Methods of treatment comprising KRAS G12C inhibitors and AURORA A inhibitors

Abstract

The present disclosure provides a method of treating cancer in a patient wherein one or more cells express a KRas G12C mutein comprising administering to a patient in need thereof an effective amount of a compound of formula: # imgabs0 # wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, A, B, and Y are as described herein, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof.

Description

[0001] The present disclosure relates to a method of treating cancer in a patient, wherein one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a KRAS G12C inhibitor or a pharmaceutically acceptable salt thereof and an Aurora A kinase inhibitor or a pharmaceutically acceptable salt thereof, to treat the cancer, 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, it has been a difficult therapeutic target. (Cox, ADDrugging theUndruggable RAS: Mission Possible? Nat. Rev. Drug Disc. 2014, 13, 828-851; Pylayeva-Gupta, 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 capable of binding to KRASG12C. WO2016 / 044772 also discloses methods of using such quinazoline derivatives. WO2020 / 0081282 and WO2021 / 118877 disclose KRASG12C inhibitors. WO2018 / 206539 and WO2020 / 178282 disclose certain heteroaryl compounds capable of binding to KRASG12C oncoprotein.

[0004] Aurora kinases consist of three highly conserved serine / threonine isoforms, Aurora A, B, and C, which regulate mitotic and meiotic processes and play distinct roles in cell cycle progression. Inhibition of Aurora A kinase activity significantly impairs mitotic progression by activating mitotic checkpoints, which leads to defects in mitotic spindle formation and prometaphase arrest, and subsequent cell death through a pro-apoptotic pathway. 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. WO 2008 / 026768, EP 2062887 and WO2009 / 104802 disclose certain aminopyridine compounds with selective inhibition of Aurora A. WO 2013 / 129443 discloses certain piperidine compounds with selective inhibition of Aurora A. WO2016 / 077161 and WO2020 / 112514 disclose certain aminopyridine compounds that inhibit Aurora A.

[0006] (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt:

[0007]

[0008] ("Aurora A Inh") is a potent and selective inhibitor of Aurora A.

[0009] As described in WO 2016 / 077161 and WO2020 / 112514, tumor growth arrest or regression was observed in many tumor types after administration of (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt to mice implanted with xenografts and PDX models.

[0010] In vitro studies of combined inhibition of KRAS G12C and Aurora A using commercially available inhibitors demonstrated synergistic antiproliferative and antitumor effects. See Lito et al., Rapid non-uniform adaptation to conformation-specific KRAS G12C inhibition, Nature. 2020 Jan;577(7790):421–425.

[0011] There is still a need to provide small molecule combinations of KRAS G12C and Aurora A inhibitors. In particular, there is a need to provide more potent orally deliverable KRAS G12C and Aurora A inhibitors that can be used to treat cancer. More particularly, there is a need to provide a combination of small molecule inhibitors that specifically inhibit KRas GTP and Aurora A activity. There is also a need to provide a combination of small molecule KRAS G12C and Aurora A inhibitors that exhibit synergistic anti-proliferative and anti-tumor effects. In addition, it is desirable to provide a combination of KRAS G12C and Aurora A inhibitors that overcome bypass of KRAS inhibitory therapy. There is also a need to provide a combination of KRAS G12C and Aurora A inhibitors that exhibit improved efficacy and reduced or minimized adverse or undesirable effects. The present disclosure addresses one or more of these needs by providing a combination of KRAS G12C and Aurora A inhibitors and methods and uses of the combination.

[0012] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula I:

[0013]

[0014] in:

[0015] A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2- or -CH2N(R6)CH2-;

[0016] B is -CH2- or -C(O)-;

[0017] Y is -C(CN)- or -N-;

[0018] R1 is -CN, -C(O)C≡CR8 or a group of the following formula

[0019]

[0020] R2 is H, methyl or -CH2CN;

[0021] R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl;

[0022] R4 is H, halogen or optionally replaced by R 10Replace 1-3 times -C 1-6 alkyl;

[0023] R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0024] R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl;

[0025] R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl;

[0026] R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl;

[0027] R 10 is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl;

[0028] R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and

[0029] R 13 is independently at each occurrence -N(CH3)2 or

[0030] or a pharmaceutically acceptable salt thereof; and

[0031] An effective amount of an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0032] The term halogen as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). The term alkyl as used herein refers to a saturated straight or branched monovalent hydrocarbon group of 1 to 6 carbon atoms, such as "-C 1-6 Alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, pentyl and hexyl. The term heteroalkyl as used herein refers to a saturated straight or branched monovalent hydrocarbon group containing 2 to 5 carbon atoms and at least one heteroatom, such as "-C 1-4 The term cycloalkyl as used herein refers to a saturated monovalent cyclic molecule having 3 to 6 carbon atoms, such as "-C 3-6 Cycloalkyl". Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term cycloheteroalkyl as used herein refers to a saturated monovalent cyclic molecule having 2 to 5 carbon atoms and at least one heteroatom, such as "-C 3-6 Examples of cycloheteroalkyl groups include, but are not limited to, pyrrolidine, piperidine, imidazolidine, pyrazolidine, and piperazine.

[0033] In the case of indicating 0, for example, -C 0-3 Alkyl-C 3-6 The alkyl component of the substituent may not be present, therefore, if R9 of Formula I is a cyclopropyl group without a leading alkyl group, the substituent would be described as -C as described for R9. 0-3 An alkyl-cyclopropyl substituent (ie, the substituent is -C0-cyclopropyl).

[0034] About R 11 and R 12 , these two groups can be combined with the nitrogen to which they are attached when chemically permitted to form a heterocycloalkyl. Examples of the heterocycloalkyl include, but are not limited to, piperidine, piperazine, and morpholine.

[0035] In one embodiment, the present disclosure provides a compound according to any one of Formula I or Formula II-VI (see below), or a pharmaceutically acceptable salt thereof, for use in treatment simultaneously, separately, or in sequential combination with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof. The present disclosure also provides a compound according to any one of Formula I or Formula II-VI, or a pharmaceutically acceptable salt thereof, for use simultaneously, separately, or in sequential combination with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer. The present disclosure also provides the use of a compound according to any one of Formula I or Formula II-VI, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer simultaneously, separately, or in sequential combination with an Aurora A kinase inhibitor or a pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof 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 or a pharmaceutically acceptable salt thereof:

[0037]

[0038] Formula Ia

[0039] wherein R1, R2, R3, R4, R5, A, B and Y are as defined above, or a pharmaceutically acceptable salt thereof; and an effective amount of an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-. In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-. In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-.

[0041] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0042] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, Y is -C(CN)-.

[0043] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, Y is -N-.

[0044] In a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is -CN, -C(O)C≡CR8. In a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0045]

[0046] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl. In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H.

[0047] In a further embodiment, in a compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 is H, halogen, methyl, methoxy, ethyl, isopropyl or cyclopropyl. In yet a further embodiment, in a compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 is halogen (preferably F or Cl).

[0048] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R4 is H or halogen. In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R4 is H, F, or Cl.

[0049] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R5 is halogen (preferably Cl).

[0050] In a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R6 is H or CH3.

[0051] In further embodiments, in the compounds of Formula I or Ia, or pharmaceutically acceptable salts thereof, R9 is H, F, Cl, -CH2F, -CF3, or -CH2OH. In yet further embodiments, in the compounds of Formula I or Ia, or pharmaceutically acceptable salts thereof, R9 is H.

[0052] In further embodiments, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R is H, -CHF, -CHF, -CHOH, -CHOCH, -CHN(CH) or -CH-morpholine. In yet further embodiments, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R is H.

[0053] In yet further embodiments, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R9 is H and R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, or -CH2-morpholine.

[0054] In yet a further embodiment, R9 is H, F, Cl, -CH2F, -CF3 or -CH2OH in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, and R7 is H in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof.

[0055] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R7 and R9 are both H.

[0056] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is -CN or -C(O)C≡CR8, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R8 is H, methyl, -CH2F or -CH2OH.

[0057] In yet a further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0058]

[0059] And in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R7 and R9 are both H.

[0060] In yet a further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is a group of the formula:

[0061]

[0062] And in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R7 is tert-butyl, and in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R9 is -CN.

[0063] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0064] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0065] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-.

[0066] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2- or -N(R6)CH2CH2-, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, B is C(O), and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R2 is H or -CH3.

[0067] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-, B is -C(O)-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0068] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0069] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R2 is H.

[0070] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R2 is H.

[0071] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R2 is H.

[0072] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, A is -OCH2CH2-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0073] In yet a further embodiment, A is -OCH2CH2- in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, and R2 is H in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof.

[0074] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, B is -C(O)-, and in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R2 is H or methyl.

[0075] In yet a further embodiment, B is -C(O)- in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, and R2 is H in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof.

[0076] In yet further embodiments, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from H, halogen or methyl.

[0077] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 or R5 is halogen.

[0078] In yet a further embodiment, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are halogen.

[0079] In yet further embodiments, in the compound of Formula I or Ia, or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from F or Cl.

[0080] In yet a further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -C(CN)-, and in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R4 is H or halogen (preferably F or Cl).

[0081] In yet a further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -N-, and in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R4 is H or halogen (preferably F or Cl).

[0082] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -C(CN)-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from methyl or halogen.

[0083] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -C(CN)-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each halogen (preferably F or Cl).

[0084] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -N-, and in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each independently selected from methyl or halogen.

[0085] In yet a further embodiment, in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -N-, and in the compound of formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each halogen (preferably F or Cl).

[0086] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2- or -CH2N(R6)CH2; in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, B is -CH2- or -C(O)-; in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -C(CN)- or -N-; in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R1 is -CN, -C(O)C≡CR8 or a group of the formula:

[0087]

[0088] In the compound of Formula I or Ia or its pharmaceutically acceptable salt, R2 is H or methyl; in the compound of Formula I or Ia or its pharmaceutically acceptable salt, R3 and R5 are each H, F, Cl or methyl; R4 is H or F; in the compound of Formula I or Ia or its pharmaceutically acceptable salt, R6 is H or methyl; in the compound of Formula I or Ia or its pharmaceutically acceptable salt, R7 is H, -CHF2, -CH2F, -CH2OH, -CH2OCH3, -CH2N(CH3)2, -CH2-morpholine or tert-butyl; in the compound of Formula I or Ia or its pharmaceutically acceptable salt, R8 is methyl, -CH2F or -CH2OH; and in the compound of Formula I or Ia or its pharmaceutically acceptable salt, R9 is H, F, Cl, -CH2F, -CF3, -CH2OH or CN; or its pharmaceutically acceptable salt.

[0089] In yet a further embodiment, in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, A is -OCH2- or -OCH2CH2-; in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, B is -CH2- or -C(O)-; in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, Y is -C(CN)- or -N-; in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R2, R7 and R8 are each H; in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R4 is H or halogen; in the compound of Formula I or Ia or a pharmaceutically acceptable salt thereof, R3 and R5 are each halogen; or a pharmaceutically acceptable salt thereof.

[0090] The present disclosure further provides a method of treating cancer in a patient, wherein one or more cells express KRasG12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula II:

[0091]

[0092] Where R is

[0093] X is Cl or F;

[0094] and m is 1 or 2;

[0095] or a pharmaceutically acceptable salt thereof, and

[0096] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0097] The present disclosure also provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula IIa:

[0098]

[0099] Where R is

[0100] X is Cl or F;

[0101] and m is 1 or 2;

[0102] or a pharmaceutically acceptable salt thereof, and

[0103] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0104] The present disclosure also provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula I, wherein the compound of Formula I is Formula Ib:

[0105]

[0106] in:

[0107] A is -OCH2- or -OCH2CH2-;

[0108] Y is -C(CN)- or -N-;

[0109] R3 is Cl or F;

[0110] When Y is C(CN) R4 is H or F; and

[0111] When Y is N, R4 is F;

[0112] or a pharmaceutically acceptable salt thereof; and an effective amount of an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0113] Another way to describe the compound of formula IIa is by formula Ib, wherein A is

[0114]

[0115] The present disclosure also provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula I or Ia selected from any one of the following Formulae III-VI:

[0116]

[0117]

[0118] or a pharmaceutically acceptable salt thereof, and

[0119] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0120] In another embodiment, the present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula III:

[0121]

[0122] or a pharmaceutically acceptable salt thereof, and

[0123] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0124] In another embodiment, the disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula IV:

[0125]

[0126] or a pharmaceutically acceptable salt thereof, and

[0127] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0128] In another embodiment, the disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula V:

[0129]

[0130] or a pharmaceutically acceptable salt thereof, and

[0131] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0132] In another embodiment, the disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of Formula VI:

[0133]

[0134] or a pharmaceutically acceptable salt thereof, and

[0135] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0136] The present disclosure also provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0137]

[0138]

[0139] or a pharmaceutically acceptable salt thereof, and

[0140] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0141] The present disclosure also provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0142]

[0143]

[0144] or a pharmaceutically acceptable salt thereof, and

[0145] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0146] The present disclosure also provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0147]

[0148] and an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0149] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0150]

[0151] or a pharmaceutically acceptable salt thereof, and

[0152] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0153] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0154]

[0155] and an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0156] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0157]

[0158] or a pharmaceutically acceptable salt thereof, and

[0159] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0160] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of the following compound

[0161]

[0162] or a pharmaceutically acceptable salt thereof, and

[0163] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0164] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of the following compound

[0165]

[0166] or a pharmaceutically acceptable salt thereof, and

[0167] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0168] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0169]

[0170] or a pharmaceutically acceptable salt thereof, and

[0171] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0172] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of the following compound

[0173]

[0174] or a pharmaceutically acceptable salt thereof, and

[0175] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0176] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of the following compound

[0177]

[0178] or a pharmaceutically acceptable salt thereof, and

[0179] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0180] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0181]

[0182] or a pharmaceutically acceptable salt thereof, and

[0183] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0184] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of the following compound

[0185]

[0186] or a pharmaceutically acceptable salt thereof, and

[0187] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0188] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of the following compound

[0189]

[0190] or a pharmaceutically acceptable salt thereof, and

[0191] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0192] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound selected from the group consisting of:

[0193]

[0194] or a pharmaceutically acceptable salt thereof, and

[0195] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0196] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of the following compound

[0197]

[0198] or a pharmaceutically acceptable salt thereof, and

[0199] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0200] The present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of the following compound

[0201]

[0202] or a pharmaceutically acceptable salt thereof, and

[0203] An Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0204] In another embodiment, a method of treating cancer in a patient, wherein one or more cells express a KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VI or Examples 1-8, further comprising wherein 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 alisertib as described in WO 2008 / 063525. In another embodiment, the Aurora A inhibitor is a pan Aurora inhibitor or a pharmaceutically acceptable salt thereof. In another embodiment, the Aurora A inhibitor is tozasertib as described in WO 2004 / 000833. In another embodiment, the Aurora A inhibitor is danusertib as described in WO 2005 / 005427. In another embodiment, the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:

[0205]

[0206] or a pharmaceutically acceptable salt thereof.

[0207] In another embodiment, the present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formula I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0208] In another embodiment, the present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formula I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt:

[0209]

[0210] In another embodiment, the present disclosure provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formula I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt:

[0211]

[0212] The present disclosure also provides a method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formula I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof.

[0213] 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 more preferred embodiments, the cancer is non-small cell lung cancer.

[0214] The present disclosure also provides a method for treating a cancer patient, comprising administering 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, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the cancer has one or more cells expressing a mutant KRasG12C protein with or without Aurora A dysregulation or overexpression. The present disclosure also provides a method for treating cancer, comprising administering 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, to a patient in need thereof, wherein the cancer is non-small cell lung cancer, and wherein one or more cells with or without Aurora A dysregulation or overexpression express KRas G12C mutant protein. The present disclosure also provides a method for treating cancer, comprising administering 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, to a patient in need thereof, wherein the cancer is colorectal cancer, and wherein one or more cells with or without Aurora A dysregulation or overexpression express KRas G12C mutant protein. The present disclosure also provides a method for treating cancer, comprising administering 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, to a patient in need thereof, wherein the cancer is pancreatic cancer, and wherein one or more cells with or without Aurora A dysregulation or overexpression express KRas G12C mutant protein.

[0215] The present disclosure also provides a method of treating cancer in a patient in need thereof, wherein the patient has a cancer determined to express KRas G12C mutant protein and Aurora A dysregulation or overexpression.

[0216] In another embodiment, the cancer is non-small cell lung cancer, wherein the cancer has one or more cells expressing KRas G12C mutant protein and / or Aurora A dysregulation or overexpression. In another embodiment, the cancer is colorectal cancer, wherein the cancer has one or more cells expressing KRas G12C mutant protein and / or Aurora A dysregulation or overexpression. In yet another embodiment, the cancer is mutant pancreatic cancer, wherein the cancer has one or more cells expressing KRas G12C mutant protein and / or Aurora A dysregulation or overexpression. In another embodiment, the disclosure includes a method of treating cancers of other sources carrying KRas G12C mutations and / or Aurora A dysregulation or overexpression.

[0217] In yet another embodiment, the present disclosure includes a method of treating cancer comprising administering an effective amount of a compound according to any one of Formula I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and an Aurora A kinase inhibitor, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C protein or dysregulated or overexpressed Aurora A. In some embodiments, prior to administering the compound, or a pharmaceutically acceptable salt thereof, or an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, the patient has a cancer determined to have one or more cells expressing a KRas G12C mutant protein. In some embodiments, the patient has a cancer having a KRAS G12C mutation.

[0218] In yet another embodiment, the present disclosure includes a method of treating cancer, comprising administering an effective amount of a compound according to any one of Formula I-VI or Examples 1-8, or a pharmaceutically acceptable salt thereof, and an Aurora A kinase inhibitor, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the compound according to any one of Formula I-VI or Examples 1-8 and the Aurora A inhibitor are administered to a patient in need thereof in a simultaneous or sequential combination. In some embodiments, the compound according to any one of Formula I-VI or Examples 1-8 and the Aurora A inhibitor are administered to a patient in need thereof in a simultaneous combination. In some embodiments, the compound according to any one of Formula I-VI or Examples 1-8 and the Aurora A inhibitor are administered to a patient in need thereof in a sequential combination. In some embodiments, the compound according to any one of Formula I-VI or Examples 1-8 is administered to a patient in need thereof before the Aurora A inhibitor is administered to a patient in need thereof. In some embodiments, the Aurora A inhibitor is administered to a patient in need thereof before the compound according to any one of Formula I-VI or Examples 1-8 is administered to a patient in need thereof.

[0219] 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 preferred embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In more preferred embodiments, the cancer is non-small cell lung cancer. In other embodiments, the cancer has one or more cancer cells expressing mutant KRas G12C protein and / or 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.

[0220] The term "pharmaceutically acceptable salt" as used herein refers to salts of compounds that are considered acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methods for preparing them can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P. Stahl et al., Second Revised Edition, Wiley-VCH, 2011 and SM Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66 (1), 1-19.

[0221] The pharmaceutical composition of the present disclosure can be prepared using pharmaceutically acceptable additives. The term "pharmaceutically acceptable additives" as used herein for pharmaceutical compositions refers to one or more carriers, diluents and excipients that are compatible with other additives of the composition or preparation and harmless to the patient. Examples of pharmaceutical compositions and preparation methods thereof can be found in "Remington: The Science and Practice of Pharmacy", edited by Loyd, V. et al., 22nd edition, Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents and excipients include the following: saline, water, starch, sugar, mannitol and silicon dioxide derivatives; adhesives such as carboxymethyl cellulose, alginate, gelatin and polyvinyl pyrrolidone; kaolin and bentonite; and polyethylene glycol.

[0222] The term "effective amount" as used herein refers to an amount effective to treat a disorder or disease, such as a cancerous lesion or the progression of abnormal cell growth and / or cell division. An attending physician as a skilled artisan can easily determine an effective amount by using conventional techniques and by observing the results obtained under similar circumstances.

[0223] The term "dose" as used herein refers to the total amount of a drug administered at one time. One example of a drug includes a compound of Formula I or a pharmaceutically acceptable salt thereof. Another example of a drug includes an Aurora A kinase inhibitor compound or a pharmaceutically acceptable salt thereof.

[0224] As used herein, the term "dosage" or "dosage frequency" refers to a dose administered at a specific frequency.

[0225] The therapeutic daily dosage of a compound of Formula I is generally in the range of about 1 mg / day or bid to 1000 mg / day or bid, more preferably 100 mg / day or bid to 900 mg / day or bid.

[0226] The therapeutic daily dose of an Aurora A inhibitor, an aminopyridine compound or a pharmaceutically acceptable salt thereof, or (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt or a pharmaceutically acceptable salt thereof is generally in the range of about 0.1 to about 100 mg. In some cases, dosage levels below the lower end of this range may be more than adequate, while in other cases, larger doses may be used for the Aurora A inhibitor, the aminopyridine compound or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt, or (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt or a pharmaceutically acceptable salt thereof. For Aurora A inhibitors, aminopyridine compounds or pharmaceutically acceptable salts thereof, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt, or (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt or pharmaceutically acceptable salts thereof, the preferred dosage is in the range of 1 to 80 mg; more preferably between 1 and 50 mg; even more preferably between 1 and 30 mg; even more preferably between 1 and 25 mg. The dose may be administered once, twice, three times or more daily.In one embodiment, an Aurora A inhibitor, an aminopyridine compound or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt, or (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt or a pharmaceutically acceptable salt thereof can be orally administered twice a day (BID) at a dose of 15 mg or 25 mg per dose. Factors to be considered in determining the effective amount or dose of a compound include: whether to administer the compound or a salt thereof; co-administration of other agents, if used; the species of the patient being treated; the size, age, sex, and general health of the patient; the degree of involvement or stage and / or severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the administered formulation; the dosing regimen chosen; and the use of other concomitant medications.

[0227] The treating physician, veterinarian or other medical personnel can determine the effective amount of the compound for treating a patient in need. The preferred pharmaceutical composition can be formulated as a tablet or capsule for oral administration, a solution for oral administration, or an injectable solution. The tablet, capsule or solution may include an amount of the compound of the present disclosure effective for treating a patient in need of treatment for cancer in which one or more cells express the KRas G12C mutant protein.

[0228] As used herein, the terms "treating" / "to treat" / "treatment" include slowing, alleviating or reversing the progression or severity of an existing symptom, disorder or condition, which may include specifically slowing the growth of cancerous lesions or the progression of abnormal cell growth and / or cell division.

[0229] As used herein, the term "patient" refers to a mammal in need of treatment. Preferably, the patient is a human in need of treatment for a cancer in which one or more cells express a KRas G12C mutant protein, such as a cancer carrying a KRas G12C mutant.

[0230] Individual isomers, enantiomers, diastereomers, and atropisomers may be separated or resolved at any convenient point in the synthesis of the following compounds by methods such as selective crystallization techniques or chiral chromatography (see, e.g., J. Jacques et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981 and EL Eliel and SH Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The present 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 rotation around a single bond. Atropisomers can be separated as separate chemical species if the energy barrier for rotation around a single bond is high enough and the interconversion rate is slow enough to allow the individual rotational isomers to be separated from each other. This disclosure contemplates all isomers, enantiomers, diastereomers, and atropisomers disclosed herein or that can be made using the compounds disclosed herein.

[0231] Any compound according to Formula I-VI or any one of Examples 1-8 is easily converted into a pharmaceutically acceptable salt and can be isolated as a pharmaceutically acceptable salt. Salt formation can occur when a pharmaceutically acceptable acid is added to form an acid addition salt. Salts can also be formed simultaneously when nitrogen or oxygen is deprotected, i.e., when a protecting group is removed. 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).

[0232] The compounds of the present disclosure or their salts can be prepared by various procedures, some of which are illustrated in the "Preparation and Examples" of WO2021 / 118877, WO2016 / 077161 and WO2020 / 112514. The specific synthetic steps of each route can be combined in different ways, or combined with steps from different routes to prepare the compounds or salts of the present disclosure. The products of each step in the following preparation can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration and crystallization.

[0233] Suitable reaction conditions for the steps of these "Preparation and Examples" are well known in the art, and the appropriate substitution of solvents and co-reagents is within the technical scope of the art. Similarly, it will be appreciated by those skilled in the art that synthetic intermediates can be separated and / or purified by various known techniques as needed or expected, and various intermediates can be used directly in subsequent synthetic steps usually with little or no purification. As an example, the compounds of "Preparation and Examples" can be separated, for example, by silica gel purification, directly separated by filtration or crystallization. In addition, it will be appreciated by the technician that in some cases, the order of introduction of moieties is unimportant. As is well understood by skilled chemists, the specific order of steps required for producing compounds of the present disclosure depends on the relative instability (liability) of the specific compounds, starting compounds, and substituted parts of the synthesis. Unless otherwise indicated, all substituents are as previously defined, and all reagents are well known and understood in the art.

[0234] The specific synthetic steps of each route can be combined in different ways, or combined with steps from different routes, to prepare the compounds or salts of the present disclosure. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration and crystallization.

[0235] The compounds of the present disclosure can be prepared in many ways known to those skilled in the art of organic synthesis. For example, the compounds of the present disclosure can be synthesized using the following methods and synthetic methods known in the field of synthetic organic chemistry or variations thereof as recognized by those skilled in the art. Preferred methods include, but are not limited to, those methods described below.

[0236] The compounds of the present disclosure can be synthesized in part by following the steps outlined in Scheme 1-1a below, which contains different orders of assembling intermediates or compounds. Starting materials can be purchased or made by known procedures reported in the literature or as shown below.

[0237] Schema 1

[0238]

[0239] In step 1 of Scheme 1, protected piperazine-2-ethanol (compound (1)) is coupled with 4-bromo-2,5-difluoro-benzoic acid (compound (2)) in amide bond formation using a coupling agent (such as CDMT) and an organic base (such as NMM) in a solvent system (such as acetonitrile and water) and an inorganic base (such as K2CO3). R is a protecting group developed for amino groups, such as carbamate and amide. Such protecting groups are well known and understood in the art, such as carbamate protecting groups, including allyloxycarbonyl, fluorenylmethoxycarbonyl or benzyloxycarbonyl. A common and preferred protecting group can be Boc. Those skilled in the art will recognize that there are many methods and reagents for amide formation resulting from the reaction of carboxylic acids and amines. For example, the reaction of an amine compound with an appropriate carboxylic acid in the presence of a coupling agent in the presence or absence of an organic base such as DIPEA or TEA can provide compound (3). Other coupling reagents include carbodiimides, such as DCC, DIC, EDCI or carbonyldiimidazoles, such as CDI. Amide coupling additives such as HOBt and HOAt can also be used to enhance the reaction. In addition, uronium or phosphonium salts of non-nucleophilic anions such as HBTU, HATU, PyBOP and PyBrOP can be used instead of more traditional coupling reagents. Additives such as DMAP can be used to enhance the reaction. Alternatively, the acyl chloride of compound (2) can be used in the presence of a base such as TEA or pyridine to obtain compound (3).

[0240] In step 2, intramolecular cyclization of compound (3) is accomplished using a suitable base such as potassium tert-butoxide, sodium tert-amylate, sodium tert-butoxide, sodium tert-pentoxide, DIPEA, TEA, DBU, sodium hydride in a solvent such as DMF to give compound 4. Other possible solvents may be NMP, DMAc, DMSO and THF. This intramolecular cyclization of compound (3) to compound (4) can be performed by slowly adding a solution of compound (3) to an excess of base to minimize impurities derived from intermolecular reactions.

[0241] In step 3, compound (4) can be chlorinated with a chlorinating agent such as trichloroisocyanuric acid or NCS in a solvent such as acetonitrile or DMF under acidic conditions using an acid such as TFA to give compound (5).

[0242] Figure 1a

[0243]

[0244] Scheme 1a illustrates the chiral synthesis of compound (5a). Compound (1a) can be prepared as described in Medicinal Chemistry route to 1, Development of an Alternative Route to the Bicyclic Piperazine, Retrosynthetic analysis of bicyclic piperazine core 2, and / or Coupling, cyclization, reduction, and Michael addition to afford Piperazine 24 in Org Proc Res Dev., 2011, 15(6). 1328-1335. Compounds (3a), (4a) and (5a) can be prepared as described in Scheme 1.

[0245] (S)-tert-Butyl 9-bromo-10-fluoro-12-oxo-1,2,4,4a,5,6-hexahydro-3H,12H-benzo[b]pyrazino[1,2-e][1,5]oxazocine-3-carboxylate was synthesized using a 7-step sequence starting from commercially available S-aspartic acid, which was the source of the stereocenter.

[0246] It is known that significant impurity exclusion can be achieved in the isolation of intermediates, including exclusion of the R-enantiomer. (S)-9-Bromo-10-fluoro-12-oxo-1,2,4,4a,5,6-hexahydro-3H,12H-benzo[b]pyrazino[1,2-e][1,5]oxazocine-3-carboxylic acid tert-butyl ester can be isolated by crystallization with significant impurity exclusion. Steps and Schemes are used to control process and reagent impurities.

[0247] The present disclosure provides a method for preparing an intermediate compound of formula IIa or a pharmaceutically acceptable salt thereof:

[0248]

[0249] Formula IIa

[0250] It includes the steps of:

[0251] By using a cyclizing base, the intermediate compound of formula II:

[0252]

[0253] Formula II,

[0254] Or an intermediate compound of formula ila:

[0255]

[0256] or a pharmaceutically acceptable salt thereof.

[0257] 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-amylate, sodium tert-amylate, potassium tert-amylate, and potassium tert-butoxide.

[0258] In another embodiment, the preparation method further comprises a cyclization solvent. In one embodiment, the cyclization solvent is N,N-dimethylformamide (DMF).

[0259] The method of preparation, wherein the cyclization step is carried out at about 0°C.

[0260] For clarity, certain stereochemical centers are not specified and certain substituents have been eliminated in the following schemes, and it is not intended to limit the teaching of the schemes in any way. It is to be understood that all stereoisomers are included. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enriched starting materials and / or reagents. Alternatively, enantiomers can be separated using methods known in the art, such as chiral chromatography or by converting enantiomers into diastereomeric salts, separating diastereomeric salts, converting diastereomeric salts into non-salt forms and separating enantiomers. Individual isomers, enantiomers and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of the disclosed compounds by methods such as selective crystallization techniques or chiral chromatography (see, e.g., J. Jacques et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981 and EL Eliel and SH Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994).

[0261] Certain abbreviations are defined as follows: “ACN” means acetonitrile; “APCI-MS” means atmospheric pressure chemical ionization mass spectrometry; “Boc” means tert-butyloxycarbonyl; “CDI” means 1,1′-carbonyldiimidazole; “CDMT” means 2-chloro-4,6-dimethoxy-1,3,5-triazine; “DCC” means 1,3-dicyclohexylcarbodiimide; “DCM” means dichloromethane; “DIC” means 1,3-diisopropylcarbodiimide; “DIPEA” or “DIEA” means N,N-diisopropylethyl amine; "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; "EtOAc" refers to ethyl acetate; "EtOH" refers to ethanol or ethyl alcohol; "HATU" refers to O-(7-azabenzotriazol-1-yl)-N, N,N',N'-Tetramethyluronium hexafluorophosphate; "HOAt" refers to 1-hydroxy-7-azobenzotriazole; "HBTU" refers to 3-[bis(dimethylamino)methylium]-3H-benzotriazole-1-oxide hexafluorophosphate; "HOBt" refers to 1-hydroxybenzotriazole hydrate; "HPLC" refers to high performance liquid chromatography; "MeOH" refers to methanol; "2-MeTHF" refers to 2-methyltetrahydrofuran; "MP(DSC)" refers to melting point as measured by differential scanning calorimetry; "MT "BE" refers to methyl tert-butyl ether; "NCS" refers to N-chlorosuccinimide; "NMM" refers to N-methylmorpholine; "NMP" refers to N-methyl-2-pyrrolidone; "NMR" refers to nuclear magnetic resonance; "PG" refers to protecting group; "PyBOP" refers to (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate); "PyBrOP" refers to bromo(tripyrrolidino)phosphonium hexafluorophosphate; "TEA" refers to triethylamine; "TFA" refers to trifluoroacetic acid; and "THF" refers to tetrahydrofuran.

[0262] 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-amylate, sodium tert-amylate, potassium tert-amylate and potassium tert-butoxide.

[0263] Preparation and Examples

[0264] Preparation 1

[0265] 4-Amino-3-chloro-2,5-difluoro-benzoic acid methyl ester

[0266]

[0267] The title compound was prepared in the same manner as in WO2021 / 118877; Preparation 31. ES / MS m / z: 222 [M+H] + .

[0268] Preparation 2

[0269] 3-Chloro-2,5-difluoro-4-iodo-benzoic acid methyl ester

[0270]

[0271] 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-difluoro-benzoic acid methyl ester (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 in vacuo and purified by flash chromatography on silica gel (10% EtOAc in hexane) to obtain the title compound (17.8 g, 54%) as a white solid. 1 H NMR (CDCl3) δ7.60 (dd, J=5.6, 7.6Hz, 1H), 3.98 (s, 3H).

[0272] Preparation 3

[0273] 3-Chloro-2,5-difluoro-4-iodo-benzoic acid

[0274]

[0275] MeOH (50 mL) was added to a solution of 3-chloro-2,5-difluoro-4-iodo-benzoic acid methyl ester (16.8 g, 50.5 mmol) in THF (125 mL). The reaction mixture was cooled in an ice bath. 1N NaOH aqueous solution (150 mL, 150 mmol) was added in three portions. The reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to remove the organic solvent. The aqueous residue was cooled with crushed ice and the pH was adjusted to ~2 with 5N HCl aqueous solution (25 mL). Extracted with EtOAc (3x). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (15.8 g, 98%). 1 H NMRδ (DMSO-d6) 13.91 (s, 1H), 7.68 (dd, J=5.8, 7.8Hz, 1H).

[0276] Preparation 4

[0277] (3R)-4-(3-Chloro-2,5-difluoro-4-iodo-benzoyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester

[0278]

[0279] HATU (3.31 g, 8.53 mmol) was added to a solution of 3-chloro-2,5-difluoro-4-iodo-benzoic acid (2.99 g, 9.39 mmol) and DIEA (6.7 mL, 38 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature for 1 hour. A solution of (3R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.92 g, 8.52 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 14 hours and at 60 ° C for 3 hours, then diluted with EtOAc and water. The organic layer was washed with water, 1 N NaOH aqueous solution and brine. The water layer was extracted with EtOAc, which was washed with brine. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10-50% EtOAc in hexane) 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] + .

[0280] Preparation 5

[0281] (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazocine-2-carboxylic acid tert-butyl ester

[0282]

[0283] The title compound was prepared in the same manner as WO2021 / 118877; Preparation 117. ES / MS m / z ( 79 Br / 81 Br)407 / 409[M-tert-butyl+H] + .

[0284] Preparation 6

[0285] (4aR)-7-Chloro-9-fluoro-8-iodo-11-oxo-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine tert-Butyl (benzoxazepin)-3-carboxylate

[0286]

[0287] Tert-butyl (3R)-4-(3-chloro-2,5-difluoro-4-iodo-benzoyl)-3-(hydroxymethyl)piperazine-1-carboxylate (4.59 g, 8.88 mmol) in DMF (150 mL) was cooled to 0 °C. Sodium hydride (0.89 g, 22 mmol, 60% by mass in paraffin oil) was added. After 4 hours at 0 °C, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with water and diethyl ether. The aqueous layer was extracted with diethyl ether (4x). The combined organic extracts were washed with water (3x) and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (15-40% EtOAc in hexanes) to give the title compound (3.82 g, 82%) as a white solid. ES / MS m / z( 35 Cl / 37 Cl) 441 / 443 [M-tert-butyl + H] - .

[0288] Preparation 7

[0289] N-(4-Bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamic acid tert-butyl ester

[0290]

[0291] The title compound was prepared in the same manner as in WO2021 / 118877; Preparation 14. ES / MS m / z ( 79 Br / 81 Br)315 / 317[M-tert-butyl+H] + .

[0292] Preparation 8

[0293] tert-Butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate

[0294]

[0295] A mixture of tert-butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophene-2-yl)carbamate (3.10 g, 8.35 mmol), bis(pinacol)diboron (21.0 g, 82.7 mmol) and potassium acetate (2.50 g, 25.5 mmol) in 1,4-dioxane (50 mL) was purged with nitrogen (direct bubbling) for 10 minutes. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1.0 g, 1.2 mmol) was added. The reaction flask was sealed and heated at 80-85 ° C for 3.5 hours. The reaction mixture was filtered through diatomaceous earth. The filtrate was diluted with water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10%-50% (20% acetone / DCM) / hexanes) to give the title compound (4.45 g, 87%). ES / MS m / z 363 [M-tert-butyl+H] + .

[0296] Preparation 9

[0297] tert-Butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborin-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate

[0298]

[0299] The title compound was prepared in the same manner as in WO2021 / 118877; Preparation 15. 1 H NMR(DMSO-d6)δ11.6(s,1H),7.61(m,1H),7.20(m,1H),3.78(s,4H),1.54(s,9H),1.03(s,6H).

[0300] Preparation 10 and 11

[0301] (13aS)-9-[2-(tert-Butyloxycarbonylamino)-3-cyano-benzothiophen-4-yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazoctate-2-carboxylic acid tert-butyl ester, P and M atropisomers

[0302]

[0303] The title compound was prepared in the same manner as WO2021 / 118877; Preparation 167. The mixture of atropisomers was separated by silica gel flash chromatography (0-30% acetone in hexanes). Preparation 10 (P atropisomer) was the first compound to elute from the column. Preparation 11 (M atropisomer) was the second compound to elute from the column. For both, ES / MS m / z ( 35 Cl / 37 Cl)657 / 659[M+H] + .

[0304] Preparation 12 and 13

[0305] (13aS)-9-[2-(tert-Butyloxycarbonylamino)-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]benzoxazoxazoctate-2-carboxylic acid tert-butyl ester, P and M atropisomers

[0306]

[0307]

[0308] (13aS)-9-bromo-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazacyclooctatetraene-2-carboxylic acid tert-butyl ester (10.0 g, 21.6 mmol), N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)-7-fluoro-benzothiophene- 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) which had been purged with nitrogen (bubbled directly) 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-dioxaborolan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (3.54 g, 8.75 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-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.

[0309] The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated in vacuo and diluted with EtOAc, water and brine. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (10-40% acetone in hexanes). Preparation 12 (P-retarsoisomer) was eluted first, followed by Preparation 13 (M-retarsoisomer). The impure fraction of the P-retarsoisomer was further purified by silica gel flash chromatography. This produced two title compounds (P-retarsoisomer, 0.35 g, 2%; M-retarsoisomer, 5.6 g, 38%). For both, ES / MS m / z 619 [M-tert-butyl+H] + .

[0310] Preparation 14 and 15

[0311] (4aR)-8-[2-(tert-Butyloxycarbonylamino)-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 -tert-Butyl 3-carboxylate, P and M atropisomers

[0312]

[0313] (4aR)-7-Chloro-9-fluoro-8-iodo-11-oxo-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine A solution of tert-butyl-3-formate (0.50 g, 1.01 mmol), tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (0.63 g, 1.51 mmol) and potassium phosphate (0.50 g, 2.36 mmol) in water (2 mL) and 1,4-dioxane (10 mL) was purged with nitrogen (bubbled directly) for 10 minutes. 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.20 g, 0.30 mmol) was added. The reaction flask was sealed and heated at 70 °C for 3 hours.

[0314] (4aR)-7-Chloro-9-fluoro-8-iodo-11-oxo-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine A solution of tert-butyl-3-formate (0.20 g, 0.40 mmol), tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (0.24 g, 0.57 mmol) and potassium phosphate (0.20 g, 0.96 mmol) in water (2.5 mL) and 1,4-dioxane (8 mL) was purged with nitrogen (bubbled directly) for 10 minutes. 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (0.080 g, 0.12 mmol) was added. The reaction flask was sealed and heated at 70°C for 5 hours.

[0315] The two reaction mixtures were combined, filtered through celite, and rinsed with EtOAc. The filtrate was diluted with MTBE and saturated aqueous sodium bicarbonate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-30% acetone in hexanes). Preparation 14 (P atropisomer) eluted first, followed by Preparation 15 (M atropisomer). The impure fraction of the P atropisomer was further purified by silica gel flash chromatography (0-100% EtOAc in hexanes). This produced the two title compounds (P atropisomer, 0.17 g, 17%; M atropisomer, 0.21 g, 21%). For both, ES / MS m / z ( 35 Cl / 37 Cl) 605 / 607 [M-tert-butyl + H] + .

[0316] Preparation 16

[0317] 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

[0318]

[0319] 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]benzoxazacyclooctatetraene-2-carboxylic acid tert-butyl ester, P-atropisomer (0.98 g, 1.5 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 3 h, concentrated in vacuo, and purified by silica gel flash chromatography (4-10% 7N ammoniated MeOH in DCM) to give the title compound (0.57 g, 84%). ES / MS m / z( 35 Cl / 37 Cl)457 / 459[M+H] + .

[0320] Preparation 17

[0321] 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazoctatetraen-9-yl]-2-amino-benzothiophene-3-carbonitrile, M atropisomer

[0322]

[0323] The title compound was prepared in the same manner as WO2021 / 118877; Preparation 187. ES / MS m / z ( 35 Cl / 37 Cl)457 / 459[M+H] + .

[0324] Preparation 18

[0325] 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, P atropisomer

[0326]

[0327] TFA (2 mL) was added to (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-tert-Butyl formate, P-atrosomer (0.018 g, 0.027 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 30 minutes, concentrated in vacuo, and purified by flash chromatography on silica gel (0-10% MeOH in DCM, then 0-10% 7N ammoniated MeOH in DCM) to give the title compound (0.013 g, 100%). ES / MS m / z ( 35 Cl / 37 Cl)461 / 463[M+H] + .

[0328] Preparation 19

[0329] 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 atropisomer

[0330]

[0331] TFA (2.5 mL) was added to (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 -tert-Butyl 3-formate, M atropisomer (0.20 g, 0.31 mmol) in an ice-cooled solution of DCM (2.5 mL). The reaction mixture was stirred at room temperature for 2 hours, concentrated in vacuo, and purified by silica gel flash chromatography (0-10% 7N ammoniated MeOH in DCM) to give the title compound (0.13 g, 89%). ES / MS m / z ( 35 Cl / 37 Cl)461 / 463[M+H] + .

[0332] Examples 1 and 2

[0333] (13aS)-9-(2-Amino-7-fluoro-1,3-benzothiazol-4-yl)-8,10-dichloro-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazoctatetraen-6-one, P and M atropisomers

[0334]

[0335] The title compound was prepared in the same manner as in WO2021 / 118877; Example 1. The mixture of atropisomers was used IC, 4.6 x 150 mm, 40% EtOH / CO2, 5 mL / min, 225 nm separation. Example 1 (P atropisomer) is the first compound to leave the column. Example 2 (M atropisomer) is the second compound to leave the column. For both, ES / MS m / z ( 35 Cl / 37 Cl)521 / 523[M+H] + .

[0336] Example 3

[0337] 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazoctatetraen-9-yl]-2-amino-benzothiophene-3-carbonitrile, P-atropisomer

[0338]

[0339] A solution of 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2,3,4,12,13,13a-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazacyclooctatetraen-9-yl]-2-amino-benzothiophene-3-carbonitrile, P-atropisomer (0.115 g, 0.252 mmol) and DIEA (0.20 mL, 1.2 mmol) in DCM (2 mL) was cooled to -78 °C. Acryloyl chloride (0.02 mL, 0.2 mmol) was added. After 5 minutes, it was diluted with a small amount of 2-propanol and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (20-100% acetone in hexanes) to give the title compound (0.091 g, 71%). ES / MS m / z( 35 Cl / 37 Cl)511 / 513[M+H] + .

[0340] Example 4

[0341] 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazoctatetraen-9-yl]-2-amino-benzothiophene-3-carbonitrile, M atropisomer

[0342]

[0343] The title compound was prepared in the same manner as in WO2021 / 118877; Example 34. ES / MS m / z ( 35 Cl / 37 Cl)511 / 513[M+H] + .

[0344] Example 5

[0345] 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazoctatetraen-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, P-atropisomer

[0346]

[0347] TFA (1 mL) was added to a solution of (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazacyclooctatetraene-2-carboxylic acid tert-butyl ester, P-atropisomer (0.025 g, 0.037 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo to give the crude deprotected material.

[0348] 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. Acryloyl chloride (0.0030 mL) in DCM (1 mL) was added. After 30 minutes, it was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (20-80% acetone in hexanes) to give the title compound (0.012 g, 61%). ES / MS m / z ( 35 Cl / 37 Cl) 529 / 531[M+H] + .

[0349] Example 6

[0350] 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,1-d][1,5]benzoxazacyclooctatetraen-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer ("KRAS G12C Inh")

[0351]

[0352] HCl gas is bubbled into (13aS)-9-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophene-4-yl]-10-chloro-8-fluoro-6-oxo-1,3,4,12,13,13a-hexahydropyrazine [2,1-d] [1,5] benzoxazopyrazine octate-2-carboxylic acid tert-butyl ester, M atropisomer (0.786g, 1.17mmol) in DCM (12mL) and 2-propanol (12mL) ice-cooled solution for 5 minutes. The reaction mixture is stirred at room temperature for 5 hours and then cooled in an ice bath. HCl gas is bubbled into the reaction mixture for 5 minutes. The reaction mixture is stirred at room temperature for 14 hours and then concentrated in vacuo. The residue is diluted twice with n-heptane and concentrated in vacuo. MTBE (50mL) is added. The mixture is stirred at room temperature for 10 minutes and then filtered to obtain the deprotected material as dihydrochloride.

[0353] The dihydrochloride salt was dissolved in water (12 mL). 2-Methyltetrahydrofuran (12 mL) was added. A solution of potassium carbonate (0.81 g, 5.82 mmol) in water (12 mL) was added. The mixture was stirred vigorously while being cooled in an ice bath. Acryloyl chloride (0.10 mL, 1.28 mmol) in 2-methyltetrahydrofuran (5 mL) was added dropwise. After 5 minutes, it was diluted with brine and 2-methyltetrahydrofuran. The aqueous layer was extracted with 2-methyltetrahydrofuran (2x). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (20-30% B / A; A: 3:1 EtOAc: Hexane; B: 4:1 EtOAc: MeOH) to give the title compound (0.409 g, 66%). ES / MS m / z( 35 Cl / 37 Cl) 529 / 531[M+H] + .

[0354] Example 7

[0355] 4-[(4aR)-7-chloro-9-fluoro-11-oxo-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine -8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, P atropisomer

[0356]

[0357] Acryloyl chloride (0.0022 mL, 0.027 mmol) was added to 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, P-reversible isomer (0.013 g, 0.027 mmol) and potassium carbonate (0.011 g, 0.082 mmol) in an ice-cooled mixture of EtOAc (0.27 mL) and water (0.27 mL). After 20 minutes, dilute with EtOAc and brine. The organic extracts are dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (20-100% acetone in hexanes) to give the title compound (0.011 g, 78%). ES / MS m / z( 35 Cl / 37 Cl)515 / 517[M+H] + .

[0358] Example 8

[0359] 4-[(4aR)-7-chloro-9-fluoro-11-oxo-3-prop-2-enoyl-2,4,4a,5-tetrahydro-1H-pyrazino[2,1-c][1,4]benzoxazepine -8-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile, M atropisomer

[0360]

[0361] Acryloyl chloride (0.25 M in DCM, 1.1 mL, 0.28 mmol) was added to 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 atropisomer (0.128 g, 0.28 mmol) and potassium carbonate (0.12 g, 0.83 mmol) in an ice-cooled mixture of EtOAc (3 mL) and water (3 mL). After 5 minutes, dilute with EtOAc and separate the layers. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-10% 7N ammoniated MeOH in DCM) to give the title compound (0.13 g, 87%). ES / MS m / z ( 35 Cl / 37 Cl)515 / 517[M+H] + .

[0362] Bioassay

[0363] The following assays demonstrate that the combinations of compounds described herein are inhibitors of KRas G12C and inhibit the growth of certain tumors in vitro and / or in vivo.

[0364] Example 1: Procedure for KRAS G12C Inh in combination with Aurora A Inh

[0365] The purpose of these studies is to evaluate the anti-tumor growth activity of KRAS G12C Inh in combination with Aurora A Inh in human NSCLC tumor xenografts or PDX models harboring KRAS G12C mutations. Synergy or additivity of the combination of KRAS G12C Inh and Aurora A Inh was observed in cell proliferation assays. In animal models, KRAS G12C Inh exhibited dose- and time-dependent inhibition of KRAS activity and downstream signaling in a group of KRAS G12C mutant NSCLC, CRC and PDAC xenografts and PDX models, and resulted in significant tumor growth inhibition / regression. In addition, when combined with Aurora A Inh, KRAS G12C Inh exhibited an additive effect in the KRAS G12C mutant in vivo model.

[0366] KRAS G12C Inh also exhibits varying degrees of anti-tumor activity in KRAS G12C mutant animal models. In order to achieve a more durable response in a wider range of tumors, combining KRAS G12C Inh with other therapies can provide excellent clinical activity. The KRAS G12C Inh combination was evaluated in a variety of KRAS G12C mutant in vivo models, including 2 lung cancer xenograft models (H358 and H1373), 1 lung cancer PDX model (EL3187) and 1 CRC xenograft model (SW837). Monotherapy with KRAS G12C Inh and Aurora A Inh alone at suboptimal doses exhibits various anti-tumor activities in these models. Based on tumor growth inhibition and tumor regression, the combination of KRAS G12C Inh and Aurora A Inh brings improved anti-tumor activity. Compared with monotherapy, this combination shows improved efficacy and has no adverse effects on body weight.

[0367] For H358 and H1373 xenograft tumor growth, 5 × 10 cells / ml of 0.2 mL Hanks balanced salt solution (HBSS):Matrigel (Corning, Cat#354234) (1:1) were added. 6Each animal was implanted subcutaneously with 100 cells into the right flank. H358 cells were implanted into NOD SCIDγ mice (20-22 g, The Jackson Laboratory, Bar Harbor, Maine), and H1373 cells were implanted into female athymic nude mice (20-22 g, Envigo RMS, Inc., Mount Comfort, Indiana). Tumor volume was measured twice a week using a caliper. When tumor volume reached 200-300 mm 3 Mice were randomized based on tumor measurements and body weight using a multi-task block randomization tool (n=5 or 6 per group). Treatment was initiated for 28 days by oral administration (gavage) of 0.2 mL of vehicle (10% N-methyl-2-pyrrolidone "NMP" / 90% 15% w / v polyvinylpyrrolidone-vinyl acetate "PVP-VA") in PEG 400, KRAS G12C Inh at 10 mg / kg QD (10% NMP / 90% 15% w / v PVP-VA in PEG400), Aurora A Inh at 57 mg / kg BID (20% w / v 2-hydroxypropyl-β-cyclodextrin "HPBCD"), or a combination of KRAS G12C Inh at 10 mg / kg QD and Aurora A Inh at 57 mg / kg BID. In the H1373 model, Aurora A Inh dosing was switched to 57 mg / kg QD starting on day 4. Statistical analysis results were summarized on day 28 of treatment for the H358 xenograft study and on day 24 of treatment for the H1373 xenograft study.

[0368] For the EL3187 PDX model, tumor fragments were implanted subcutaneously into the right hind flank of female athymic nude Foxn1 nu feeder mice (20-22 g, Envigo RMS, Inc., Mount Comfort, Indiana). Once tumor volume reached 800-1000 mm 3 Animals were sacrificed and tumors were harvested using sterile technique. Fresh tumors, passage 4, were cut into 10-15 mm 3 The fragments were collected and placed in cold Gibco Hibernate medium, and then the pooled tumor fragments were implanted subcutaneously into the animals using a 10g trochar needle. When the tumor volume reached 200-300mm 3At 14:00, mice were randomized into groups (n=5 per group). Treatment was started for 22 days by oral administration (gavage) of 0.2 mL of vehicle (10% NMP / 90% 15% w / v PVP-VA in PEG 400), KRAS G12C Inh at 3 mg / kg QD (10% NMP / 90% 15% w / v PVP-VA in PEG 400), Aurora A Inh at 57 mg / kg BID (20% w / v HPBCD in sterile water), or a combination of KRAS G12C Inh at 3 mg / kg QD and Aurora A Inh at 57 mg / kg BID. Statistical analysis results were summarized on day 22 of treatment.

[0369] Table 1 - Tumor growth inhibition of KRAS G12C inhibitors in combination with Aurora A inhibitors in the H358 lung xenograft model

[0370]

[0371] Table 1 shows data from the H358 NSCLC xenograft model comparing monotherapy of KRAS G12C Inh and monotherapy of Aurora A Inh vs. combination therapy of KRAS G12C Inh and Aurora A Inh. Treatment with the combination of KRAS G12C Inh and Aurora A Inh demonstrated in vivo efficacy in the H358 NSCLC xenograft model relative to either monotherapy, and resulted in 55.3% tumor regression.

[0372] Table 2 - Tumor growth inhibition of KRAS G12C inhibitors in combination with Aurora A inhibitors in the H1373 lung xenograft model

[0373] *The dosing regimen of Aurora A Inh was changed from 57 mg / kg BID to 57 mg / kg QD on day 4 of treatment and for the remainder of the study

[0374] Table 2 shows data from the H1373 NSCLC xenograft model comparing monotherapy of KRAS G12C Inh and monotherapy of Aurora A Inh vs. combination therapy of KRAS G12C Inh and Aurora A Inh. Treatment with a combination of KRAS G12C Inh and Aurora A Inh demonstrated in vivo efficacy in the H1373 NSCLC xenograft model relative to either monotherapy, and resulted in 25.3% tumor regression.

[0375] Table 3 - Tumor growth inhibition of KRAS G12C inhibitors in combination with Aurora A inhibitors in the EL3187 (lung) PDX model

[0376]

[0377] Table 3 shows data for the EL3187 NSCLC PDX model, which compares monotherapy of KRAS G12C Inh and monotherapy of Aurora A Inh vs. combination therapy of KRAS G12C Inh and Aurora A Inh. Treatment with a combination of KRAS G12C Inh and Aurora A Inh exhibited significant in vivo efficacy in the EL3187 NSCLC PDX model relative to either monotherapy, and resulted in 88.6% tumor regression.

[0378] % Delta T / C is calculated when the endpoint tumor volume in the treatment group is equal to or higher than the baseline tumor volume. The formula is 100*(T-T0) / (C-C0), where T and C are the average endpoint tumor volumes in the treatment or control group, respectively. T0 and C0 are the average baseline tumor volumes in those groups.

[0379] % Tumor Regression was calculated when the endpoint tumor volume in the treatment group was lower than the baseline tumor volume. The formula is 100*(T-T0) / T0, where T0 is the mean baseline tumor volume of the treatment group.

[0380] Additional implementation plans:

[0381] Embodiment 1. A method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of the formula:

[0382]

[0383] in:

[0384] A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2- or -CH2N(R6)CH2-;

[0385] B is -CH2- or -C(O)-;

[0386] Y is -C(CN)- or -N-;

[0387] R1 is -CN, -C(O)C≡CR8 or a group of the following formula

[0388]

[0389] R2 is H, methyl or -CH2CN;

[0390] R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl;

[0391] R4 is H, halogen or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0392] R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0393] R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl;

[0394] R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl;

[0395] R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl;

[0396] R 10 is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl;

[0397] R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and

[0398] R 13 is independently at each occurrence -N(CH3)2 or

[0399] or a pharmaceutically acceptable salt thereof; and

[0400] An effective amount of an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0401] Embodiment 2. A compound of the following formula:

[0402]

[0403] in:

[0404] A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2- or -CH2N(R6)CH2-;

[0405] B is -CH2- or -C(O)-;

[0406] Y is -C(CN)- or -N-;

[0407] R1 is -CN, -C(O)C≡CR8 or a group of the following formula

[0408]

[0409] R2 is H, methyl or -CH2CN;

[0410] R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl;

[0411] R4 is H, halogen or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0412] R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0413] R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl;

[0414] R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl;

[0415] R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl;

[0416] R 10 is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl;

[0417] R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and

[0418] R 13 is independently at each occurrence -N(CH3)2 or

[0419] or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination therapy with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

[0420] Embodiment 3. A compound of the following formula:

[0421]

[0422] in:

[0423] A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2- or -CH2N(R6)CH2-;

[0424] B is -CH2- or -C(O)-;

[0425] Y is -C(CN)- or -N-;

[0426] R1 is -CN, -C(O)C≡CR8 or a group of the following formula

[0427]

[0428] R2 is H, methyl or -CH2CN;

[0429] R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl;

[0430] R4 is H, halogen or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0431] R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0432] R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl;

[0433] R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl;

[0434] R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl;

[0435] R 10is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl;

[0436] R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and

[0437] R 13 is independently at each occurrence -N(CH3)2 or

[0438] or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof for treating cancer.

[0439] Embodiment 4. Use of a compound of the following formula or a pharmaceutically acceptable salt thereof in combination with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the manufacture of a medicament for treating cancer:

[0440]

[0441] in:

[0442] A is -OCH2-, -N(R6)CH2-, -OCH2CH2-, -N(R6)CH2CH2-, -CH2OCH2- or -CH2N(R6)CH2-;

[0443] B is -CH2- or -C(O)-;

[0444] Y is -C(CN)- or -N-;

[0445] R1 is -CN, -C(O)C≡CR8 or a group of the following formula

[0446]

[0447] R2 is H, methyl or -CH2CN;

[0448] R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl;

[0449] R4 is H, halogen or optionally replaced by R10 Replace 1-3 times -C 1-6 alkyl;

[0450] R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl;

[0451] R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl;

[0452] R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl;

[0453] R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl;

[0454] R 10 is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl;

[0455] R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 may combine to form a heterocycloalkyl group; and

[0456] R 13 is independently at each occurrence -N(CH3)2 or

[0457] Embodiment 5. The method, compound or use according to any one of embodiments 1-4, wherein A is -OCH2CH2-, or a pharmaceutically acceptable salt thereof.

[0458] Embodiment 6. The method, compound or use according to any one of embodiments 1-5, wherein B is -C(O)-, or a pharmaceutically acceptable salt thereof.

[0459] Embodiment 7. The method, compound or use according to any one of embodiments 1-6, wherein Y is -C(CN)-, or a pharmaceutically acceptable salt thereof.

[0460] Embodiment 8. The method, compound or use according to any one of embodiments 1-6, wherein Y is -N-, or a pharmaceutically acceptable salt thereof.

[0461] Embodiment 9. The method, compound or use according to any one of embodiments 1 to 8, wherein R1 is a group of the formula

[0462]

[0463] And wherein R7 is H, F, Cl, methyl, ethoxy, ethyl, isopropyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0464] Embodiment 10. The method, compound or use according to any one of embodiments 1 to 9, wherein R1 is a group of the formula

[0465]

[0466] And wherein R9 is H, F, Cl, -CHF2, -CF3 or -CH2OH, or a pharmaceutically acceptable salt thereof.

[0467] Embodiment 11. The method, compound or use according to any one of embodiments 1-8, wherein R1 is -CN or -C(O)C≡CR8, or a pharmaceutically acceptable salt thereof.

[0468] Embodiment 12. The method, compound or use according to any one of embodiments 1-11, wherein R2 is H or methyl, or a pharmaceutically acceptable salt thereof.

[0469] Embodiment 13. The method, compound or use according to any one of embodiments 1-12, wherein R3 is H, F, Cl, methyl, methoxy, ethyl, isopropyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0470] Embodiment 14. The method, compound or use according to any one of embodiments 1-13, wherein R4 is H, F or Cl, or a pharmaceutically acceptable salt thereof.

[0471] Embodiment 15. The method, compound or use according to any one of embodiments 1-14, wherein R5 is H, -CHF2, -CH2F, -CH2OH or -CH2OCH3, or a pharmaceutically acceptable salt thereof.

[0472] Embodiment 16. The method, compound or use according to any one of embodiments 1 to 15, wherein the compound is of the formula:

[0473]

[0474] or a pharmaceutically acceptable salt thereof.

[0475] Embodiment 17. The method, compound or use according to any one of embodiments 1-4, 6, 9, 10, 12-16, wherein the compound is of the formula:

[0476]

[0477] Where R is

[0478] X is Cl or F;

[0479] and m is 1 or 2,

[0480] or a pharmaceutically acceptable salt thereof.

[0481] Embodiment 18. The method, compound or use according to any one of embodiments 1-4, 6, 9, 10, 12-17, wherein the compound is of the formula:

[0482]

[0483] Where R is

[0484] X is Cl or F;

[0485] and m is 1 or 2,

[0486] or a pharmaceutically acceptable salt thereof.

[0487] Embodiment 19. The method, compound or use according to any one of embodiments 1-4, 6, 9, 10, 12-16, wherein the compound is of the formula:

[0488]

[0489] in:

[0490] A is -OCH2- or -OCH2CH2-;

[0491] Y is C(CN) or N;

[0492] R3 is Cl or F;

[0493] When Y is C(CN) R4 is H or F; and

[0494] When Y is N and R4 is F,

[0495] or a pharmaceutically acceptable salt thereof.

[0496] Embodiment 20. The method, compound or use according to any one of embodiments 1-4 or 6-19, wherein A is

[0497]

[0498] Embodiment 21. The method, compound or use according to any one of embodiments 1-4, 6, 9, 10, 12-20, wherein the compound is:

[0499]

[0500] or a pharmaceutically acceptable salt thereof.

[0501] Embodiment 22. The method, compound or use according to any one of embodiments 1-4, 6, 9, 10, 12-21, wherein the compound is:

[0502]

[0503] Embodiment 23. The method, compound or use according to any one of embodiments 1-4, 6, 9, 10, 12-22, wherein the compound is:

[0504]

[0505]

[0506] or a pharmaceutically acceptable salt thereof.

[0507] Embodiment 24. The method, compound or use according to embodiment 23, which is selected from the following compounds:

[0508]

[0509] or a group consisting of pharmaceutically acceptable salts thereof.

[0510] Embodiment 25. The method, compound or use according to embodiment 23 or 24, which is selected from the group consisting of:

[0511]

[0512] Embodiment 26. The method, compound or use according to embodiment 23, which is selected from the following compounds:

[0513]

[0514] or a group consisting of pharmaceutically acceptable salts thereof.

[0515] Embodiment 27. The method, compound or use according to embodiment 23 or 26, which is selected from the group consisting of:

[0516]

[0517] Embodiment 28. The method, compound or use according to embodiment 23, which is selected from the following compounds:

[0518]

[0519] or a group consisting of pharmaceutically acceptable salts thereof.

[0520] Embodiment 29. The method, compound or use according to any one of Embodiments 23, 24, 25 or 28, wherein the compound is

[0521]

[0522] or a pharmaceutically acceptable salt thereof.

[0523] Embodiment 30. The method, compound or use according to any one of embodiments 23, 26, 27 or 28, wherein the compound is

[0524]

[0525] or a pharmaceutically acceptable salt thereof.

[0526] Embodiment 31. The method, compound or use according to embodiment 23, which is selected from the following compounds:

[0527]

[0528] or a group consisting of pharmaceutically acceptable salts thereof.

[0529] Embodiment 32. The method, compound or use according to any one of Embodiments 23, 24, 25 or 31, wherein the compound is

[0530]

[0531] or a pharmaceutically acceptable salt thereof.

[0532] Embodiment 33. The method, compound or use according to any one of Embodiments 23, 26, 27 or 31, wherein the compound is

[0533]

[0534] or a pharmaceutically acceptable salt thereof.

[0535] Embodiment 34. The method, compound or use according to embodiment 23, which is selected from the following compounds:

[0536]

[0537] or a group consisting of pharmaceutically acceptable salts thereof.

[0538] Embodiment 35. The method, compound or use according to any one of embodiments 23, 24, 25 or 34, wherein the compound is

[0539]

[0540] or a pharmaceutically acceptable salt thereof.

[0541] Embodiment 36. The method, compound or use according to any one of embodiments 23, 26, 27 or 34, wherein the compound is

[0542]

[0543] or a pharmaceutically acceptable salt thereof.

[0544] Embodiment 37. The method, compound or use according to embodiment 23, which is selected from the following compounds:

[0545]

[0546] or a group consisting of pharmaceutically acceptable salts thereof.

[0547] Embodiment 38. The method, compound or use according to any one of embodiments 23, 24, 25 or 37, wherein the compound is

[0548]

[0549] or a pharmaceutically acceptable salt thereof.

[0550] Embodiment 39. The method, compound or use according to any one of Embodiments 23, 26, 27 or 37, wherein the compound is

[0551]

[0552] or a pharmaceutically acceptable salt thereof.

[0553] Embodiment 40. The method, compound or use according to any one of embodiments 1-0, wherein the Aurora A inhibitor is selected from the group consisting of an Aurora A selective inhibitor or a pharmaceutically acceptable salt thereof, alisertib, a pan Aurora inhibitor or a pharmaceutically acceptable salt thereof, tauzerti, danaseti, an aminopyridine compound or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[ A group consisting of 3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt.

[0554] Embodiment 41. A 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-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0555] Embodiment 42. A method, compound or use according to any one of embodiments 1 to 41, wherein the Aurora A inhibitor is selected from the group consisting of (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid, (2R, 4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid, -yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt.

[0556] Embodiment 43. A 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-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt.

[0557] Embodiment 44. The method, compound or use according to any one of embodiments 1-43, 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.

[0558] Embodiment 45. The method, compound or use according to any one of embodiments 1-44, wherein the cancer is non-small cell lung cancer and wherein one or more cells with or without Aurora A dysregulation or overexpression express KRasG12C mutant protein.

[0559] Embodiment 46. The method, compound or use according to any one of embodiments 1-44, wherein the cancer is colorectal cancer and wherein one or more cells with or without Aurora A dysregulation or overexpression express KRasG12C mutant protein.

[0560] Embodiment 47. The method, compound or use according to any one of embodiments 1-44, wherein the cancer is pancreatic cancer and wherein one or more cells with or without Aurora A dysregulation or overexpression express KRas G12C mutant protein.

[0561] Embodiment 48. The method, compound or use according to any one of Embodiments 1-44, wherein the patient has a cancer having a KRAS G12C mutation.

[0562] Embodiment 49. The method, compound or use according to any one of embodiments 1-48, wherein prior to administration of the compound or a pharmaceutically acceptable salt thereof or the Aurora A inhibitor or a pharmaceutically acceptable salt thereof, the patient has a cancer determined to have one or more cells expressing the KRas G12C mutant protein.

[0563] Embodiment 50. The method, compound or use according to any one of embodiments 1-49, wherein said compound and said Aurora A inhibitor are administered to a patient in need thereof in simultaneous or sequential combination.

[0564] Embodiment 51. The method, compound or use according to any one of embodiments 1-50, wherein the compound of formula or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered to a patient in need thereof in simultaneous combination.

[0565] Embodiment 52. The method, compound or use according to any one of embodiments 1-50, wherein the compound of formula or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered to a patient in need thereof in sequential combination.

[0566] Embodiment 53. The method, compound or use according to any one of embodiments 1-52, wherein the compound of the formula or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof prior to administering the Aurora A inhibitor or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0567] Embodiment 54. The method, compound or use according to any one of embodiments 1-52, wherein the Aurora A inhibitor or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof prior to administering the compound of the formula or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Claims

1. A method of treating cancer in a patient, wherein one or more cells express KRas G12C mutant protein, comprising administering to a patient in need thereof an effective amount of a compound of the formula: in: 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 R2 is H, methyl or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl; R4 is H, halogen or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl; R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl; R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl; R 10 is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl; R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 can combine to form a heterocycloalkyl group; and R 13 is independently at each occurrence -N(CH3)2 or or a pharmaceutically acceptable salt thereof; and An effective amount of an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

2. A compound of the formula: in: 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 R2 is H, methyl or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl; R4 is H, halogen or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl; R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl; R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl; R 10 is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl; R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 can combine to form a heterocycloalkyl group; and R 13 is independently at each occurrence -N(CH3)2 or or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination therapy with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof.

3. A compound of the formula: in: 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 R2 is H, methyl or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl; R4 is H, halogen or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl; R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl; R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl; R 10 is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl; R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 can combine to form a heterocycloalkyl group; and R 13 is independently at each occurrence -N(CH3)2 or or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof for treating cancer.

4. Use of a compound of the following formula or a pharmaceutically acceptable salt thereof in combination with an Aurora A inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially in the manufacture of a medicament for treating cancer: in: 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 R2 is H, methyl or -CH2CN; R3 and R5 are each independently H, halogen, -C 0-3 Alkyl-cyclopropyl, optionally replaced by R 10 Replace 1-3 times -C 1-6 Alkyl or optionally R 10 Replace 1-3 times -OC 1-6 alkyl; R4 is H, halogen or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R6 is H or optionally replaced by R 10 Replace 1-3 times -C 1-6 alkyl; R7 is H, halogen, -NR 11 R 12 、-CH2NR 11 R 12 , optionally R 10 or R 13 Replace 1-3 times -C 1-6 Alkyl, -C 0-3 Alkylcyclopropyl or optionally R 10 or R 13 Replace 1-3 times -OC 1-6 alkyl; R8 is H, optionally replaced by R 10 Replace 1-3 times -C 1-4 Alkyl or optionally R 10 Replace 1-3 times -C 3-6 Cycloalkyl; R9 is H, halogen, -CN, -C 0-3 Alkyl-C 3-6 Cycloalkyl or optionally R 10 Replace 1-3 times -C 1-6 alkyl; R 10 is independently at each occurrence halogen, oxygen, hydroxyl, -C 1-4 Alkyl or -OC 1-4 alkyl; R 11 and R 12 Each independently is H, -C 1-4 Alkyl or -C 1-4 Heteroalkyl, where R 11 and R 12 can combine to form a heterocycloalkyl group; and R 13 is independently at each occurrence -N(CH3)2 or 5. The method, compound or use according to any one of claims 1 to 4, wherein A is -OCH2CH2-, or a pharmaceutically acceptable salt thereof.

6. The method, compound or use according to any one of claims 1 to 5, wherein B is -C(O)-, or a pharmaceutically acceptable salt thereof.

7. The method, compound or use according to any one of claims 1 to 6, wherein Y is -C(CN)-, or a pharmaceutically acceptable salt thereof.

8. The method, compound or use according to any one of claims 1 to 6, wherein Y is -N-, or a pharmaceutically acceptable salt thereof.

9. The method, compound or use according to any one of claims 1 to 8, wherein R1 is a group of the formula And wherein R7 is H, F, Cl, methyl, ethoxy, ethyl, isopropyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

10. The method, compound or use according to any one of claims 1 to 9, wherein R1 is a group of the formula And wherein R9 is H, F, Cl, -CHF2, -CF3 or -CH2OH, or a pharmaceutically acceptable salt thereof.

11. The method, compound or use according to any one of claims 1 to 8, wherein R1 is -CN or -C(O)C≡CR8, or a pharmaceutically acceptable salt thereof.

12. The method, compound or use according to any one of claims 1 to 11, wherein R2 is H or methyl, or a pharmaceutically acceptable salt thereof.

13. The method, compound or use according to any one of claims 1 to 12, wherein R3 is H, F, Cl, methyl, methoxy, ethyl, isopropyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

14. The method, compound or use according to any one of claims 1 to 13, wherein R4 is H, F or Cl, or a pharmaceutically acceptable salt thereof.

15. The method, compound or use according to any one of claims 1 to 14, wherein R5 is H, -CHF2, -CH2F, -CH2OH or -CH2OCH3, or a pharmaceutically acceptable salt thereof.

16. The method, compound or use according to any one of claims 1 to 15, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof.

17. The method, compound or use according to any one of claims 1-4, 6, 9, 10, 12-16, wherein the compound is of the formula: Where R is X is Cl or F; and m is 1 or 2, or a pharmaceutically acceptable salt thereof.

18. The method, compound or use according to any one of claims 1-4, 6, 9, 10, 12-17, wherein the compound is of the formula: Where R is X is Cl or F; and m is 1 or 2, or a pharmaceutically acceptable salt thereof.

19. The method, compound or use according to any one of claims 1-4, 6, 9, 10, 12-16, wherein the compound is of the formula: in: A is -OCH2- or -OCH2CH2-; Y is C(CN) or N; R3 is Cl or F; When Y is C(CN) R4 is H or F; and When Y is N and R4 is F, or a pharmaceutically acceptable salt thereof.

20. The method, compound or use according to any one of claims 1-4 or 6-19, wherein A is 21. The method, compound or use according to any one of claims 1-4, 6, 9, 10, 12-20, wherein the compound is: or a pharmaceutically acceptable salt thereof.

22. The method, compound or use according to any one of claims 1-4, 6, 9, 10, 12-21, wherein the compound is:

23. The method, compound or use according to any one of claims 1-4, 6, 9, 10, 12-22, wherein the compound is: or a pharmaceutically acceptable salt thereof.

24. The method, compound or use according to claim 23, which is selected from the following compounds: or a group consisting of pharmaceutically acceptable salts thereof.

25. The method, compound or use according to claim 23 or 24, which is selected from the group consisting of:

26. The method, compound or use according to claim 23, which is selected from the following compounds: or a group consisting of pharmaceutically acceptable salts thereof.

27. The method, compound or use according to claim 23 or 26, which is selected from the group consisting of:

28. The method, compound or use according to claim 23, which is selected from the following compounds: or a group consisting of pharmaceutically acceptable salts thereof.

29. The method, compound or use according to any one of claims 23, 24, 25 or 28, wherein the compound is or a pharmaceutically acceptable salt thereof.

30. The method, compound or use according to any one of claims 23, 26, 27 or 28, wherein the compound is or a pharmaceutically acceptable salt thereof.

31. The method, compound or use according to claim 23, which is selected from the following compounds: or a group consisting of pharmaceutically acceptable salts thereof.

32. The method, compound or use according to any one of claims 23, 24, 25 or 31, wherein the compound is or a pharmaceutically acceptable salt thereof.

33. The method, compound or use according to any one of claims 23, 26, 27 or 31, wherein the compound is or a pharmaceutically acceptable salt thereof.

34. The method, compound or use according to claim 23, which is selected from the following compounds: or a group consisting of pharmaceutically acceptable salts thereof.

35. The method, compound or use of any one of claims 23, 24, 25 or 34, wherein the compound is or a pharmaceutically acceptable salt thereof.

36. The method, compound or use of any one of claims 23, 26, 27 or 34, wherein the compound is or a pharmaceutically acceptable salt thereof.

37. The method, compound or use according to claim 23, which is selected from the following compounds: or a group consisting of pharmaceutically acceptable salts thereof.

38. The method, compound or use of any one of claims 23, 24, 25 or 37, wherein the compound is or a pharmaceutically acceptable salt thereof.

39. The method, compound or use of any one of claims 23, 26, 27 or 37, wherein the compound is or a pharmaceutically acceptable salt thereof.

40. The method, compound or use according to any one of claims 1 to 39, wherein the Aurora A inhibitor is selected from the group consisting of an Aurora A selective inhibitor or a pharmaceutically acceptable salt thereof, alisertib, a pan Aurora inhibitor or a pharmaceutically acceptable salt thereof, tauzerti, danaseti, an aminopyridine compound or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[ A group consisting of 3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt.

41. The method, compound or use of any one of claims 1-40, wherein the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid or a pharmaceutically acceptable salt thereof.

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

43. The method, compound or use of any one of claims 1-42, wherein the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridinyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salt.

44. The method, compound or use according to any one of claims 1-43, 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.

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

46. ​​The method, compound or use of any one of claims 1-44, wherein the cancer is colorectal cancer and wherein one or more cells with or without Aurora A dysregulation or overexpression express KRas G12C mutant protein.

47. The method, compound or use of any one of claims 1-44, wherein the cancer is pancreatic cancer and wherein one or more cells with or without Aurora A dysregulation or overexpression express KRas G12C mutant protein.

48. The method, compound or use of any one of claims 1-44, wherein the patient has a cancer with a KRASG12C mutation.

49. The method, compound or use of any one of claims 1-48, wherein prior to administration of the compound or a pharmaceutically acceptable salt thereof or the Aurora A inhibitor or a pharmaceutically acceptable salt thereof, the patient has a cancer determined to have one or more cells expressing a KRas G12C mutant protein.

50. The method, compound or use according to any one of claims 1-49, wherein the compound and the Aurora A inhibitor are administered to a patient in need thereof in simultaneous or sequential combination.

51. The method, compound or use according to any one of claims 1-50, wherein the compound of formula or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered to a patient in need thereof in a simultaneous combination.

52. The method, compound or use according to any one of claims 1-50, wherein the compound of formula or a pharmaceutically acceptable salt thereof and the Aurora A inhibitor or a pharmaceutically acceptable salt thereof are administered to a patient in need thereof in sequential combination.

53. The method, compound or use of any one of claims 1-52, wherein the compound of the formula or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof prior to administering the Aurora A inhibitor or a pharmaceutically acceptable salt thereof to a patient in need thereof.

54. The method, compound or use according to any one of claims 1 to 52, wherein the Aurora A inhibitor or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof prior to administering a compound of the formula or a pharmaceutically acceptable salt thereof to a patient in need thereof.

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