KRAS inhibitors

Abstract

The present invention provides compounds of the formula, wherein A, Z, G, R1, R2, and R4 are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof to treat patients with cancer. [Formula 1] TIFF2026513780000222.tif28129

Description

[Technical Field]

[0001] background The MAPK / ERK signaling pathway transmits extracellular stimuli to the nucleus, thereby regulating a variety of cellular responses, including cell proliferation, differentiation, and apoptosis. The KRas protein initiates the MAPK / ERK signaling pathway and functions as a switch involved in inducing cell division. In its inactive state, KRas binds to guanosine diphosphate (GDP), effectively sending a negative signal that suppresses cell division. In response to extracellular signals, KRas is allosterically activated, enabling nucleotide exchange between GDP and guanosine triphosphate (GTP). In its GTP-bound active state, KRas recruits and activates proteins necessary for the propagation of growth factor-induced signaling, as well as other cellular signaling receptors. Examples of proteins recruited by KRas-GTP include c-Raf and PI3 kinase. As a GTPase, KRas converts bound GTP back to GDP, thereby deactivating itself and again transmitting signals to suppress cell division. KRas gain-of-function mutations exhibit increased GTP binding and decreased ability to convert GTP to GDP. As a result, MAPK / ERK signaling, which promotes the proliferation of cancer cells, increases. Missense mutations in KRas at codon 12 are the most common and significantly reduce GTPase activity.

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

[0003] To date, research has focused on KRas G12C variant inhibitors (for example, International Publication Nos. 2019 / 099524, 2020 / 081282, 2020 / 101736, 2020 / 146613, and 2021 / 118877 disclose KRas G12C inhibitors), while International Publication No. 2021 / 041671 discloses KRas G12D small molecule inhibitors, and International Publication No. 2017 / 011920 discloses KRas G12C, G12D, and G12V small molecule inhibitors.

[0004] There remains a need to provide alternative small molecule KRas inhibitors. Specifically, there is a need to provide more potent, orally deliverable KRas inhibitors useful for the treatment of cancer. More specifically, there is a need to provide small molecule inhibitors that specifically inhibit KRas GTP activity. There is also a need to provide small molecule KRas inhibitors that exhibit higher efficacy with the same or reduced KRas inhibitory activity. Furthermore, there is a demand for KRas inhibitors that exhibit better pharmacokinetic / pharmacodynamic properties. There is also a need to provide more potent KRas inhibitors that exhibit increased efficacy with reduced or minimized adverse or undesirable effects. Furthermore, there is a need to provide more potent KRas inhibitors that exhibit selective inhibitory preference for KRas G12C, G12D, and / or G12V variants than HRAS or NRAS. The present invention addresses one or more of these needs by providing a novel KRas inhibitor. [Overview of the Initiative]

[0005] A compound of formula I,

[0006] [ka] During the ceremony, A is -C(H)- or -N-, Z is -C(R 3c )- or -N-, G is -C(R 3b )- or -N-, R1 is the basis of the following equation,

[0007] [ka] In the formula, n is 0, 1, or 2. Y is either -N(R8)- or -O-, L is a 5-6 member heteroaryl containing 1-3 heteroatoms selected from O, N, or S, and the 5-6 member heteroaryl is C 3~6It may optionally be condensed with a cycloalkyl ring to form a bicyclic ring structure. R2 is H, halogen, or methyl. R 3b and R 3c are each independently H, halogen, or methyl. R4 is H, methyl, -CH2-OH, -O-R5-R6, -O-R6, an N-linked cyclic amine, or azetidine, optionally substituted with NR7R7, where R5 is -CH2-, -CH(CH3)-, or -CH2-CH2-, and R6 is H, C 1~3 alkyl, C 2~3 heteroalkyl, C 3~6 cycloalkyl, C 4~6 heterocycloalkyl, or 2-oxo-1,3-dihydrobenzimidazole, where C 1~3 alkyl, C 3~6 cycloalkyl, or C 4~6 heterocycloalkyl is optionally substituted with one or more halogens, hydroxyl, methoxy, NR7R7, C 1~4 alkyl, or C 1~4 alkenyl, C 1~4 alkyl is optionally substituted with one or more halogens or hydroxyl, C 3~6 cycloalkyl or C 4~6 heterocycloalkyl is 1~4 optionally condensed with C 3~6 alkyl to form a bicyclic ring, or C 4~6 cycloalkyl or C 1~3 heterocycloalkyl is optionally bridged with C R4 is an N-linked cyclic amine or a group of the following formula:

[0008]

Chemical formula

[0009] [ka] is hexahydro-1H-furo[3,4-c]pyrrole, each E 2a is independently C 1~3 alkylene optionally substituted with one or more hydroxyls, E5 is -O-, -CR 7a R 7a -, or -NR 9a -, each R7 is independently H or C 1~3 alkyl, each R 7a is independently H, halogen, CN, hydroxyl, C 1~3 alkoxy, or C 1~3 alkyl optionally substituted with one or more halogens or hydroxyls, each R8 is independently H or C 1~3 alkyl, each R 8a is independently C 1~3 alkyl, R9 is H, -CO-C 1~3 alkyl, -CO-NR8R8, -NR 9a R 9a , C 1~4 alkyl, or C 3~6 cycloalkyl, C 1~4 alkyl or C 3~6 cycloalkyl is optionally substituted with one or more halogens, R 9a is independently H, optionally substituted C 1~3 alkyl or -CO-C 1~3 alkyl, optionally substituted C 1~3 alkyl is optionally substituted with one or more halogens, R 10 is H, or C 1~3 alkyl optionally substituted with one or more deuteriums, a compound, or a pharmaceutically acceptable salt thereof is provided herein.

[0010] Methods of using compounds of formula I, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable compositions thereof for the treatment of cancer, specifically lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer. The method comprises administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a patient in need.

[0011] Compounds of formula I and pharmaceutically acceptable salts thereof for use in therapy are further provided herein. Compounds of formula I and pharmaceutically acceptable salts thereof for use in the treatment of cancer, specifically lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer are additionally provided herein. The use of compounds of formula I, or pharmaceutically acceptable salts thereof, in the manufacture of agents for the treatment of cancer, specifically lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer is also additionally provided herein. [Modes for carrying out the invention]

[0012] Novel inhibitors of KRas gain-of-function mutants G12C, G12D, and / or G12V are described herein. These novel compounds can address the need for inhibitors of KRas GTP activity in gain-of-function mutants in the treatment of cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. The present invention relates to a compound of formula I,

[0013] [ka] The present invention provides a compound, or a pharmaceutically acceptable salt thereof, in which A, Z, G, R1, R2, and R4 are as defined above.

[0014] As used herein, the term "halogen" means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term "alkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon radical having from 1 to a specific number of carbon atoms, for example, "C 1~4 alkyl" or "C 1~3 alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso-butyl. As used herein, the term "cycloalkyl" means a saturated cyclic monovalent hydrocarbon radical containing a specific number of carbon atoms, for example, "C 4~6 cycloalkyl". Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. As used herein, the term "heteroalkyl" means a saturated straight-chain or branched-chain monovalent hydrocarbon radical containing a specific number of atoms including both carbon atoms and one or more heteroatoms, for example, "C 2~3 heteroalkyl" and "C 2~4 heteroalkyl". For example, C4 heteroalkyl means a saturated straight-chain or branched-chain monovalent hydrocarbon radical containing at least 1 carbon atom and at least 1 heteroatom, and the total number of carbon and heteroatoms is 4 atoms in total. As used herein, the term "heterocycloalkyl" means a saturated cyclic heteroalkyl group containing a specific number of atoms including both carbon atoms and one or more heteroatoms, for example, "C 4~6This term means "heterocycloalkyl." Examples of heterocycloalkyls include, but are not limited to, dioxane, tetrahydrofuran, piperidine, piperazine, azetazine, and pyrrolidine. As used herein, the term heteroaryl, used alone or as part of a larger phrase such as heteroaralkyl or heteroaralkoxy, refers to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, having 6, 10, or 14 π electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, including oxidized forms of nitrogen or sulfur, and quaternized forms of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. As used herein, the term heteroaryl also refers to a group in which a heteroaromatic ring is condensed with one or more aryl, alicyclic, or heterocyclyl rings, and the radical or bond site is located on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido2,3-b-1,4-oxazine-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term heteroaryl may be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic, any of which may include optionally substituted rings.The term heteroaralkyl refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties are independently and arbitrarily substituted.

[0015] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple unsaturated moies, but not to include aryl or heteroaryl moies as defined herein.

[0016] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is H, methyl, -CH2-OH, -O-R5-R6, -O-R6, N-linked cyclic amine, or azetidine, which is optionally substituted with NR7R7, R5 is -CH2-, -CH(CH3)-, or -CH2-CH2-, and R6 is H, C 1~3 Alkyl, C 2~3 Heteroalkyl, C 3~6 Cycloalkyl, C 4~6 Heterocycloalkyl, or 2-oxo-1,3-dihydrobenzimidazole, C 1~3 Alkyl, C 3~6 Cycloalkyl, or C 4~6 Heterocycloalkyl contains one or more halogens, hydroxyl, methoxy, NR7R7, C 1~4 Alkyl, or C 1~4 It is optionally substituted with an alkenyl, C 1~4 The alkyl group is optionally substituted with one or more halogens or hydroxyls, C 3~6 Cycloalkyl or C 4~6 Heterocycloalkyl is C 1~4 It optionally condenses with alkyl to form a bicyclic ring, or C 3~6 Cycloalkyl or C 4~6 Heterocycloalkyl is C 1~3 Selectively crosslinked with alkyl, or R4 is an N-linked cyclic amine or a group of the following formula:

[0017] [ka] N-linked cyclic amines, N-linked, i. R 4a and R 4b Azetidine substituted with ii. Pyrrolidine, piperidine, piperazine, morpholine, imidazole, or pyrazole, each of which is C 1~3 They are optionally crosslinked by alkylene, each containing one or more halogens, hydroxyls, and C 1~3 Alkoxy, -NR 6a R 6a , azetidine, C 1~3 Imidazoles optionally substituted with alkyl or methyl groups, and azetidine is optionally substituted with hydroxyl or C groups. 1~3 Optionally substituted with an alkoxy, C 1~3 Alkyl, halogen-NR 6a R 6a Alternatively, pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole, which are optionally substituted with hydroxyl, iii. 2,6-Diazabicyclo[3.2.0]heptane, 3,6-Diazabicyclo[3.2.0]heptane, 3-Azabicyclo[3.1.0]hexane, 3-Azabicyclo[3.2.0]heptane, Octahydro-1H-pyrrolo[3,4-b]pyridine, Octahydro-6-pyrrolo[3,4-b]pyrazine, Octahydropyrrolo[1,2-a]pyrazine, Octahydropyrrolo[3,2-b]pyrrole, Octahydropyrrolo[3,4-b][1,4]oxazine, Octahydropyrrolo[3,4-b]pyrrole, Octahydropyrrolo[3,4-c]pyrrole, Tetrahydrofloxacin[3,4- d]Oxazole-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane, each containing one or more halogens, -NR 6a R 6a Alternatively, -NR 6a R 6a C is optionally replaced by 1~32,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-6-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c] Pyrrole, tetrahydrofloo[3,4-d]oxazole-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane, R 4a However, NR 4c R 4d , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, wherein cyclopropyl, azetidine, pyrrolidine, piperidine or morpholine is a halogen, hydroxyl, C 1~3 Alkoxy or -NR 6a R 6a It is optionally replaced by, Each R 6b However, independently, H, triduteromethyl, C 3~5 C is optionally substituted with cycloalkyl or hydroxyl groups. 1~3 It is alkyl, R9 is H, -CO-C 1~3 Alkyl, -NR 9a R 9a , C 1~4 Alkyl, or C 3~6 It is a cycloalkyl, C 1~4 Alkyl or C 3~6The cycloalkyl group is optionally substituted with one or more halogens.

[0018] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:

[0019] [ka] In the formula, n is 0, 1, or 2. Y is either -N(R8)- or -O-, L is a 5-6 member heteroaryl containing 1-3 heteroatoms selected from O, N, or S, and the 5-6 member heteroaryl is C 3~6 It may optionally condense with a cycloalkyl ring to form a bicyclic ring structure. R2 is H, halogen, or methyl. R4 is optionally substituted with NR7R7, consisting of H, methyl, -CH2-OH, -O-R5-R6, -O-R6, N-linked cyclic amine, or azetidine, where R5 is -CH2-, -CH(CH3)-, or -CH2-CH2-, and R6 is H, C 1~3 Alkyl, C 2~3 Heteroalkyl, C 3~6 Cycloalkyl, C 4~6 Heterocycloalkyl, or 2-oxo-1,3-dihydrobenzimidazole, C 1~3 Alkyl, C 3~6 Cycloalkyl, or C 4~6 Heterocycloalkyl contains one or more halogens, hydroxyl, methoxy, NR7R7, C 1~4 Alkyl, or C 1~4 It is optionally substituted with an alkenyl, C 1~4 The alkyl group is optionally substituted with one or more halogens or hydroxyls, C 3~6 Cycloalkyl or C 4~6 Heterocycloalkyl is C 1~4 It optionally condenses with alkyl to form a bicyclic ring, or C 3~6 Cycloalkyl or C 4~6Heterocycloalkyl is C 1~3 Selectively crosslinked with alkyl groups, R9, H, C 1~4 Alkyl, or C 3~6 A cycloalkyl or a pharmaceutically acceptable salt thereof, C 1~4 Alkyl or C 3~6 The cycloalkyl group is optionally substituted with one or more halogens.

[0020] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is a group of the following formula:

[0021] [ka] L is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from O, N, or S, and the 5-membered heteroaryl is C 3~6 It may optionally condense with a cycloalkyl ring to form a bicyclic ring structure. R4 is optionally substituted with NR7R7, consisting of H, methyl, -CH2-OH, -O-R5-R6, -O-R6, or azetidine, R5 is -CH2-, -CH(CH3)-, or -CH2-CH2-, and R6 is H, C 1~3 Alkyl, C 2~3 Heteroalkyl, C 3~6 Cycloalkyl, C 4~6 Heterocycloalkyl, or 2-oxo-1,3-dihydrobenzimidazole, C 1~3 Alkyl, C 3~6 Cycloalkyl, or C 4~6 Heterocycloalkyl contains one or more halogens, hydroxyl, methoxy, NR7R7, C 1~4 Alkyl, or C 1~4 It is optionally substituted with an alkenyl, C 1~4 The alkyl group is optionally substituted with one or more halogens or hydroxyls, C 3~6 Cycloalkyl or C 4~6 Heterocycloalkyl is C 1~4 It optionally condenses with alkyl to form a bicyclic ring, or C3~6 Cycloalkyl or C 4~6 Heterocycloalkyl is C 1~3 Selectively crosslinked with alkyl groups, R9, H, C 1~4 Alkyl, or C 3~6 A cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -N-.

[0023] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(R3b)-.

[0024] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(R3b)- and R3b is H or a halogen.

[0025] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(F)-.

[0026] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(H)-.

[0027] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(CH3)-.

[0028] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, Z is -N-.

[0029] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, Z is -C(R3c)-.

[0030] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, Z is -C(R3c)- and R3c is H or a halogen.

[0031] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, Z is -C(H)-.

[0032] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, Z is -C(F)-.

[0033] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -N- and Z is -C(R3c)-.

[0034] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -N- and Z is -C(H)-.

[0035] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -N- and Z is -C(F)-.

[0036] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(R3b)- and Z is -N-.

[0037] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(R3b)-, R3b is H or a halogen, and Z is -N-.

[0038] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(F)- and Z is -N-.

[0039] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(H)- and Z is -N-.

[0040] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, G is -C(CH3)- and Z is -N-.

[0041] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R3b and R3c are each independently H or a halogen.

[0042] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-.

[0043] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-.

[0044] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R2 is F or Cl.

[0045] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, and R2 is F.

[0046] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, and R2 is F.

[0047] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, and R2 is F.

[0048] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, and R2 is F.

[0049] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, and R2 is F.

[0050] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, and R2 is F.

[0051] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(H)-, and R2 is F.

[0052] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(H)-, and R2 is F.

[0053] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(H)-, and R2 is F.

[0054] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(H)-, and R2 is F.

[0055] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, and R2 is F.

[0056] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, and R2 is F.

[0057] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(F)-, and R2 is F.

[0058] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(F)-, and R2 is F.

[0059] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(F)-, and R2 is F.

[0060] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(F)-, and R2 is F.

[0061] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(F)-, and R2 is F.

[0062] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, and R2 is F.

[0063] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, and R2 is Cl.

[0064] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, and R2 is Cl.

[0065] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, and R2 is Cl.

[0066] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, and R2 is Cl.

[0067] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, and R2 is Cl.

[0068] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, and R2 is Cl.

[0069] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(H)-, and R2 is Cl.

[0070] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(H)-, and R2 is Cl.

[0071] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(H)-, and R2 is Cl.

[0072] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(H)-, and R2 is Cl.

[0073] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, and R2 is Cl.

[0074] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, and R2 is Cl.

[0075] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(F)-, and R2 is Cl.

[0076] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(F)-, and R2 is Cl.

[0077] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(F)-, and R2 is Cl.

[0078] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(F)-, and R2 is Cl.

[0079] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(F)-, and R2 is Cl.

[0080] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, and R2 is Cl.

[0081] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R9 is H, -CO-C1-3 alkyl, -NR9aR9a, C1-4 alkyl, or C3-6 cycloalkyl.

[0082] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R9 is H, C1-4 alkyl, or C3-6 cycloalkyl.

[0083] In one embodiment of any compound of formula I or a pharmaceutically acceptable salt thereof, Y is -N(R8)-.

[0084] In one embodiment of any compound of formula I or a pharmaceutically acceptable salt thereof, Y is -O-.

[0085] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is a five-membered heteroaryl that optionally condenses with a cyclohexyl ring to form a bicyclic ring.

[0086] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is a five-membered heteroaryl that optionally condenses with a cyclohexyl ring to form a bicyclic ring, and the five-membered heteroaryl is selected from oxazole, isothiazole, thiazole, thiadiazole, imidazole, oxadiazole, triazole, isoxazole, or pyrazole.

[0087] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from oxazole, isothiazole, thiazole, thiadiazole, imidazole, oxadiazole, triazole, isoxazole, pyrazole, 4,5,6,7-tetrahydro-1,2-benzoxazole, or 4,5,6,7-tetrahydro-1H-indazole.

[0088] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from oxazole, isothiazole, thiazole, thiadiazole, imidazole, oxadiazole, triazole, isoxazole, or pyrazole.

[0089] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is a 5-6 membered heteroaryl compound containing 1-3 heteroatoms selected from O, N, or S, and the 5-6 membered heteroaryl compound may optionally condense with a C3-6 cycloalkyl ring to form a bicyclic ring structure.

[0090] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, N, or S, wherein the 5-6 membered heteroaryl is selected from oxazole, isothiazole, thiazole, thiadiazole, imidazole, oxadiazole, triazole, isoxazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine.

[0091] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from oxazole, isothiazole, thiazole, thiadiazole, imidazole, oxadiazole, triazole, isoxazole, pyrazole, 4,5,6,7-tetrahydro-1,2-benzoxazole, 4,5,6,7-tetrahydro-1H-indazole, pyridine, pyridazine, pyrimidine, or pyrazine.

[0092] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from oxazole, isothiazole, thiazole, thiadiazole, imidazole, oxadiazole, triazole, isoxazole, or pyrazole.

[0093] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, L is selected from pyridine, pyridazine, pyrimidine, or pyrazine.

[0094] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0095] [ka] Selected from.

[0096] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0097] [ka] Selected from.

[0098] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0099] [ka] Selected from.

[0100] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0101] [ka] Selected from.

[0102] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0103] [ka] Selected from.

[0104] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0105] [ka] Selected from.

[0106] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0107] [ka] Selected from.

[0108] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0109] [ka] Selected from.

[0110] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

[0111] [ka] Selected from.

[0112] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is selected from H, methyl, -CH2-OH, -O-R5-R6, -O-R6, N-linked cyclic amine, or azetidine, which are optionally substituted with NR7R7, R5 is -CH2-, -CH(CH3)-, or -CH2-CH2-, and R6 is H, C 1~3 Alkyl, C 2~3Heteroalkyl, C 3~6 Cycloalkyl, C 4~6 Heterocycloalkyl, or 2-oxo-1,3-dihydrobenzimidazole, C 1~3 Alkyl, C 3~6 Cycloalkyl, or C 4~6 Heterocycloalkyl contains one or more halogens, hydroxyl, methoxy, NR7R7, C 1~4 Alkyl, or C 1~4 It is optionally substituted with an alkenyl, C 1~4 The alkyl group is optionally substituted with one or more halogens or hydroxyls, C 3~6 Cycloalkyl or C 4~6 Heterocycloalkyl is C 1~4 It optionally condenses with alkyl to form a bicyclic ring, or C 3~6 Cycloalkyl or C 4~6 Heterocycloalkyl is C 1~3 It is an alkyl group that is optionally crosslinked, or a pharmaceutically acceptable salt thereof.

[0113] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is N-linked, i. R 4a and R 4b Azetidine substituted with a. Pyrrolidine, piperidine, piperazine, morpholine, imidazole, or pyrazole, each of which is C 1~3 They are optionally crosslinked by alkylene, each containing one or more halogens, hydroxyls, and C 1~3 Alkoxy, -NR 6a R 6a , azetidine, C 1~3 Imidazoles optionally substituted with alkyl or methyl groups, and azetidine is optionally substituted with hydroxyl or C groups. 1~3 Optionally substituted with an alkoxy, C 1~3 Alkyl, halogen-NR 6a R 6aAlternatively, pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole, which are optionally substituted with hydroxyl, b. 2,6-Diazabicyclo[3.2.0]heptane, 3,6-Diazabicyclo[3.2.0]heptane, 3-Azabicyclo[3.1.0]hexane, 3-Azabicyclo[3.2.0]heptane, Octahydro-1H-pyrrolo[3,4-b]pyridine, Octahydro-6-pyrrolo[3,4-b]pyrazine, Octahydropyrrolo[1,2-a]pyrazine, Octahydropyrrolo[3,2-b]pyrrole, Octahydropyrrolo[3,4-b][1,4]oxazine, Octahydropyrrolo[3,4-b]pyrrole, Octahydropyrrolo[3,4-c]pyrrole, Tetrahydrofloxacin[3,4- d]Oxazole-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane, each containing one or more halogens, -NR 6a R 6a or -NR 6a R 6a C is optionally replaced by 1~32,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-6-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c These are pyrrole, tetrahydrofloo[3,4-d]oxazole-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane.

[0114] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is N-linked, i. R 4a and R 4b Azetidine substituted with ii. Pyrrolidine, piperidine, piperazine, or morpholine, each of which is C 1~3 They are optionally crosslinked by alkylenes, each containing one or more halogens, hydroxyls, and -NRs. 6a R 6a , imidazole or C 1~3 The imidazole is optionally substituted with alkyl, and the C is optionally substituted with methyl. 1~3 Alkyl, -NR 6a R 6a Alternatively, pyrrolidine, piperidine, piperazine, or morpholine, which are optionally substituted with hydroxyl, iii. Octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,4-c]pyrrole, 1,6-diazaspiro[3.3]heptane, or 1,6-diazaspiro[3.4]octane, each containing one or more halogens or C 1~3 It is an N-linked cyclic amine selected from octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,4-c]pyrrole, 1,6-diazaspiro[3.3]heptane, or 1,6-diazaspiro[3.4]octane, which is optionally substituted with an alkyl group.

[0115] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula:

[0116] [ka]

[0117] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula:

[0118] [ka] E2 and E4 are each independently and optionally substituted with one or more hydroxyls or halogens. 1~3 It is an alkylene, and E2 and E4 are bonded or C 1~3 E3 can be optionally crosslinked with alkylene, such that E3 is -O-, -CR7R7-, -NR9-, or -CO-NR 6a - is either a pharmaceutically acceptable salt thereof.

[0119] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0120] [ka] That is the case.

[0121] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is methyl, methoxy, -CH2-OH,

[0122] [ka] Selected from.

[0123] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is methyl, methoxy, -CH2-OH,

[0124] [ka] Selected from.

[0125] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0126] [ka] Selected from.

[0127] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0128] [ka] Selected from.

[0129] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0130] [ka] Selected from.

[0131] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is an N-linked cyclic amine.

[0132] [ka] is.

[0133] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0134] [Chemical formula] is.

[0135] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is an N-linked cyclic amine

[0136] [Chemical formula] is.

[0137] In the above embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula

[0138] [Chemical formula] E2 and E4 can be optionally crosslinked by a bond or C 1~3 alkylene. Examples of these compounds of formula I are shown below.

[0139] [Chemical formula] <00009!0> or a pharmaceutically acceptable salt thereof.

[0140] In the above embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the following formula

[0141] [Chemical formula] E3 can be -CO-NR 6b -. Examples of these compounds of formula I are shown below.

[0142]

Chem.

[0143] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0144]

Chem.

[0145]

Chem.

[0146]

Chem.

[0147]

Chem.

[0148]

Chem.

[0149]

Chem.

[0150]

Chem.

[0151]

Chem.

[0152] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0153] [ka]

[0154] [ka]

[0155] [ka]

[0156] [ka]

[0157] [ka] It is an N-linked cyclic amine selected from the following.

[0158] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0159] [ka] It is an N-linked cyclic amine selected from the following.

[0160] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

[0161] [ka] It is an N-linked cyclic amine selected from the following.

[0162] In the above embodiments of the compounds of formula I, the chemical diagrams are shown monotonically without chiral information. These compounds often have multiple chiral centers and are intended to exist in various forms with various combinations of chiral centers. In addition, these compounds may have various enantiomers, diastereomers, and atropisomers, which are included herein.

[0163] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.

[0164] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using an isotopic labeling reagent or a pharmaceutically acceptable salt thereof instead of a non-isotopic labeling reagent.

[0165] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, the compound is a deuterium-labeled compound of any one of the compounds and pharmaceutically acceptable salts thereof described herein.

[0166] Further compounds of formula I or pharmaceutically acceptable salts thereof, wherein the compounds are

[0167] [ka]

[0168] [ka] It is selected from or a pharmaceutically acceptable salt thereof.

[0169] Further compounds of formula I or pharmaceutically acceptable salts thereof, wherein the compounds are

[0170] [ka] It is selected from or a pharmaceutically acceptable salt thereof.

[0171] Further compounds of formula I or pharmaceutically acceptable salts thereof, wherein the compounds are

[0172] [ka]

[0173] [ka] It is selected from or a pharmaceutically acceptable salt thereof.

[0174] The chemical diagrams of the compounds described above include representations of the chiral aspects of the specific compounds shown. However, the chemical diagrams of the compounds described above do not include all possible chiral features of those compounds, and the chiral representations shown are not intended to exclude changes to the indicated chiral aspects. Therefore, alternative chiral versions of the compounds, as well as different combinations of chiral attributes, are contemplated and included herein.

[0175] A method for treating cancer is further provided herein, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof. In this method, cancer may be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, gastric cancer, or esophageal cancer. More specifically, in this method, cancer may be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In one embodiment, cancer may be non-small cell lung cancer. In one embodiment, cancer may be pancreatic cancer. In one embodiment, cancer may be colorectal cancer.

[0176] A method for treating cancer is also provided herein, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. In this method, the cancer may be non-small cell lung cancer, pancreatic cancer, or colorectal cancer having one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. In one embodiment, the cancer is non-small cell lung cancer having one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. In one embodiment, the cancer is mutant pancreatic cancer having one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. In one embodiment, the cancer is colorectal cancer having one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0177] A method for treating patients having cancer with KRas G12C, G12D, and / or G12V mutations is further provided herein, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof. In this method, cancers having KRas G12C, G12D, and / or G12V mutations can be defined as KRas G12C, G12D, and / or G12V mutant lung cancer, KRas G12C, G12D, and / or G12V mutant pancreatic cancer, KRas G12C, G12D, and / or G12V mutant cervical cancer, KRas G12C, G12D, and / or G12V mutant esophageal cancer, KRas G12C, G12D, and / or G12V mutant endometrial cancer, KRas G12C, G12D, and / or G12V mutant ovarian cancer, KRas G12C, G12D, and / or G12V mutant bile duct cancer, and KRas G12C, G12D, and / or G12V mutant colorectal cancer. In one embodiment, cancer having KRas G12C, G12D, and / or G12V mutations can be defined as KRas G12C, G12D, and / or G12V mutant non-small cell lung cancer. In one embodiment, cancer having KRas G12C, G12D, and / or G12V mutations can be defined as KRas G12C, G12D, and / or G12V mutant pancreatic cancer. In one embodiment, cancer having KRas G12C, G12D, and / or G12V mutations can be defined as KRas G12C, G12D, and / or G12V mutant colorectal cancer.

[0178] This specification further provides a method for modulating mutant KRas G12C, G12D, and / or G12V enzymes in patients requiring modulation of these mutant KRas G12C, G12D, and / or G12V enzymes by administering a compound conforming to Formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises inhibiting the human mutant KRas G12C, G12D, and / or G12V enzymes.

[0179] Also provided herein are methods for treating cancer in patients requiring cancer treatment, wherein the patient has cancer determined to express KRas G12C, G12D, and / or G12V mutant proteins. The method comprises administering to the patient an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof. The G12C, G12D, and / or G12V mutant status of one or more cancer cells can be determined by several assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained and subjected to sequencing and / or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, for example, in advanced cancer. Non-exclusive examples of sequencing and PCR techniques used to determine mutational status (e.g., G12C, G12D, and / or G12V mutational status in one or more cancer cells or circulating cell-free DNA) include direct sequencing, next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrosequencing and multi-sample profiling.

[0180] Compounds conforming to Formula I or pharmaceutically acceptable salts thereof for use in therapy are further provided herein. The compounds or pharmaceutically acceptable salts thereof may be for use in the treatment of cancer. In this use in the treatment of cancer, cancer may be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. More specifically, cancer may be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In one embodiment, cancer is non-small cell lung cancer. In one embodiment, cancer is pancreatic cancer. In one embodiment, cancer is colorectal cancer. Cancer may have one or more cancer cells expressing mutant KRas G12C, G12D, and / or G12V proteins, for example, KRas G12C, G12D, and / or G12V mutant lung cancer, KRas G12C, G12D, and / or G12V mutant pancreatic cancer, KRas G12C, G12D, and / or G12V mutant cervical cancer, KRas G12C, G12D, and / or G12V mutant esophageal cancer, KRas G12C, G12D, and / or G12V mutant endometrial cancer, KRas G12C, G12D, and / or G12V mutant ovarian cancer, KRas G12C, G12D, and / or G12V mutant cholangiocarcinoma, and KRas G12C, G12D, and / or G12V mutant colorectal cancer. In these uses, the cancer is selected from KRas G12C, G12D, and / or G12V mutant non-small cell lung cancer, KRas G12C, G12D, and / or G12V mutant colorectal cancer, and KRas G12C, G12D, and / or G12V mutant pancreatic cancer. Additionally, the cancer may be non-small cell lung cancer in which one or more cells express KRas G12C, G12D, and / or G12V mutant proteins. Furthermore, the cancer may be colorectal cancer in which one or more cells express KRas G12C, G12D, and / or G12V mutant proteins. Additionally, the cancer may be pancreatic cancer in which one or more cells express KRas G12C, G12D, and / or G12V mutant proteins.Patients may have cancer that has been determined to have one or more cells expressing KRas G12C, G12D, and / or G12V variant proteins prior to administration of the compound or a pharmaceutically acceptable salt thereof. Patients may have been treated in different therapeutic courses prior to being treated as described herein.

[0181] Compounds provided herein according to Formula I, or pharmaceutically acceptable salts thereof, may also be used in the manufacture of agents for the treatment of cancer. When used in the manufacture of agents, cancer may be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. More specifically, cancer may be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In one embodiment, cancer is non-small cell lung cancer. In one embodiment, cancer is pancreatic cancer. In one embodiment, cancer is colorectal cancer. Cancer may have one or more cancer cells expressing mutant KRas G12C, G12D, and / or G12V proteins. When cancer cells express KRas G12C, G12D, and / or G12V proteins, the cancer can be selected from KRas G12C, G12D, and / or G12V mutant non-small cell lung cancer, KRas G12C, G12D, and / or G12V mutant colorectal cancer, and KRas G12C, G12D, and / or G12V mutant pancreatic cancer.

[0182] A method for treating cancer is also provided herein, comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and one or more of the following: PD-1 inhibitors, PD-L1 inhibitors, CDK4 / CDK6 inhibitors, EGFR inhibitors, ERK inhibitors, Aurora A inhibitors, SHP2 inhibitors, platinum agents, and pemetrexed, or pharmaceutically acceptable salts thereof, wherein the cancer has one or more cells expressing variant KRas G12C, G12D, and / or G12V proteins. Further provided herein are compounds according to Formula I, or pharmaceutically acceptable salts thereof, for use in the treatment of cancer, either simultaneously, separately, or sequentially, in combination with one or more of the following: PD-1 or PD-L1 inhibitors, CDK4 / CDK6 inhibitors, EGFR inhibitors, ERK inhibitors, Aurora A inhibitors, SHP2 inhibitors, platinum agents, and pemetrexed, or pharmaceutically acceptable salts thereof. Additional combinations are provided, for use simultaneously, separately, or sequentially in the treatment of cancer, comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and one or more of the following: PD-1 or PD-L1 inhibitors, CDK4 / CDK6 inhibitors, EGFR inhibitors, ERK inhibitors, Aurora A inhibitors, SHP2 inhibitors, platinum agents, and pemetrexed, or pharmaceutically acceptable salts thereof.

[0183] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, wherein the cancer has one or more cells expressing variant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with, a PD-1 or PD-L1 inhibitor for use in the treatment of cancer. Additionally provided are combinations comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor for use in combination, separately, or sequentially with, a PD-1 or PD-L1 inhibitor for use in the treatment of cancer. As used herein, the PD-1 or PD-L1 inhibitor may be pembrolizumab, nivolumab, semiprimab, cintirimab, atezolizumab, avelumab, durvalumab, or rodapilimab. As described herein, cancer may be non-small cell lung cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; cancer may be colorectal cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; or cancer may be mutant pancreatic cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0184] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds according to Formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additional combinations are provided for use simultaneously, separately, or sequentially in the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins, comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof. As used herein, the CDK4 / CDK6 inhibitor may be abemaciclib, the CDK4 / CDK6 inhibitor may be palbociclib, or the CDK4 / CDK6 inhibitor may be ribociclib. As described herein, cancer may be non-small cell lung cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; cancer may be colorectal cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; and cancer may be mutant pancreatic cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0185] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing variant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, simultaneously, separately, or sequentially, for the treatment of cancer. Additional combinations are provided, comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with, separately, or sequentially, for the treatment of cancer. As used herein, the EGFR inhibitor may be erlotinib, the EGFR inhibitor may be afatinib, the EGFR inhibitor may be gefitinib, and the EGFR inhibitor may be cetuximab. As described herein, cancer may be non-small cell lung cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; cancer may be colorectal cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; or cancer may be mutant pancreatic cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0186] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds conforming to Formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additional combinations are provided, comprising a compound conforming to Formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for use in combination with, separately, or sequentially with, an ERK inhibitor. As used herein, the ERK inhibitor may be LY3214996, the ERK inhibitor may be LTT462, or the ERK inhibitor may be KO-947. As described herein, cancer may be non-small cell lung cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; cancer may be colorectal cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; and cancer may be mutant pancreatic cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins.This method also includes treating cancers of other organs that have KRas G12C, G12D, and / or G12V variants.

[0187] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with, an Aurora A inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additionally provided are combinations comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor for use in combination with, separately, or sequentially with, a cancer. As used herein, Aurora A inhibitors are aricertib, tozacertib, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole- The salts may be (3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:2-methylpropan-2-amine (1:1) salts, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salts, or pharmaceutically acceptable salts thereof. In one embodiment, the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazole-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid.As described herein, cancer may be non-small cell lung cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; cancer may be colorectal cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; and cancer may be mutant pancreatic cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0188] Also provided is a method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with, separately, or sequentially with, an SHP2 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additional combinations are provided, comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor for use in combination with, separately, or sequentially with, an SHP2 inhibitor. As used herein, the SHP2 inhibitor or a pharmaceutically acceptable salt thereof may be a type I SHP2 inhibitor or a type II SHP2 inhibitor. Examples of type I SHP2 inhibitors include, but are not limited to, PHPS1, GS-493, NSC-87877, NSC-117199, and cefsulodine, as well as their pharmaceutically acceptable salts. Examples of type II SHP2 inhibitors include, but are not limited to, JAB-3068, JAB-3312, RMC-4550, RMC-4630, SHP099, SHP244, SHP389, SHP394, TNO155, RG-6433, and RLY-1971, as well as their pharmaceutically acceptable salts. Additional examples of SHP2 inhibitors include, but are not limited to, BBP-398, IACS-15509, IACS-13909, X37, ERAS-601, SH3809, HBI-2376, ETS-001, and PCC0208023, as well as their pharmaceutically acceptable salts. This method also includes treating cancers of other organs with KRas G12C, G12D, and / or G12V mutant protein mutations.As described herein, cancer may be non-small cell lung cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; cancer may be colorectal cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; and cancer may be mutant pancreatic cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0189] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with a platinum agent or a pharmaceutically acceptable salt thereof, separately, or sequentially, for the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additional combinations are provided, comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, for use simultaneously, separately, or sequentially, for the treatment of cancer. As used herein, the platinum agent may be cisplatin, carboplatin, or oxaliplatin. As described herein, cancer may be non-small cell lung cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; cancer may be colorectal cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; and cancer may be mutant pancreatic cancer in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0190] A method for treating cancer is also provided, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided are compounds according to formula I, or pharmaceutically acceptable salts thereof, for use in combination with pemetrexed, separately, or sequentially, for the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additionally provided are combinations comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, for use in combination with pemetrexed, separately, or sequentially, for the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. As described herein, the cancer may be colorectal cancer having one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins, or the cancer may be mutant pancreatic cancer having one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0191] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that is considered acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and SMBerge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 1977, 66(1), 1–19.

[0192] Pharmaceutical compositions containing the compound of Formula I described herein may be prepared using pharmaceutically acceptable additives. As used herein with respect to pharmaceutical compositions, the term “pharmaceutically acceptable additive” refers to one or more carriers, diluents, and excipients that are compatible with other additives in the composition or preparation and are not harmful to the patient. Examples of processes for pharmaceutical compositions and their preparations can be found in “Remington: The Science and Practice of Pharmacy,” Loyd, V., et al. Eds., 22. nd This can be found in Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include physiological saline, water, starch, sugar, mannitol, and silica derivatives; binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethyl glycol.

[0193] As used herein, the term “effective dose” refers to the amount of medication that is effective in achieving a desired therapeutic outcome, such as the treatment of a disorder or disease, for example, a cancerous lesion or the progression of abnormal cell proliferation and / or cell division. Factors to be considered in determining the effective dose or dosage of a compound include: whether the compound or a salt thereof is administered; if used, concomitant administration of other drugs; the type of patient being treated; the patient’s size, age, sex, and overall health status; the degree or involvement or severity of the disorder; the individual patient’s response; the mode of administration; the bioavailability characteristics of the preparation being administered; the chosen administration regimen; and the use of other concomitant medications.

[0194] A treating physician, veterinarian, or other healthcare professional may determine an effective dose of the compound for the treatment of a patient requiring treatment. The pharmaceutical composition may be formulated as tablets or capsules for oral administration, as a solvent for oral administration, or as a solvent for injection. The tablets, capsules, or solvent may contain an effective dose of the compound of the present invention for the treatment of a patient requiring treatment for cancer.

[0195] As used herein, the terms “to treat,” “to cure,” or “to treat” include slowing, managing, delaying, reducing, preventing, reversing, preventing, or improving the progression or severity of an existing symptom, disorder, or condition, which may include specifically slowing the growth of a cancerous lesion or the progression of abnormal cell proliferation and / or cell division. Treatment does not necessarily mean the complete disappearance of all symptoms of the disorder or disease.

[0196] As used herein, the term “patient” refers to a mammal in need of treatment. Specifically, a patient may be a human being in need of treatment for cancer, for example, cancer with KRas G12C, G12D, and / or G12V variant protein mutations.

[0197] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "AcOH" or "HOAc" refers to acetic acid, "AIBN" refers to azobisisobutyronitrile, "Alloc" refers to an allyloxycarbonyl group, "aq." refers to aqueous solution, "atm" refers to atmospheric pressure, "Boc-Gly-OH" refers to N-(tert-butoxycarbonyl)glycine, and "BrettPhos" refers to 2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triiso "Propyl-1,1'-biphenyl" refers to propyl-1,1'-biphenyl, "BroP" refers to bromotris(dimethylamino)phosphonium hexafluorophosphate, "Cbz" refers to the benzyloxycarbonyl group, "Cbz-Cl" refers to benzyl chloroformate, "conc." indicates concentrated, "CSI" refers to chlorosulfonyl isocyanate, "CV" refers to column volume, "DCM" refers to dichloromethane, and "DIAD" refers to diisopropyl azodicarboxylate (diisopropyl "(dippf)Rh(cod)BF4" refers to [1,4-bis(diphenylphosphino)butane](1,5-cyclooctadiene)rhodium(I)tetrafluoroborate, "DMAP" refers to 4-dimethylaminopyridine, and "DMEA" refers to N,N-dimethylethylamine. "DMEM" refers to Dulbecco's modified Eagle medium, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "DNA" refers to deoxyribonucleic acid, "DPEPhosPdCl2" refers to dichlorobis(diphenylphosphinophenyl) ether palladium(II), "DTT" refers to dithiothreitol, and "EDTA" refers to ethylenediaminetetraacetic acid. "EGTA" refers to ethylene glycol-bis(b-aminoethyl ether)-N,N,N',N'-tetraacetic acid is used, "ELISA" refers to enzyme-linked immunosorbent assay. "ERK" refers to extracellular signal-regulated kinase, "siRNA" refers to ethyl acetate, "Et2O" refers to diethyl ether, "EtOH" refers to ethanol, "FA" refers to formic acid, "FBS" refers to fetal bovine serum, "Fmoc" refers to fluorenylmethyloxycarbonyl group, "GDP" refers to guanosine diphosphate, "GTP" refers to guanosine triphosphate, "h" refers to time, and "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] refers to pyridinium 3-oxide hexafluorophosphate, "Hex" or "hex" refers to hexane or hexanes, "HPLC" refers to high-performance liquid chromatography, "HRP" refers to horseradish peroxidase, and "IPA" refers to isopropyl alcohol. "(2S)-pyrrolidine-2yl]methanol refers to [(2S)-pyrrolidine-2yl]methanol, "MAPK" refers to mitogen-activated protein kinase, "mCPBA" refers to 3-chloroperoxybenzoic acid, "Me" refers to a methyl group, "MeOH" refers to methanol, "min" refers to minutes, and "methyl tert-butyl" refers to methanol. "ether, MTBE" refers to methyl tert-butyl ether, "NaBH(OAc)3" refers to sodium triacetoxyborohydride, "NaOMe" refers to sodium methoxide, "NBS" refers to N-bromosuccinimide, "NCS" refers to N-chlorosuccinimide, "N-methyl-L-prolinol" refers to [(2S)-1-methylpyrrolidine-2-yl]methanol, "NMM" refers to N-methylmorpholine, "NMP" refers to 1-methylpyrrolidine-2-one, "NIS" refers to N-iodosuccinimide, "PCR" refers to polymerase chain reaction, and "Pd-117" refers to dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II), CAS 205319-06-8 refers to "Pd-118," which refers to 1,1'-bis(di-tert-butylphosphin)ferrocenepalladium dichloride, CAS 95408-45-0, "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium(0), and "Pd(dppf)Cl2" refers to [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) is the term, "Pd(OAc)2" refers to palladium(II) acetate, "Pd(PPh3)4" refers to tetrakis(triphenylphosphine)palladium(O)", "PE" refers to petroleum ether or diethyl ether, "Ph" refers to phenyl, "RBF" refers to a round-bottom flask, "RPMI" refers to Roswell Park Memorial Laboratory, "RT" refers to room temperature, and "RuPhos" refers to 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, CAS 787618-22-8 is the reference, "sat." refers to saturated, "SCX" refers to strong cation exchange, "SelectFluor(trademark)" refers to 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate), "SPE" refers to solid-phase extraction, "SPhos" refers to 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, and "TBAF" refers to tetrabutylammonium fluoride. Fluoride) refers to, "TBDMSCl" refers to tert-butyldimethylsilyl chloride, "TBDMS" refers to the tert-butyldimethylsilyl group, "tBu" refers to the tert-butyl group, "t-BuOH" refers to tert-butanol or tert-butyl alcohol, "A" refers to triethylamine, "TES" refers to triethylsilane, "Tf2O" refers to trifluoromethanesulfonic anhydride, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "TMEDA" refers to tetramethylethylenediamine, "t, R" refers to the retention time, "XantPhos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "XPhos" refers to 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl, "XPhos Palladacycle G2" refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), CAS 1310584-14-5, "XPhos Palladacycle Gen.4" or "XPhos Pd "G4" refers to methanesulfonate(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), CAS 1599466-81-5.

[0198] Individual isomers, enantiomers, diastereomers, and atropisomers can be separated or divided at any convenient point in the synthesis of the compounds listed below by selective crystallization techniques or chiral chromatography, etc. (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions," John Wiley and Sons, Inc., 1981, and ELEliel and SHWilen, "Stereochemistry of Organic Compounds," Wiley-Interscience, 1994). The molecules described herein include 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 isolated as distinct chemical species if the energy barrier to rotation around the single bond is sufficiently high and the interconversion rate is sufficiently slow to separate the individual rotational isomers from each other. This specification is intended to include all isomers, enantiomers, diastereomers, and atropisomers that are possible with or can be produced using the compounds disclosed herein. In the molecules described herein, only those molecules for which the absolute conformation (or atropisomer conformation) of the chiral center is known use the nomenclature rules or chemical formulas depicted to indicate chirality or atropisomerism. Those skilled in the art will readily understand and identify when other chiral centers are present in the molecules described herein.

[0199] Any compound of formula I that can chemically form a salt can be readily converted to a pharmaceutically acceptable salt and isolated as such. Salt formation can occur upon addition of a pharmaceutically acceptable acid to form an acid addition salt. Salts can also be formed simultaneously upon deprotection of nitrogen or oxygen, i.e., upon removal of a protecting group. Examples of 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).

[0200] The compounds of the present invention, or salts thereof, can be prepared by various procedures, some of which are described in the following schemes, preparations, and examples. The specific synthesis steps of each described pathway may be combined in different ways, or combined with steps from different pathways, to prepare the compounds of the present invention or salts thereof. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization.

[0201] Preparation 1 5-Fluorisobenzofuran-1(3H)-one

[0202] [ka] (2-bromo-5-fluorophenyl)methanol (500 g, 2.44 mol) and TEA (474.6 mL, 3.41 mol, 1.4 equivalents) were stirred in ACN (2500 mL) to a mixture of these. Pd(OAc)2 (10.95 g, 48.77 mmol, 0.02 equivalents) and XantPhos (42.33 g, 73.16 mmol, 0.03 equivalents) were added at room temperature, and the mixture was stirred at 120 °C for 3 days under 10 atm carbon monoxide. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with H2O (1,000 mL) and then extracted with HCl (2 × 2000 mL). The combined organic layers were washed with brine (2 × 1,000 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was ground with 10:1 hexane / HCl (1,100 mL) and then filtered. The filtered cake was dried at 50°C for approximately 18 hours to obtain the title compound (300g, 81%) as a yellow solid. MS(ES)m / z=153(M+1).

[0203] Preparation 2 4-Bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one

[0204] [ka] 5-Fluorisobenzofuran-1(3H)-one (300 g, 1.97 mol) was stirred in H2SO4 (1,500 mL) and HNO3 (273.38 g, 4.348 mol, 2.2 equivalents) was added dropwise at 65°C. The reaction mixture was stirred for 1 hour and then cooled to room temperature. 1,3-Dibromo-5,5-Dimethylimidazolidin-2,4-dione (2,255.43 g, 7.88 mol, 4 equivalents) was added in small amounts over 20 minutes and stirred at room temperature for approximately 18 hours. The mixture was poured into ice / water (pre-treated with 3 kg of Na2SO3) and filtered. The filtered cake was dissolved in ELISA (3,000 mL), washed with saturated Na2CO3 aqueous solution (2 × 1,000 mL) and brine (2 × 1,000 mL), dried over anhydrous Na2SO4, and concentrated. The residue was ground with 10:1 hexane / siRNA (660 mL), filtered, and dried at 50°C for approximately 18 hours to obtain the title compound (270 g, 49%) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 5.51 (s, 2H).

[0205] Preparation 3 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran

[0206] [ka] To a stirred mixture of 4-bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one (270 g, 978 mmol) in DCM (2,500 mL), DIBAL-H (1 M THF solution, 1,467 mL, 1.467 mol, 1.5 equivalents) was added dropwise under N2 at -78°C. The reaction mixture was stirred at -78°C for 5 hours, and then quenched with 5N NaOH (300 mL) at -78°C. The resulting mixture was warmed to room temperature and then concentrated. The residue was diluted with HCl (2,500 mL), washed with brine (2 × 1,000 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue was ground with 10:1 hexane / HCl (550 mL) and filtered. The solid was dried (190 g, 683.4 mmol), then dissolved in DCM (1,500 mL), and treated with droplets of Et3SiH (662 mL, 4.10 mol, 6 equivalents) at 0°C. The reaction mixture was stirred at 0°C for 20 minutes. TFA (152 mL, 2.05 mol, 3 equivalents) was added dropwise at 0°C. The ice bath was removed, and the reaction mixture was stirred at room temperature for approximately 18 hours. The reaction mixture was concentrated to an oily substance, diluted with ELISA (2,000 mL), washed with saturated Na2CO3 aqueous solution (2 × 500 mL) and brine (2 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the title compound (110 g, 42%), which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ8.16 (d, J=6.2Hz, 1H), 5.18-5.15 (m, 2H), 5.11-5.06 (m, 2H).

[0207] Preparation 4 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine

[0208] [ka] 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (110 g, 420 mmol) and NH4Cl (112.3 g, 2.10 mol, 5 equivalents) were stirred in EtOH (1,000 mL) and H2O (200 mL). Fe (117.22 g, 2.09 mol, 5 equivalents) was added in small amounts at room temperature, and the mixture was stirred at 80°C for approximately 18 hours. The mixture was filtered and concentrated. The mixture was diluted with H2O (500 mL) and extracted with siRNA (2 × 1,000 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with silica (25%~50% siRNA / hexane) to obtain the title compound (70 g, 72%) as a yellow solid. MS(ES)m / z=231(M+1).

[0209] Preparation 5 (4-Chloro-1,2-phenylene)dimethanol

[0210] [ka] A mixture of LiAlH4 (1.9 L, 2.74 mol, 2 equivalents, 2.5 M THF solution) and THF (1 L) was stirred, and a solution of 4-chlorophthalic anhydride (250 g, 1.34 mol, 1.00 equivalent) in THF (500 mL) was added dropwise under N2 at -20°C. The resulting mixture was stirred under N2 at 45°C for 30 minutes. The reaction was quenched by adding H2O (1.5 L) and 15% NaOH (500 mL) at room temperature. The mixture was filtered, and the filter cake was washed with MTBE (3 × 250 mL). The filtrate was extracted with MTBE (3 × 1.5 L). The combined organic layers were washed with brine (2 × 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (219.5 g, 93%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ7.45-7.36(m,2H),7.28(dd,J=8.2Hz,1H),5.40-5.13(m,2H),4.54(s,2H),4.49(s,2H).

[0211] Preparation 6 5-Chloro-1,3-dihydroisobenzofuran

[0212] [ka] (4-chloro-1,2-phenylene)dimethanol (219.5 g, 1.271 mol) and dimethyl carbonate (458.2 g, 5.082 mol, 4 equivalents) were stirred in ACN (3 L) to a mixture of these, to which NaOMe (137.4 g, 2.544 mol, 2 equivalents) was added in small amounts at room temperature. The resulting mixture was stirred at 80°C under N2 for approximately 18 hours. The mixture was concentrated under reduced pressure, diluted with H2O (2 L), and extracted with SiO2 (3 × 2 L). The combined organic layers were washed with brine (2 × 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with silica (hexane / SiO2 in a 10:1-8:1 ratio) to obtain the title compound (165 g, 82%) as a light brown solid. 1 H NMR (300MHz, DMSO-d6) δ7.42-7.37 (m, 1H), 7.33 (d, J = 1.4Hz, 2H), 4.99 (s, 4H).

[0213] Preparation 7 5-Chloro-6-nitro-1,3-dihydroisobenzofuran

[0214] [ka] A solution of 5-chloro-1,3-dihydroisobenzofuran (110 g, 712 mmol) in H2SO4 (700 mL) was dropwise packed at -5°C to 0°C with a solution of KNO3 (64.74 g, 640 mmol, 0.9 equivalents) in H2SO4 (200 mL) at -5°C to 0°C. The resulting mixture was stirred at 0°C for a further 30 minutes, and then slowly added to stirred ice-cold H2O. The precipitated solid was collected by filtration and washed with H2O (3 × 1 L). The filtration cake was dried in vacuum to obtain the title compound (110 g, 77%) as a light brown solid, which was used in the next step without further purification. 1H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 7.75 (s, 1H), 5.07-5.02 (m, 4H).

[0215] Preparation 8 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran

[0216] [ka] 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (179.1 g, 626.3 mmol, 1 equivalent) was added in small amounts at -10°C to a stirred solution of 5-chloro-6-nitro-1,3-dihydroisobenzofuran (125 g, 626 mmol) in H2SO4 (700 mL). The mixture was stirred at -10°C for 1 hour, and then slowly added to stirred ice-cold H2O. The precipitated solid was collected by filtration and washed with H2O (3 × 0.5 L). The filtration cake was dried in vacuum and purified with silica (hexane / siRNA in a 10:1-5:1 ratio) to obtain the title compound (83.5 g, 47.9%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ8.07(d,J=1.1Hz,1H),5.19(dt,J=2.3,1.1Hz,2H),5.08(t,2H).

[0217] Preparation 9 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine

[0218] [ka] 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran (37.0 g, 133 mmol) and NH4Cl (42.64 g, 797.2 mmol, 6 equivalents) were stirred in EtOH (200 mL) and H2O (40 mL). Fe (44.52 g, 797.2 mmol, 6 equivalents) was added in small amounts at room temperature. The resulting mixture was stirred at 80°C for approximately 18 hours. The resulting mixture was filtered while still hot, and the filter cake was washed with siRNA (3 × 500 mL). The filtrate was concentrated under reduced pressure and purified with silica (hexane / siRNA in a 15:1-10:1 ratio) to obtain the title compound (25 g, 76%) as a pale yellow solid. MS(ES)m / z = 248 (M+1).

[0219] Preparation 10 N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamate ethyl]carbamate

[0220] [ka] To a solution of 7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (20.4 g, 87.9 mmol) in DCM (550 mL), ethoxycarbonyl isothiocyanate (9.7 mL, 82 mmol, 0.93 equivalents) was slowly packed using an additive funnel, and the mixture was stirred at room temperature for approximately 4 hours. The solid was filtered. The filtrate was concentrated and suspended in DCM (100 mL) and hexane (350 mL), and stirred at room temperature. The resulting filtered solid and the previously filtered solid were dried under vacuum at 50°C for 2 hours. The batches were combined to obtain the title compound (32.6 g, quantitatively) as a white solid. MS(ES)m / z=363(M+1).

[0221] Preparation 11 N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamate ethyl]carbamate

[0222] [ka] 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine was used in a manner similar to that of Preparation 10 to obtain the title compound (14 g, 92%) as a white solid. MS(ES)m / z=379(M+1).

[0223] Preparation 12 (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate ethyl

[0224] [ka] A 2 L three-necked RBF equipped with an overhead stirrer, dropping funnel, and thermocouple was filled with a suspension of N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamate ethyl (32.6 g, 89.8 mmol) in acetone (450 mL). Solid K2CO3 (37.2 g, 269 mmol, 3.00 equivalent) was added in several portions, followed by the dropwise addition of EtI (7.2 mL, 90 mmol, 1.0 equivalent) over 20 minutes. The mixture was stirred at room temperature for approximately 18 hours. The solid was filtered, the filtrate was concentrated, and partitioned between DCM (500 mL) and H2O (500 mL). The organic layer was further washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with silica (0-30% toluene / hexane) to obtain the title compound (30.9 g, 85.6%) as a white solid. MS(ES)m / z=391(M+1).

[0225] Preparation 13 (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate ethyl

[0226] [ka] Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamate]carbamate was used in a manner similar to that of Preparation 12 to obtain the title compound (15.4 g, crude) as a brown solid. MS(ES)m / z=407(M+1).

[0227] Preparation 14 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazolin-1-ol

[0228] [ka] A 2 L four-necked RBF was equipped with an overhead stirrer, dropping funnel, N2 inlet, and thermocouple, and purged with N2. 300 mL of anhydrous NMP was added. The mixture was heated to 175°C. In a second flask, 22.63 g, 57.83 mmol of (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate ethyl (NMP) and 100 mL of anhydrous NMP were combined and stirred under N2 until a homogeneous solution was obtained. When the first flask reached 175°C, the contents of the second flask were poured into the dropping funnel and rapidly added dropwise to the hot NMP. After 30 minutes, the heat was turned off and the reaction mixture was cooled to 45°C. 500 mL of H2O was slowly added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered, rinsed with H2O (300 mL), and dried under vacuum at 50°C for approximately 18 hours to obtain the title compound (15.2 g, 73%) as an off-white solid. MS(ES)m / z=363(M+1).

[0229] Preparation 15 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol

[0230] [ka] Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate was used in a manner similar to that of Preparation 14 to obtain the title compound (11.4 g, 86%) as a white solid. MS(ES)m / z=361(M+1).

[0231] Preparation 1B 6-Bromo-3-(ethylthio)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofl[3,4-f]quinazoline

[0232] [ka] A mixture of 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (30.1 g, 87.3 mmol) in DMF was heated to approximately 70°C to dissolve the solid, and then cooled to 40°C. Diisopropylethylamine (30.4 mL, 175 mmol) and 2-(chloromethoxyethyl)trimethylsilane (23.2 mL, 131 mmol) were added to this mixture. The reaction mixture was stirred at 40°C for 1 hour, then cooled to room temperature and extracted with water (1 L) and ethylethanol (500 mL). The layers were separated, the organic layer was washed with brine (2 × 500 mL), dried on magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound (49.2 g, purity 85%) as a yellow oil. MS(ES)m / z=475(M+1).

[0233] Preparation 1C 6-Bromo-5-chloro-3-(ethylthio)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofl[3,4-f]quinazoline

[0234] [ka] Using 6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol in a manner similar to that of Preparation 1B, the title compound (10.5 g, 96%) was obtained as a pink solid. MS(ES)m / z=491(M+1).

[0235] Preparation 16 6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazoline

[0236] [ka] A 5 L three-necked RBF equipped with a dropping funnel, thermocouple, and overhead stirrer was filled with a 1,000 mL solution of DCM (50 mL, 646 mmol, 4 equivalents) of DMF (100 mL) and placed in an ice / water bath to cool to approximately 4°C. Oxalyl chloride (50.0 mL, 576 mmol, 4 equivalents) was added dropwise using an addition funnel over approximately 40 minutes. After the addition was complete, the reaction mixture was stirred at approximately 4°C for 15 minutes. Solid 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (50.4 g, 140 mmol) was added to the reaction mixture in several portions, and the resulting suspension was stirred at approximately 4°C for 30 minutes. The ice bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Then, H2O (1 L) was added, and the mixture was stirred for 15 minutes. The mixture was partitioned, the organic layer was washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with silica eluted with DCM / hexane (60%-90%) to obtain the title compound (45.1 g, 89%) as a white solid. MS(ES)m / z=363(M+1).

[0237] Preparation 17 6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazoline

[0238] [ka] 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazolin-1-ol was used in a manner similar to that of Preparation 16 to obtain the title compound (0.81 g, 77%) as a yellow solid. MS(ES)m / z=382(M+1).

[0239] Preparation 2C 6-Bromo-3-(ethylthio)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofl[3,4-f]quinazoline

[0240] [ka] Potassium tert-butoxide (2.68 mL, 23.2 mmol) was added in three portions to a mixture of 6-bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazoline (6.50 g, 17.9 mmol) and 2-(trimethylsilyl)ethane-1-ol (3.04 mL, 21.5 mmol) in 60 mL of THF at 0°C. The mixture was stirred at room temperature. After 1 hour, the mixture was diluted with saturated ammonium chloride aqueous solution and then extracted with methyl THF (200 mL). The organic matter was dried on magnesium sulfate and concentrated under reduced pressure to obtain the crude title compound (7.5 g, 94%) as a white solid. MS(ES)m / z=445(M+1).

[0241] Preparation 18 6-Bromo-5-chloro-N-((5-ethyl-1,3,4-oxadiazole-2-yl)methyl)-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazoline-1-amine

[0242] [ka] Triethylamine (0.367 mL, 2.63 mmol) was added to a mixture of 6-bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofl[3,4-f]quinazoline (0.500 g, 1.32 mmol) and (5-ethyl-1,3,4-oxadiazole-2-yl)methanamine hydrochloride (0.280 g, 1.71 mmol) in isopropanol (20 mL). The mixture was heated at 80 °C. After 1 hour, the mixture was filtered, and the solid was washed with DCM. The filtrate was concentrated under reduced pressure, and the residue was purified with silica eluted at 60% ethyl in DCM to obtain the product. The solids from filtration and column purification were combined to obtain the title compound (0.437 g, 71%) as a white solid. MS(ES)m / z=472(M+1).

[0243] Preparation 19 6-Bromo-5-chloro-3-(ethylthio)-N-((4,5,6,7-tetrahydrobenzo[d]isoxazole-3-yl)methyl)-7,9-dihydrofl[3,4-f]quinazoline-1-amine

[0244] [ka] (4,5,6,7-tetrahydrobenzo[d]isoxazole-3-yl)methaneamine was used in a manner similar to that of Preparation 18 to obtain the title compound (0.47 g, 67%) as a white solid. MS(ES)m / z=497(M+1).

[0245] Preparation 3C (2S,3S)-3-(dimethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate tert-butyl

[0246] [ka] A mixture of (2S,3S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-3-carboxylic acid (2.00 g, 8.72 mmol), hexafluorophosphate azabenzotriazole tetramethyluranium (4.98 g, 13.1 mmol), and dimethylamine (2 M in THF; 8.72 mL, 17.5 mmol) in DCM (30 mL) was treated with diisopropylethylamine (4.56 mL, 26.2 mmol). The mixture was stirred at 25°C. After 18 hours, the mixture was concentrated under reduced pressure, and the crude residue was purified by reverse-phase purification using elution in 0-100% ACN in 0.1% formic acid in water to obtain the crude title compound (2.51 g) as a yellow oil. MS(ES) m / z = 20¹ (M+1, -tBu).

[0247] Preparation 4C (2S,3S)-2-methyl-3-(4-methylpiperazine-1-yl)pyrrolidine-1-carboxylate tert-butyl

[0248] [ka] The procedure text in this specification for the components (S)-2-methyl-3-oxopyrrolidine-1-carboxylate tert-butyl (2.20 g, 11.0 mmol), 1-methylpiperazine (1.66 g, 16.6 mmol), and acetic acid (0.63 mL, 11.0 mmol) were dissolved in DCM (15 mL), to which sodium triacetoxyborohydride (3.74 g, 17.7 mmol) was added in small amounts. The mixture was stirred at room temperature. After 28 hours, the mixture was cooled to 0°C and diluted with saturated sodium bicarbonate aqueous solution. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude title compound (3.18 g) as a yellow oil. MS(ES)m / z=284(M+1).

[0249] Preparation 5C (2S,3S)-3-(isopropylamino)-2-methylpyrrolidine-1-carboxylate tert-butyl

[0250] [ka] (2S,3S)-3-amino-2-methylpyrrolidine-1-carboxylate tert-butyl (0.500 g, 2.50 mmol), acetone (0.275 mL, 3.74 mmol), and sodium triacetoxyborohydride (1.59 mL, 7.49 mmol) were dissolved in methanol (6 mL). The mixture was heated at 50°C. After 18 hours, the mixture was cooled, concentrated under reduced pressure, and diluted with saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with toluene (3 × 50 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude title compound (0.600 g) as a colorless oil. MS(ES)m / z=243(M+1).

[0251] The compounds listed in Table 1 below were prepared in the same manner as described in Preparation 5C. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0252] Table 1: [Table 1] 1 A mixture of transpyrrolidine isomers 2 A mixture of cispirolidine isomers

[0253] Preparation 16C (2S,3S)-N-isopropyl-2-methylpyrrolidine-3-amine dihydrochloride

[0254] [ka] A mixture of (2S,3S)-3-(isopropylamino)-2-methylpyrrolidine-1-carboxylate tert-butyl (0.600 g, 2.48 mmol) in DCM (3 mL) was mixed with HCl (4 M in 1,4-dioxane; 3 mL). The mixture was stirred at room temperature. After 6 hours, the mixture was concentrated under reduced pressure to obtain the crude title compound (0.533 g) as a yellow solid. MS(ES)m / z=143(M+1).

[0255] The compounds listed in Table 2 below were prepared in the same manner as described in Preparation 16C. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0256] Table 2: [Table 2] 1 A mixture of transpyrrolidine isomers 2 A mixture of cispirolidine isomers

[0257] Preparation 29C N,N-dimethyl-1-((2S,3R)-2-methylpyrrolidine-3-yl)methaneamine

[0258] [ka] A mixture of (2S,3S)-N,N,2-trimethylpyrrolidine-3-carboxamide hydrochloride (0.80 g, 4.15 mmol) in 1,4-dioxane (15 mL) at 0°C was treated with lithium aluminum hydride (2 M in THF; 8.30 mL, 16.6 mmol). The reaction mixture was stirred at 0°C for 30 minutes, then heated at 70°C for 3 hours and at 85°C for 5 hours. The mixture was cooled to 0°C and quenched with water (6 mL), 15% NaOH aqueous solution (9 mL), and water (6 mL). The mixture was warmed to room temperature, anhydrous sodium sulfate was added, and the mixture was stirred for 30 minutes. The resulting mixture was filtered, and the filter cake was washed with EtOAC and DCM. The combined filtrate was concentrated under reduced pressure and diluted with DCM. The mixture was dried over anhydrous Na2SO4, filtered, washed with DCM, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.56 g, 95%) as a yellow oil. MS(ES)m / z=143(M+1).

[0259] Preparation 30C (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl

[0260] [ka] A solution of 1-(tert-butyl)2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (53 g, 214 mmol) in THF (100 mL) was treated with lithium chloride (20 g, 472 mmol) under nitrogen. The mixture was cooled to 0°C, and sodium borohydride (20.3 g, 536 mmol) and ethanol (200 mL) were added. The reaction mixture was stirred under nitrogen at 0°C for 1 hour and at room temperature for 48 hours. The mixture was diluted with THF (50 mL), acidified to approximately pH 4 with 10% citric acid aqueous solution, concentrated under reduced pressure, and volatiles were removed. The residual substance was diluted with water (200 mL) and extracted with DCM (3 × 200 mL). The combined organic matter was washed with brine (2 × 200 mL), dried on anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude title compound (41.4 g). MS(ES)m / z=164(M+1,-tBu).

[0261] Preparation 31C (2S,4R)-4-fluoro-2-formylpyrrolidine-1-carboxylate tert-butyl

[0262] [ka] A mixture of (2S,4R)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl (40 g, 182 mmol) in THF (150 mL) at 0°C was treated with des-martin periodinane (116 g, 274 mmol) under nitrogen. The reaction mixture was stirred under nitrogen at 0°C for 24 hours, concentrated under reduced pressure, and diluted with ethyl acetate (200 mL). The mixture was treated with saturated sodium bicarbonate aqueous solution (300 mL) and extracted with ethyl acetate (2 × 400 mL). The combined organic matter was washed with saturated sodium sulfate aqueous solution (5 × 200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified with silica eluted with 20% ethyl acetate in petroleum ether to obtain the title compound (9.6 g, 19%) as a yellow / green oil. MS(ES)m / z=162(M+1,-tBu).

[0263] Preparation 32C (2S,4R)-2-formyl-4-methoxypyrrolidine-1-carboxylate tert-butyl

[0264] [ka] A mixture of 1-(tert-butyl)2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (18 g, 69.4 mmol) in DCM (400 mL) at -78°C was treated by dropwise addition of diisobutylaluminum hydride (1 M in DCM; 146 mL, 146 mmol). The reaction mixture was stirred at -78°C for 3 hours, diluted with MeOH (30 mL), slowly added to saturated potassium sodium tartrate aqueous solution (500 mL) at 0°C, stirred for 3 hours, and extracted with DCM (3 × 400 mL). The combined organic matter was filtered and concentrated under reduced pressure. The residue was purified with silica eluted with 40-50% ethylethanol in petroleum ether to obtain the title compound (10.3 g, 65%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ9.38(dd,1H),4.08-3.96(m,1H),3.94(dq,1H),3.52-3.36(m,2H),3.23 (s,3H),2.21-2.08(m,1H),2.01-1.87(m,1H),1.38(d,9H).

[0265] Preparation 33C (2S,4R)-4-fluoro-2-((S)-1-hydroxyethyl)pyrrolidine-1-carboxylate tert-butyl

[0266] [ka] A solution of (2S,4R)-4-fluoro-2-formylpyrrolidine-1-carboxylate tert-butyl (9.4 g, 43.3 mmol) in THF (50 mL) at -65°C was treated with methylmagnesium bromide (3 M in THF; 43.3 mL, 130 mmol). The reaction mixture was stirred overnight at room temperature, then cooled to 0°C and diluted with saturated ammonium chloride aqueous solution (5 mL). The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic matter was washed with brine (2 × 100 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase purification using elution with 15-45% ACN in (water; 10 mM ammonium bicarbonate containing 0.05% ammonium hydroxide) to obtain the racemic title compound (4.1 g, 37%) as a white oil. MS(ES)m / z = 178(M+1, -tBu).

[0267] Chiral separation was performed using a chiral SFC ((S,S)-Whelk-O1), 30 × 250 mm, 10% (1:2EtOH:hexane) in CO2, 90 mL / min, and the title compound was obtained as the second elution fraction (1.4 g, white oily substance after lyophilization). MS(ES) m / z = 178 (M+1, -tBu). Note that the desired target was the first elution peak in silica gel column chromatography using 5:1DCM:MTBE (see references).

[0268] The compounds listed in Table 3 below were prepared in the same manner as described in Preparation 33C. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0269] Table 3: [Table 3] 1 Chiral SFC; Phenomenex Lux Cellulose-2, 50 x 250 mm, 25% EtOH in CO2, 200 mL / min, isomer 2; 1H NMR (400MHz, DMSO-d6) δ4.65(d,1H), 3.95-3.81(m,3H), 3.53(d,1H), 3.18(s,4H), 2.04-1.80(m,2H), 1.39(s,9H), 0.92(d,3H).

[0270] Preparation 35C (S)-1-((2S,4R)-4-fluoro-1-methylpyrrolidine-2-yl)ethane-1-ol

[0271] [ka] A mixture of (2S,4R)-4-fluoro-2-((S)-1-hydroxyethyl)pyrrolidine-1-carboxylate tert-butyl (1.3 g, 5.57 mmol) in 20 mL of THF at 0°C was treated with lithium aluminum hydride (1 M in THF; 16.7 mL, 16.7 mmol). The reaction mixture was stirred at room temperature for 1 hour, then heated at 60°C for 16 hours. The mixture was cooled to 0°C and quenched with water (0.6 mL), 10 M NaOH aqueous solution (0.6 mL), and water (1.8 mL). The resulting mixture was filtered, and the filter cake was washed with THF (3 × 10 mL). The combined filtrate was concentrated under reduced pressure to obtain the crude title compound (0.53 g). MS(ES) m / z = 148 (M+1).

[0272] The compounds listed in Table 4 below were prepared in the same manner as described in Preparation 35C. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0273] Table 4: [Table 4] 1 1 H NMR(300MHz,DMSO-d6)δ4.42(s,1H),3.74(dtd,1H),3.61(p,1H),3.24-3.13(m ,4H),2.36(td,1H),2.28(s,3H),2.11(dd,1H),1.77-1.55(m,2H),0.95(d,3H).

[0274] Preparation 1A (1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol

[0275] [ka] 1-(methoxycarbonyl)cyclopropane-1-carboxylic acid (1.69 g, 11.4 mmol), oxalyl chloride (1.1 mL, 12.0 mmol), DCM (30 mL), and DMF (0.05 mL) were combined under nitrogen and stirred at room temperature for 40 minutes.

[0276] (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (1.64 g, 12.1 mmol) and triethylamine (7.5 mL, 54 mmol) were added to the crude acid chloride mixture. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was dissolved in toluene (40 mL) and water (10 mL). The layers were separated, and the organic layers were washed with aqueous KHSO4 solution (1 M, 10 mL), saturated aqueous NaHCO3 solution (10 mL), and brine (10 mL). The organic matter was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)cyclopropane-1-carboxylate methyl (1.34 g, 50%).

[0277] Crude methyl ester was mixed with THF (19 mL) and cooled to 0°C. Lithium aluminum hydride (2.3 M, 8.5 mL, 20.0 mmol in 2-MeTHF) was added dropwise, the mixture was stirred for 30 minutes, and then warmed to room temperature. After 3 hours, the reaction mixture was quenched with sodium sulfate decahydrate (until foaming stopped), diluted with THF, and filtered. The solid was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to obtain the title compound (1.00 g, 91%) as a colorless oil without further purification. MS(ES)m / z=184(M+1).

[0278] Preparation 2A (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl

[0279] [ka] Ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate. A solution of 2-(4-chloro-5-fluoropyridine-3-yl)acetonitrile (11.8 g, 56.1 mmol) in DMF (112 mL) was cooled to 0°C. Potassium tert-butoxide (7.00 g, 61.1 mmol) was added. After 15 minutes, ethoxycarbonyl isothiocyanate (7.45 mL, 61.8 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature overnight. The reaction mixture was poured into an ice / water mixture (1.5 L), stirred until all the ice had melted, and filtered through diatomaceous earth. The solid was dried overnight in a vacuum oven (60°C) and separated from the diatomaceous earth to obtain ethyl N-(3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (11.9 g, 79%) as a solid. MS(ES)m / z=266(M+1).

[0280] 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile. A suspension of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (11.9 g, 44.4 mmol) in DMSO (90 mL) was cooled to 0°C. NaOH (5 M aqueous solution, 90 mL) was added dropwise over 15 minutes. The reaction mixture was heated to 105°C over 1 hour, and then cooled to room temperature. The reaction mixture was poured into an ice / water mixture (1.8 L), stirred until all the ice had melted, and filtered through diatomaceous earth. The solid was dried overnight in a vacuum oven (50°C) and separated from the diatomaceous earth to obtain crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile.

[0281] (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl. A mixture of crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (8.6 g, 44.4 mmol), DCM (90 mL), DMF (90 mL), and N,N-diisopropylethylamine (15.5 mL, 88.9 mmol) was cooled to 0°C. 4-dimethylaminopyridine (0.54 g, 4.42 mmol) and di-tert-butyl dicarbonate (14.6 g, 66.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the remaining substance was diluted with DCM (400 mL) and 5% citric acid aqueous solution (250 mL). The aqueous phase was washed twice with DCM. The combined organic phases were washed with saturated NaHCO3 aqueous solution, dried over MgSO4, filtered, and concentrated to obtain tert-butyl N-(3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate (7.5 g, 58%) as a brown solid. MS(ES)m / z = 294(M+1).

[0282] 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide. 3-chloroperoxybenzoic acid (9.00 g, 40.2 mmol) was added to a solution of (3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl (7.85 g, 26.8 mmol) in DCM (180 mL). The reaction mixture was stirred overnight at room temperature, then cooled to 0°C over approximately 15 minutes. The solid was collected by filtration and dried in a vacuum oven (60°C). The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified with silica eluted with 0-6% MeOH / DCM. The fraction containing the desired substance was combined with the solid obtained by filtration and concentrated to obtain tert-butyl N-(3-cyano-7-fluoro-5-oxide-thieno[3,2-c]pyridine-5-ium-2-yl)carbamate (7.26 g, 88%) as an off-white solid. MS(ES)m / z=310(M+1).

[0283] (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl. A suspension of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (5.27 g, 17.0 mmol) in 1,2-dichloroethane (34 mL) was cooled to 0°C. A solution of phosphoryl chloride (32 mL, 344 mmol) in 1,2-dichloroethane (34 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, then stirred at 45°C for 90 minutes, and cooled to room temperature. The reaction mixture was diluted with 1,2-dichloroethane (100 mL) and added to a mixture of saturated NaHCO3 aqueous solution (500 mL), NaOH (5M aqueous solution, 40 mL), and ice. Solid NaHCO3 was added to the stirred mixture to maintain a pH of approximately 6-7. The phases were separated once foaming ceased. The aqueous phase was extracted three times with DCM. The combined organic phases were dried over MgSO4 and filtered. The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified with silica eluted with 50-100% DCM / hexane. The fraction containing the desired substance was concentrated to obtain the title compound (3.87 g, 69%) as a white solid. MS(ES)m / z=328(M+1).

[0284] Preparation 3A 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylate methyl

[0285] [ka] N2 was passed through a 5 mL THF solution of methyl thioglycolate (0.18 mL, 2.0 mmol, 1 equivalent) and filled with a 60% NaH mineral oil (0.101 g, 2.53 mmol, 1.24 equivalents) solution at room temperature. Gas generation was observed and a precipitate formed in the flask. The reaction mixture was stirred at room temperature for 20 minutes. A 5 mL THF solution of 2-bromo-3,6-difluorobenzaldehyde (0.475 g, 2.04 mmol) was slowly added via syringe over approximately 2 minutes. The reaction mixture was stirred at room temperature for 9 hours. Additional methyl thioglycolate (0.1 mL, 1 mmol, 0.5 equivalents) and a 60% sodium hydride mineral oil (0.050 g, 1.3 mmol, 0.6 equivalents) solution were added, and stirring was continued at room temperature for approximately 18 hours. The mixture was diluted with siRNA and washed with saturated NH4Cl aqueous solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified with silica eluted with 2% MTBE / hexane to obtain the title compound (0.346 g, 59%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.23-8.19 (dd, J = 4.49, 8.9 Hz, 1H), 8.05 (s, 1H), 7.62 (t, J = 9.0Hz, 1H), 3.93 (s, 3H).

[0286] Preparation 4A 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid

[0287] [ka] A solution of methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate (19.2 g, 66.4 mmol, 1 equivalent) in MeOH (130 mL) and THF (130 mL) was filled with 5N NaOH (66 mL, 330 mmol, 5 equivalents) and stirred at room temperature for 40 minutes. The mixture was concentrated and H2O (500 mL) was added. The pH was adjusted to approximately 2 with 5N HCl. The mixture was extracted with Depositphotos (2 × 500 mL), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The solid was dried under vacuum at 50°C to obtain the title compound (17.6 g, 96%) as a white solid. MS(ES)m / z=229(M-1-CO2).

[0288] Preparation 5A (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl

[0289] [ka] A solution of 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid (1.5 g, 5.5 mmol) in t-butanol (30 mL) was filled with TEA (1.5 mL, 11 mmol, 2.0 equivalents) and diphenyl phosphoryl azide (1.5 mL, 6.9 mmol, 1.3 equivalents), and the mixture was heated at 95 °C for 1 hour. The mixture was cooled and concentrated. The residue was purified with silica eluted with MTBE / hexane (4%~20%) to obtain the title compound (0.987 g, 52%) as a white solid. MS(ES)m / z=290(M+1).

[0290] Preparation 6A (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl

[0291] [ka] A mixture of tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (3.08 g, 8.90 mmol), bis(neopentyl glycolate)diboron (4.02 g, 17.8 mmol, 2 equivalents), and KOAc (2.62 g, 26.7 mmol, 3 equivalents) in 1,4-dioxane (70 mL, 819.9 mmol) was sparged with N2 for 20 minutes. Pd(ddpf)Cl2 (0.69 g, 0.90 mmol, 0.1 equivalent) was added to the mixture. The reaction mixture was sonicated for 3 minutes, then subjected to a vacuum / N2 refill cycle (3 times) and heated at 100°C for 3 hours. The mixture was cooled to room temperature, filtered through diatomaceous earth, and rinsed with 1:4 siRNA / hexane. The filtrate was concentrated, and the residue was purified with silica (0-40% MTBE / hexane) to obtain the title compound (2.95 g, 87%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ10.81-10.79(bs,1H),7.84-7.74(dd,J=5.07,8.59,1 H),7.14(s,1H),6.94-6.88(m,1H),3.89(bs,4H),1.49(s,10H),1.03(s,6H).

[0292] Preparation 20 (3-Cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0293] [ka] 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (0.80 g, 2.32 mmol), (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (1.12 g, 2.78 mmol), and cesium carbonate (2.27 g, 6.95 mmol) were combined in DMF (12 mL), and the mixture was degassed by sparging with argon for 10 minutes. Dichloro[bis(2-(diphenylphosphino)phenyl) ether]palladium(II) (Pd-117, 0.166 g, 0.232 mmol) was added, and the mixture was heated to 100 °C. After 24 hours, the mixture was concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% MeOH in DCM to obtain the title compound (0.96 g, 74%) as a yellow solid. MS(ES)m / z=557(M+1).

[0294] The compounds listed in Table 5 below were prepared in the same manner as described in Preparation 20. The compounds were purified using various methods that would be obvious to those skilled in the art.

[0295] Table 5: [Table 5-1]

[0296] [Table 5-2] 1 Preparative chiral HPLC; Phenomenex Lux Cellulose-5, 30 x 150 mm, 18-30% heptane (1:1 MeOH:EtOH), 42.5 mL / min 2 Chiral SFC; Chiralpak-IC, 50 x 250 mm, 25% in CO2 (MeOH containing 0.2% dimethylethylamine), 300 g / min

[0297] Preparation 9A (3-Cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0298] [ka] A mixture of (4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (0.750 g, 1.41 mmol) and acetonitrile (10 mL) was stirred at -40°C. Slowly, sulfur isocyanatidic acid chloride (0.184 mL, 2.12 mmol) was added, and the mixture was heated to 0°C. After the starting material was consumed (monitored by LC-MS), the mixture was cooled to 0°C. DMF (4 mL) was slowly added. Once the reaction was complete (monitored by LC-MS), the mixture was diluted with DCM (20 mL) and saturated ammonium chloride aqueous solution (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 × 30 mL). The combined extracts were passed through a hydrophobic frit and concentrated under reduced pressure to obtain the crude title compound. MS(ES)m / z=557(M+1).

[0299] Preparation 3B (3-Cyano-4-(3-(ethylthio)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0300] [ka] (4-(3-(ethylthio)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl, atrop isomer 1 was used in a manner similar to that of Preparation 9A to obtain the title compound (19.2 g, purity 87%, 94%) as a white solid. MS(ES)m / z=687(M+1). Pure atrop isomer from Preparation 2B, chiral purification.

[0301] Preparation 39C (4-(5-chloro-3-(ethylthio)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0302] [ka] (4-(5-chloro-3-(ethylthio)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 9A to obtain the crude title compound (13.6 g) as a yellow solid. MS(ES)m / z=703(M+1).

[0303] Preparation 4B (3-Cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0304] [ka] To a mixture of (3-cyano-4-(3-(ethylthio)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (19.2 g, 26.3 mmol) in THF (192 mL), activated molecular sieve (4 angstroms, 38 g), followed by tetrabutylammonium fluoride (1 M in THF, 105 mL, 105 mmol). The reaction mixture was heated in a bath at 80°C for 9 hours and then cooled to room temperature. Additional activated molecular sieve (4 angstroms, 17 g) was added, and the reaction mixture was heated overnight in a bath at 80°C and then cooled to room temperature. The mixture was filtered, and the filtered cake was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure, diluted with 2-methyltetrahydrofuran (300 mL), and washed with water (3 × 300 mL). The combined aqueous layer was extracted with 2-methyltetrahydrofuran (300 mL). The combined organic layer was washed with 5% citric acid aqueous solution (300 mL), dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified with silica eluted with 0-60% ethyl acetate in cyclohexane to obtain the title compound (9.42 g) as a yellow foam. MS(ES) m / z = 557 (M+1). Pure atropisomer and chiral purification from preparation 2B.

[0305] Preparation 40C (4-(5-chloro-3-(ethylthio)-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0306] [ka] (4-(5-chloro-3-(ethylthio)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 4B to obtain the crude title compound (4.0 g) as a yellow solid. MS(ES)m / z=573(M+1).

[0307] The compounds listed in Table 6 below were prepared in the same manner as described in Preparation 16. The compounds were purified using various methods that would be obvious to those skilled in the art.

[0308] Table 6: [Table 6] 1 Pure atropisomers and chiral purification from preparation 7A

[0309] Preparation 5B 6-Bromo-1-chloro-3-(ethylsulfinyl)-5-fluoro-7,9-dihydrofl[3,4-f]quinazoline

[0310] [ka] To a mixture of 6-bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofl[3,4-f]quinazoline (2 g, 6 mmol) in 30 mL of DCM at 0°C, potassium peroxobisulfate (0.7 M in water; 8 mL, 6 mmol) was added. The resulting mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred overnight. Water and DCM were added, and the layers were separated. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound (1.48 g, approximately 55:45 sulfoxide:sulfone). MS(ES)m / z=379(M+1).

[0311] The compounds listed in Table 7 below were prepared in the same manner as described in Preparation 18. The compounds were purified using various methods that would be obvious to those skilled in the art.

[0312] Table 7: [Table 7-1]

[0313] [Table 7-2]

[0314] [Table 7-3]

[0315] [Table 7-4] 1 Pure atropisomers and chiral purification from preparation 7A

[0316] Preparation 24 (4-(5-chloro-3-(ethylthio)-1-((1-isopropyl-1H-1,2,3-triazole-4-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0317] [ka] A mixture of 1,4-dioxane (10 mL), 4-5-chloro-3-(ethylthio)-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (0.120 g, 0.209 mmol), (1-isopropyl-1,2,3-triazole-4-yl)methanol (0.059 g, 0.418 mmol), bromotriisopropylphosphonium hexafluorophosphate (0.161 g, 0.418 mmol), and 1,8-diazabicyclo(5.4.0)undeca-7-ene (0.159 g, 1.05 mmol) was stirred at 80°C under nitrogen. After 4 hours, the mixture was diluted with DCM (50 mL) and concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% MeOH in DCM to obtain the title compound (0.110 g, 75%) as an off-white solid. MS(ES)m / z=696(M+1).

[0318] Preparation 45C (4-(5-chloro-3-(ethylthio)-1-((pyridazin-3-ylmethyl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0319] [ka] To a stirred solution of (4-(5-chloro-3-(ethylthio)-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (4.0 g, 6.98 mmol) and bromotris(dimethylamino)phosphanium (8.13 g, 20.9 mmol) in acetonitrile (150 mL), diisopropylethylamine (4.51 g, 34.9 mmol) was added dropwise at room temperature under nitrogen. The mixture was stirred under nitrogen at 50°C for 2 hours, then concentrated under reduced pressure and diluted with water (100 mL). The mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase purification using elution with 50-100% ACN in water (containing 0.1% ammonium hydroxide) to obtain the title compound (3.7 g) as a yellow solid. MS(ES)m / z=664(M+1).

[0320] Preparation 46C (4-(5-chloro-3-(ethylsulfinyl)-1-((pyridazin-3-ylmethyl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0321] [ka] A solution of (4-(5-chloro-3-(ethylthio)-1-((pyridazine-3-ylmethyl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (1.20 g, 1.81 mmol) and oxone (0.608 g, 3.62 mmol) in 4:1 dioxane:water (60 mL) was stirred at room temperature under nitrogen for 1 hour, then concentrated under reduced pressure and diluted with water (200 mL). The mixture was extracted with ELISA (2 × 100 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude title compound (1.13 g) as a yellow solid. MS(ES) m / z = 680 (M+1).

[0322] Preparation 22A 6-Bromo-3-(ethylsulfinyl)-5-fluoro-7,9-dihydrofl[3,4-f]quinazolin-1-ol

[0323] [ka] A mixture of 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (18.03 g, purity 87%, 45.44 mmol) in DCM (450 mL) and EtOH (450 mL) was to which a solution of hexaammonium heptamolybdate tetrahydrate (2.05 g, 1.76 mmol) in water (approximately 5 mL) was added. Hydrogen peroxide (20 mL, 35% by weight, 230 mmol) was added dropwise over 10-15 minutes (using a water bath to maintain the internal temperature at approximately 16°C). After 24 hours, an additional hydrogen peroxide (10 mL, 35% by weight, 110 mmol) was added dropwise. After 3 days, water (60 mL) was added, and the mixture was concentrated under reduced pressure to remove most of the DCM. The resulting suspension was filtered, washed with water (2 × 200 mL), washed with EtOH (2 × 200 mL), and dried in a vacuum oven (40°C) to obtain the title compound (16.2 g, 82%, approximately 87:13 sulfoxide:sulfone) as an off-white solid. MS(ES)m / z=361,363(M+1,Br).

[0324] Preparation 12B (3-Cyano-4-(3-(ethylsulfonyl)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl

[0325] [ka] (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 22A to obtain the title compound (6.6 g, 91%, approximately 14:86 sulfoxide:sulfone) as a white solid. MS(ES)m / z=589(M+1). Pure atropisomer from Preparation 2B, chiral purification.

[0326] Preparation 25 (4-(5-chloro-3-(ethylsulfonyl)-1-((1-isopropyl-1H-1,2,3-triazole-4-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0327] [ka] A mixture of (4-(5-chloro-3-(ethylthio)-1-((1-isopropyl-1H-1,2,3-triazole-4-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (0.100 g, 0.144 mmol) and mCPBA (0.062 g, 0.360 mmol) in DCM (10 mL) was stirred at room temperature under nitrogen. After 2 hours, the mixture was diluted with water (30 mL) and extracted with DCM (3 × 50 mL). The combined organic matter was concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% MeOH in DCM to obtain the title compound (0.090 g, 86%) as a white solid. MS(ES)m / z=728(M+1).

[0328] The compounds listed in Table 8 below were prepared in the same manner as described in Preparation 25. The compounds were purified using various methods that would be obvious to those skilled in the art.

[0329] Table 8: [Table 8-1]

[0330] [Table 8-2]

[0331] [Table 8-3]

[0332] [Table 8-4]

[0333] [Table 8-5] 1 Pure atropisomers and chiral purification from preparation 7A

[0334] Preparation 30 (4-(5-chloro-1-((1-isopropyl-1H-1,2,3-triazole-4-yl)methoxy)-3-(((S)-1-methylpyrrolidine-2-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0335] [ka] To a solution of (S)-(1-methylpyrrolidine-2-yl)methanol (0.038 g, 0.33 mmol) in THF (6 mL) at 0°C, lithium bis(trimethylsilyl)amide (1 M in THF, 0.27 mL, 0.27 mmol) was added under nitrogen at 0°C. After 10 minutes, a solution of (4-(5-chloro-3-(ethylsulfonyl)-1-((1-isopropyl-1H-1,2,3-triazole-4-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (0.080 g, 0.11 mmol) in THF (3 mL) was added dropwise. The mixture was warmed to room temperature. After 4 hours, the reaction mixture was diluted with water (20 mL) and extracted with DCM (4 × 50 mL). The combined organic matter was concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% MeOH in DCM to obtain the title compound (0.080 g, 97%) as a white solid. MS(ES)m / z = 749 (M+1).

[0336] The compounds listed in Table 9 below were prepared in the same manner as described in Preparation 30. The compounds were purified using various methods that would be obvious to those skilled in the art.

[0337] Table 9: [Table 9-1]

[0338] [Table 9-2]

[0339] [Table 9-3]

[0340] [Table 9-4]

[0341] [Table 9-5] 1 Pure atropisomers and chiral purification from preparation 7A

[0342] Preparation 39A (4-(5-chloro-3-((S)-3-(dimethylamino)pyrrolidine-1-yl)-1-(((5-ethyl-1,3,4-oxadiazole-2-yl)methyl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0343] [ka] (4-(5-chloro-1-(((5-ethyl-1,3,4-oxadiazole-2-yl)methyl)amino)-3-(ethylsulfonyl)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (0.065 g, 0.091 mmol) was mixed with diisopropylethylamine (0.32 mL, 1.8 mmol), (S)-N,N-dimethylpyrrolidine-3-amine (0.052 g, 0.46 mmol), and acetonitrile (2 mL). The reaction mixture was heated to 70°C. After 3 hours, the mixture was concentrated under reduced pressure. The residue was purified with silica eluted with 0-40% MeOH in DCM to obtain the title compound (0.050 g, 75%) as a pale yellow solid. MS(ES)m / z = 734(M+1).

[0344] The compounds listed in Table 10 below were prepared in the same manner as described in Preparation 39A. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0345] Table 10: [Table 10-1]

[0346] [Table 10-2]

[0347] [Table 10-3]

[0348] [Table 10-4]

[0349] [Table 10-5]

[0350] [Table 10-6]

[0351] [Table 10-7]

[0352] [Table 10-8] 1 Pure atropisomer and chiral purification from preparation 2B 2 Pure atropisomers and chiral purification from preparation 7A 3 A mixture of transpyrrolidine isomers 4 A mixture of cispirolidine isomers

[0353] Preparation 47A 6-Bromo-1-chloro-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazoline

[0354] [ka] A mixture of N-(chloromethylene)-N-methylmethaneaminium chloride (6.0 g, 50 mmol) in DCM (80 mL) was cooled to 0°C under nitrogen. 6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (5.0 g, 10 mmol) was added gradually over 2 minutes. After stirring at 0°C for 5 minutes, the reaction mixture was warmed to room temperature. After 18 hours, the mixture was filtered. The solid was washed with water, washed with DCM, and dried under reduced pressure. The solid was dissolved in DCM and cooled to 0°C. N-(chloromethylene)-N-methylmethaneaminium chloride (3.0 g, 20 mmol) was added gradually over 2 minutes. After stirring at 0°C for 5 minutes, the reaction mixture was warmed to room temperature. After 18 hours, the mixture was quenched with ice / water (100 mL) and then filtered. The solid was washed with water and dried under reduced pressure to obtain the title compound (0.050 g, 75%) as a white solid. MS(ES)m / z=460(M+1).

[0355] The compounds listed in Table 11 below were prepared in the same manner as described in Preparation 47A. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0356] Table 11: [Table 11] 1 Pure atropisomer and chiral purification from preparation 2B

[0357] Preparation 36B 1-(1-(((6-bromo-1-chloro-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazoline-3-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethaneamine

[0358] [ka] To a mixture of 6-bromo-3-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-1-ol (1.5 g, 3.64 mmol) and diisopropylethylamine (1.90 mL, 10.9 mmol) in toluene (25 mL), POCl3 (1.02 mL, 10.9 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 110 °C for 1 hour, then concentrated under reduced pressure and diluted with ELISA (300 mL). The resulting mixture was washed with saturated aqueous NaHCO3 (100 mL), water (2 × 100 mL), and brine (100 mL), then dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (1.2 g). MS(ES)m / z=430(M+1).

[0359] The compounds listed in Table 12 below were prepared in the same manner as described in Preparation 18. The compounds were purified using various methods that would be obvious to those skilled in the art.

[0360] Table 12: [Table 12-1]

[0361] [Table 12-2]

[0362] [Table 12-3]

[0363] [Table 12-4]

[0364] [Table 12-5] 1 Pure atropisomer and chiral purification from preparation 2B

[0365] Preparation 51A 5-(6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-1-yl)amino)methyl)-3-cyclopropyl-1H-1,2,4-triazole-1-carboxylate tert-butyl

[0366] [ka] Triethylamine (0.175 mL, 1.26 mL) and 4-dimethylaminopyridine (0.0077 g, 0.063 mmol) were added to a mixture of 6-bromo-N-((3-cyclopropyl-1H-1,2,4-triazole-5-yl)methyl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazoline-1-amine (0.35 g, 0.63 mmol) and di-tert-butyl dicarbonate (0.27 g, 1.26 mmol) under nitrogen. The mixture was stirred at room temperature. After 2 hours, the mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified with silica eluted with MeOH treated with 0-10% ammonia in DCM to obtain the title compound (0.19 g, 46%, mixture of Boc-triazole isomers) as a white solid. MS(ES)m / z=662(M+1).

[0367] The compounds listed in Table 13 below were prepared in the same manner as described in Preparation 51A. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0368] Table 13: [Table 13]

[0369] Preparation 52A 5-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine-4-yl)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-1-yl)amino)methyl)-3-cyclopropyl-1H-1,2,4-triazole-1-carboxylate tert-butyl

[0370] [ka] Under nitrogen, the mixture was evenly divided into five reaction vials and 5-(((6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-1-yl)amino)methyl)-3-cyclopropyl-1H-1,2,4-triazole-1-carboxylate tert-butyl (0.25 g, 0.38 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (0.17 g, 0.76 mmol), potassium acetate (0.11 g, 1.13 mmol), Pd-117 (CAS#205319-06-8; 0.054 g, 0.076 mmol), and toluene (4.7 mL) were added. Each reaction mixture was purged with nitrogen and stirred at 90°C. After 30 minutes, each was diluted with DCM, filtered through diatomaceous earth, and concentrated under reduced pressure to obtain (1-(((1-tert-butoxycarbonyl)-3-cyclopropyl-1H-1,2,4-triazole-5-yl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)boronic acid in a new reaction vial. MS(ES)m / z=628(M+1).

[0371] The crude (1-(((1-tert-butoxycarbonyl)-3-cyclopropyl-1H-1,2,4-triazole-5-yl)methyl)amino)-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)boronic acid is equally divided into five reaction vials, and (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl) 0.124 g, 0.38 mmol) tert-butyl carbamate, [2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl] (0.036 g, 0.076 mmol), chloro(clotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) (0.051 g, 0.076 mmol), toluene (12.6 mL), and 1,4-dioxane (3.15 mL) were added. The mixtures were divided equally under nitrogen, and solutions of dipotassium hydrogen phosphate (1 M in water, 1.13 mL, 1.13 mmol) and water (1.70 mL) were added dropwise. Each reaction mixture was stirred at 90°C. After 40 minutes, each was diluted with DCM / MeOH. The mixtures were combined, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was purified with silica eluted with 0-10% ammonia-treated MeOH in DCM to obtain the title compound (0.21 g). MS(ES)m / z=875(M+1).

[0372] The compounds listed in Table 14 below were prepared in the same manner as described in Preparation 52A. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0373] Table 14: [Table 14-1]

[0374] [Table 14-2]

[0375] [Table 14-3]

[0376] [Table 14-4]

[0377] Preparation 81C (3-Cyano-4-(3-(ethylsulfonyl)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl)tert-butyl carbamate

[0378] [ka] (3-cyano-4-(3-(ethylthio)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 25 to obtain the crude title compound (1.05 g) as a yellow solid. MS(ES)m / z=720(M+1).

[0379] Preparation 82C (3-Cyano-4-(3-(ethylsulfonyl)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl) tert-butyl carbamate

[0380] [ka] (3-cyano-4-(3-(ethylthio)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 22A to obtain the crude title compound (4.2 g, 70%) as a yellow solid. MS(ES)m / z=690(M+1).

[0381] Preparation 83C (3-Cyano-7-Fluoro-4-(5-Fluoro-3-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-Dihydrofluoro[3,4-f]Quinazolin-6-yl)Thieno[3.2-c]Pyridine-2-yl)Tert-butyl Carbamate

[0382] [ka] (3-cyano-4-(3-(ethylsulfonyl)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl and (S)-1-((S)-1-methylpyrrolidine-2-yl)ethane-1-ol were used in a manner similar to that of Preparation 30 to obtain the title compound (0.60 g, 52%) as a yellow solid. MS(ES)m / z=755(M+1).

[0383] Preparation 84C (3-Cyano-7-Fluoro-4-(5-Fluoro-3-((S)-1-((2S,4R)-4-Fluoro-1-methylpyrrolidine-2-yl)ethoxy)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-Dihydrofluoro[3,4-f]Quinazolin-6-yl)Thieno[3.2-c]Pyridine-2-yl)Tert-butyl Carbamate

[0384] [ka] (3-cyano-4-(3-(ethylsulfonyl)-5-fluoro-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl and (S)-1-((2S,4R)-4-fluoro-1-methylpyrrolidine-2-yl)ethane-1-ol were used in a manner similar to that of Preparation 30 to obtain the title compound (0.37 g, 60%) as a white solid. MS(ES)m / z=773(M+1).

[0385] Preparation 85C (3-Cyano-4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl) tert-butyl carbamate

[0386] [ka] (3-cyano-4-(3-(ethylsulfonyl)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl and (2S,3S)-N,N,2-trimethylpyrrolidine-3-amine dihydrochloride were used in a manner similar to that of Preparation 39A to obtain the title compound (1.9 g, 60%) as a yellow solid. MS(ES)m / z=724(M+1).

[0387] Preparation 86C (3-Cyano-7-Fluoro-4-(5-Fluoro-1-Hydroxy-3-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-7,9-Dihydrofluoro[3,4-f]Quinazolin-6-yl)Thieno[3,2-c]Pyridine-2-yl)Tert-butyl Carbamate

[0388] [ka] (3-cyano-7-fluoro-4-(5-fluoro-3-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 4B to obtain the title compound (0.38 g, 75%) as a yellow solid. MS(ES)m / z=625(M+1).

[0389] Preparation 87C (4-(5-chloro-1-hydroxy-3-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl

[0390] [ka] (4-(5-chloro-3-((S)-1-((S)-1-methylpyrrolidine-2-yl)ethoxy)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 4B to obtain the title compound (2.0 g, 73%) as a yellow solid. MS(ES)m / z=640(M+1).

[0391] Preparation 88C (4-(5-chloro-1-hydroxy-3-((S)-1-((2S,4R)-4-methoxy-1-methylpyrrolidine-2-yl)ethoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl) tert-butyl carbamate

[0392] [ka] (4-(5-chloro-3-((S)-1-((2S,4R)-4-methoxy-1-methylpyrrolidine-2-yl)ethoxy)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 4B to obtain the title compound (0.40 g, 68%) as a yellow solid. MS(ES)m / z=669(M+1).

[0393] Preparation 89C (3-Cyano-7-Fluoro-4-(5-Fluoro-3-((S)-1-((2S,4R)-4-Fluoro-1-methylpyrrolidine-2-yl)ethoxy)-1-Hydroxy-7,9-Dihydrofluoro[3,4-f]Quinazolin-6-yl)Thieno[3.2-c]Pyridine-2-yl)Tert-butyl Carbamate

[0394] [ka] (3-cyano-7-fluoro-4-(5-fluoro-3-((S)-1-((2S,4R)-4-fluoro-1-methylpyrrolidine-2-yl)ethoxy)-1-((2-(trimethylsilyl)ethoxy)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 4B to obtain the title compound (0.11 g, 33%) as a yellow solid. MS(ES)m / z=643(M+1).

[0395] Preparation 90C (3-Cyano-4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl) tert-butyl carbamate

[0396] [ka] (3-cyano-4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1-(2-(trimethylsilyl)ethoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 4B to obtain the title compound (1.4 g, 86%) as a yellow solid. MS(ES)m / z=624(M+1).

[0397] Preparation 91C (4-(1-chloro-3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl) tert-butyl carbamate

[0398] [ka] (3-cyano-4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 47A to obtain the title compound (0.55 g, 100%) as a yellow solid. MS(ES)m / z=642(M+1).

[0399] Preparation 92C (3-Cyano-4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1-((pyridazin-3-ylmethyl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl) tert-butyl carbamate

[0400] [ka] (4-(1-chloro-3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl and pyridazine-3-ylmethaneamine dihydrochloride were used in a manner similar to that of Preparation 18 to obtain the crude title compound (0.30 g, 100%) as a red solid. MS(ES)m / z=715(M+1).

[0401] Preparation 93C (3-Cyano-4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-1-(((R)-1-methyl-2-oxopyrrolidine-3-yl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-2-yl) tert-butyl carbamate

[0402] [ka] (4-(1-chloro-3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidine-1-yl)-5-fluoro-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridine-2-yl)carbamate tert-butyl and (R)-3-amino-1-methylpyrrolidine-2-one 4-methylbenzene sulfonate were used in a manner similar to that of Preparation 18 to obtain the crude title compound (0.30 g, 100%) as a red solid. MS(ES)m / z=720(M+1).

[0403] Preparation 54A (4-(5-chloro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1-((pyridazine-4-ylmethyl)amino)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl

[0404] [ka] To a solution of (4-(5-chloro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-1-hydroxy-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (0.082 g, 0.12 mmol) in acetonitrile (1.5 mL), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.13 g, 0.24 mmol) and diisopropylethylamine (0.064 mL, 0.37 mmol) were added. The mixture was stirred at room temperature. After 1 hour, pyridazine-4-ylmethaneamine hydrochloride (0.036 g, 0.24 mmol) was added. After 2.5 hours, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase purification with elution in 0% to 50% ACN in water to obtain the title compound (0.070 g, 75%). MS(ES)m / z = 761(M+1).

[0405] The compounds listed in Table 15 below were prepared in the same manner as described in Preparation 54A. Similar coupling agents, such as bromotris(dimethylamino)phosphonium hexafluorophosphate, may be substituted. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0406] Table 15: [Table 15-1]

[0407] [Table 15-2]

[0408] [Table 15-3]

[0409] [Table 15-4]

[0410] Example 1 2-Amino-4-(5-Chloro-1-(((5-Cyclopropyl-1,3,4-Oxadiazole-2-yl)methyl)amino)-3-(((S)-1-Methylpyrrolidine-2-yl)methoxy)-7,9-Dihydrofluoro[3,4-f]Quinazolin-6-yl)-7-Fluorobenzo[b]Thiophen-3-Carbonitrile

[0411] [ka] To a solution of (4-(5-chloro-1-hydroxy-3-(((S)-1-methylpyrrolidine-2-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophene-2-yl)carbamate tert-butyl (0.030 g, 0.048 mmol) in acetonitrile (1 mL), (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.016 g, 0.031 mmol) and 1,8-diazabicyclo(5.4.0)undeca-7-ene (0.0095 g, 0.062 mmol) were added. The mixture was stirred at room temperature. After 3 hours, (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.016 g, 0.031 mmol) was added. After 2 hours, 5-cyclopropyl-1,3,4-oxadiazole-2-yl)methaneamine (0.033 g, 0.24 mmol) was added. After 2 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and TFA (1 mL) was added. After 1 hour, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase purification by elution in 0.1% formic acid in water with 80% ACN, and the title compound (0.008 g, 20%) was obtained as a white solid after lyophilization. MS(ES)m / z=647(M+1).

[0412] The compounds listed in Table 16 below were prepared in the same manner as described in Example 1. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0413] Table 16: [Table 16-1]

[0414] [Table 16-2]

[0415] [Table 16-3]

[0416] [Table 16-4]

[0417] [Table 16-5]

[0418] [Table 16-6] 1 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 40-100% heptane (1:1 MeOH:EtOH), 42.5 mL / min 2 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 20-100% EtOH in heptane, 50 mL / min 3 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 20-100% in heptane (1:1 MeOH:EtOH), 42.5 mL / min 4 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-100% EtOH in heptane, 50 mL / min 5 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-65% EtOH in heptane, 50 mL / min

[0419] Example 25 2-Amino-4-(5-Chloro-1-(((5-ethyl-1,3,4-oxadiazole-2-yl)methyl)amino)-3-(((S)-1-methylpyrrolidine-2-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile

[0420] [ka] To a solution of (4-(5-chloro-1-(((5-ethyl-1,3,4-oxadiazole-2-yl)methyl)amino)-3-(((S)-1-methylpyrrolidine-2-yl)methoxy)-7,9-dihydrofluoro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate tert-butyl (0.090 g, 0.12 mmol) in DCM (2 mL), TFA (1 mL) was added. The mixture was stirred at room temperature. After 1 hour, the mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase purification by elution with 80% ACN in (95:5 water:MeOH) to obtain the title compound (0.008 g, 20%) as a white solid after lyophilization. MS(ES)m / z=635(M+1).

[0421] The compounds listed in Table 17 below were prepared in the same manner as described in Example 25. The compounds were purified using various methods that would be apparent to those skilled in the art.

[0422] Table 17: [Table 17-1]

[0423] [Table 17-2]

[0424] [Table 17-3]

[0425] [Table 17-4]

[0426] [Table 17-5]

[0427] Table 17-6

[0428] Table 17-7

[0429] Table 17-8

[0430] Table 17-9

[0431] Table 17-10

[0432] Table 17-11

[0433] Table 17-12

[0434] Table 17-13

[0435] Table 17-14

[0436] Table 17-15

[0437] Table 17-16

[0438] Table 17-17

[0439] Table 17-18

[0440] Table 17-19

[0441] Table 17-20

[0442] Table 17-21

[0443] Table 17-22

[0444] Table 17-23

[0445] Table 17-24

[0446] Table 17-25

[0447] [Table 17-26]

[0448] [Table 17-27]

[0449] [Table 17-28] 1 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-80% EtOH in heptane, 50 mL / min 2 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-50% heptane (1:1 MeOH:EtOH), 50 mL / min 3 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-60% heptane (1:1 MeOH:EtOH), 50 mL / min 4 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-60% heptane (1:1 MeOH:EtOH), 50 mL / min 5 Reverse phase; 25-100% acetonitrile in C18 (5 mM ammonium acetate in 95:5 water:MeOH). 6 Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-50% EtOH in heptane, 42.5 mL / min 7 Chiral SFC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 34% in CO2 (MeOH containing 0.1% isopropylamine), 50 mL / min 8Pure atropisomers and chiral purification from preparation 7A 9 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 20-90% EtOH in heptane, 50 mL / min 10 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 20-100% EtOH in heptane, 50 mL / min 11 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 25-95% EtOH in heptane, 42.5 mL / min 12 Reverse phase; C18, 25-100% acetonitrile in (0.1% formic acid in water) 13 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 20-90% EtOH in heptane, 50 mL / min 14 Reverse phase; 28-100% acetonitrile in C18 (5 mM ammonium acetate in 95:5 water:MeOH). 15 Reverse phase; C18, 5-100% (95:5 acetonitrile:water) in (10 mM ammonium bicarbonate, pH 10, 5% MeOH) 16 Reverse phase; 5-100% acetonitrile in C18 (5 mM ammonium acetate in 95:5 water:MeOH). 17 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-85% EtOH in heptane, 50 mL / min 18 Reverse phase; 26-100% acetonitrile in C18 (5 mM ammonium acetate in 95:5 water:MeOH). 19 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 20-80% EtOH in heptane, 50 mL / min 20Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-65% heptane (1:1 MeOH:EtOH), 50 mL / min 21 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-82% EtOH in heptane, 40 mL / min 22 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-75% EtOH in heptane, 50 mL / min 23 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-80% EtOH in heptane, 50 mL / min 24 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 15-85% EtOH in heptane, 50 mL / min 25 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-50% heptane (1:1 MeOH:EtOH), 50 mL / min 26 Preparative chiral HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 10-70% heptane (EtOH containing 0.1% isopropylamine), 42.5 mL / min 27 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-45% in heptane (1:1 MeOH:EtOH), 42.5 mL / min 28 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 × 150 mm, 10-75% in heptane (1:1 MeOH:EtOH (containing 0.1% isopropylamine)), 42.5 mL / min 29Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-75% in heptane (1:1 MeOH:EtOH (containing 0.1% isopropylamine)), 50 mL / min 30 Pure atropisomer and chiral purification from preparation 2B 31 Atropisomer 1 was obtained by reverse-phase filtration with C18 and 38-40% acetonitrile in (10 mM ammonium bicarbonate in water). Atropisomer 2 was further purified by reverse-phase filtration with C18 and 36-50% acetonitrile in (10 mM ammonium bicarbonate in water containing 0.05% ammonium hydroxide). 32 Preparative chiral HPLC; Chiral IA, 30 × 250 mm, 50% EtOH in (10 mM ammonia-treated methanol in hexane), 40 mL / min 33 Preparative chiral HPLC; Chiral AD-3, 30 x 100 mm, 50% EtOH in methanol treated with 10 mM ammonia in hexane, 40 mL / min 34 Preparative chiral HPLC; Chiral IA, 30 × 250 mm, 50% EtOH in (10 mM ammonia-treated methanol in hexane), 40 mL / min 35 Pure trans isomer, preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 × 150 mm, 10-100% in heptane (EtOH containing 0.1% isopropylamine), 37.5 mL / min 36 Pure cis isomers, preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30 × 150 mm, 10-75% in heptane (1:1 MeOH:0.1% EtOH containing isopropylamine), 37.5 mL / min 37 Pure trans isomer, preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 × 150 mm, 15-50% in heptane (EtOH containing 0.1% isopropylamine), 35.0 mL / min 38Pure cis isomer, preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 × 150 mm, 15-100% in heptane (EtOH containing 0.1% isopropylamine), 35.0 mL / min 39 Pure trans isomer, preparative chiral-HPLC; Phenomenex Lux Cellulose-2, 30 × 150 mm, 10-90% in heptane (EtOH containing 0.1% isopropylamine), 42.5 mL / min 40 Preparative chiral HPLC; Chiral NX(2), 30 × 250 mm, 30% EtOH in (10 mM ammonia-treated methanol in hexane), 40 mL / min 41 Preparative chiral HPLC; Chiral NX(2), 30 × 250 mm, 30% EtOH in (10 mM ammonia-treated methanol in hexane), 40 mL / min 42 Preparative chiral HPLC; Chiral NX(2), 30 × 250 mm, 30% EtOH in (10 mM ammonia-treated methanol in hexane), 40 mL / min

[0450] Biological assays The following assays demonstrate that the exemplified compounds are potent inhibitors of KRas G12C, G12D, and / or G12V, inhibiting the growth of certain tumors in vitro and / or in vivo.

[0451] Cellular Phospho-ERK AlphaLISA® assay for KRAS inhibition The objective of these assays was to quantify the ability of test compounds to selectively inhibit KRAS signaling in cells exhibiting KRAS amplification and expressing activated KRAS G12 mutations (Table 14). Cancer cell lines used in this study were selected based on the presence of homozygous activated KRAS G12 mutations or KRAS gene amplification. In addition, these assays were performed on a set of RAS-free mouse embryonic fibroblasts (MEFs) manipulated to express only KRAS wild-type, HRAS, and NRAS, respectively (Table 14). KRAS selectivity of test compounds was confirmed using MEF cells.

[0452] Table 14: Cell line information [Table 18]

[0453] The activity of the compound is determined by measuring the change in phosphorylation levels of the downstream effectors, extracellular signal-regulated kinases 1 and 2 (ERK1 / 2), in cells treated with the compound. The phosphorylation level of ERK-1 / 2 is measured using the AlphaLISA® SureFire® Ultra® p-ERK1 / 2(Thr202 / Tyr204) assay kit (number ALSU-PERK-A50K, PerkinElmer® Waltham, MA). The AlphaLISA® assay is a quantitative sandwich immunoassay that can be used to detect phosphorylation of target proteins from cell lysates using bead-based alpha technology. This assay kit contains two antibodies, one of which binds to the phosphorus-Thr202 / Tyr204 epitope on ERK-1 / 2, and the other which recognizes distinct sites on the protein. One of these antibodies is biotinylated and conjugated to streptavidin-coated Alpha donor beads, while the other antibody is conjugated to AlphaLISA® acceptor beads. The donor and acceptor beads are brought close together during phosphorylation of ERK-1 / 2 in cell lysates. When the donor beads are excited with 600 nm wavelength light, the photosensitizer within the beads converts ambient oxygen to an excited singlet state. If the acceptor beads are within 200 nm of this reaction, the singlet oxygen reacts with the acceptor, resulting in chemiluminescence emission. The amount of light measured is proportional to the amount of phosphorylated ERK-1 / 2 in the lysate. The AlphaLISA®, SureFire®, and Ultra® p-ERK 1 / 2 (Thr202 / Tyr204) assay kit includes AlphaLISA® antibody conjugate donor beads and acceptor beads, lysis buffer concentrate, and a set of proprietary buffers (activation buffer, reaction buffer 1, reaction buffer 2, and dilution buffer).

[0454] To perform these assays, the test compounds and controls were acoustically dispensed into a white 384-well assay plate (Proxiplate-384, PerkinElmer No. 6008280) in a 10-point 3-fold dilution series in 30 nL of DMSO (Labcyte ECHO®, San Jose, CA). Cells were then added to the assay plate (HBSS, Sigma No. 55021C, 10% FBS, GIBCO No. 10082-147) in 8 μL / well of assay medium at cell line-specific densities (Table 14). In each well, the final compound concentration ranged from 0.5 to 10,000 nM, and the final DMSO concentration was 0.375%. The maximum signal control well contained only 0.375% DMSO (negative control), and the minimum signal control well contained 10,000 nM of the control compound (positive control). Cells in suspension are incubated with the test compound and reference compound at 37°C / 5% CO2 for 2 hours. After 2 hours of incubation, cells are lysed by adding 2 μL of AlphaLISA® lysis buffer concentrate (5-fold) supplemented with a protease / phosphatase inhibitor cocktail (Thermo Scientific No. 78442). The assay plate is covered with an opaque lid and shaken at 750 rpm for 30 minutes at room temperature on a multi-plate shaker (Heidolph, Schwabach, Germany) to induce cell lysis. During lysis, AlphaLISA® acceptor beads are diluted 1:50 in the prepared buffer mixture (1:1 AlphaLISA® reaction buffers 1 and 2 and 1:25 dilution of AlphaLISA® activation buffer). After cell lysis, the plate is briefly centrifuged and 5 μL / well of the prepared acceptor beads is added. The plate is then covered and incubated in the dark at room temperature for 2 hours. During the incubation of the acceptor beads, the donor beads are prepared by diluting Alpha streptavidin donor beads in AlphaLISA® dilution buffer at a ratio of 1:50. After incubation of the acceptor beads, 5 μL / well of the donor bead mixture is added to the plate. The plate is then covered and incubated in the dark at room temperature for 2 hours.After this incubation period, the AlphaLISA signal is read using a PHERAstar® FSX multimode plate reader (BMG Labtech, Ortenberg, Germany) equipped with an AlphaLISA®-compatible optical cube.

[0455] The raw signals obtained from the AlphaLISA® assay are analyzed using Geneda Screener® 17.0.3. Within this program, the data are normalized to 32 wells treated with an inhibitory control (maximum inhibition / positive control) and 32 wells treated with 0.375% DMSO alone (minimum inhibition / negative control) to calculate the compound's activity %.

[0456]

number

[0457]

number

[0458] The above assays tested the compounds of the examples shown herein and demonstrated their ability to reduce the levels of phosphorylated ERK-1 / 2 in cells expressing KRAS and KRAS variants. G12C (Examples 1~10, 12, 13, 15, 16, 18~20, 22, 23, 25, 28, 1A, 3A~5A, 7A~12A, 14A, 15A, 17A~20A, 22A~26A, 28A, 29A, 31A~35A, 37A~39A, 41A~ 43A, 45A, 47A, 49A, 51A, 52A, 2B~4B, 7B, 10B~12B, 14B, 15B, 18B~22B, 24B~28B, 31B, 1C~4C, 6C, 8C, 10C, 12C~36C, 38C, and 40C~44C), KRAS G12D (Examples 1, 2, 5, 6, 9, 10, 13, 15, 16, 18~20, 22, 23, 25, 28, 1A, 3A~5A, 7A~12A, 14A, 15A, 17A, 18A, 20A, 22A, 24A~26A, 28A, 31A, 32A, KRAS G12V (Examples 1~10, 12, 13, 15, 16, 18~20, 22, 23, 25~29, 1A, 3A~5A, 7A~12A, 14A, 15A, 17A~20A, 22A, 24A~26A, 28A~35A, 37A~39A, 41A, 43A , 45A, 47A, 49A, 51A, 52A, 2B, 4B, 5B, 7B, 10B~16B, 18B~25B, 27B, 31B, 1C~4C, 6C, 8C, 10C, 12C~34C, 36C, 38C, 40C, and 42C~44C), or KRASWT (Examples 1-10, 12, 13, 15, 16, 18-20, 22, 23, 25, 27-29, 1A, 3A-5A, 7A-12A, 14A, 15A, 17 A~20A, 22A, 24A~26A, 28A, 29A, 31A, 32A, 34A, 35A, 37A, 39A, 41A, 43A, 45A, 47A, 49A, It showed inhibition of constitutive RAS activity in cells expressing 51A, 52A, 3B, 4B, 7B, 11B, 12B, 14B, 16B, 19B, 20B, 22B, 24B, 31B, 3C, 4C, 6C, 8C, 10C, 12C-36C, 38C, 40C, and 42C-44C), and the relative IC50 was less than 500 nM. The compounds in Examples 1-6, 8-11, 14-21, 24, 26, 1A, 2A, 4A-6A, 8A-16A, 19A-23A, 25A, 27A, 29A-33A, 36A, 38A, 40A, 42A, 44A-52A, 1B-10B, 13B-18B, 21-23B, 25B-30B, 1C-9C, 11C, 20C, 21C, 24C, 26C, 32C, 35C, 37C, 39C, and 41C-44C were tested in the above mouse embryonic fibroblast cell line assays (MEF-NRAS, MEF-HRAS), and all showed a relative IC50 greater than 2 μM. The compounds of Examples 1, 3-6, 8-10, 12, 13, 15, 16, 18-20, 22, 23, 25, 26, 28, 1A, 3A-12A, 14A, 15A, 17A-20A, 22A-26A, 28A-35A, 37A-39A, 41A, 43A, 45A, 47A, 49A, 51A, 52A, 2B-5B, 7B, 8B, 10B, 11B, 13B-16B, 18B-25B, 27B, 31B, 2C, 4C, 6C, 8C, 10C, 13C-34C, 38C, 40C, and 42C-44C were subjected to the three assays described above (SW620, MEF-NRAS, and MEF-HRAS Cellular Phospho-ERK). Tested using the AlphaLISA® assay, all showed a significant (i.e., more than 10-fold) selective inhibitory preference against the KRas G12V mutant compared to HRAS and NRAS.

[0459] These data demonstrate that the compound of formula I described herein is a potent inhibitor of KRAS-expressing human cancer cells, and that it has the ability to inhibit KRAS G12C, G12D, or G12V variants with significantly selective inhibitory preference over HRAS or NRAS.

[0460] Table 15: Abbreviations [Table 19]

Claims

1. A compound of the formula, 【Chemistry 1】 During the ceremony, A is -C(H)- or -N-, Z is -C(R ３ｃ ) - or -N-, G is -C(R ３ｂ ) - or -N-, R １ However, this is the basis of the following equation, 【Chemistry 2】 In the formula, n is 0, 1, or 2. Y is -N(R ８ ) - or -O-, L is a 5-6 member heteroaryl compound containing 1 to 3 heteroatoms selected from O, N, or S, and the 5-6 member heteroaryl compound is C ３～６ It may optionally condense with a cycloalkyl ring to form a bicyclic ring structure. R ２ However, it is H, halogen, or methyl, R ３ｂ , and R ３ｃ Each of these is independently H, halogen, or methyl. R ４ is NR ７ R ７ optionally substituted with H, methyl, -CH ２ -OH, -O-R ５ -R ６ , -O-R ６ , an N-linked cyclic amine, or azetidine, and R ５ is -CH ２ -, -CH(CH ３ ), or -CH ２ -CH ２ -, and R ６ is H, C １～３ alkyl, C ２～３ heteroalkyl, C ３～６ cycloalkyl, C ４～６ heterocycloalkyl, or 2-oxo-1,3-dihydrobenzimidazole, and the C １～３ alkyl, the C ３～６ cycloalkyl, or the C ４～６ heterocycloalkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, NR ７ R ７ , C １～４ alkyl, or C １～４ alkenyl, and the C １～４ alkyl is optionally substituted with one or more halogen or hydroxyl, and the C ３～６ cycloalkyl or the C ４～６ heterocycloalkyl is optionally condensed with the C １～４ alkyl to form a bicyclic ring, or the C ３～６ cycloalkyl or the C ４～６ heterocycloalkyl is optionally bridged with C １～３ alkyl, or R ４ However, it is an N-linked cyclic amine or a group of the following formula, 【Transformation 3】 The N-linked cyclic amine is N-linked, i. R ４ａ and R ４ｂ Azetidine substituted with ii. Pyrrolidine, piperidine, piperazine, morpholine, diazepane, imidazole, or pyrazole, each of which is C １～３ Selectively crosslinked by alkylene, each containing one or more halogens; hydroxyl; -NR ６ａ R ６ａ (1-methylpiperidine-4-yl)oxy; optionally -NR ６ａ R ６ａ C replaced by １～３ Alkoxy; one or more halogens, -NR ６ａ R ６ａ , or C substituted with hydroxyl １～３ Alkyl; an imidazole optionally substituted with methyl; a monocyclic ring selected from azetidine, piperidine, piperazine, morpholine, oxazepane, or diazepane; a bicyclic ring selected from hexahydro-1H-flu[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, or octahydropyrrolo[1,2-a]pyrazine; or optionally substituted with a spirocyclic ring selected from 4,7-diazaspiro[2.5]octane, 2-oxa-7-azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, or 2-azaspiro[3.3]heptane, wherein the monocyclic ring is C １～３ Selectively crosslinked by alkylene, one or more halogens, hydroxyl, -CN, C １～３ Alkoxy, -NR １０ R １０ Cyclopropyl, oxetane, -CO-C １～３ Alkyl, or hydroxyl, C １～３ Alkoxy, -NR １０ R １０ , halogen, or -CF ３ C is optionally replaced by １～３ The two rings or spiro rings may be optionally substituted with alkyl groups, and each of them may be optionally substituted with methyl or halogen groups, or iii. iii. 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.1]octane, 2,6-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, 2-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-1H-pyrrolo[3,2-b]pyrid Octahydro-6H-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofloo[3,4-d]oxazole-2(3H)-one, hexahydro-1H-floo[3,4-b]pyrrole, octahydro- 1H-pyrrolo[3,2-b]pyridine, (3as,6as)-tetrahydro-1H,4H-3a,6a-(methanooxymethano)pyrrolo[3,4-c]pyrrole, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2, 6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.4]octane, 2,7-diazaspiro[4.4]nonane, 2-oxa-6-azaspiro[3.4]octane, or 1-oxa-7-azaspiro[4.4]nonane, each containing one or more halogens, -NR ６ａ R ６ａ , or -NR ６ａ R ６ａ Alternatively, C is optionally substituted with a hydroxyl group. １～３ 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.1]octane, 2,6-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, 2-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro Dro-1H-pyrrolo[3,2-b]pyridine, octahydro-6H-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofloo[3,4-d]oxazole-2(3H)-one, hexahydro-1H-floo[ 3,4-b]pyrrole, octahydro-1H-pyrrolo[3,2-b]pyridine, (3as,6as)-tetrahydro-1H,4H-3a,6a-(methanooxymethano)pyrrolo[3,4-c]pyrrole, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5- These are diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, 5-azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.4]octane, 2,7-diazaspiro[4.4]nonane, 2-oxa-6-azaspiro[3.4]octane, or 1-oxa-7-azaspiro[4.4]nonane. R ４ａ However, NR ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, or morpholine is a halogen, hydroxyl, C １～３ Alkoxy, or -NR ６ａ R ６ａ It is optionally replaced by, R ４ｂ However, H, hydroxyl, or C １～３ It is alkyl, R ４ｃ However, independently, they are cyclopropyl or oxetane. R ４ｄ However, independently, C １～３ It is alkyl, Each R ６ａ However, independently, it is either H or deuterium. Each R ６ｂ However, independently, H, triduteromethyl, C ３～５ Cycloalkyl, N-methylpyrrolidine, tetrahydrofuran, tetrahydropyran, bicyclo[1.1.1]pentan-1-yl, bicyclo[1.1.1]pentan-1-ol, or one or more deuterium, hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH ２ C is optionally replaced by １～３ Alkyl, and the C ３～５ The cycloalkyl group is optionally substituted with one or more hydroxyl or methyl groups. E １ However, -O-C １～３ C is optionally substituted with alkylene or one or more halogens. １～３ It is alkylene, E ２ and E ４ are each independently C optionally substituted with one or more hydroxyls, C １～３ alkoxy, or halogen, and are C １～３ alkylene, and E ２ and E ４ can be optionally crosslinked by a bond or C １～３ alkylene, E ３ is -O-, -CR ７ａ R ７ａ -, -NR ９ａ -, or -CO-NR ６ｂ -, or The ring 【Chemistry 4】 However, it is hexahydro-1H-fl[3,4-c]pyrrole, Each E ２ａ However, independently, C is optionally substituted with one or more hydroxyls. １～３ It is alkylene, E ５ However, -O-, -CR ７ａ R ７ａ -, or -NR ９ａ - and Each R ７ However, independently, H or C １～３ It is alkyl, Each R ７ａ However, independently, H, halogen, CN, hydroxyl, C １～３ C is optionally substituted with an alkoxy or one or more halogens or hydroxyls. １～３ It is alkyl, Each R ８ However, each independently, H or C １～３ It is alkyl, Each R ８ａ However, independently, C １～３ It is alkyl, R ９ However, H, -CO-C １～３ Alkyl, -CO-NR ８ R ８ , -NR ９ａ R ９ａ , C １～４ Alkyl, or C ３～６ It is a cycloalkyl, and the C １～４ Alkyl or the C ３～６ The cycloalkyl group is optionally substituted with one or more halogens. R ９ａ However, each is independent of H and C which is optionally substituted. １～３ Alkyl or -CO-C １～３ The alkyl group is the C which is optionally substituted. １～３ The alkyl group is optionally substituted with one or more halogens, R １０ However, C is optionally substituted with H or one or more deuterium atoms. １～３ A compound that is alkyl, or a pharmaceutically acceptable salt thereof.

2. R ４ However, NR ７ R ７ H, methyl, -CH are optionally substituted. ２ -OH, -O-R ５ -R ６ , -O-R ６ , N-linked cyclic amine, or azetidine, R ５ However, -CH ２ -, -CH(CH ３ ) -, or -CH ２ -CH ２ - and R ６ However, H, C １～３ Alkyl, C ２～３ Heteroalkyl, C ３～６ Cycloalkyl, C ４～６ The C is a heterocycloalkyl or 2-oxo-1,3-dihydrobenzimidazole. １～３ alkyl, the C ３～６ Cycloalkyl, or the C ４～６ Heterocycloalkyl contains one or more halogens, hydroxyl, methoxy, NR ７ R ７ , C １～４ Alkyl, or C １～４ The C is optionally substituted with an alkenyl. １～４ The alkyl group is optionally substituted with one or more halogens or hydroxyls, and the C ３～６ Cycloalkyl or the aforementioned C ４～６ The heterocycloalkyl is the C １～４ It optionally condenses with an alkyl group to form a bicyclic ring, or the C ３～６ Cycloalkyl or the aforementioned C ４～６ Heterocycloalkyl is C １～３ Selectively crosslinked with alkyl, or R ４ However, it is an N-linked cyclic amine or a group of the following formula, 【Transformation 5】 The N-linked cyclic amine is N-linked, i. R ４ａ and R ４ｂ Azetidine substituted with ii. Pyrrolidine, piperidine, piperazine, morpholine, imidazole, or pyrazole, each of which is C １～３ They are optionally crosslinked by alkylene, and each contains one or more halogens, hydroxyls, and C １～３ Alkoxy, -NR ６ａ R ６ａ , azetidine, C １～３ The azetidine is optionally substituted with an imidazole optionally substituted with an alkyl or methyl group, wherein the azetidine is optionally substituted with a hydroxyl or C group. １～３ The C is optionally substituted with an alkoxy. １～３ alkyl is halogen-NR ６ａ R ６ａ Alternatively, pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole, which are optionally substituted with hydroxyl, iii. 2,6-Diazabicyclo[3.2.0]heptane, 3,6-Diazabicyclo[3.2.0]heptane, 3-Azabicyclo[3.1.0]hexane, 3-Azabicyclo[3.2.0]heptane, Octahydro-1H-pyrrolo[3,4-b]pyridine, Octahydro-6-pyrrolo[3,4-b]pyrazine, Octahydropyrrolo[1,2-a]pyrazine, Octahydropyrrolo[3,2-b]pyrrole, Octahydropyrrolo[3,4-b][1,4]oxazine, Octahydropyrrolo[3,4-b]pyrrole, Octahydropyrrolo[3,4-c]pyrrole, Tetrahydrofloxacin[3,4- d] Oxazole-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane, each containing one or more halogens, -NR ６ａ R ６ａ Or -NR ６ａ R ６ａ C is optionally replaced by １～３ 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-6-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c] Pyrrole, tetrahydrofloo[3,4-d]oxazole-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane. R ４ａ However, NR ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, or morpholine is a halogen, hydroxyl, C １～３ Alkoxy or -NR ６ａ R ６ａ It is optionally replaced by, Each R ６ｂ However, independently, H, triduteromethyl, C ３～５ C is optionally substituted with cycloalkyl or hydroxyl groups. １～３ It is alkyl, R ９ However, H, -CO-C １～３ Alkyl, -NR ９ａ R ９ａ , C １～４ Alkyl, or C ３～６ A compound according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

3. R ３ｂ and R ３ｃ However, each is independently either H or halogen, R １ However, this is the basis of the following equation, 【Transformation 6】 In the formula, n is 0, 1, or 2. Y is -N(R ８ ) - or -O-, L is a 5-6 member heteroaryl compound containing 1 to 3 heteroatoms selected from O, N, or S, and the 5-6 member heteroaryl compound is C ３～６ It may optionally condense with a cycloalkyl ring to form a bicyclic ring structure. R ２ However, it is H, halogen, or methyl, R ４ However, NR ７ R ７ H, methyl, -CH are optionally substituted. ２ -OH, -O-R ５ -R ６ , -O-R ６ , N-linked cyclic amine, or azetidine, R ５ However, -CH ２ -, -CH(CH ３ ) -, or -CH ２ -CH ２ - and R ６ However, H, C １～３ Alkyl, C ２～３ Heteroalkyl, C ３～６ Cycloalkyl, C ４～６ The C is a heterocycloalkyl or 2-oxo-1,3-dihydrobenzimidazole. １～３ alkyl, the C ３～６ Cycloalkyl, or the C ４～６ Heterocycloalkyl contains one or more halogens, hydroxyl, methoxy, NR ７ R ７ , C １～４ Alkyl, or C １～４ The C is optionally substituted with an alkenyl. １～４ The alkyl group is optionally substituted with one or more halogens or hydroxyls, and the C ３～６ Cycloalkyl or the aforementioned C ４～６ The heterocycloalkyl is the C １～４ It optionally condenses with an alkyl group to form a bicyclic ring, or the C ３～６ Cycloalkyl or the aforementioned C ４～６ Heterocycloalkyl is C １～３ Selectively crosslinked with alkyl groups, R ９ However, H, C １～４ Alkyl, or C ３～６ A cycloalkyl or a pharmaceutically acceptable salt thereof, wherein C １～４ Alkyl or the C ３～６ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is optionally substituted with one or more halogens.

4. R １ However, this is the basis of the following equation, 【Transformation 7】 L is a five-membered heteroaryl compound containing one to three heteroatoms selected from O, N, or S, and the five-membered heteroaryl compound is C ３～６ It may optionally condense with a cycloalkyl ring to form a bicyclic ring structure. R ４ However, NR ７ R ７ H, methyl, -CH are optionally substituted. ２ -OH, -O-R ５ -R ６ , -O-R ６ , or azetidine, R ５ However, -CH ２ -, -CH(CH ３ ) -, or -CH ２ -CH ２ - and R ６ However, H, C １～３ Alkyl, C ２～３ Heteroalkyl, C ３～６ Cycloalkyl, C ４～６ The C is a heterocycloalkyl or 2-oxo-1,3-dihydrobenzimidazole. １～３ alkyl, the C ３～６ Cycloalkyl, or the C ４～６ Heterocycloalkyl contains one or more halogens, hydroxyl, methoxy, NR ７ R ７ , C １～４ Alkyl, or C １～４ The C is optionally substituted with an alkenyl. １～４ The alkyl group is optionally substituted with one or more halogens or hydroxyls, and the C ３～６ Cycloalkyl or the aforementioned C ４～６ The heterocycloalkyl is the C １～４ It optionally condenses with an alkyl group to form a bicyclic ring, or the C ３～６ Cycloalkyl or the aforementioned C ４～６ Heterocycloalkyl is C １～３ Selectively crosslinked with alkyl groups, R ９ However, H, C １～４ Alkyl, or C ３～６ A compound according to any one of claims 1 to 3, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 4, wherein G is -N-, or a pharmaceutically acceptable salt thereof.

6. G is -C(R ３ｂ ) - a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

7. R ３ｂ However, the compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein F.

8. A compound according to any one of claims 1 to 7, wherein Z is -N-, or a pharmaceutically acceptable salt thereof.

9. Z is -C(R ３ｃ ) - a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

10. R ３ｃ The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein the compound is H or F.

11. R ３ｂ , and R ３ｃ A compound according to any one of claims 1 to 4, 6, or 9, or a pharmaceutically acceptable salt thereof, wherein each is independently H or a halogen.

12. A compound according to any one of claims 1 to 11, wherein A is -N-, or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of claims 1 to 11, wherein A is -C(H)-, or a pharmaceutically acceptable salt thereof.

14. R ２ A compound according to any one of claims 1 to 13, wherein the compound is F or Cl, or a pharmaceutically acceptable salt thereof.

15. R ２ A compound according to any one of claims 1 to 13, wherein F is present, or a pharmaceutically acceptable salt thereof.

16. R ２ A compound according to any one of claims 1 to 13, wherein the compound is Cl, or a pharmaceutically acceptable salt thereof.

17. R １ but, 【Transformation 8】 A compound according to any one of claims 1 or 5 to 16, selected from the above, or a pharmaceutically acceptable salt thereof.

18. R １ but, 【Chemistry 9】 A compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from the above.

19. R １ but, 【Chemistry 10】 A compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from the above.

20. R １ but, 【Chemistry 11】 A compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from the above.

21. R １ but, 【Chemistry 12】 A compound according to claim 17, or a pharmaceutically acceptable salt thereof, selected from the above.

22. R ４ but, 【Chemistry 13】 A compound according to any one of claims 1 to 21, selected from, or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

24. A method for treating a cancer patient, comprising administering an effective amount of the pharmaceutical composition according to claim 23 to a patient in need of treatment, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

25. A method for treating a cancer patient, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

26. The method according to claim 24 or 25, wherein the patient has cancer in which it has been determined that one or more cells expressing the KRas G12D mutant protein are present prior to administration of the compound or a pharmaceutically acceptable salt thereof.

27. The method according to claim 24 or 25, wherein the patient has cancer determined to have one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins prior to administration of the compound or a pharmaceutically acceptable salt thereof.

28. The method according to any one of claims 24 to 27, wherein the cancer is non-small cell lung cancer.

29. The method according to any one of claims 24 to 27, wherein the cancer is colorectal cancer.

30. The method according to any one of claims 24 to 27, wherein the cancer is pancreatic cancer.

31. The method according to any one of claims 24, 25, and 28-30, wherein one or more cells express the KRas G12D mutant protein.

32. The method according to any one of claims 24, 25, and 28-30, wherein one or more cells express KRas G12C, G12D, and / or G12V mutant proteins.

33. A method for treating a patient having cancer with a KRas G12D mutation, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

34. A method for treating a patient having cancer with a KRas G12C, G12D, and / or G12V mutation, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

35. The method according to claim 33 or 34, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, mutated ovarian cancer, bile duct cancer, and colorectal cancer.

36. The method according to claim 35, wherein the cancer is non-small cell lung cancer.

37. The method according to claim 35, wherein the cancer is colorectal cancer.

38. The method according to claim 35, wherein the cancer is pancreatic cancer.

39. The method according to any one of claims 24 to 38, wherein the patient is also administered one or more of the following: a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salt thereof.

40. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, for use in therapeutic purposes.

41. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

42. The aforementioned cancer has a KRas G12D mutation, and the compound for use according to claim 41, or a pharmaceutically acceptable salt thereof.

43. The aforementioned cancer has the KRas G12C, G12D, and / or G12V mutations, the compound for use according to claim 41, or a pharmaceutically acceptable salt thereof.

44. The compound for use according to any one of claims 41 to 43, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

45. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in combination with, separately, or sequentially with one or more of the following: a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, an SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof.

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