows: 【Chemistry 24】 The therapeutic agent or use according to claim 22, or a pharmaceutically acceptable salt thereof.

29. The aforementioned compound is as follows: 【Chemistry 25】 The therapeutic agent or use according to claim 22, or a pharmaceutically acceptable salt thereof.

30. The aforementioned compound is as follows: 【Chemistry 26】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, The therapeutic agent or use according to claim 22.

31. The aforementioned compound is as follows: 【Chemistry 27】 The therapeutic agent or use according to claim 22, or a pharmaceutically acceptable salt thereof.

32. The aforementioned compound is as follows: 【Chemistry 28】 The therapeutic agent or use according to claim 22, or a pharmaceutically acceptable salt thereof.

33. The aforementioned compound is as follows: 【Chemistry 29】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, The therapeutic agent or use according to claim 22.

34. The aforementioned compound is as follows: 【Transformation 30】 The therapeutic agent or use according to claim 22, or a pharmaceutically acceptable salt thereof.

35. The aforementioned compound is as follows: 【Chemistry 31】 The therapeutic agent or use according to claim 22, or a pharmaceutically acceptable salt thereof.

36. below: 【Chemistry 32】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof, The therapeutic agent or use according to claim 22.

37. The aforementioned compound is as follows: 【Transformation 33】 The therapeutic agent or use according to claim 22, or a pharmaceutically acceptable salt thereof.

38. The aforementioned compound is as follows: 【Transformation 34】 The therapeutic agent or use according to claim 22, or a pharmaceutically acceptable salt thereof.

39. The aurora A inhibitor is an aurora A selective inhibitor or a pharmaceutically acceptable salt thereof, alicertib, a pan-aurora inhibitor or a pharmaceutically acceptable salt thereof, tozacertib, danucertib, an aminopyridine compound or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluoro- A therapeutic agent or use according to claim 1 or 3, selected from the group consisting of phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropane-2-amine (1:1) salt and (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt.

40. The therapeutic agent or use according to claim 1 or 3, wherein the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

41. The Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl A therapeutic agent or use according to claim 1 or 3, selected from the group consisting of (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methylpiperidine-4-carboxylic acid:amine (1:1) salt.

42. The therapeutic agent or use according to claim 1 or 3, wherein the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt.

43. The therapeutic agent or use according to claim 1 or 3, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

44. The therapeutic agent or use according to claim 1 or 3, wherein the cancer is non-small cell lung cancer, and one or more cells express the KRas G12C mutant protein with or without Aurora A dysregulation or overexpression.

45. The therapeutic agent or use according to claim 1 or 3, wherein the cancer is colorectal cancer, and one or more cells express the KRas G12C mutant protein with or without Aurora A dysregulation or overexpression.

46. The therapeutic agent or use according to claim 1 or 3, wherein the cancer is pancreatic cancer, and one or more cells express the KRas G12C mutant protein with or without Aurora A dysregulation or overexpression.

47. The therapeutic agent or use according to claim 1 or 3, wherein the patient has cancer having a KRAS G12C mutation.

48. The therapeutic agent or use according to claim 1 or 3, wherein the patient has cancer that has been determined to have one or more cells expressing the KRas G12C mutant protein prior to administration of the compound of formula I or a pharmaceutically acceptable salt thereof, or the Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

49. The therapeutic agent or use according to claim 1 or 3, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered to the patient simultaneously or sequentially.

50. The therapeutic agent or use according to claim 1 or 3, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered to the patient in combination at the same time.

51. The therapeutic agent or use according to claim 1 or 3, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered to the patient in a sequential combination.

52. The therapeutic agent or use according to claim 1 or 3, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the patient, and then the Aurora A inhibitor or a pharmaceutically acceptable salt thereof is administered to the patient in need.

53. The therapeutic agent or use according to claim 1 or 3, wherein the Aurora A inhibitor or a pharmaceutically acceptable salt thereof is administered to the patient, and then the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the patient.

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