KRAS inhibitors

Abstract

To provide more potent, orally deliverable KRas inhibitors that are useful for treating cancer.SOLUTION: The invention provides a compound of the formula in the figure, where: A is -C(H)- or -N-; Z is -C(R3c)- or -N-; G is -C(R3b)- or -N-; R1 is H or the like; R2 is H, halogen, or methyl; R3b and R3c are each independently H, halogen, or methyl; and R4 is a N-linked cyclic amine or the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] Background technology The MAPK / ERK signaling pathway transmits extracellular stimuli to the nucleus, thereby regulating diverse 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 and inhibiting cell division. In response to extracellular signals, KRas is allosterically activated, allowing the nucleotide exchange of GDP with guanosine triphosphate (GTP). In its GTP-bound active state, KRas recruits and activates proteins required for the propagation of growth factor-induced signaling, as well as other cell signaling receptors. Examples of proteins recruited by KRas-GTP are c-Raf and PI3 kinase. KRas, as a GTPase, converts bound GTP back to GDP, thereby returning itself to its inactive state and again propagating the signal to inhibit cell division. KRas gain-of-function mutations exhibit an increased degree of GTP binding and a decreased ability to convert GTP to GDP, resulting in increased MAPK / ERK signaling that promotes cancer cell proliferation. KRas missense mutations at codon 12 are the most common mutations and result in a significant decrease in GTPase activity. [Background technology]

[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, it remains 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 mutant inhibitors (e.g., WO 2019 / 099524, WO 2020 / 081282, WO 2020 / 101736, WO 2020 / 146613, and WO 2021 / 118877 disclose KRas G12C inhibitors), while WO 2021 / 041671 discloses KRas G12D small molecule inhibitors and WO 2017 / 011920 discloses KRas G12C, G12D, and G12V small molecule inhibitors.

[0004] There remains a need to provide alternative small molecule KRas inhibitors. In particular, there is a need to provide more potent, orally deliverable KRas inhibitors useful in the treatment of cancer. More particularly, there is a need to provide small molecule inhibitors that specifically inhibit KRas GTP activity. Furthermore, there is a demand to provide 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 inhibition, preferentially inhibiting KRas G12D mutant over KRas wild type. Furthermore, there is a need to provide more potent KRas inhibitors that exhibit selective inhibition, preferentially inhibiting KRas G12C, G12D, and / or G12V mutant over HRAS or NRAS. Furthermore, there is a need to provide more potent KRas inhibitors that exhibit selective inhibition, preferentially inhibiting KRas G12C, G12D, and G12V mutants over HRAS or NRAS. These panKRas inhibitors may be KRas wild-type inhibitors or may be more selective than KRas wild-type. The present invention addresses one or more of these needs by providing novel KRas inhibitors. Summary of the Invention

[0005] Formula I: [ka] A compound represented by the formula: 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 H or a group of the formula [ka] R2 is H, halogen, or methyl; R 3b , and R 3c are each independently H, halogen, or methyl; R4 is an N-linked cyclic amine or a group of the formula: [ka] Based on The N-linked cyclic amine is an N-linked iR 4a and R 4b azetidine substituted with ii. Pyrrolidine, piperidine, piperazine, morpholine, diazepane, imidazole, or pyrazole, each of which is represented by C 1~3 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, -NR 6a R 6a , (1-methylpiperidin-4-yl)oxy, optionally -NR 6a R 6a C replaced with 1~3 Alkoxy, optionally one or more halogens, -NR 6a R 6a or hydroxyl-substituted C 1~3 a monocyclic ring selected from alkyl, imidazole optionally substituted with methyl, azetidine, piperidine, piperazine, morpholine, oxazepane, or diazepane; a bicyclic ring selected from hexahydro-1H-furo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, or octahydropyrrolo[1,2-a]pyrazine; or a spiro 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; 1~3 Optionally bridged by alkylene and one or more of halogen, hydroxyl, -CN, C 1~3 Alkoxy, -NR 10 R 10 , cyclopropyl, oxetane, -CO-C 1~3Alkyl or hydroxyl, C 1~3 Alkoxy, -NR 10 R 10 , C optionally substituted with halogen or -CF 1~3 which may be optionally substituted with alkyl, or 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]pyridine Lysine, 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, Tetrahydrofuro[3,4-d]oxazol-2(3H)-one, Hexahydro-1H-furo[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 of which is selected from the group consisting of one or more halogens, -NR 6a R 6a , or -NR 6a R6a or C optionally substituted with hydroxyl 1~3 is optionally substituted with alkyl; R 4a But NR 4c R 4d , cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine or imidazole, and cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine or morpholine is halogen, hydroxyl, C 1~3 Alkoxy or -NR 6a R 6a and optionally substituted with R 4b is H, hydroxyl, or C 1~3 is alkyl, R 4c is independently cyclopropyl or oxetane; R 4d But independently, C 1~3 is alkyl, R5 is trideuteromethyl, oxetane, or one or more of halogen, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, oxetane, cyclopropyl, imidazole, pyrazole, -CO-NR 6a R 6a , -O-(CH2)2-OR 6a , or -O-CO-C 1~3 C optionally substituted with alkyl 1~4 alkyl, cyclopropyl is optionally substituted with hydroxyl or hydroxymethyl, imidazole or pyrazole is optionally substituted with hydroxyl or one or more hydroxyls; 1~3 each optionally substituted with alkyl; R 5a But, C 1~3 is alkylene, each R6 is independently H or deuterium; Each R 6a are independently H, trideuteromethyl, C 3~5Cycloalkyl, N-methylpyrrolidine, tetrahydrofuran, tetrahydropyran, bicyclo[1.1.1]pentan-1-yl, bicyclo[1.1.1]pentan-1-ol, or C optionally substituted with one or more deuterium, hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH 1~3 Alkyl, C 3~5 cycloalkyl is optionally substituted with one or more hydroxyl or methyl; E1 is -OC 1~3 Alkylene or C optionally substituted with one or more halogens 1~3 is alkylene, E2 and E4 each independently represent one or more hydroxyl, C 1~3 C optionally substituted with alkoxy or halogen 1~3 alkylene, and E2 and E4 are a bond or C 1~3 can be optionally bridged by alkylene, and E3 is -O-, -CR7R7-, -NR9-, or -CO-NR 6a -or- ring [ka] is hexahydro-1H-furo[3,4-c]pyrrole, Each E 2a is independently selected from the group consisting of C, optionally substituted with one or more hydroxyls; 1~3 is alkylene, E5 is -O-, -CR7R7-, or -NR9-; Each R7 is independently H, halogen, CN, hydroxyl, C 1~3 Alkoxy or C optionally substituted with one or more halogens or hydroxyls 1~3 is alkyl, Each R8 is independently selected from C 1~3 is alkyl, R9 is, independently at each occurrence, H, optionally substituted C 1~3Alkyl or -CO-C 1~3 Alkyl, optionally substituted C 1~3 the alkyl is optionally substituted with one or more halogens; R 10 is H or C optionally substituted with one or more deuterium atoms; 1~3 Provided herein are compounds, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

[0006] Also provided herein are methods of using the compounds of formula I, their pharma- ceutical acceptable salts, and pharmaceutical 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, comprising administering a therapeutically effective amount of the compound of formula I, or a pharma- ceutical acceptable salt thereof, to a patient in need thereof.

[0007] Further provided herein is the compound of formula I, and its pharmaceutically acceptable salts, for use in therapy.Additionally provided herein is the compound of formula I, and its pharmaceutically acceptable salts, for use in the treatment of cancer, particularly lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.Additionally provided herein is the use of the compound of formula I, or its pharmaceutically acceptable salts, in the manufacture of a medicament for the treatment of cancer, particularly lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Novel inhibitors of KRas gain-of-function mutations 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 mutations 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. Some of these novel KRas inhibitor compounds are selective for KRas G12D mutants over wild-type KRas (and possibly other mutants such as G12C or G12V). Additionally, some of these novel KRas inhibitor compounds are non-selective, inhibiting both wild-type KRas and KRas G12D mutants (and / or possibly other mutants such as G12C or G12V). Also, some of these novel KRas inhibitor compounds are non-selective, inhibiting both wild-type KRas and Kras G12C, G12D, and / or G12V mutants.

[0009] The present invention relates to a compound of formula I: [ka] A compound represented by the formula: The present invention provides a compound, or a pharma- ceutically acceptable salt thereof, wherein A, Z, G, R1, R2, and R4 are as defined above.

[0010] 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 or branched chain monovalent hydrocarbon radical of one to a specified number of carbon atoms, e.g., "C 1~4 Alkyl" or "C 1~3 Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso-butyl. As used herein, the term alkylene refers to a saturated straight or branched chain divalent hydrocarbon radical of one to the specified number of carbon atoms, e.g., "C 1~3Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, 1-propylene, and isopropylene. 1~3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 1-propoxy, and isopropoxy.

[0011] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, R4 is an N-linked cyclic amine or a group of the following formula: [ka] Based on The N-linked cyclic amine is an N-linked iR 4a and R 4b azetidine substituted with ii. Pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole, each of which is represented by C 1~3 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, C 1~3 Alkoxy, -NR 6a R 6a , Azetidine, Piperazine, Morpholine, C 1~3 and optionally substituted imidazole optionally substituted with alkyl or methyl, and azetidine optionally substituted with hydroxyl or C 1~3 Optionally substituted with alkoxy, piperazine is optionally substituted with methyl, C 1~3 Alkyl may contain one or more halogens, -NR 6a R 6a or optionally substituted with hydroxyl, or 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, octahexa ... Drop-1H-pyrrolo[3,4-b]pyridine, Octahydro-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, tetrahydrofuro[3,4-d]oxazol-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, 5-azaspiro[2.4]heptane, or 2-oxa-6-azaspiro[3.4]octane, each of which is selected from the group consisting of one or more halogens, -NR 6a R 6a or -NR 6a R 6a C optionally substituted with 1~3 is optionally substituted with alkyl; R 4a But -NR 4c R 4d , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, and cyclopropyl, azetidine, pyrrolidine, piperidine or morpholine is halogen, hydroxyl, C 1~3 Alkoxy or -NR 6a R 6a and optionally substituted with Each R 6aare independently H, trideuteromethyl, C 3~5 Cycloalkyl, tetrahydrofuran, tetrahydropyran, bicyclo[1.1.1]pentan-1-yl, or C optionally substituted with one or more hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH 1~3 Alkyl, C 3~5 The cycloalkyl is optionally substituted with one or more hydroxyl or methyl.

[0012] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, R4 is an N-linked cyclic amine or a group of the formula: [ka] Based on The N-linked cyclic amine is an N-linked iR 4a and R 4b azetidine substituted with ii. Pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole, each of which is represented by C 1~3 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, C 1~3 Alkoxy, -NR 6a R 6a , Azetidine, C 1~3 and optionally substituted imidazole optionally substituted with alkyl or methyl, and azetidine optionally substituted with hydroxyl or C 1~3 Optionally substituted with alkoxy, C 1~3 Alkyl is halogen -NR 6a R 6a or optionally substituted with hydroxyl, or 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, tetrahydrofuro[3,4- d] oxazol-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 of which is selected from the group consisting of one or more halogens, -NR 6a R 6a or -NR 6a R 6a C optionally substituted with 1~3 is optionally substituted with alkyl; R 4a But NR 4c R 4d , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, and cyclopropyl, azetidine, pyrrolidine, piperidine or morpholine is halogen, hydroxyl, C 1~3 Alkoxy or -NR 6a R 6a and optionally substituted with Each R 6a are independently H, trideuteromethyl, C 3~5 C optionally substituted with cycloalkyl or hydroxyl 1~3 It is an alkyl.

[0013] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, R 3b , and R 3c are each independently H or halogen, and R4 is an N-linked cyclic amine or a group of the formula: [ka] Based on The N-linked cyclic amine is an N-linked iR 4a and R 4b azetidine substituted with ii. pyrrolidine, piperidine, piperazine, or morpholine, each of which is represented by C 1~3 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, -NR 6a R 6a , imidazole or C 1~3 optionally substituted with alkyl, imidazole optionally substituted with methyl, C 1~3 The alkyl is -NR 6a R 6a or hydroxyl, or 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 of which is selected from the group consisting of one or more halogens or C 1~3 optionally substituted with alkyl; R 4a But NR 4c R 4d , cyclopropyl, azetidine, pyrrolidine, morpholine, wherein cyclopropyl, azetidine, pyrrolidine, or morpholine is halogen, or -NR 6a R 6a and optionally substituted with R 4b But H or C 1~3 is alkyl, R 4c is independently cyclopropyl or oxetane; R 4d But independently, C 1~3 is alkyl, R5 is trideuteromethyl, oxetane, or one or more of halogen, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, oxetane, cyclopropyl, imidazole, pyrazole, -CO-NR 6a R 6a , -O-(CH2)2-OR 6a , or -O-CO-C 1~3 C optionally substituted with alkyl 1~4 alkyl, cyclopropyl is optionally substituted with hydroxyl or hydroxymethyl, imidazole or pyrazole is optionally substituted with hydroxyl or one or more hydroxyls; 1~3 each optionally substituted with alkyl; R 5a But, C 1~3 is alkylene, each R6 is independently H or deuterium; Each R 6a are independently H or C 1~3 is alkyl, E1 is -OC 1~3 Alkylene or C optionally substituted with one or more halogens 1~3 is alkylene, E2 and E4 are each independently C optionally substituted with one or more hydroxyl or halogen. 1~3 alkylene, and E2 and E4 are a bond or C 1~3 may be optionally bridged by alkylene, Each E 2a is independently selected from the group consisting of C, optionally substituted with one or more hydroxyls; 1~3 is alkylene, E3 is -O-, -CR7R7-, -NR9-, or -CO-NR 6a - and E5 is -O-, -CR7R7-, or -NR9-; Each R7 is independently H, halogen, CN, hydroxyl, C 1~3 Alkoxy or C optionally substituted with one or more halogens or hydroxyls 1~3 is alkyl, Each R8 is independently selected from C 1~3 is alkyl, R9 is, independently at each occurrence, H, optionally substituted C 1~3 Alkyl or -CO-C 1~3 Alkyl, optionally substituted C 1~3 The alkyl is optionally substituted with one or more halogens.

[0014] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, R 3b , and R 3c are each independently H or halogen, and R4 is of the formula: [ka] Based on E1 is C optionally substituted with one or more halogens 1~3 is alkylene, E2 and E4 are each independently a C optionally substituted with one or more hydroxyls 1~3 alkylene, and E2 and E4 are a bond or C 1~3 may be optionally bridged by alkylene, E3 is -O-, -CR7R7-, -NR9-, or -CO-NR 6a - and Each R 6a are independently H or C 1~3 is alkyl, Each R7 is independently H, halogen, hydroxyl, C 1~3 Alkoxy or C optionally substituted with one or more halogens or hydroxyls 1~3 is alkyl, R9 is independently H, C 1~3 Alkyl or -CO-C 1~3 It is an alkyl.

[0015] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is --N--.

[0016] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, G is -C(R 3b )-.

[0017] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, G is -C(R 3b )- and R 3b is H or a halogen.

[0018] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -C(F)-.

[0019] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is --C(Cl)--.

[0020] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is --C(H)--.

[0021] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -C(CH3)-.

[0022] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, Z is --N--.

[0023] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, Z is -C(R 3c )-.

[0024] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, Z is -C(R 3c )- and R 3c is H or a halogen.

[0025] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, Z is --C(H)--.

[0026] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, Z is --C(F)--.

[0027] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -N- and Z is -C(R 3c )-.

[0028] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -N- and Z is -C(H)-.

[0029] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -N- and Z is -C(F)-.

[0030] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -C(R 3b )- and Z is -N-.

[0031] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -C(R 3b )- and R 3b is H or halogen, and Z is -N-.

[0032] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -C(F)- and Z is -N-.

[0033] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -C(Cl)- and Z is -N-.

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

[0035] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, G is -C(CH3)- and Z is -N-.

[0036] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, R 3b , and R 3c are each independently H or halogen.

[0037] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, A is --N--.

[0038] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, A is --C(H)--.

[0039] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, R2 is F or Cl.

[0040] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, and R2 is F.

[0041] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, and R2 is F.

[0042] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, and R2 is F.

[0043] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, and R2 is F.

[0044] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, and R2 is F.

[0045] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, and R2 is F.

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

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

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

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

[0050] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, and R2 is F.

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

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

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

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

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

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

[0057] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, and R2 is F.

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

[0059] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, and R2 is Cl.

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

[0061] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, and R2 is Cl.

[0062] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, and R2 is Cl.

[0063] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, and R2 is Cl.

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

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

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

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

[0068] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, and R2 is Cl.

[0069] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, and R2 is Cl.

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

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

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

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

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

[0075] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, and R2 is Cl.

[0076] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is H.

[0077] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0078] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, R2 is F, R1 is H, and R4 is an N-linked cyclic amine.

[0079] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0080] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, R2 is F, R1 is H, and R4 is an N-linked cyclic amine.

[0081] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, R2 is F, R1 is H, and R4 is an N-linked cyclic amine.

[0082] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, R2 is F, R1 is H, and R4 is an N-linked cyclic amine.

[0083] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(H)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0084] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(H)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0085] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(H)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0086] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(H)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0087] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0088] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0089] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(F)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0090] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(F)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0091] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(F)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0092] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(F)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0093] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(F)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0094] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, R2 is F, R1 is H and R4 is an N-linked cyclic amine.

[0095] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -N-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0096] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -N-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0097] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -N-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0098] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -N-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0099] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -N-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0100] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -N-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0101] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(H)-, R2 is Cl, R1 is H and R4 is an N-linked cyclic amine.

[0102] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(H)-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0103] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(H)-, R2 is Cl, R1 is H and R4 is an N-linked cyclic amine.

[0104] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(H)-, R2 is Cl, R1 is H and R4 is an N-linked cyclic amine.

[0105] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(H)-, R2 is Cl, R1 is H and R4 is an N-linked cyclic amine.

[0106] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(H)-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0107] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(F)-, G is -C(F)-, R2 is Cl, R1 is H and R4 is an N-linked cyclic amine.

[0108] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(F)-, G is -C(F)-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0109] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -C(H)-, G is -C(F)-, R2 is Cl, R1 is H and R4 is an N-linked cyclic amine.

[0110] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -C(H)-, G is -C(F)-, R2 is Cl, R1 is H and R4 is an N-linked cyclic amine.

[0111] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -C(H)-, Z is -N-, G is -C(F)-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0112] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, A is -N-, Z is -N-, G is -C(F)-, R2 is Cl, R1 is H, and R4 is an N-linked cyclic amine.

[0113] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is of the formula: [ka] is the basis.

[0114] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is of the formula: [ka] is the basis.

[0115] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R5 is a C optionally substituted with one or more hydroxyl, methoxy or oxetane. 1~4 It is an alkyl.

[0116] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R5 is a C optionally substituted with one or more hydroxyl or methoxy. 1~4 It is an alkyl.

[0117] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is of the formula: [ka] where R 5a is ethylene.

[0118] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is of the formula: [ka] wherein R5 is a C optionally substituted with one or more hydroxyl, methoxy or oxetane. 1~4 is alkyl, preferably R 5a is ethylene.

[0119] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is of the formula: [ka] wherein R5 is a C optionally substituted with one or more hydroxyl or methoxy groups. 1~4 is alkyl, preferably R 5a is ethylene.

[0120] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is [ka] [ka] is selected from.

[0121] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is [ka] is selected from.

[0122] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R1 is [ka] is selected from.

[0123] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, the ring [ka] But hexahydro-1H-furo[3,4-c]pyrrole: [ka] It is.

[0124] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is R 4a and R 4b is an N-linked azetidine substituted with

[0125] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is an N-linked pyrrolidine, piperidine, piperazine, or morpholine, each of which is selected from the group consisting of C 1~3 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, -NR 6a R 6a , imidazole or C 1~3 optionally substituted with alkyl, imidazole optionally substituted with methyl, C1~3 The alkyl is -NR 6a R 6a or optionally substituted with hydroxyl.

[0126] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, R4 is an N-linked octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,4-c]pyrrole, 1,6-diazaspiro[3.3]heptane, or 1,6-diazaspiro[3.4]octane, each of which is selected from the group consisting of one or more halogens, or C 1~3 It is optionally substituted with alkyl.

[0127] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is an N-linked pyrrolidine, piperidine, piperazine, morpholine, imidazole, or pyrazole, each of which is selected from the group consisting of C 1~3 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, C 1~3 Alkoxy, -NR 6a R 6a , Azetidine, C 1~3 and optionally substituted imidazole optionally substituted with alkyl or methyl, and azetidine optionally substituted with hydroxyl or C 1~3 Optionally substituted with alkoxy, C 1~3 The alkyl is -NR 6a R 6a or optionally substituted with hydroxyl.

[0128] In one embodiment of a compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is selected from the group consisting of N-linked 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, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrazine ... ]pyrrole, tetrahydrofuro[3,4-d]oxazol-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[3.3]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 of which is selected from the group consisting of one or more halogens, -NR 6a R 6a or -NR 6a R 6a C optionally substituted with 1~3 It is optionally substituted with alkyl.

[0129] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0130] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] [ka] [ka] [ka] [ka] is an N-linked cyclic amine selected from:

[0131] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0132] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0133] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] [ka] [ka] [ka] is selected from.

[0134] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] [ka] is an N-linked cyclic amine selected from:

[0135] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0136] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0137] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] [ka] [ka] [ka] is selected from.

[0138] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] [ka] is selected from.

[0139] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0140] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0141] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0142] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0143] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0144] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0145] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0146] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0147] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0148] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is an N-linked cyclic amine selected from:

[0149] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is of the following formula: [ka] Based on a) A is -C(H)-, Z is -C(F)-, G is -N-, R2 is F and R1 is H, or b) A is -N-, Z is -C(F)-, G is -N-, R2 is F and R1 is H; or c) A is -C(H)-, Z is -C(H)-, G is -N-, R2 is F and R1 is H, or d) A is -N-, Z is -C(H)-, G is -N-, R2 is F and R1 is H; or e) A is -C(H)-, Z is -N-, G is -N-, R2 is F and R1 is H; or f) A is -N-, Z is -N-, G is -N-, R2 is F and R1 is H; or g) A is -C(H)-, Z is -C(F)-, G is -C(H)-, R2 is F and R1 is H, or h) A is -N-, Z is -C(F)-, G is -C(H)-, R2 is F and R1 is H; or i) A is -C(H)-, Z is -C(H)-, G is -C(H)-, R2 is F and R1 is H; j) A is -N-, Z is -C(H)-, G is -C(H)-, R2 is F and R1 is H; or k) A is -C(H)-, Z is -N-, G is -C(H)-, R2 is F and R1 is H; or l) A is -N-, Z is -N-, G is -C(H)-, R2 is F and R1 is H, or m) A is -C(H)-, Z is -C(F)-, G is -C(F)-, R2 is F and R1 is H, or n) A is -N-, Z is -C(F)-, G is -C(F)-, R2 is F and R1 is H, or o) A is -C(H)-, Z is -C(H)-, G is -C(F)-, R2 is F and R1 is H, or p) A is -N-, Z is -C(H)-, G is -C(F)-, R2 is F and R1 is H, or q) A is -C(H)-, Z is -N-, G is -C(F)-, R2 is F and R1 is H, or r) A is -N-, Z is -N-, G is -C(F)-, R2 is F and R1 is H, or s) A is -C(H)-, Z is -C(F)-, G is -N-, R2 is Cl and R1 is H; or t) A is -N-, Z is -C(F)-, G is -N-, R2 is Cl and R1 is H; or u) A is -C(H)-, Z is -C(H)-, G is -N-, R2 is Cl and R1 is H; or v) A is -N-, Z is -C(H)-, G is -N-, R2 is Cl and R1 is H, or w) A is -C(H)-, Z is -N-, G is -N-, R2 is Cl and R1 is H, or x) A is -N-, Z is -N-, G is -N-, R2 is Cl and R1 is H, or y) A is -C(H)-, Z is -C(F)-, G is -C(H)-, R2 is Cl and R1 is H, or z) A is -N-, Z is -C(H)-, G is -C(H)-, R2 is Cl and R1 is H, or aa) A is -N-, Z is -C(H)-, G is -C(H)-, R2 is Cl and R1 is H, or bb) A is -C(H)-, Z is -N-, G is -C(H)-, R2 is Cl and R1 is H, or cc) A is -N-, Z is -N-, G is -C(H)-, R2 is Cl and R1 is H, or dd) A is -C(H)-, Z is -C(F)-, G is -C(F)-, R2 is Cl and R1 is H; or ee) A is -N-, Z is -C(F)-, G is -C(F)-, R2 is Cl and R1 is H; or ff) A is -C(H)-, Z is -C(H)-, G is -C(F)-, R2 is Cl and R1 is H, or gg) A is -N-, Z is -C(H)-, G is -C(F)-, R2 is Cl and R1 is H, or hh) A is -C(H)-, Z is -N-, G is -C(F)-, R2 is Cl and R1 is H, or ii) A is -N-, Z is -N-, G is -C(F)-, R2 is Cl and R1 is H.

[0150] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0151] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0152] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0153] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] wherein preferably each R6 is H.

[0154] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0155] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0156] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0157] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0158] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] It is.

[0159] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0160] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0161] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0162] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0163] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0164] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] It is.

[0165] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] It is.

[0166] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] wherein preferably each R6 is H.

[0167] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] It is.

[0168] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] wherein preferably each R6 is H.

[0169] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0170] In one embodiment of the compound of formula I or a pharma- ceutically acceptable salt thereof, R4 is [ka] is selected from.

[0171] In one of the above embodiments of the compound of formula I, or a pharma- ceutically acceptable salt thereof, R4 is a group represented by the following formula: [ka] where E2 and E4 are a bond or C 1~3Examples of these compounds of formula I are shown below, which may be optionally bridged by alkylene. [ka] or a pharma- ceutically acceptable salt thereof.

[0172] In one of the above embodiments of the compound of formula I, or a pharma- ceutically acceptable salt thereof, R4 is a group represented by the following formula: [ka] where E3 is -CO-NR 6a --It can be.

[0173] Examples of these compounds of formula I are shown below. [ka] or a pharma- ceutically acceptable salt thereof.

[0174] In the above embodiment of the compound of formula I, the chemical diagram is shown simply without chiral information.It is contemplated that these compounds often have multiple chiral centers and exist in various forms with various combinations of chiral centers.In addition, these compounds have various enantiomers, diastereomers, and atropisomers that may exist and are included herein.

[0175] In one embodiment of a compound of Formula I or a pharma- ceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharma- ceutically acceptable salt thereof.

[0176] It will be appreciated that isotopic derivatives can be prepared using any of a variety of techniques recognized in the art. For example, isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein by substituting an isotopically labeled reagent, or a pharma- ceutically acceptable salt thereof, for a non-isotopically labeled reagent.

[0177] In one embodiment of the compound of Formula I or a pharma- ceutically acceptable salt thereof, the compound is a deuterium-labeled compound of any one of the compounds described herein and pharma- ceutically acceptable salts thereof.

[0178] In the compounds of the present invention, any atom that is not specifically designated as a particular isotope is meant to represent the stable isotope of that atom.Unless otherwise specified, when an atom is specifically designated as "H" or "hydrogen", it is understood that the atom has hydrogen in its natural abundance isotopic composition.Also, unless otherwise specified, when an atom is specifically designated as "D" or "deuterium", it is understood that the atom has deuterium in an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.

[0179] A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0180] A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0181] A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0182] A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0183] A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0184] A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0185] A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0186] A compound of formula I or a pharma- ceutically acceptable salt thereof, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0187] The chemical diagrams of the compounds above include representations of the chiral aspects of the particular compounds shown. However, the chemical diagrams of the compounds above do not include all possible chiral features of those compounds, and the chiral representations shown are not intended to exclude variations to the chiral aspects shown. Thus, alternative chiral versions of the compounds, as well as different combinations of chiral attributes, are contemplated and included herein.

[0188] Also provided herein are pharmaceutical compositions comprising a compound according to Formula I, or a pharma- ceutically acceptable salt thereof (examples include, but are not limited to, the compounds disclosed herein), and a pharma- ceutically acceptable carrier, diluent, or excipient.

[0189] Further provided herein is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof. In this method, the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, gastric cancer, or esophageal cancer. In this method, the cancer can be more specifically non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In one embodiment, the cancer can be non-small cell lung cancer. In one embodiment, the cancer can be pancreatic cancer. In one embodiment, the cancer can be colorectal cancer.

[0190] Also provided herein is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12D protein. In this method, the cancer can be non-small cell lung cancer, pancreatic cancer, or colorectal cancer, having one or more cells expressing KRas G12D mutant protein. In one embodiment, the cancer is non-small cell lung cancer, having one or more cells expressing KRas G12D mutant protein. In one embodiment, the cancer is mutant pancreatic cancer, having one or more cells expressing KRas G12D mutant protein. In one embodiment, the cancer is colorectal cancer, having one or more cells expressing KRas G12D mutant protein. The method also includes treating cancers of other origins that have KRas G12D mutant. Also provided herein is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically 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 can 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 in other organs that have KRas G12C, G12D, and / or G12V mutants.

[0191] Further provided herein is a method of treating a patient with a cancer having a KRas G12D mutation, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof. In this method, the cancer having a KRas G12D mutation can be KRas G12D mutant lung cancer, KRas G12D mutant pancreatic cancer, KRas G12D mutant cervical cancer, KRas G12D mutant esophageal cancer, KRas G12D mutant endometrial cancer, KRas G12D mutant ovarian cancer, KRas G12D mutant cholangiocarcinoma, and KRas G12D mutant colorectal cancer. In one embodiment, the cancer having a KRas G12D mutation can be KRas G12D mutant non-small cell lung cancer. In one embodiment, the cancer having a KRas G12D mutation can be KRas G12D mutant pancreatic cancer. In one embodiment, the cancer harboring a KRas G12D mutation may be a KRas G12D mutant colorectal cancer.

[0192] Further provided herein is a method of treating a patient having a cancer harboring 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 formula I, or a pharma- ceutically acceptable salt thereof. In this method, the cancer harboring a KRas G12C, G12D, and / or G12V mutation can be a KRas G12C, G12D, and / or G12V mutant lung cancer, a KRas G12C, G12D, and / or G12V mutant pancreatic cancer, a KRas G12C, G12D, and / or G12V mutant cervical cancer, a KRas G12C, G12D, and / or G12V mutant esophageal cancer, a KRas G12C, G12D, and / or G12V mutant endometrial cancer, a KRas G12C, G12D, and / or G12V mutant ovarian cancer, a KRas G12C, G12D, and / or G12V mutant cholangiocarcinoma, and a KRas G12C, G12D, and / or G12V mutant colorectal cancer. In one embodiment, the cancer with KRas G12C, G12D, and / or G12V mutations can be KRas G12C, G12D, and / or G12V mutant non-small cell lung cancer. In one embodiment, the cancer with KRas G12C, G12D, and / or G12V mutations can be KRas G12C, G12D, and / or G12V mutant pancreatic cancer. In one embodiment, the cancer with KRas G12C, G12D, and / or G12V mutations can be KRas G12C, G12D, and / or G12V mutant colorectal cancer.

[0193] Additionally provided herein is a method of modulating mutant KRas G12D enzyme in a patient in need of such modulation by administering a compound according to formula I, or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises inhibiting human mutant KRas G12D enzyme. Additionally provided herein is a method of modulating mutant KRas G12C, G12D, and / or G12V enzyme in a patient in need of such modulation by administering a compound according to formula I, or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises inhibiting human mutant KRas G12C, G12D, and / or G12V enzyme.

[0194] Also provided herein is a method of treating cancer in a patient in need of cancer treatment, where the patient has a cancer determined to express KRas G12D mutant protein. The method comprises administering to the patient an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof. Also provided herein is a method of treating cancer in a patient in need of cancer treatment, where the patient has a cancer determined to express KRas G12C, G12D, and / or G12V mutant protein. 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 mutation 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 cancers. Non-limiting 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, as well as pyrosequencing and multi-analyte profiling.

[0195] Further provided herein is a compound according to formula I or a pharma- ceutically acceptable salt thereof for use in therapy. The compound or a pharma- ceutically acceptable salt thereof may be for use in the treatment of cancer. In the case of this use in the treatment of cancer, the cancer may be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. The cancer may more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is colorectal cancer. The cancer may have one or more cancer cells expressing mutant KRas G12D protein, for example, KRas G12D mutant lung cancer, KRas G12D mutant pancreatic cancer, KRas G12D mutant cervical cancer, KRas G12D mutant esophageal cancer, KRas G12D mutant endometrial cancer, KRas G12D mutant ovarian cancer, KRas G12D mutant cholangiocarcinoma, and KRas G12D mutant colorectal cancer. In these uses, the cancer is selected from KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer. Additionally, the cancer may be non-small cell lung cancer, and one or more cells express the G12D mutant protein. Furthermore, the cancer may be colorectal cancer, and one or more cells express the KRas G12D mutant protein. Additionally, the cancer may be pancreatic cancer, and one or more cells express a KRas G12D mutant protein. The patient may have a cancer that is determined to have one or more cells that express a KRas G12D mutant protein prior to administration of the compound or a pharma- ceutically acceptable salt thereof.The cancer may have one or more cancer cells expressing mutant KRas G12C, G12D, and / or G12V proteins, and can be, 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 can be non-small cell lung cancer, where one or more cells express KRas G12C, G12D, and / or G12V mutant proteins. Furthermore, the cancer can be colorectal cancer, where one or more cells express KRas G12C, G12D, and / or G12V mutant proteins. Additionally, the cancer can be pancreatic cancer, where one or more cells express KRas G12C, G12D, and / or G12V mutant proteins. The patient may have a cancer that has been determined to have one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins prior to administration of the compound or a pharma- ceutically acceptable salt thereof. The patient may have been treated with a different course of therapy prior to being treated as described herein.

[0196] The compounds provided herein according to formula I, or pharma- ceutically acceptable salts thereof, may also be used to manufacture a medicament for the treatment of cancer. When used to manufacture a medicament, the cancer may be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. The cancer may more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is colorectal cancer. The cancer may have one or more cancer cells that express mutant KRas G12D protein. When the cancer cells express KRas G12D protein, the cancer may be selected from KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer. The cancer may have one or more cancer cells that express mutant KRas G12C, G12D, and / or G12V proteins. If the cancer cells express KRas G12C, G12D, and / or G12V proteins, the cancer may 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.

[0197] Also provided herein is a method of treating cancer comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, and one or more of 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 pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells that express a mutant KRas G12D protein. Also provided herein is a method of treating cancer comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, and one or more of 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 pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins.Further provided herein is a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer in simultaneous, separate, or sequential combination with 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 a pharma- ceutically acceptable salt thereof. Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and one or more of 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 a pharma- ceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of cancer.

[0198] Also provided is a method of 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 a PD-1 or PD-L1 inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Also provided is a method of 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 a PD-1 or PD-L1 inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a PD-1 or PD-L1 inhibitor for use in the treatment of cancer. Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor for simultaneous, separate or sequential use in the treatment of cancer. As used herein, the PD-1 or PD-L1 inhibitor may be pembrolizumab, the PD-1 or PD-L1 inhibitor may be nivolumab, the PD-1 or PD-L1 inhibitor may be cemiplimab, the PD-1 or PD-L1 inhibitor may be sintilimab, the PD-1 or PD-L1 inhibitor may be atezolizumab, the PD-1 or PD-L1 inhibitor may be avelumab, the PD-1 or PD-L1 inhibitor may be durvalumab, or the PD-1 or PD-L1 inhibitor may be lodapilimab. As described herein, the cancer can be a non-small cell lung cancer, where the cancer has one or more cells that express a KRas G12D mutant protein, the cancer can be a colorectal cancer, where the cancer has one or more cells that express a KRas G12D mutant protein, or the cancer can be a mutant pancreatic cancer, where the cancer has one or more cells that express a KRas G12D mutant protein. The method also includes treating cancers of other origins that have a KRas G12D mutant.As described herein, the cancer may be non-small cell lung cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, the cancer may be colorectal cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, or the cancer may be mutant pancreatic cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins. The methods also include treating cancers of other organs that have KRas G12C, G12D, and / or G12V mutants.

[0199] Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. As used herein, the CDK4 / CDK6 inhibitor can be abemaciclib, the CDK4 / CDK6 inhibitor can be palbociclib, or the CDK4 / CDK6 inhibitor can be ribociclib. As described herein, the cancer can be non-small cell lung cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, the cancer can be colorectal cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, and the cancer can be mutant pancreatic cancer, where the cancer has one or more cells expressing KRas G12D mutant protein. The method also includes treating cancers of other origins that have KRas G12D mutant. Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells that express mutant KRas G12C, G12D, and / or G12V proteins.Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins.Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharma- ceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins.As used herein, the CDK4 / CDK6 inhibitor can be abemaciclib, the CDK4 / CDK6 inhibitor can be palbociclib, or the CDK4 / CDK6 inhibitor can be ribociclib. As described herein, the cancer can be non-small cell lung cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, the cancer can be colorectal cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, and the cancer can be mutant pancreatic cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins. The methods also include treating cancers in other organs that have KRas G12C, G12D, and / or G12V mutants.

[0200] Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer. Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, for simultaneous, separate, or sequential use in 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, the cancer can be a non-small cell lung cancer, where the cancer has one or more cells that express a KRas G12D mutant protein, the cancer can be a colorectal cancer, where the cancer has one or more cells that express a KRas G12D mutant protein, or the cancer can be a mutant pancreatic cancer, where the cancer has one or more cells that express a KRas G12D mutant protein. The method also includes treating cancers of other origins that have a KRas G12D mutant.

[0201] Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer. Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor, or a pharma- ceutically acceptable salt thereof, for simultaneous, separate, or sequential use in 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, the cancer may be non-small cell lung cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, the cancer may be colorectal cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, or the cancer may be mutant pancreatic cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins. The methods also include treating cancers of other organs that have KRas G12C, G12D, and / or G12V mutants.

[0202] Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an ERK inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an ERK inhibitor, or a pharma- ceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V protein. Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Also provided is a method of treating cancer comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V. Further provided is a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V protein. Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an ERK inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells that express a mutant KRas G12D protein.Further provided is a compound according to formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins.Additionally provided is a combination comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate or sequential use in the treatment of cancer.As used herein, the ERK inhibitor can be LY3214996, the ERK inhibitor can be LTT462, or the ERK inhibitor can be KO-947. As described herein, the cancer may be non-small cell lung cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, the cancer may be colorectal cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, and the cancer may be mutant pancreatic cancer, where the cancer has one or more cells expressing KRas G12D mutant protein. The method also includes treating cancers of other origins that have KRas G12D mutations. As described herein, the cancer may be non-small cell lung cancer, where the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant protein, the cancer may be colorectal cancer, where the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant protein, and the cancer may be mutant pancreatic cancer, where the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant protein. The methods also include treating cancers in other organs that harbor KRas G12C, G12D, and / or G12V mutations.

[0203] Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an Aurora A inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate or sequential use in the treatment of cancer. Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to Formula I, or a pharma- ceutically 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 is a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additionally provided is a combination comprising a compound according to Formula I, or a pharma- ceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer.As used herein, Aurora A inhibitors include alisertib, tozasertib, (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, (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:2-methylpropan-2-amine (1:1) salt, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt, or a pharma- ceutically acceptable salt 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-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid. As described herein, the cancer can be non-small cell lung cancer, the cancer can have one or more cells expressing KRas G12D mutant protein, the cancer can be colorectal cancer, the cancer can have one or more cells expressing KRas G12D mutant protein, the cancer can be mutant pancreatic cancer, the cancer can have one or more cells expressing KRas G12D mutant protein. The method also includes treating cancers of other origins that have KRas G12D mutant. As described herein, the cancer may be non-small cell lung cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins; the cancer may be colorectal cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins; and the cancer may be mutant pancreatic cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins.The methods also include treating cancers in other organs that harbor KRas G12C, G12D, and / or G12V mutations.

[0204] Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an SHP2 inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an SHP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an SHP2 inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V protein. Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with an SHP2 inhibitor, or a pharma- ceutically acceptable salt thereof, for the treatment of cancer, where the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and an SHP2 inhibitor, for simultaneous, separate or sequential use in the treatment of cancer. As used herein, an SHP2 inhibitor, or a pharma- ceutically acceptable salt thereof, can 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 cefsulodin, and pharma- ceutically acceptable salts thereof. 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, and pharma- ceutically acceptable salts thereof.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, and pharma- ceutically acceptable salts thereof.As described herein, the cancer may be non-small cell lung cancer, in which the cancer has one or more cells expressing KRas G12D mutant protein, the cancer may be colorectal cancer, in which the cancer has one or more cells expressing KRas G12D mutant protein, and the cancer may be mutant pancreatic cancer, in which the cancer has one or more cells expressing KRas G12D mutant protein.The method also includes treating cancers of other origins that have KRas G12D mutant. As described herein, the cancer can be non-small cell lung cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, the cancer can be colorectal cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, and the cancer can be mutant pancreatic cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins. The methods also include treating cancers in other organs that have KRas G12C, G12D, and / or G12V mutants.

[0205] Also provided is a method of 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 a platinum agent, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Also provided is a method of 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 a platinum agent, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V protein. Further provided is a compound according to formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a platinum agent, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and a platinum agent for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the platinum agent can be cisplatin, the platinum agent can be carboplatin, or the platinum agent can be oxaliplatin. As described herein, the cancer can be non-small cell lung cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, the cancer can be colorectal cancer, where the cancer has one or more cells expressing KRas G12D mutant protein, or the cancer can be mutant pancreatic cancer, where the cancer has one or more cells expressing KRas G12D mutant protein. The method also includes treating cancers of other origins that have KRas G12D mutant. As used herein, the platinum agent can be cisplatin, the platinum agent can be carboplatin, or the platinum agent can be oxaliplatin.As described herein, the cancer can be non-small cell lung cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, the cancer can be colorectal cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, and the cancer can be mutant pancreatic cancer, where the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins. The methods also include treating cancers in other organs that have KRas G12C, G12D, and / or G12V mutants.

[0206] Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and pemetrexed, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with pemetrexed for the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and pemetrexed for simultaneous, separate, or sequential use in the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12D protein. As described herein, the cancer has one or more cells expressing mutant KRas G12D protein. Additionally, a platinum agent may be administered to the patient (the platinum agent may be cisplatin, carboplatin, or oxaliplatin). As described herein, the cancer may be colorectal cancer, where the cancer has one or more cells expressing a mutant KRas G12D protein, or the cancer may be mutant pancreatic cancer, where the cancer has one or more cells expressing a mutant KRas G12D protein. The method also includes treating cancers of other origins that have a KRas G12D mutation. Also provided is a method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and pemetrexed, where the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided is a compound according to formula I, or a pharma- ceutically acceptable salt thereof, for use in simultaneous, separate or sequential combination with pemetrexed for the treatment of cancer, wherein the cancer has one or more cells that express mutant KRas G12C, G12D, and / or G12V proteins.Additionally provided is a combination comprising a compound according to formula I, or a pharma- ceutically acceptable salt thereof, and pemetrexed for simultaneous, separate or sequential use in the treatment of cancer, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. As described herein, the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. In addition, a platinum agent may be administered to the patient (the platinum agent may be cisplatin, carboplatin, or oxaliplatin). 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 methods also include treating cancers in other organs that harbor KRas G12C, G12D, and / or G12V mutations.

[0207] The term "pharmaceutical acceptable salt" as used herein refers to a salt of a compound that is deemed acceptable for clinical and / or veterinary use. Examples of pharmaceutical acceptable salts and the general methodology for their preparation can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P.Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M.Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. In one embodiment of the compound of formula I or a pharmaceutical acceptable salt thereof, the pharmaceutical acceptable salt is a mineral acid salt. Examples of mineral acids include, but are not limited to, HCl, H2SO4, H3PO4, and HNO3. In another embodiment, the pharmaceutical acceptable salt is a sulfonate salt. Examples of sulfonic acids include, but are not limited to, para-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, and trifluoromethanesulfonic acid.

[0208] Pharmaceutical compositions containing the compounds of formula I described herein may be prepared using pharma- ceutically acceptable excipients. The term "pharmaceutical acceptable excipients" as used herein for pharmaceutical compositions refers to one or more carriers, diluents, and excipients that are compatible with other excipients of the composition or formulation and are not harmful to the patient. Examples of pharmaceutical compositions and processes for their preparation are described in "Remington: The Science and Practice of Pharmacy", Loyd, V., et al. Eds., 22 ndEd., Mack Publishing Co., 2012. Non-limiting examples of pharma- ceutically acceptable carriers, diluents, and excipients include saline, water, starch, sugars, mannitol, and silica derivatives; binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethyl glycols.

[0209] As used herein, the term "effective amount" refers to an amount that is a dosage that is effective to achieve a desired therapeutic result, such as the treatment of a disorder or disease, e.g., a cancerous lesion or the progression of abnormal cell proliferation and / or cell division. Factors to be considered in determining the effective amount or dose of a compound include: whether the compound or its salt is administered, if used, the co-administration of other drugs, the type of patient being treated, the size, age, sex, and general health of the patient, the extent or involvement or severity of the disorder, the response of the individual patient, the mode of administration, the bioavailability characteristics of the administered preparation, the selected dosing regimen, and the use of other concomitant drugs.

[0210] The treating physician, veterinarian, or other medical professional will be able to determine the effective amount of the compound for treating the patient in need of treatment. The pharmaceutical composition can be formulated as a tablet or capsule for oral administration, as a solution for oral administration, or as a solution for injection. The tablet, capsule, or solution can contain an effective amount of the compound of the present invention to treat the patient in need of treatment for cancer.

[0211] As used herein, the terms "treating," "treat," or "treatment" include slowing, managing, retarding, alleviating, arresting, reversing, preventing, or ameliorating 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 indicate the complete disappearance of all disorder or disease symptoms.

[0212] As used herein, the term "patient" refers to a mammal in need of treatment. In particular, a patient can be a human in need of treatment for cancer, e.g., cancer with KRas G12C, G12D and / or G12V mutations.

[0213] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "AcOH" or "HOAc" refers to acetic acid, "AIBN" refers to azobisisobutyronitrile, "Alloc" refers to allyloxycarbonyl group, "aq." refers to aqueous, "atm" refers to atmosphere, "Boc-Gly-OH" refers to N-(tert-butoxycarbonyl)glycine, "BrettPhos" refers to 2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-trimethylphenylphosphino, and "AcOH" refers to acetic acid. isopropyl-1,1'-biphenyl, "BroP" refers to bromotris(dimethylamino)phosphonium hexafluorophosphate, "Cbz" refers to 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, "DIAD" refers to diisopropyl azodicarboxylate, and "DIBA" refers to dichloromethane. "L-H" refers to diisobutylaluminum hydride, "DIEA" and "DIPEA" refer to N,N-diisopropylethylamine, "(dippf)Rh(cod)BF4" refers to [1,4-bis(diphenylphosphino)butane](1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, "DMAP" refers to 4-dimethylaminopyridine, "DMEA" refers to N,N-dimethylethylamine, and "DMEM" refers to 1,4-bis(diphenylphosphino)butane. "D" refers to Dulbecco's modified Eagle's medium, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "DNA" refers to deoxyribonucleic acid, "DPEPhosPdCl2" refers to dichlorobis(diphenylphosphinophenyl)etherpalladium(II), "DTT" refers to dithiothreitol, "EDTA" refers to ethylenediaminetetraacetic acid, and "EGTA" refers to ethylene glycol-bis(b-aminoethyl ether)-N,N,N',N'-tetraacetic acid, "ELISA" refers to enzyme-linked immunosorbent assay, "ERK" refers to extracellular signal-regulated kinase, "EtOAc" 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]pyridinium 3-oxide hexafluorophosphate," "Hex" or "hex" refers to hexane or hexanes, "HPLC" refers to high performance liquid chromatography, "HRP" refers to horseradish peroxidase, "IPA" refers to isopropyl alcohol, "IPAm" refers to isopropylamine, "KOAc" refers to potassium acetate, "LC-ES / MS" refers to liquid chromatography-electrospray mass spectrometry, "LC / MS" refers to liquid chromatography-mass spectrometry, "LiHMDS" refers to lithium bis(trimethylsilyl)amide, "L-prolinol" refers to [(2S)-pyrrolidin-2yl]methanol, "MAPK" refers to mitogen-activated protein kinase, "mCPBA" refers to 3-chloro-peroxybenzoic acid, "Me" refers to a methyl group, "MeOH" refers to methanol, "min" refers to minutes, "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-methylpyrrolidin-2-yl]methanol, "NMM" refers to N-methylmorpholine, "NMP" refers to 1-methylpyrrolidin-2-one, "NIS" refers to N-iodosuccinimide, "PCR" refers to polymerase chain reaction, "Pd-117" refers to dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II), CAS 205319-06-8, "Pd-118" refers to 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride, CAS 95408-45-0, "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium(0), and "Pd(dppf)Cl2" refers to [1,"Pd(OAc)2" refers to palladium(II) acetate; "Pd(PPh3)4" refers to tetrakis(triphenylphosphine)palladium(0); "PE" refers to petroleum ether or diethyl ether; "Ph" refers to phenyl; "RBF" refers to round bottom flask; "RPMI" refers to Roswell Park Memorial Institute; "RT" refers to room temperature; "RuPhos" refers to 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, CAS 787618-22-8, "sat." refers to saturated, "SCX" refers to strong cation exchange, "SelectFluor™" refers to 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), "SPE" refers to solid phase extraction, "SPhos" refers to 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl, "TBAF" refers to tetrabutylammonium fluoride, and "TBDMSCl" refers to tert-butyldiammonium fluoride. "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "TMEDA" refers to tetramethylethylenediamine, "t, R" refers to retention time, "XantPhos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "XPhos" refers to 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-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 methanesulfonato(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), CAS 1599466-81-5.

[0214] Individual isomers, enantiomers, diastereomers, and atropisomers can be separated or resolved at any convenient point in the synthesis of the compounds listed below by methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and EL Eliel and SH Wilen, "Stereochemistry of Organic Compounds", Wiley-Interscience, 1994). The molecules described herein include compounds that are atropisomers and can exist in different conformations or as different rotamers. Atropisomers are compounds that exist in different conformations resulting from restricted rotation around a single bond. Atropisomers can be isolated as separate chemical species if the energy barrier for rotation around a single bond is high enough and the interconversion rate is slow enough to separate the individual rotamers from each other. This specification is intended to include all isomers, enantiomers, diastereomers, and atropisomers that are possible for the compounds disclosed herein or that can be made using the compounds disclosed herein. In the molecules described herein, only those molecules in which the absolute configuration (or atropisomeric configuration) of the chiral center is known use the naming convention or chemical formula drawn to indicate chirality or atropisomerism. Those skilled in the art will be able to easily understand and identify when other chiral centers are present in the molecules described herein.

[0215] Any one of the compounds of formula I that can chemically form salts can be easily converted into pharma- ceutically acceptable salts and isolated as pharma-ceutically acceptable salts. Salt formation can occur upon addition of a pharma- ceutically 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).

[0216] The compounds of the present invention, or salts thereof, can be prepared by a variety of procedures, some of which are illustrated in the following schemes, preparations, and examples. The specific synthetic steps of each of the routes described may be combined in different ways or combined with steps of different routes to prepare the compounds or salts of the present invention. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.

[0217] Preparation 1 5-Fluoroisobenzofuran-1(3H)-one [ka] To a stirred mixture of (2-bromo-5-fluorophenyl)methanol 500 g, 2.44 mol) and TEA (474.6 mL, 3.41 mol, 1.4 equiv) in ACN (2500 mL) was added Pd(OAc)2 (10.95 g, 48.77 mmol, 0.02 equiv) and XantPhos (42.33 g, 73.16 mmol, 0.03 equiv) at room temperature and then stirred at 120 °C under 10 atm of carbon monoxide for 3 days. The reaction was cooled to room temperature and concentrated. The residue was diluted with H2O (1,000 mL) and then extracted with EtOAc (2 x 2000 mL). The combined organic layers were washed with brine (2 x 1,000 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was triturated with 10:1 hexanes / EtOAc (1,100 mL) and then filtered. The filter cake was dried at 50° C. for about 18 hours to give the title compound (300 g, 81%) as a yellow solid. MS (ES) m / z=153 (M+1).

[0218] Preparation 2 4-Bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one [ka] To a stirred mixture of 5-fluoroisobenzofuran-1(3H)-one (300 g, 1.97 mol) in H2SO4 (1,500 mL) was added HNO3 (273.38 g, 4.348 mol, 2.2 equiv) dropwise at 65 °C. The reaction was stirred for 1 h and then cooled to room temperature. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (2,255.43 g, 7.88 mol, 4 equiv) was added in small portions over 20 min and stirred at room temperature for about 18 h. The mixture was poured into ice / water (pretreated with 3 kg Na2SO3) and filtered. The filter cake was dissolved in EtOAc (3,000 mL), washed with saturated aqueous Na2CO3 (2 x 1,000 mL), brine (2 x 1,000 mL), dried over anhydrous Na2SO4, and concentrated. The residue was triturated with 10:1 hexanes / EtOAc (660 mL), filtered, and dried at 50° C. for approximately 18 h to give 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).

[0219] Preparation 3 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran [ka] To a stirred mixture of 4-bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one (270 g, 978 mmol) in DCM (2,500 mL) was added DIBAL-H (1 M in THF, 1,467 mL, 1.467 mol, 1.5 equiv) dropwise under N2 at -78 °C. The reaction was stirred at -78 °C for 5 h and then quenched with 5N NaOH (300 mL) at -78 °C. The resulting mixture was allowed to warm to room temperature and then concentrated. The residue was diluted with EtOAc (2,500 mL), washed with brine (2 x 1,000 mL), dried over anhydrous Na2SO4, and concentrated. The residue was triturated with 10:1 hexanes / EtOAc (550 mL) and filtered. The solid was dried (190 g, 683.4 mmol) and then dissolved in DCM (1,500 mL) and treated dropwise with EtSiH (662 mL, 4.10 mol, 6 equiv) at 0 °C. The reaction was stirred at 0 °C for 20 min. TFA (152 mL, 2.05 mol, 3 equiv) was added dropwise at 0 °C. The ice bath was removed and the reaction was stirred at room temperature for about 18 h. The reaction was concentrated to an oil, which was diluted with EtOAc (2,000 mL), washed with saturated aqueous NaCO (2 x 500 mL) and brine (2 x 500 mL), dried over anhydrous NaSO, filtered and concentrated to give 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 = 6.2 Hz, 1H), 5.18-5.15 (m, 2H), 5.11-5.06 (m, 2H).

[0220] Preparation 4 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine [ka] To a stirred mixture of 4-bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (110 g, 420 mmol) and NH4Cl (112.3 g, 2.10 mol, 5 equiv.) in EtOH (1,000 mL) and HO (200 mL) was added Fe (117.22 g, 2.09 mol, 5 equiv.) in small portions at room temperature and then stirred at 80 °C for about 18 h. The mixture was filtered and concentrated. The mixture was diluted with HO (500 mL) and extracted with EtOAc (2 x 1,000 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on silica (25%-50% EtOAc / Hexanes) to give the title compound (70 g, 72%) as a yellow solid. MS (ES) m / z = 231 (M+1).

[0221] Preparation 5 (4-Chloro-1,2-phenylene)dimethanol [ka] A solution of 4-chlorophthalic anhydride (250 g, 1.34 mol, 1.00 equiv) in THF (500 mL) was added dropwise to a stirred mixture of LiAlH4 (1.9 L, 2.74 mol, 2 equiv, 2.5 M in THF) in THF (1 L) at −20° C. under N2. The resulting mixture was stirred at 45° C. under N2 for 30 min. The reaction was quenched by the addition of 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 give 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).

[0222] Preparation 6 5-Chloro-1,3-dihydroisobenzofuran [ka] To a stirred mixture of (4-chloro-1,2-phenylene)dimethanol (219.5 g, 1.271 mol) and dimethyl carbonate (458.2 g, 5.082 mol, 4 equiv.) in ACN (3 L) was added NaOMe (137.4 g, 2.544 mol, 2 equiv.) in small portions at room temperature. The resulting mixture was stirred at 80 °C under N for about 18 h. The mixture was concentrated under reduced pressure, diluted with H2O (2 L) and extracted with EtOAc (3 x 2 L). The combined organic layers were washed with brine (2 x 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica (10:1 to 8:1 hexanes / EtOAc) to give 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).

[0223] Preparation 7 5-Chloro-6-nitro-1,3-dihydroisobenzofuran [ka] A solution of 5-chloro-1,3-dihydroisobenzofuran (110 g, 712 mmol) in H2SO4 (700 mL) at -10°C was dropwise charged with a solution of KNO3 (64.74 g, 640 mmol, 0.9 equiv) in H2SO4 (200 mL) at -5°C to 0°C. The resulting mixture was stirred at 0°C for an additional 30 min and then slowly added to stirred ice-cold H2O. The precipitated solid was collected by filtration and washed with H2O (3 x 1 L). The filter cake was dried in vacuum to give 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) δ8.05 (s, 1H), 7.75 (s, 1H), 5.07-5.02 (m, 4H).

[0224] Preparation 8 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran [ka] To a stirred solution of 5-chloro-6-nitro-1,3-dihydroisobenzofuran (125 g, 626 mmol) in H2SO4 (700 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (179.1 g, 626.3 mmol, 1 equiv) in small portions at -10 °C. The mixture was stirred at -10 °C for 1 h and then slowly added to stirred ice-cold H2O. The precipitated solid was collected by filtration and washed with H2O (3 x 0.5 L). The filter cake was dried in vacuum and purified on silica (10:1 to 5:1 hexanes / EtOAc) to give the title compound (83.5 g, 47.9%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.07 (d, J = 1.1 Hz, 1H), 5.19 (dt, J = 2.3, 1.1 Hz, 2H), 5.08 (t, 2H).

[0225] Preparation 9 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine [ka] To a stirred mixture of 4-bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran (37.0 g, 133 mmol) and NH4Cl (42.64 g, 797.2 mmol, 6 equiv) in EtOH (200 mL) and HO (40 mL) was added Fe (44.52 g, 797.2 mmol, 6 equiv) in small portions at room temperature. The resulting mixture was stirred at 80 °C for about 18 h. The resulting mixture was filtered hot and the filter cake was washed with EtOAc (3 x 500 mL). The filtrate was concentrated under reduced pressure and purified on silica (15:1 to 10:1 hexanes / EtOAc) to give the title compound (25 g, 76%) as a pale yellow solid. MS (ES) m / z = 248 (M+1).

[0226] Preparation 10 N-(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide [ka] To a stirred solution of 7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine (6.00 g, 24.1 mmol) and 3-ethoxyprop-2-enoyl chloride (4.06 g, 30.2 mmol) in THF (50 mL) was added pyridine (3.82 g, 48.3 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the product (6.00 g, 66.0%) as a yellow solid. MS (ES) m / z=346 (M+1).

[0227] Preparation 11 N-(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide [ka] 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine was used in a manner similar to the method of Preparation 10 to give the title compound (1.4 g, 89%) as a pale yellow solid. MS (ES) m / z=332 (M+1).

[0228] Preparation 12 4-Bromo-5-chloro-3,6-dihydrofuro[3,4-f]quinolin-7(1H)-one [ka] To a stirred solution of H2SO4 (20 mL) was added N-(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide (6.10 g, 17.6 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature for about 18 h. The mixture was slowly added to stirred ice-cold water (200 mL). The precipitated solid was collected by filtration and washed with H2O (3 x 100 mL). The filter cake was dried under vacuum to give the product (5.00 g, 87.0%) as a yellow solid. MS (ES) m / z = 300 (M+1).

[0229] Preparation 13 4-Bromo-5-fluoro-3,6-dihydrofuro[3,4-f]quinolin-7(1H)-one [ka] N-(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide was used in a manner similar to that described for Preparation 12 to give the title compound (1.2 g, quantitative yield) as a brown solid. MS (ES) m / z=284 (M+1).

[0230] Preparation 14 4-Bromo-5,7-dichloro-1,3-dihydrofuro[3,4-f]quinoline [ka] To a stirred solution of 4-bromo-5-chloro-3,6-dihydrofuro[3,4-f]quinolin-7(1H)-one (5.00 g, 16.6 mmol) in DMF (20 mL) was added POCl3 (9.30 mL, 99.8 mmol) dropwise at 0 °C. The resulting mixture was stirred at 90 °C for 2 h. The mixture was slowly added to stirred ice-cold water (200 mL). The precipitated solid was collected by filtration and washed with H2O (3 x 100 mL). The filter cake was dried under vacuum to give the product (3.50 g, 62.7%) as a yellow solid. MS (ES) m / z = 318 (M+1).

[0231] Preparation 15 4-Bromo-7-chloro-5-fluoro-1,3-dihydrofuro[3,4-f]quinoline [ka] A stirred suspension of 4-bromo-5-fluoro-3,6-dihydrofuro[3,4-f]quinolin-7(1H)-one (1.2 g, 4.2 mmol) in DCM (40 mL) was charged with (chloromethylene)dimethyliminium chloride (2.2 g, 17 mmol, 4 equiv.) and stirred at room temperature for approximately 18 h. The reaction was diluted with DCM and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give a solid which was triturated with a small amount of DCM. The solid was filtered, washed with a small amount of DCM, and air-dried to give batch 1. The filtrate was concentrated and purified on silica gel eluting with EtOAc / Hexanes (0% to 80%) to give batch 2. Both batches were combined to give the title compound (1.0 g, 78%) as a brown solid. MS (ES) m / z=304 (M+1).

[0232] Preparation 16 (1-(((4-bromo-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)oxy)methyl)cyclopropyl)methanol [ka] To a solution of (1-(hydroxymethyl)cyclopropyl)methanol (1.52 g, 14.9 mmol) in DMF (30 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 15 mL, 15.0 mmol) under nitrogen at 0° C. After 15 min, a solution of 4-bromo-7-chloro-5-fluoro-1,3-dihydrofuro[3,4-f]quinoline (1.50 g, 4.96 mmol) in DMF (8 mL) was added dropwise. The reaction mixture was heated to 50° C. After 2 h, the reaction mixture was diluted with water (100 mL) and extracted with DCM (3×200 mL). The combined organics were washed with water (3×100 mL) and then with brine (3×100 mL). The organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.35 g, crude). MS(ES) m / z=368(M+1).

[0233] Preparation 17 (1-(((4-bromo-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)oxy)methyl)cyclopropyl)methanesulfonate methyl [ka] A mixture of (1-(((4-bromo-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)oxy)methyl)cyclopropyl)methanol (1.35 g, 3.66 mmol) and THF (10 mL) was cooled to 0° C. under nitrogen. Diisopropylethylamine (4.74 g, 36.7 mmol) was added. The mixture was stirred for 20 min and then warmed to room temperature. Methanesulfonic anhydride (3.19 g, 18.4 mmol) was added dropwise. After 2 h, the reaction mixture was concentrated under reduced pressure to give the crude title compound. MS (ES) m / z=446 (M+1).

[0234] Preparation 18 4-Bromo-5-fluoro-7-((1-(morpholinomethyl)cyclopropyl)methoxy)-1,3-dihydrofuro[3,4-f]quinoline [ka] To a mixture of methyl (1-(((4-bromo-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)oxy)methyl)cyclopropyl)methanesulfonate (2.22 g, crude, 4.93 mmol) and DMF (50 mL) was added diisopropylethylamine (4.76 g, 24.6 mmol) at room temperature under nitrogen. The mixture was stirred for 10 min, morpholine (1.29 g, 10.1 mmol) was added dropwise and then heated at 90 °C. After 3 h, the reaction mixture was diluted with EtOAc (200 mL) and washed with brine (3 x 50 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica eluting with 25-50% EtOAc in PE to give the title compound (0.40 g, 18%) as a yellow solid. MS (ES) m / z = 437 (M+1).

[0235] Preparation 19 N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl) Carbamothioyl]Ethyl Carbamate [ka] A solution of 7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (20.4 g, 87.9 mmol) in DCM (550 mL) was slowly charged with ethoxycarbonyl isothiocyanate (9.7 mL, 82 mmol, 0.93 equiv) via addition funnel and then stirred at room temperature for about 4 hours. The solid was filtered. The filtrate was concentrated and suspended in DCM (100 mL) and hexanes (350 mL) and stirred at room temperature. The resulting filtered solid and the previous filtered solid were dried under vacuum at 50° C. for 2 hours. The batches were combined to give the title compound (32.6 g, quantitative yield) as a white solid. MS (ES) m / z=363 (M+1).

[0236] Preparation 1A Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate [ka] 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine was used in a manner similar to the method of Preparation 19 to give the title compound (14 g, 92%) as a white solid. MS (ES) m / z=379 (M+1).

[0237] Preparation 20 Ethyl (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate [ka] A 2 L three-neck RBF equipped with an overhead stirrer, dropping funnel, and thermocouple was charged with a suspension of ethyl N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate (32.6 g, 89.8 mmol) in acetone (450 mL). To this was added solid K2CO3 (37.2 g, 269 mmol, 3.00 equiv.) in portions, followed by EtI (7.2 mL, 90 mmol, 1.0 equiv.) dropwise over 20 min. The mixture was stirred at room temperature for approximately 18 h. The solids were filtered and 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 on silica (0-30% EtOAc / Hexanes) to give the title compound (30.9 g, 85.6%) as a white solid. MS (ES) m / z=391 (M+1).

[0238] Preparation 2A Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate [ka] Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate was used in a manner similar to that of Preparation 20 to give the title compound (15.4 g, crude) as a brown solid. MS (ES) m / z=407 (M+1).

[0239] Preparation 21 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol [ka] A 2 L 4-neck RBF was equipped with an overhead stirrer, dropping funnel, N2 inlet, and thermocouple and purged with N2. NMP (anhydrous, 300 mL) was added. The mixture was heated to 175°C. In a second flask, ethyl (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate (22.63 g, 57.83 mmol) and NMP (anhydrous, 100 mL) were combined and stirred under N2 until a homogenous solution was obtained. Once the first flask reached 175°C, the contents of the second flask were poured into the dropping funnel and added dropwise rapidly to the hot NMP. After 30 min, the heat was turned off and the reaction was cooled to 45°C. H2O (500 mL) was slowly added and the mixture was stirred at room temperature for 1 h. The solid was filtered, rinsed with HO (300 mL) and dried under vacuum at 50° C. for approximately 18 h to give the title compound (15.2 g, 73%) as an off-white solid. MS (ES) m / z=363 (M+1).

[0240] Preparation 3A 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol [ka] Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate was used in a manner similar to the method of Preparation 21 to give the title compound (11.4 g, 86%) as a white solid. MS (ES) m / z=361 (M+1).

[0241] Preparation 22 6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline [ka] A 5 L 3-neck RBF equipped with an addition funnel, thermocouple, and overhead stirrer was charged with a solution of DMF (50 mL, 646 mmol, 4 equiv) in DCM (1,000 mL) and placed in an ice / water bath to cool to about 4° C. Oxalyl chloride (50.0 mL, 576 mmol, 4 equiv) was added dropwise via addition funnel over about 40 min. After addition was complete, the reaction was stirred at about 4° C. for 15 min. Solid 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (50.4 g, 140 mmol) was added portionwise to the reaction mixture and the resulting suspension was stirred at about 4° C. for 30 min. The ice bath was removed and the reaction was allowed to warm to room temperature and stir for 1 h. HO (1 L) was then added and the mixture was stirred for 15 min. The mixture was partitioned and the organic layer was washed with brine (1 L), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica eluting with DCM / Hexanes (60%-90%) to give the title compound (45.1 g, 89%) as a white solid. MS (ES) m / z=363 (M+1).

[0242] Preparation 1B 6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline [ka] 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol was used in a manner similar to that of Preparation 22 to give the title compound (7.5 g, 63%) as a yellow solid. MS (ES) m / z=379 (M+1).

[0243] Preparation 23 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline [ka] To a mixture of 6-bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline (6.50 g, 17.9 mmol) and tetramethylethylenediamine (2.28 g, 19.7 mmol) in THF (100 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.73 g, 1.00 mmol) and sodium cyanoborohydride (in small portions, 2.25 g, 35.8 mmol) at room temperature. The reaction mixture was stirred overnight under nitrogen, diluted with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica eluting with 16-20% EtOAc in PE to give the title compound (5.0 g, 75%) as a yellow solid. MS (ES) m / z=329 (M+1).

[0244] Preparation 2B 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline [ka] 6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline was used in a manner similar to that of Preparation 23 to give the title compound (1.2 g, 57%) as a yellow solid. MS (ES) m / z=345 (M+1).

[0245] Preparation 24 8-(6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester [ka] A suspension of 6-bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline (21.0 g, 57.8 mmol) in ACN (580 mL) was charged with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (15.2 g, 69.5 mmol, 1.20 equiv.) and DIPEA (40 mL, 229 mmol, 4 equiv.) and stirred at room temperature for 90 min. H2O (1 L) was added slowly via addition funnel and the mixture was stirred at room temperature for 1 h. The solid was filtered, rinsed with H2O (500 mL), and dried under vacuum at 50 °C to give the title compound (31 g, quantitative yield) as a white solid with MS (ES) m / z = 539 (M+1).

[0246] Preparation 3B 8-(6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester [ka] 6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline was used in a manner similar to that of Preparation 24 to give the title compound (6 g, 75%) as a yellow solid. MS (ES) m / z=555 (M+1).

[0247] Preparation 25 6-Bromo-1-(3-((R)-2-((tert-butyldimethylsilyl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline [ka] 3-((R)-2-((tert-butyldimethylsilyl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octane was used in a manner similar to that described for Preparation 24 to give the title compound (4.7 g, 95%) as a brown solid.

[0248] Preparation 26 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylate methyl ester [ka] A solution of methyl thioglycolate (0.18 mL, 2.0 mmol, 1 equiv) in THF (5 mL) was flushed with N2 and charged with a solution of NaH (60% by weight) in mineral oil (0.101 g, 2.53 mmol, 1.24 equiv) at room temperature. Gas evolution was observed and a precipitate formed in the flask. The reaction was stirred at room temperature for 20 min. A solution of 2-bromo-3,6-difluorobenzaldehyde (0.475 g, 2.04 mmol) in THF (5 mL) was added slowly via syringe over approximately 2 min. The reaction was stirred at room temperature for 9 h. Additional methyl thioglycolate (0.1 mL, 1 mmol, 0.5 equiv) and a solution of sodium hydride (60% by weight) in mineral oil (0.050 g, 1.3 mmol, 0.6 equiv) were added and stirring was continued at room temperature for approximately 18 h. The mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica eluting with 2% MTBE / Hexane to give 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 = 9.0 Hz, 1H), 3.93 (s, 3H).

[0249] Preparation 27 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid [ka] A solution of methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate (19.2 g, 66.4 mmol, 1 equiv) in MeOH (130 mL) and THF (130 mL) was charged with 5N NaOH (66 mL, 330 mmol, 5 equiv) and stirred at room temperature for 40 min. The mixture was concentrated and H2O (500 mL) was added. The pH was adjusted to about 2 with 5N HCl. The mixture was extracted with EtOAc (2 x 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 give the title compound (17.6 g, 96%) as a white solid. MS (ES) m / z = 229 (M-1-CO2).

[0250] Preparation 28 tert-Butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate [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 charged with TEA (1.5 mL, 11 mmol, 2.0 equiv) and diphenylphosphoryl azide (1.5 mL, 6.9 mmol, 1.3 equiv) and heated at 95° C. for 1 h. The mixture was cooled and concentrated. The residue was purified on silica eluting with MTBE / Hexanes (4%-20%) to give the title compound (0.987 g, 52%) as a white solid. MS (ES) m / z=290 (M+1).

[0251] Preparation 29 tert-Butyl (4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-5-fluorobenzo[b]thiophene-2-yl)carbamate [ka] A mixture of tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (3.08 g, 8.90 mmol) and bis(neopentylglycolato)diboron (4.02 g, 17.8 mmol, 2 equiv.) and KOAc (2.62 g, 26.7 mmol, 3 equiv.) in 1,4-dioxane (70 mL, 819.9 mmol) was sparged with N2 for 20 min. To the mixture was added Pd(ddpf)Cl2 (0.69 g, 0.90 mmol, 0.1 equiv.). The reaction was sonicated for 3 min, then subjected to vacuum / N2 refill cycles (3x) and heated at 100 °C for 3 h. The mixture was cooled to room temperature and filtered through diatomaceous earth, rinsing with 1:4 EtOAc / hexanes. The filtrate was concentrated and the residue was purified on silica (0-40% MTBE / hexanes) to give 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).

[0252] Preparation 30 tert-Butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate [ka] Ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A solution of 2-(4-chloro-5-fluoropyridin-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 min, ethoxycarbonyl isothiocyanate (7.45 mL, 61.8 mmol) was added dropwise. The reaction mixture was allowed to warm slowly 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 give ethyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate (11.9 g, 79%) as a solid. MS (ES) m / z=266 (M+1).

[0253] 2-Amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile. A suspension of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (11.9 g, 44.4 mmol) in DMSO (90 mL) was cooled to 0° C. NaOH (5 M aqueous, 90 mL) was added dropwise over 15 min. The reaction mixture was heated to 105° C. for 1 h and then cooled to room temperature. The reaction mixture was poured into an ice / water mixture (1.8 L), stirred until all 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 give crude 2-amino-7-fluoro-thieno[3,2-c]pyridine-3-carbonitrile.

[0254] tert-Butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. 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 h. The solvent was removed under reduced pressure and the remaining material was diluted with DCM (400 mL) and 5% aqueous citric acid (250 mL). The aqueous phase was washed twice with DCM. The combined organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to give tert-butyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate (7.5 g, 58%) as a brown solid. MS (ES) m / z=294 (M+1).

[0255] 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 tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (7.85 g, 26.8 mmol) in DCM (180 mL). The reaction mixture was stirred at room temperature overnight and then cooled to 0° C. over approximately 15 min. 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 on silica eluting with 0-6% MeOH / DCM. Fractions containing the desired material were combined with the solid obtained by filtration and concentrated to give tert-butyl N-(3-cyano-7-fluoro-5-oxide-thieno[3,2-c]pyridin-5-ium-2-yl)carbamate (7.26 g, 88%) as an off-white solid. MS (ES) m / z=310 (M+1).

[0256] tert-Butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. 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 min, at 45° C. for 90 min, and cooled to room temperature. The reaction mixture was diluted with 1,2-dichloroethane (100 mL) and added to a mixture of saturated aqueous NaHCO3 (500 mL), NaOH (5 M aqueous, 40 mL), and ice. Solid NaHCO3 was added to the stirred mixture to maintain the pH at approximately 6-7. Once effervescence ceased, the phases were separated. The aqueous phase was extracted 3 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 on silica eluting with 50-100% DCM / hexanes. Fractions containing the desired material were concentrated to give the title compound (3.87 g, 69%) as a white solid. MS (ES) m / z=328 (M+1).

[0257] Preparation 1C tert-Butyl (4-bromo-7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl)carbamate [ka] 3-Bromo-5-chloro-4-((4-methoxybenzyl)thio)pyridine. To a solution of 3-bromo-4,5-dichloropyridine (10.0 g, 44.1 mmol) in acetonitrile (90 mL) was added potassium carbonate (6.70 g, 48.5 mmol). The mixture was cooled to 0° C. and (4-methoxyphenyl)methanethiol (6.6 mL, 46.3 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was diluted with water (200 mL) and EtOAc (300 mL) and the layers were then separated. The aqueous layer was extracted with EtOAc (2×300 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on silica eluting with 0-60% EtOAc in heptane. Fractions containing the desired material were concentrated to give 3-bromo-5-chloro-4-((4-methoxybenzyl)thio)pyridine (8.6 g, 57%) as a white solid. MS (ES) m / z=344 (M+1).

[0258] 2-(5-chloro-4-((4-methoxybenzyl)thio)pyridin-3-yl)malononitrile. To a pressure vessel containing a solution of malonitrile (2.44 g, 37.0 mmol) in 1,4-dioxane (160 mL) was added a mixture of sodium tert-butoxide (7.11 g, 74.0 mmol) in THF (36 mL). The mixture was stirred for 15 min and then 3-bromo-5-chloro-4-((4-methoxybenzyl)thio)pyridine (8.50 g, 24.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.85 g, 2.47 mmol) were added. The reaction vessel was sealed and the reaction mixture was heated at 85° C. overnight. The reaction mixture was filtered and the solids were washed with EtOAc. The combined filtrate was concentrated under reduced pressure and then diluted with DCM. The mixture was filtered and the solid was washed with DCM to give 2-(5-chloro-4-((4-methoxybenzyl)thio)pyridin-3-yl)malononitrile (7.5 g, 92%) as a yellow solid. MS (ES) m / z=330 (M+1).

[0259] 2-Amino-7-chlorothieno[3,2-c]pyridine-3-carbonitrile. Trifluoroacetic acid (5 mL) was added to a mixture of 2-(5-chloro-4-((4-methoxybenzyl)thio)pyridin-3-yl)malononitrile (0.740 g, 2.24 mmol) in DCM (25 mL). The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. The residue was diluted with DCM (5 mL) and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was diluted with 4:1 hexanes:EtOAc (30 mL) and stirred for 30 min. The mixture was filtered and the solid was washed with a minimum of 4:1 hexanes:EtOAc to give 2-amino-7-chlorothieno[3,2-c]pyridine-3-carbonitrile (0.28 g, 60%) as a brown solid. MS (ES) m / z=210 (M+1).

[0260] (7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl) tert-butyl carbamate. 2-Amino-7-chlorothieno[3,2-c]pyridin-3-carbonitrile was used in a similar manner to that of Preparation 30 ((3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl) tert-butyl carbamate in the intermediate step) to obtain (7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl) tert-butyl carbamate (0.85 g, 52%) as a white solid. MS (ES) m / z=310 (M+1).

[0261] 2-((tert-butoxycarbonyl)amino)-7-chloro-3-cyanothieno[3,2-c]pyridine 5-oxide. 3-Chloroperoxybenzoic acid (75% by weight, 4.0 g, 17 mmol) was added to a solution of tert-butyl (7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl)carbamate (4.1 g, 13 mmol) in DCM (60 mL). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The material was purified on silica eluting with 0-10% MeOH in DCM. Fractions containing the desired material were concentrated to give 2-((tert-butoxycarbonyl)amino)-7-chloro-3-cyanothieno[3,2-c]pyridine 5-oxide (4.3 g, 90%) as a white solid. MS(ES) m / z=326(M+1).

[0262] tert-Butyl (4-bromo-7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl)carbamate. Molecular sieves (4A, 4 g) were added to a mixture of 2-((tert-butoxycarbonyl)amino)-7-chloro-3-cyanothieno[3,2-c]pyridine 5-oxide (4.4 g, 12 mmol), tetrabutylammonium bromide (5.9 g, 18 mmol), and p-toluenesulfonic anhydride (6.0 g, 18 mmol) in THF (300 mL). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The material was purified on silica eluting with 0-100% EtOAc in hexanes. The combined fractions were purified on silica eluting with MeOH in DCM. Fractions containing the desired material from both silica purifications were combined and concentrated to give the title compound (3.0 g, 63%) as an off-white solid. MS (ES) m / z=388 (M+1).

[0263] Preparation 4B tert-Butyl (4-chloro-7-methylthieno[3,2-c]pyridin-2-yl)carbamate [ka] Methyl 4-chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylate. 2,4-Dichloro-5-methyl-pyridine-3-carbaldehyde (7.25 g, 38.2 mmol), potassium carbonate (10.5 g, 76.0 mmol), and DMF (127 mL) were combined and heated at 70° C. overnight and cooled to room temperature. The reaction mixture was added to water (500 mL) and filtered. The solid was rinsed with water and dried to give methyl 4-chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylate (8.30 g, 90%) as a white solid. MS (ES) m / z=242 (M+1).

[0264] 4-Chloro-7-methylthieno[3,2-c]pyridine-2-carboxylic acid. 4-Chloro-7-methylthieno[3,2-c]pyridine-2-carboxylate was used in a manner similar to that of Preparation 27 to give 4-chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylic acid (6.5 g, 84%) as a white solid. MS (ES) m / z=228 (M+1).

[0265] (4-chloro-7-methylthieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl. 4-Chloro-7-methylthieno[3,2-c]pyridine-2-carboxylic acid was used in a similar manner to the method of preparation 28 to give the title compound (0.83 g, 63%). MS (ES) m / z=299 (M+1).

[0266] Preparation 1D tert-Butyl (4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate [ka] (2-Chloro-5-fluoropyridin-3-yl)methyl methanesulfonate. Methanesulfonic anhydride (11.0 g, 63.2 mmol) was added dropwise to a solution of (2-chloro-5-fluoropyridin-3-yl)methanol (7.86 g, 48.7 mmol) and diisopropylethylamine (12.6 mL, 73.0 mmol) in THF (200 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The mixture was poured into water / ice and diluted with 1:1 MTBE:EtOAc. The layers were separated and the aqueous layer was extracted with 1:1 MTBE:EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude (2-chloro-5-fluoropyridin-3-yl)methyl methanesulfonate (11.9 g). MS (ES) m / z=240 (M+1).

[0267] 2-(2-Chloro-5-fluoropyridin-3-yl)acetonitrile. Trimethylsilylnitrile (7.80 mL, 59.6 mmol) was added dropwise to a solution of (2-chloro-5-fluoropyridin-3-yl)methyl methanesulfonate (11.9 g, 49.7 mmol) in THF (125 mL) and acetonitrile (125 mL) at 0° C. Then tetrabutylammonium fluoride (1 M in THF; 59.6 mL, 59.6 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h, then concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) and washed with a mixture of saturated aqueous sodium bicarbonate and brine. The aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-50% EtOAc in hexanes. Combine the mixed fractions and purify on silica eluting with 0-5% (10% MeOH in DCM) to give 2-(2-chloro-5-fluoropyridin-3-yl)acetonitrile (5.60 g, 66%) as a yellow oil which solidifies in the freezer.

[0268] Ethyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate. 2-(2-chloro-5-fluoropyridin-3-yl)acetonitrile was used in a manner similar to that of Preparation 30 (Substep ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate) to obtain ethyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate (24.8 g, 80%) as a brown solid. MS (ES) m / z=266 (M+1).

[0269] 2-Amino-5-fluorothieno[2,3-b]pyridine-3-carbonitrile. Ethyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate was used in a manner similar to that of Preparation 30 (substep 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile) to give 2-amino-5-fluorothieno[2,3-b]pyridine-3-carbonitrile (17.4 g, 100%) as a brown solid.

[0270] tert-Butyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate. 2-Amino-5-chlorothieno[2,3-b]pyridin-3-carbonitrile was used in a manner similar to that of Preparation 30 (substep (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate tert-butyl) to obtain tert-butyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate (19.6 g, 73%) as a brown solid. MS (ES) m / z=294 (M+1).

[0271] 2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide. tert-Butyl (3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate was used in a manner similar to that of Preparation 30 (Substep 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide) to obtain 2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide (10.5 g, 94%) as a white solid. MS (ES) m / z=310 (M+1).

[0272] 6-Bromo-2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide. To a suspension of 2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide (10.5 g, 31.4 mmol) in DCM (150 mL) and EtOAc (150 mL) at 0° C. was added N-bromosuccinimide (6.21 g, 31.4 mmol) followed by THF (30 mL). The reaction mixture was allowed to warm to room temperature and stirred for 72 h, then diluted with THF (10 mL). The mixture was treated with silica (10 g) and the solvent was removed under reduced pressure. The remaining solid was purified on silica, eluting with 0-50% in DCM (10% EtOAc in DCM) to give 6-bromo-2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide (8.50 g, 70%). MS (ES) m / z=388 (M+1).

[0273] tert-Butyl (6-bromo-4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate. To a suspension of 6-bromo-2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorothieno[2,3-b]pyridine 7-oxide (8.35 g, 21.5 mmol) in THF (108 mL) was added dropwise bis(trimethylsilyl)amine (5.40 mL, 25.8 mmol). The mixture was cooled to 0° C. and 2,2,2-trichloroacetyl chloride (24.0 mL, 215 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes, then heated to 45° C. and stirred for 18 hours. The mixture was diluted with aqueous NaOH (1N, 190 mL), DCM (500 mL), and saturated aqueous sodium bicarbonate. A precipitate formed and was removed by filtration. The solid was dissolved in THF / EtOAc. The solution was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (6-bromo-4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate (5.60 g, 61%). MS (ES) m / z=406 (M+1).

[0274] tert-Butyl (4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate. A reaction vessel containing tert-butyl (6-bromo-4-chloro-3-cyano-5-fluorothieno[2,3-b]pyridin-2-yl)carbamate (4.00 g, 9.74 mmol) and sodium formate (0.662 g, 9.74 mmol) in DMF (49 mL) was flushed with nitrogen for 30 minutes and then tetrakis(triphenylphosphine)palladium(0) (2.25 g, 1.95 mmol) was added. The reaction vessel was sealed and stirred at 80° C. for 18 hours. Additional tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.95 mmol) was added. The reaction vessel was sealed and stirred at 80° C. for 25 h, then poured into water / ice and diluted with 1:1 MTBE:EtOAc. The layers were separated and the aqueous layer was extracted two more times with 1:1 MTBE:EtOAc. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica eluting with 0-30% EtOAc in hexanes. The mixed fractions were combined and purified on silica eluting with 0-10% in DCM (10% EtOAc in DCM) to give the title compound (0.80 g, 25%). MS (ES) m / z=328 (M+1).

[0275] Preparation 31 8-(6-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester [ka] A 250 mL three-neck RBF equipped with a thermocouple, condenser, and N2 sparge line was charged with a suspension of tert-butyl 8-(6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.00 g, 9.27 mmol) and tert-butyl (4-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (5.53 g, 13.9 mmol, 1.5 equiv.) in 1,4-dioxane (100 mL) and HO (31 mL). The heating temperature was set to 70° C. and heating was started. At the same time, N2 sparging was started. When the internal temperature reached approximately 45°C, the sparge line was removed and K3PO4 (2.95 g, 13.9 mmol, 1.5 equiv) and Pd-118 (0.620 g, 0.932 mmol, 0.10 equiv) were added. The reaction temperature was allowed to reach 70°C and stirred for 90 min. The reaction was cooled to room temperature, after which the mixture was diluted with EtOAc, washed with H2O and partitioned. The aqueous phase was extracted with EtOAc (100 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. MTBE (50 mL) was added and the mixture was sonicated for 20 min. The solid was filtered to give the product as batch 1. The filtrate was concentrated and the residue was purified on silica eluting with EtOAc / hexanes (0-30%). The product-containing fractions were concentrated to give a brown foam which was dissolved in DCM (20 mL) and treated dropwise with hexanes (60 mL) with rapid stirring for 1 h. The resulting solid was filtered and rinsed with hexanes (50 mL) to give the product as batch 2. These two batches were combined to give the title compound (6.4 g, 88%) as a white solid. MS (ES) m / z=726 (M+1).

[0276] The following compounds in Table 1 were prepared in a similar manner as described in Preparation 31. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 1: [Table 1]

[0277] Preparation 32 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester [ka] tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (9.00 g, 12.4 mmol) and THF (180 mL) were combined in a flask. The flask was placed in a −45° C. bath under nitrogen. ((chlorosulfonyl)imino)methanone (7.90 g, 55.8 mmol) was added. After 4 h, the cold reaction mixture was poured into DMF (270 mL) and stirred at 0° C. for 1 h. The mixture was diluted with EtOAc (1 L) and then washed with water (2×300 mL) and brine (2×200 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica eluting with 20-30% EtOAc in PE to give the title compound (6.5 g, 70%) as a white solid. MS (ES) m / z=751 (M+1).

[0278] Preparations 8B and 9B tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, atropisomer 1 and atropisomer 2 [ka] Chiral separation of tert-butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (supercritical fluid chromatography; CHIRALPAK AD-H, 50×250 mm, 30% EtOH:70% CO2, 180 mL / min) was carried out to give the title compounds (atropisomer 1 3.20 g, atropisomer 2 3.25 g). MS (ES) m / z=751 (M+1) for both.

[0279] Preparation 10B tert-Butyl (4-(5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate [ka] Tert-butyl (4-(5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate was used in a manner similar to the method of Preparation 32 to give the title compound (0.69 g, 82%) as a yellow solid. MS (ES) m / z=557 (M+1).

[0280] Preparation 11B 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester [ka] 8-(6-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl was used in a manner similar to the method of Preparation 32 to give the title compound (0.72 g, 50%) as a yellow solid. MS (ES) m / z=767 (M+1).

[0281] Preparation 12B tert-Butyl (4-chloro-3-cyano-7-methylthieno[3,2-c]pyridin-2-yl)carbamate [ka] Tert-butyl (4-chloro-7-methylthieno[3,2-c]pyridin-2-yl)carbamate was used in a manner similar to that of Preparation 32 to give the title compound (0.54 g, 31%). MS (ES) m / z=324 (M+1).

[0282] Preparation 6A tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate [ka] A mixture of tert-butyl (4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.750 g, 1.41 mmol) and acetonitrile (10 mL) was stirred at -40°C. Sulfur isocyanatide acid chloride (0.184 mL, 2.12 mmol) was added slowly and the mixture was allowed to warm to 0°C. After the starting material was consumed (monitored by LCMS), the mixture was cooled to 0°C. DMF (4 mL) was added slowly. Once the reaction was complete (monitored by LCMS), the mixture was diluted with DCM (20 mL) and saturated aqueous ammonium chloride solution (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 30 mL). The combined extracts were passed through a hydrophobic frit and concentrated under reduced pressure to give the crude title compound: MS (ES) m / z=557 (M+1).

[0283] The following compounds in Table 2 were prepared in a similar manner as described in Preparation 22. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 2: [Table 2]

[0284] The following compounds in Table 3 were prepared in a similar manner as described in Preparation 23. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 3: [Table 3]

[0285] Preparations 13B and 14B tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate, atropisomer 1 and atropisomer 2 [ka] Chiral separation of tert-butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (supercritical fluid chromatography; CHIRALPAK IG, 20×250 mm, 35% isopropanol (with 0.5% dimethylethylamine):65% CO, 80 mL / min) was performed to give the title compounds (atropisomer 1 0.995 g, atropisomer 2 0.990 g). MS (ES) m / z=541 (M+1) for both.

[0286] Preparation 33 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester [ka] To a solution of tert-butyl 8-(6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (25.0 g, 46.3 mmol) and 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (20.9 g, 92.7 mmol) in 1,4-dioxane (300 mL), potassium acetate (13.6 g, 139 mmol) and dichloropalladium;{2-[2-(diphenylphosphanyl)phenoxy]phenyl}diphenylphosphane (4.98 g, 6.95 mmol) were added at room temperature under nitrogen. The mixture was stirred at 85° C. overnight and then filtered. The filter cake was washed with 1,4-dioxane (2×100 mL). The filtrate was concentrated under reduced pressure and purified on silica eluting with 0-20% EtOAc in PE to give tert-butyl 8-(6-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (23 g, 87%) as a yellow solid.

[0287] To a stirred mixture of tert-butyl 8-(6-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (6.99 g, 12.2 mmol) and tert-butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (4.00 g, 12.2 mmol) in toluene (150 mL) was added potassium phosphate (7.77 g, 36.6 mmol), [2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl] (1.75 g, 3.66 mmol), and XPhos Palladacycle Gen 4 (CAS 1599466-81-5; 0.026 g, 0.031 mmol) was added at room temperature under nitrogen. The mixture was stirred at 80° C. for 4 h, then diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica eluting with 0-45% EtOAc in PE to give the title compound (6.0 g, 65%) as a yellow solid. MS (ES) m / z=752 (M+1).

[0288] The following compounds in Table 4 were prepared in a similar manner as described in Preparation 33. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 4: [Table 4-1] (Continuation of Table 4) [Table 4-2] 1 Preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 10-65% EtOH in heptane, 42.5 mL / min

[0289] Preparation 37 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester [ka] To a solution of tert-butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (8.4 g, 11.2 mmol) in DCM (100 mL) was added mCPBA (4.05 g, 23.5 mmol) in small portions at 0° C. The reaction mixture was stirred at 0° C. for 3 h. The mixture was diluted with DCM (800 mL) and washed with saturated aqueous NaHCO3 (3×400 mL) and brine (2×300 mL). The organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with 0-10% MeOH in DCM to give the title compound (8.3 g, 95%) as an off-white solid. MS (ES) m / z=784 (M+1).

[0290] The following compounds in Table 5 were prepared in a similar manner as described in Preparation 37. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 5: [Table 5-1] (Continuation of Table 5) [Table 5-2] (Continuation of Table 5) [Table 5-3] 1Single atropisomer (from precursor of preparation 17B) 2 Single atropisomer (from precursor of preparation 18B) 3 Single atropisomer (from precursor of preparation 14B) 4 Single atropisomer (from precursor of preparation 9B)

[0291] Preparation 41 tert-Butyl (4-(1-(3-((R)-2-((tert-butyldimethylsilyl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate [ka] (4-(1-(3-((R)-2-((tert-butyldimethylsilyl)oxy)propyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)tert-butyl carbamate (4 g, 5 mmol), hexaammonium heptamolybdate tetrahydrate (1 g, 1 mmol), and hydrogen peroxide (8 mL, 35 wt % in water, 100 mmol) were combined in DCM (30 mL) and EtOH (30 mL). The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. Diluted with water (100 mL) and stirred for 30 min. The resulting solid was filtered and dried in a vacuum oven (45° C.) to give the title compound (2 g, 50%) as a white solid. MS (ES) m / z=856 (M+1).

[0292] Preparation 28B (1-(((3aR,6aS)-Tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)cyclopropyl)methanol [ka] To a stirred solution of ethyl 1-(bromomethyl)cyclopropane-1-carboxylate (1.5 g, 7.2 mmol) and (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (0.82 g, 7.2 mmol) in acetonitrile (15 mL) was added potassium carbonate (2.00 g, 14.5 mmol) at room temperature under nitrogen. The mixture was stirred at room temperature for 3 h and then filtered. The filter cake was washed with acetonitrile (2×20 mL). The combined filtrate was concentrated under reduced pressure to give crude ethyl 1-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H)-yl)methyl)cyclopropane-1-carboxylate (1.2 g, 69%) as a colorless oil. MS (ES) m / z=240 (M+1).

[0293] The crude ethyl ester (1.2 g, 5.0 mmol) was mixed with THF (10 mL) and cooled to 0° C. under nitrogen. Lithium aluminum hydride (2.5 M in THF, 10 mL, 25 mmol) was added dropwise and the mixture was stirred at room temperature. After 1 h, the reaction mixture was cooled to 0° C. and quenched with water (0.95 g), aqueous NaOH (0.95 g), and water (3×0.95 g). The resulting mixture was filtered. The filter cake was washed with THF (3×100 mL). The combined filtrate was concentrated under reduced pressure to give crude (1-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)cyclopropyl)methanol (0.75 g, 76%) as a colorless oil. MS (ES) m / z=198 (M+1).

[0294] Preparation 42 (1-((4-fluoropiperidin-1-yl)methyl)cyclopropyl)methanol [ka] 1-(Methoxycarbonyl)cyclopropane-1-carboxylic acid (0.800 g, 5.55 mmol), oxalyl chloride (0.54 mL, 6.11 mmol), DCM (13.9 mL) and DMF (0.022 mL) were combined, stirred at room temperature for 1 h and concentrated under reduced pressure to give crude methyl 1-(chlorocarbonyl)cyclopropane-1-carboxylate.

[0295] The crude acid chloride was combined with 4-fluoropiperidine (0.59 mL, 5.55 mmol) and triethylamine (3.87 mL, 27.8 mmol) in DCM (13.9 mL). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in EtOAc (30 mL) and washed with aqueous KHSO4 (1 M, 30 mL) and saturated aqueous NaHCO3 (30 mL). The organics were dried over magnesium sulfate and concentrated under reduced pressure to give crude methyl 1-(4-fluoropiperidine-1-carbonyl)cyclopropane-1-carboxylate (0.93 g, 73%).

[0296] The crude methyl ester was mixed with THF (20 mL) and cooled to 0° C. Lithium aluminum hydride (2M in THF, 4.05 mL, 8.10 mmol) was added dropwise and the mixture was stirred at room temperature. After 1 h, the reaction mixture was diluted with EtOAc (20 mL). Water (0.31 mL), aqueous NaOH (2M, 0.31 mL), and water (0.62 mL) were added successively. The mixture was stirred at room temperature. After 30 min, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the title compound (0.60 g, 79%) as a colorless oil without further purification. MS (ES) m / z=188 (M+1).

[0297] The following compounds in Table 6 were prepared in a similar manner as described in Preparation 42. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 6: [Table 6-1] (Continuation of Table 6) [Table 6-2] (Continuation of Table 6) [Table 6-3] 1 Using tert-butyl 2-(2,6-diazaspiro[3.3]heptan-2-yl)acetate 2 Uses deuterated lithium aluminum hydride

[0298] Preparation 29B (3S,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester [ka] To a solution of 1-(tert-butyl)3-ethyl (3R,4S)-4-aminopyrrolidine-1,3-dicarboxylate (0.100 g, 0.387 mmol) in THF (3 mL) was added lithium aluminum hydride (1M in diethyl ether, 0.465 mL, 0.465 mmol). The reaction mixture was stirred at 0° C. for 3 h and then diluted with MTBE (5 mL), water (5 drops, at which point effervescence ceased), and aqueous NaOH (15%, 5 drops). The mixture was stirred at room temperature. After 15 min, the mixture was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (0.084 g, 100%) without further purification.

[0299] Preparation 30B (3R,4S)-tert-butyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate [ka] (3S,4R)-1-(tert-butyl)3-ethyl 4-aminopyrrolidine-1,3-dicarboxylate was used in a manner similar to the method of Preparation 29B to give the crude title compound (0.100 g, 100%).

[0300] Preparation 31B (2S,3S)-tert-Butyl 3-((tert-butoxycarbonyl)amino)-2-methylpyrrolidine-1-carboxylate [ka] (2S,3S)-tert-Butyl 3-amino-2-methylpyrrolidine-1-carboxylate (0.450 g, 2.25 mmol), Boc-anhydride (0.687 g, 3.15 mmol) and diisopropylethylamine (1.96 mL, 11.2 mmol) were combined in chloroform (10 mL). The reaction mixture was stirred at room temperature overnight and diluted with saturated aqueous ammonium chloride (20 mL). The mixture was extracted with DCM (3×20 mL). The combined organic layers were passed through a hydrophobic frit and the filtrate was concentrated under reduced pressure to give the crude title compound (0.60 g, 90%) without further purification. MS (ES) m / z=323 (M+Na).

[0301] Preparation 4D 3-(Azetidin-1-yl)-4-hydroxypyrrolidine-1-carboxylate tert-butyl ester [ka] A mixture of tert-butyl 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (3 g, 20 mmol) and azetidine (1 mL, 20 mmol) in water (20 mL) was heated at 80° C. for 4.5 h and then cooled to room temperature. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase purification eluting with 20% ACN in aqueous NH4HCO3 buffered at pH 9 to give the title compound (2.4 g, 60%) as a white solid. MS (ES) m / z=243 (M+1). The title compound is a mixture of trans isomers.

[0302] The following compounds in Table 7 were prepared in a similar manner as described in Preparation 4D. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 7: [Table 7] 1 Pure trans isomer, analysis of preparations 5D and 6D by analytical chiral SFC; Chiralpak-IC, 25-50% isopropanol in CO2 (with 0.2% isopropylamine) shows that preparation 6D elutes first and preparation 5D elutes second 2 Pure trans isomer, preparative chiral-SFC; Chiralpak-AD, 20 x 250 mm, 20% MeOH (with 0.5% dimethylethylamine) in CO2, 65 g / min shows preparation 7D elutes second 3 Mixture of trans isomers 4 Pure trans isomer, preparative chiral-SFC; Chiralpak-AD, 20 x 250 mm, 25% MeOH in CO2 (with 0.5% dimethylethylamine), 80 mL / min 5 Trans isomer 6 Pure trans isomer, preparative chiral-SFC; Chiralpak-AD, 20 x 250 mm, 10% MeOH in CO2 (with 0.5% dimethylethylamine), 80 mL / min

[0303] Preparation 32B (2S,3S)-tert-Butyl 3-((tert-butoxycarbonyl)(methyl)amino)-2-methylpyrrolidine-1-carboxylate [ka] To a 0° C. solution of tert-butyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-methylpyrrolidine-1-carboxylate (0.300 g, 1.00 mmol) in DMF (4.5 mL) was added sodium hydride (0.044 g, 1.10 mmol). The reaction mixture was stirred at room temperature for 30 min and then cooled to 0° C. Iodomethane (0.068 mL, 1.10 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then diluted with saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with DCM (3×20 mL). The combined organic layers were passed through a hydrophobic frit and the filtrate was concentrated under reduced pressure to give the crude title compound without further purification.

[0304] The following compounds in Table 8 were prepared in a similar manner as described in Preparation 32B. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 8: [Table 8-1] (Continuation of Table 8) [Table 8-2] 1 Pure trans isomer isolated in preparation 7D 2 Mixture of trans isomers 3 Pure trans isomer isolated in preparations 9D and 10D 4 Mixture of trans isomers 5 Mixture of cis isomers

[0305] Preparation 24D (2R,3S)-tert-butyl 2-methyl-3-(4-methylpiperazin-1-yl)pyrrolidine-1-carboxylate [ka] 2-Chloro-N-(2-chloroethyl)-N-methylethan-1-amine hydrochloride (0.481 g, 2.50 mmol) was added to a mixture of (2R,3S)-tert-butyl 3-amino-2-methylpyrrolidine-1-carboxylate (0.50 g, 2.50 mmol), potassium carbonate (1.73 g, 12.5 mmol), and potassium iodide (0.0104 g, 0.062 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 82° C. for 16 h and at room temperature overnight, then cooled, diluted with DCM, and filtered to remove solids. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase purification, eluting with a gradient of ACN (with 0.1% formic acid) in water, to give the title compound (0.319 g, 45%) as a yellow solid. MS (ES) m / z=284 (M+1).

[0306] Preparation 25D (2S,3R)-2-Methyl-3-(4-methylpiperazin-1-yl)pyrrolidine-1-carboxylate tert-butyl ester [ka] (2S,3R)-tert-butyl 3-amino-2-methylpyrrolidine-1-carboxylate was used in a manner similar to that of Preparation 24D to give the title compound (0.298 g, 42%). MS (ES) m / z=284 (M+1).

[0307] Preparation 15C (2S,3S)-tert-Butyl 3-(dimethylcarbamoyl)-2-methylpyrrolidine-1-carboxylate [ka] A mixture of (2S,3S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-3-carboxylic acid (1.00 g, 4.36 mmol), azabenzotriazole tetramethyluranium hexafluorophosphate (2.49 g, 6.54 mmol), and dimethylamine (2M in THF; 4.36 mL, 8.72 mmol) in DCM (30 mL) was treated with diisopropylethylamine (2.28 mL, 13.1 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified on silica eluting with 0-100% EtOAc in heptane to give the title compound (1.08 g, 97%). MS (ES) m / z=201 (M+1, -tBu).

[0308] The following compounds in Table 9 were prepared in a similar manner as described in Preparation 15C. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 9: [Table 9]

[0309] Preparation 16C (S)-tert-Butyl 3-(3-methoxyazetidin-1-yl)pyrrolidine-1-carboxylate [ka] 3-Methoxyazetidine (0.0985 g, 1.13 mmol) and diisopropylethylamine (0.433 mL, 2.49 mmol) were added to (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (0.300 g, 1.13 mmol). The reaction mixture was stirred at 80° C. for 17 h. The mixture was diluted with MeOH (1 mL). The material was purified on strong cation exchange medium (25 g), eluting first with MeOH and then with 2M ammoniated MeOH. The basic fractions were concentrated under reduced pressure to give the crude title compound, which was used as is.

[0310] Preparation 17C (S)-tert-Butyl 3-((cyclopropylmethyl)(methyl)amino)pyrrolidine-1-carboxylate [ka] 1-Cyclopropyl-N-methylmethanamine was used in a similar manner to the method of Preparation 16C to give the crude title compound, which was used directly.

[0311] The following compounds in Table 10 were prepared in a similar manner as described in Preparation 16C. In some cases, the tosylate was used instead of the mesylate. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 10: [Table 10-1] (Continued from Table 10) [Table 10-2] (Continuation of Table 10) [Table 10-3] (Continuation of Table 10) [Table 10-4] (Continuation of Table 10) [Table 10-5] (Continuation of Table 10) [Table 10-6] 1 Preparative chiral SFC; Chiralpak-AD, 20 x 250 mm, 20% MeOH in CO2 (with 0.5% dimethylethylamine), 80 mL / min

[0312] The following compounds in Table 11 were prepared in a similar manner as described in Preparation 32B. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 11: [Table 11]

[0313] Preparation 122D (S)-3-(Piperazin-1-yl)pyrrolidine-1-carboxylate benzyl [ka] To a solution of (S)-tert-butyl 4-(1-((benzyloxy)carbonyl)pyrrolidin-3-yl)piperazine-1-carboxylate (0.562 g, 1.30 mmol) in DCM (4 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 4.5 h. The mixture was concentrated. The residue was purified on strong cation exchange medium (10 g) and eluted first with MeOH and then with 2M ammoniated MeOH. The basic fractions were concentrated under reduced pressure to give the title compound (0.306 g, 79%) as a brown oil. MS (ES) m / z=290 (M+1).

[0314] Preparation 33B (3S,4S)-3-(Dimethylamino)-4-methoxypyrrolidine-1-carboxylate tert-butyl ester [ka] (3S,4S)-tert-Butyl 3-methoxy-4-(methylamino)pyrrolidine-1-carboxylate (0.500 g, 2.17 mmol), formaldehyde (37 wt% in water; 0.97 mL, 13.0 mmol) and sodium triacetoxyborohydride (2.76 g, 13.0 mmol) were dissolved in MeOH (6 mL). The reaction mixture was stirred at 50° C. for 18 h. The mixture was concentrated under reduced pressure, poured into saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (0.53 g) as a waxy solid. MS (ES) m / z=245 (M+1).

[0315] The following compounds in Table 12 were prepared in a similar manner as described in Preparation 33B. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 12: [Table 12-1] (Continued from Table 12) [Table 12-2] (Continued from Table 12) [Table 12-3] (Continued from Table 12) [Table 12-4] (Continued from Table 12) [Table 12-5] (Continued from Table 12) [Table 12-6] (Continued from Table 12) [Table 12-7] 1 Mixture of trans isomers 2 Mixture of cis isomers 3 Mixture of trans isomers 4 Mixture of cis isomers 5 Preparative chiral HPLC; Chiralpak-IF, 20 x 250 mm, 5% hexane (with 10 mM ammoniated methanol): 95% EtOH, 20 mL / min 6 Sodium borodeuteride was used 7 Impurities in Preparation 154D

[0316] The following compounds in Table 13 were prepared in a similar manner as described in Preparation 122D. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 13: [Table 13]

[0317] Preparation 163D (2S,3S)-2-Methyl-3-(4-methylpiperazin-1-yl)pyrrolidine-1-carboxylate tert-butyl ester [ka] To a solution of (S)-tert-butyl 2-methyl-3-oxopyrrolidine-1-carboxylate (2.20 g, 11.0 mmol), 1-methylpiperazine (1.66 g, 16.6 mmol), and acetic acid (0.63 mL, 11.0 mmol) in DCM (15 mL) was added sodium triacetoxyborohydride (3.74 g, 17.7 mmol) in small portions. The mixture was stirred at room temperature. After 28 h, the mixture was cooled to 0° C. and diluted with saturated aqueous sodium bicarbonate. 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 give the crude title compound (3.18 g) as a yellow oil. MS (ES) m / z=284 (M+1).

[0318] The following compounds in Table 14 were prepared in a similar manner as described in Preparation 163D. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 14: [Table 14-1] (Continued from Table 14) [Table 14-2]

[0319] Preparation 186D (3S,4R)-tert-butyl 3-hydroxy-4-(isopropyl(methyl)amino)pyrrolidine-1-carboxylate [ka] To a solution of (3R,4S)-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (1.00 g, 4.94 mmol) in acetone (20 mL) was added 20% palladium hydroxide on carbon (0.50 g). The mixture was hydrogenated under a hydrogen atmosphere (balloon) at room temperature for 2 h and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to give crude (1.3 g) tert-butyl (3S,4R)-3-hydroxy-4-(isopropylamino)pyrrolidine-1-carboxylate as a grey solid. MS (ES) m / z=245 (M+1).

[0320] (3S,4R)-tert-butyl 3-hydroxy-4-(isopropylamino)pyrrolidine-1-carboxylate (1.30 g, 5.32 mmol) and (HCHO) n To a solution of (0.32 g, 10.6 mmol) in methanol (20 mL) was added 20% palladium hydroxide on carbon (0.75 g). The mixture was hydrogenated under a hydrogen atmosphere (balloon) at room temperature for 2 h and then filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL). The resulting mixture was washed with saturated aqueous sodium carbonate (50 mL), water (2×50 mL), and brine (50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.1 g) as a yellow oil. MS (ES) m / z=259 (M+1).

[0321] The following compounds in Table 15 were prepared in a similar manner as described in Preparation 186D. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 15: [Table 15]

[0322] Preparation 54B (3S,4S)-4-Methoxy-N,N-dimethylpyrrolidin-3-amine dihydrochloride [ka] To a solution of (3S,4S)-tert-butyl 3-(dimethylamino)-4-methoxypyrrolidine-1-carboxylate (0.53 g, 2.17 mmol) in DCM (6 mL) was added HCl (4M in 1,4-dioxane; 4 mL, 16.0 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was diluted with DCM and concentrated under reduced pressure (3 cycles) to give the crude title compound (0.48 g, quantitative) as a yellow solid. MS (ES) m / z=145 (M+1).

[0323] The following compounds in Table 16 were prepared in a similar manner as described in Preparation 54B. In some cases, TFA was used instead of HCl. Compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 16: [Table 16-1] (Continued from Table 16) [Table 16-2] (Continued from Table 16) [Table 16-3] (Continued from Table 16) [Table 16-4] (Continued from Table 16) [Table 16-5] (Continued from Table 16) [Table 16-6] (Continued from Table 16) [Table 16-7] (Continued from Table 16) [Table 16-8] (Continued from Table 16) [Table 16-9] (Continued from Table 16) [Table 16-10] (Continued from Table 16) [Table 16-11] (Continued from Table 16) [Table 16-12] (Continued from Table 16) [Table 16-13] (Continued from Table 16) [Table 16-14] (Continued from Table 16) [Table 16-15] (Continued from Table 16) [Table 16-16] (Continued from Table 16) [Table 16-17] (Continued from Table 16) [Table 16-18] (Continued from Table 16) [Table 16-19] (Continued from Table 16) [Table 16-20] 1 Mixture of trans isomers 2 Pure trans isomer isolated in preparations 5D and 6D 3 Pure trans isomer isolated in preparation 7D 4 Mixture of trans isomers 5 Pure trans isomer isolated in preparation 7D 6 Mixture of trans isomers 7 Pure isomers separated in preparations 89D and 90D 8 Trans isomer 9 Pure trans isomer isolated in preparations 9D and 10D 10 Mixture of trans isomers 11 Trans isomer 12 Mixture of cis isomers 13 Mixture of trans isomers 14 Mixture of trans isomers (nitrogen and oxygen substituents) 15 Pure trans isomer (nitrogen and oxygen substituents) 16 Pure trans isomer (nitrogen and oxygen substituents) 17 Pure cis isomer (nitrogen and oxygen substituents) 18 Pure trans isomers separated in preparations 12D and 13D 19 By-products from impurities in preparation 348D

[0324] Preparation 81B (1S,5R)-N,N-Dimethyl-3-azabicyclo[3.1.0]hexan-1-amine [ka] Benzyl (1S,5R)-1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate. A mixture of tert-butyl ((1S,5R)-3-azabicyclo[3.1.0]hexane-1-yl)carbamate (0.250 g, 1.26 mmol) and triethylamine (0.47 mL, 3.28 mmol) in DCM (2.5 mL) was cooled to -78 °C. A solution of benzyl chloroformate (0.195 mL, 1.32 mmol) in DCM (1.1 mL) was added slowly over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was quenched by the slow addition of 1 M aqueous HCl (2.5 mL), stirred for several minutes, and passed through a hydrophobic filter. The aqueous material trapped by the filter was extracted with DCM (2 x 10 mL). The organic layers with the original filtrate were combined and concentrated under reduced pressure. The crude material was purified on silica eluting with 0-50% acetone in cyclohexane to give benzyl (1S,5R)-1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.395 g, 88%) as a white solid. MS (ES) m / z=277 (M+1-tButyl).

[0325] (1S,5R)-1-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate benzyl. Trifluoroacetic acid (1.69 mL) was added to a solution of (1S,5R)-1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate benzyl (0.392 g, 1.10 mmol) in DCM (6 mL). The reaction mixture was stirred at room temperature for 3 h and then concentrated under reduced pressure. The residue was purified on strong cation exchange medium (10 g) and eluted first with MeOH and then with 2M ammonia-treated MeOH. The basic fractions were concentrated under reduced pressure to give (1S,5R)-1-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate benzyl (0.246 g, 95%) as a colorless oil. MS (ES) m / z=233 (M+1).

[0326] (1S,5R)-1-(Dimethylamino)-3-azabicyclo[3.1.0]hexane-3-benzyl carboxylate. Paraformaldehyde (1.62 g, 51.3 mmol) was added portionwise to a solution of (1S,5R)-1-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.243 g, 1.03 mmol) in formic acid (2.0 mL). The reaction mixture was stirred at 100° C. for 2 h and then cooled to room temperature. The mixture was diluted with water, the pH was adjusted to about 14 with 4N aqueous NaOH, and diluted with MTBE (50 mL). The layers were separated and the aqueous layer was extracted with MTBE (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give (1S,5R)-1-(dimethylamino)-3-azabicyclo[3.1.0]hexane-3-benzyl carboxylate (0.279 g, quantitative) as a yellow oil. MS (ES) m / z=261 (M+1).

[0327] (1S,5R)-N,N-Dimethyl-3-azabicyclo[3.1.0]hexane-1-amine. (1S,5R)-1-(Dimethylamino)-3-azabicyclo[3.1.0]hexane-3-carboxylate benzyl (0.279 g, 1.05 mmol) and palladium(II) hydroxide (20 wt% on carbon; 0.111 g) were combined in MeOH (3 mL). The mixture was cycled between vacuum and nitrogen three times, then exposed to hydrogen (1 atm) and stirred overnight. The mixture was filtered through diatomaceous earth and the solid was washed with MeOH. The combined filtrate was concentrated under reduced pressure to give the title compound (0.120 g, 72%) as an orange solid. MS (ES) m / z=127 (M+1).

[0328] The following compounds in Table 17 were prepared in a similar manner as described in Preparation 81B. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 17: [Table 17]

[0329] Preparations 362D and 363D Benzyl 8-(dimethylamino)-2-oxa-6-azaspiro[3.4]octane-6-carboxylate, isomers 1 and 2 [ka] N,N-Dimethyl-2-oxa-6-azaspiro[3.4]octan-8-amine was used in a manner similar to that of Preparation 81B (substep (1S,5R)-1-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate benzyl) to give the racemic compound (0.50 g, 53%). MS (ES) m / z=291 (M+1). The title compound isomers 1 and 2 were separated by preparative chiral-SFC; Chiralpak-IG, 20×250 mm, 30% (MeOH with 0.5% dimethylethylamine) in CO2, 80 mL / min.

[0330] Preparation 85B (S)-N,N-Bis(methyl-d3)pyrrolidin-3-amine [ka] (S)-3-((tert-butoxycarbonyl)(methyl-d3)amino)benzylpyrrolidine-1-carboxylate. To a 0° C. suspension of sodium hydride (60 wt %; 0.15 g, 3.7 mmol) in DMF (2 mL) was slowly added a solution of (S)-3-((tert-butoxycarbonyl)amino)benzylpyrrolidine-1-carboxylate (1.0 g, 3.1 mmol) in DMF (5 mL). The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. The reaction mixture was stirred at room temperature for 30 min and then cooled to 0° C. Iodomethane-d3 (0.22 mL, 3.4 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified on silica eluting with 0-100% EtOAc in heptane to give (S)-benzyl 3-((tert-butoxycarbonyl)(methyl-d3)amino)pyrrolidine-1-carboxylate (0.98 g, 93%) as a colorless oil.

[0331] (S)-(methyl-d3)(pyrrolidin-3-yl)carbamate tert-Butyl. Pd / C (10 wt%; 0.28 g) was added to a solution of (S)-3-((tert-butoxycarbonyl)(methyl-d3)amino)pyrrolidine-1-carboxylate benzyl (0.900 g, 2.67 mmol) in MeOH (10 mL). The reaction mixture was exposed to hydrogen (1 atm) and stirred. After completion of the reaction (monitored by LC-MS), the mixture was filtered through diatomaceous earth and the solid was washed with MeOH. The combined filtrate was concentrated under reduced pressure to give (S)-(methyl-d3)(pyrrolidin-3-yl)carbamate tert-butyl (0.516 g, 95%) as a waxy solid.

[0332] (S)-N,N-bis(methyl-d3)pyrrolidin-3-amine. Lithium aluminum deuteride (0.160 g, 3.81 mmol) was added to a solution of (S)-(methyl-d3)(pyrrolidin-3-yl)tert-butylcarbamate (0.516 g, 2.54 mmol). The reaction mixture was stirred at room temperature for 30 min and then at 70° C. for 6 h. A Fieser workup of the aluminum hydride reaction was performed. The filtrate was concentrated under reduced pressure to give the crude title compound which was used without further purification.

[0333] Preparation 72C N,N-Dimethyl-1-((2S,3R)-2-methylpyrrolidin-3-yl)methanamine [ka] Lithium aluminum hydride (1M in ether, 13.7 mL, 13.7 mmol) was added to a solution of (2S,3S)-N,N,2-trimethylpyrrolidine-3-carboxamide hydrochloride (0.660 g, 3.43 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. A Fieser workup of the aluminum hydride reaction was performed. The filtrate was concentrated under reduced pressure to give the crude title compound (0.405 g, 83%) which was used without further purification. MS (ES) m / z=143 (M+1).

[0334] The following compounds in Table 18 were prepared in a similar manner as described in Preparation 72C. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 18: [Table 18]

[0335] Preparation 73C 2-Methyl-2,6-diazabicyclo[3.2.1]octane, mixture of cis isomers [ka] Lithium aluminum hydride (2M in THF; 1.7 mL, 3.4 mmol) was added to THF (3.4 mL) under nitrogen at 0 °C. A solution of tert-butyl 2,6-diazabicyclo[3.2.1]octane-2-carboxylate (mixture of cis isomers; 0.330 g, 1.49 mmol) in THF (1.7 mL) was added dropwise over 1-2 min. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. Additional lithium aluminum hydride (2M in THF; 1.7 mL, 3.4 mmol) was added at room temperature and the reaction mixture was stirred for a total of 6 days. The mixture was diluted with THF (10 mL) and cooled to 0 °C. Distilled water (0.32 mL), 1 M aqueous NaOH (0.32 mL), and distilled water (1.0 mL) were added dropwise. The mixture was allowed to warm to room temperature and stirred for 15 min. Magnesium sulfate was added, the mixture was filtered, and the solid was washed with DCM. The combined filtrate was concentrated under reduced pressure to give the crude title compound (0.143 g) as a yellow oil. MS (ES) m / z=127 (M+1).

[0336] The following compounds in Table 19 were prepared in a manner similar to that described in Preparation 73C. In some cases, lithium aluminum deuteride was used instead of lithium aluminum hydride. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 19: [Table 19]

[0337] Preparation 369D (R)-tert-Butyl 4-(pyrrolidin-3-yl)piperazine-1-carboxylate [ka] (R)-tert-Butyl 4-(1-((benzyloxy)carbonyl)pyrrolidin-3-yl)piperazine-1-carboxylate (1.44 g, 3.70 mmol) and palladium hydroxide on carbon (0.104 g) were placed in a flask. The flask was cycled through vacuum and nitrogen three times. EtOH (10 mL) was added. The flask was placed under hydrogen (balloon) and the reaction mixture was stirred at room temperature for 16 h. The mixture was filtered through diatomaceous earth and the filter cake was washed with EtOH. The combined filtrate was concentrated under reduced pressure to give the title compound (0.89 g, 94%). MS (ES) m / z=256 (M+1).

[0338] The following compounds in Table 20 were prepared in a similar manner as described in Preparation NEW. In some cases, the benzyl protecting group was removed. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 20: [Table 20] 1 Mixture of trans isomers 2 Mixture of cis isomers 3 Pure isomers separated in preparations 142D and 143D 4 Pure isomers separated in preparations 362D and 363D

[0339] Preparation 57 tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] To a solution of (1-(morpholinomethyl)cyclopropyl)methanol (0.980 g, 5.74 mmol) in THF (10 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 3.44 mL, 3.44 mmol) at room temperature. After 10 min, a solution of tert-butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.900 g, 1.15 mmol) in THF (10 mL) was added dropwise. After 2 h, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (2×200 mL) and brine (100 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica eluting with PE / EtOAc (1:1) to give the title compound (0.720 g, 73%) as an off-white solid. MS (ES) m / z=861 (M+1).

[0340] The following compounds in Table 21 were prepared in a similar manner as described in Preparation 57. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 21: [Table 21-1] (Continued from Table 21) [Table 21-2] (Continued from Table 21) [Table 21-3] (Continued from Table 21) [Table 21-4] (Continued from Table 21) [Table 21-5] (Continued from Table 21) [Table 21-6] (Continued from Table 21) [Table 21-7] (Continued from Table 21) [Table 21-8] (Continued from Table 21) [Table 21-9]

[0341] Preparation 38A tert-Butyl (3-cyano-7-fluoro-4-(5-fluoro-3-(3-morpholinoazetidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridin-2-yl)carbamate [ka] To tert-butyl (3-cyano-4-(3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (0.200 g, 0.349 mmol) was added diisopropylethylamine (0.180 g, 1.39 mmol), 4-(azetidin-3-yl)morpholine (0.099 g, 0.70 mmol), and THF (3 mL). The reaction mixture was heated to 70° C. After 1 h, the mixture was concentrated under reduced pressure. The residue was purified on strong cation exchange medium (10 g) and eluted first with MeOH and then with 2M ammoniated MeOH. The basic fractions were concentrated under reduced pressure to give the title compound (0.170 g, 78%) as a brown solid. MS(ES) m / z=622(M+1).

[0342] The following compounds in Table 22 were prepared in a similar manner as described in Preparation 38A. Different bases were used in place of diisopropylethylamine, such as sodium hydride or lithium bis(trimethylsilyl)amide. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 22: [Table 22-1] (Continued from Table 22) [Table 22-2] (Continued from Table 22) [Table 22-3] (Continued from Table 22) [Table 22-4] (Continued from Table 22) [Table 22-5] (Continued from Table 22) [Table 22-6] (Continued from Table 22) [Table 22-7] (Continued from Table 22) [Table 22-8] (Continued from Table 22) [Table 22-9] (Continued from Table 22) [Table 22-10] (Continued from Table 22) [Table 22-11] (Continued from Table 22) [Table 22-12] (Continued from Table 22) [Table 22-13] (Continued from Table 22) [Table 22-14] (Continued from Table 22) [Table 22-15] (Continued from Table 22) [Table 22-16] (Continued from Table 22) [Table 22-17] (Continued from Table 22) [Table 22-18] (Continued from Table 22) [Table 22-19] (Continued from Table 22) [Table 22-20] (Continued from Table 22) [Table 22-21] (Continued from Table 22) [Table 22-22] (Continued from Table 22) [Table 22-23] (Continued from Table 22) [Table 22-24] (Continued from Table 22) [Table 22-25] (Continued from Table 22) [Table 22-26] (Continued from Table 22) [Table 22-27] (Continued from Table 22) [Table 22-28] (Continued from Table 22) [Table 22-29] (Continued from Table 22) [Table 22-30] (Continued from Table 22) [Table 22-31] (Continued from Table 22) [Table 22-32] (Continued from Table 22) [Table 22-33] (Continued from Table 22) [Table 22-34] (Continued from Table 22) [Table 22-35] (Continued from Table 22) [Table 22-36] (Continued from Table 22) [Table 22-37] (Continued from Table 22) [Table 22-38] (Continued from Table 22) [Table 22-39] (Continued from Table 22) [Table 22-40] (Continued from Table 22) [Table 22-41] (Continued from Table 22) [Table 22-42] (Continued from Table 22) [Table 22-43] (Continued from Table 22) [Table 22-44] (Continued from Table 22) [Table 22-45] (Continued from Table 22) [Table 22-46] (Continued from Table 22) [Table 22-47] (Continued from Table 22) [Table 22-48] (Continued from Table 22) [Table 22-49] (Continued from Table 22) [Table 22-50] (Continued from Table 22) [Table 22-51] (Continued from Table 22) [Table 22-52] (Continued from Table 22) [Table 22-53] (Continued from Table 22) [Table 22-54] (Continued from Table 22) [Table 22-55] (Continued from Table 22) [Table 22-56] (Continued from Table 22) [Table 22-57] (Continued from Table 22) [Table 22-58] (Continued from Table 22) [Table 22-59] (Continued from Table 22) [Table 22-60] (Continued from Table 22) [Table 22-61] (Continued from Table 22) [Table 22-62] (Continued from Table 22) [Table 22-63] 1 Preparations 47A and 48A represent the separated trans isomer pair. 2 Preparation 78A - both trans isomers are present 3 Starting material - 4-bromo-7-chloro-5-fluoro-1,3-dihydrofuro[3,4-f]quinoline 4 Starting material - 4-bromo-5,7-dichloro-1,3-dihydrofuro[3,4-f]quinoline 5 Single atropisomer (from precursor of preparation 17B) 6 Single atropisomer (from precursor of preparation 18B) 7 Single atropisomer (from precursor of preparation 9B) 8 Single atropisomer (from precursor of preparation 14B) 9 Mixture of trans isomers 10 Mixture of trans isomers 11 Pure trans isomer isolated in preparations 5D and 6D 12 Pure trans isomer isolated in preparation 7D 13 Mixture of trans isomers 14 Pure trans isomer isolated in preparation 7D 15 Mixture of trans isomers 16Pure isomers separated in preparations 89D and 90D 17 Mixture of trans isomers 18 Pure trans isomer isolated in preparations 9D and 10D 19 Mixture of trans isomers 20 Mixture of trans isomers 21 Mixture of trans isomers 22 Mixture of trans isomers 23 Mixture of cis isomers 24 Mixture of trans isomers 25 Mixture of trans isomers (nitrogen and oxygen substituents) 26 Pure trans isomer (nitrogen and oxygen substituents) 27 Pure trans isomer (nitrogen and oxygen substituents) 28 Pure cis isomer (nitrogen and oxygen substituents) 29 Mixture of cis isomers 30 Pure trans isomers separated in preparations 12D and 13D 31 Pure isomers separated in preparations 142D and 143D 32 By-products from impurities in preparation 583D 33 Upon completion, the reaction was concentrated and the material was deprotected with TFA in DCM.

[0343] Preparation 88 tert-Butyl 8-(3-((1-((4-acetylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl, ethanesulfonyl chloride, and 1-(piperazin-1-yl)ethan-1-one were used in a manner similar to the methods of Preparations 17 and 18 to give the title compound (0.064 g, 62%) as a yellow solid. MS (ES) m / z=902 (M+1).

[0344] Preparation 89 6-Bromo-3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline [ka] (1-(((6-bromo-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-3-yl)oxy)methyl)-2,2-difluorocyclopropyl)methanol, methanesulfonic anhydride, and morpholine were used in a manner similar to the methods of Preparations 17 and 18 to give the title compound (1.5 g, 61%) as a yellow solid. MS (ES) m / z=474 (M+1).

[0345] Preparations 90 and 91 6-Bromo-3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline, Isomer 1 and Isomer 2 [ka] Chiral separation of 6-bromo-3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline (supercritical fluid chromatography; CHIRALPAK IG, 30×250 mm, 45% 1:1 DCM:MeOH (with 0.1% 2M ammoniated methanol):55% CO, 100 mL / min) was performed to give the title compounds (isomer 1 0.63 g, isomer 2 0.52 g) as yellow solids. For both, MS (ES) m / z=474 (M+1).

[0346] Preparation 193B 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-formylcyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester [ka] tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.37 g, 0.47 mmol), DCM (4.7 mL), and Dess-Martin periodinane (0.24 g, 0.56 mmol) were combined. The reaction mixture was stirred for 3 h. A small amount of Dess-Martin periodinane was added. After a further 1 h, the mixture was diluted with DCM and aqueous sodium bicarbonate and then stirred vigorously for 10 min. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.34 g, 91%). MS (ES) m / z=790 (M+1).

[0347] Preparation 194B tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(((S)-2-(fluoromethyl)azetidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-formylcyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl (0.165 g, 0.209 mmol), DCM (0.81 mL), and MeOH (0.25 mL) were combined. (S)-2-(fluoromethyl)azetidine 2,2,2-trifluoroacetate (79 wt%, 0.107 g, 0.418 mmol) was added as a solution in DCM (0.5 mL). The reaction mixture was stirred for 5 min and then sodium triacetoxyborohydride (0.155 g, 0.731 mmol) was added. The reaction mixture was stirred overnight and then loaded onto a strong cation exchange cartridge. The cartridge was eluted with MeOH (75 mL) followed by ammoniated methanol. The latter fraction was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-20% ammoniated MeOH in DCM to give the title compound (0.15 g, 84%). MS (ES) m / z=863 (M+1).

[0348] Preparation 195B tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(((S)-2-(methoxymethyl)azetidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] (S)-2-(Methoxymethyl)azetidine 2,2,2-trifluoroacetate was used in a manner similar to the method of Preparation 194B to give the title compound (0.080 g, 48%). MS (ES) m / z=875 (M+1).

[0349] The following compounds in Table 23 were prepared in a similar manner as described in Preparations 17 and 18 using tert-butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolidin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 23: [Table 23-1] (Continued from Table 23) [Table 23-2]

[0350] Preparation 92 tert-Butyl (3-cyano-4-(3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolidin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate, isomer 1 [ka] 6-Bromo-3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline, isomer 1, was used in a manner similar to that of Preparation 33 to give the title compound (0.36 g, 59%) as a yellow solid. MS (ES) m / z=687 (M+1).

[0351] Preparation 93 tert-Butyl (3-cyano-4-(3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate, isomer 2 [ka] 6-Bromo-3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline, isomer 2, was used in a manner similar to that of Preparation 33 to give the title compound (0.50 g, 63%) as a yellow solid. MS (ES) m / z=687 (M+1).

[0352] Preparation 95A tert-Butyl (3-cyano-4-(7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate [ka] (S)-1-(4-bromo-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)-N,N-dimethylpyrrolidin-3-amine was used in a manner similar to that of Preparation 33 to give the title compound (0.32 g, 21%). MS (ES) m / z=593 (M+1).

[0353] Preparation 196B tert-Butyl (3-cyano-4-(7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate [ka] (S)-1-(4-bromo-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)-N,N-dimethylpyrrolidin-3-amine was used in a manner similar to that of Preparation 33 to give the title compound (0.060 g, 8%). MS (ES) m / z=609 (M+1).

[0354] The following compounds in Table 24 were prepared in a similar manner as described in Preparation 33. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 24: [Table 24]

[0355] The following compounds in Table 25 were prepared in a similar manner as described in Preparation 33B. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 25: [Table 25-1] (Continued from Table 25) [Table 25-2]

[0356] Preparation 94 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile [ka] To a stirred mixture of tert-butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.720 g, 0.836 mmol) in DCM (10 mL) was added TFA (10 mL) at room temperature. After 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) and washed with saturated aqueous NaHCO3 (200 mL), water (200 mL), and brine (100 mL). The organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound. MS(ES) m / z=661(M+1).

[0357] The following compounds in Table 26 were prepared in a similar manner as described in Preparation 94. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 26: [Table 26-1] (Continued from Table 26) [Table 26-2] (Continued from Table 26) [Table 26-3] (Continued from Table 26) [Table 26-4] (Continued from Table 26) [Table 26-5] (Continued from Table 26) [Table 26-6] (Continued from Table 26) [Table 26-7] (Continued from Table 26) [Table 26-8] (Continued from Table 26) [Table 26-9] (Continued from Table 26) [Table 26-10] (Continued from Table 26) [Table 26-11] (Continued from Table 26) [Table 26-12] (Continued from Table 26) [Table 26-13] 1 Single atropisomer (from precursor of preparation 9B)

[0358] Example 1 2-Amino-7-fluoro-4-(5-fluoro-1-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile [ka] To a solution of 4-(1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (0.150 g, 0.227 mmol) in DCM (2 mL) and MeOH (2 mL) was added (R)-2-hydroxypropanal (0.042 g, 0.568 mmol). After 5 min, sodium cyanoborohydride (0.043 g, 0.681 mmol) was added in small portions. The reaction mixture was stirred at room temperature for 1 h and then diluted with water. The mixture was extracted with 10:1 DCM:MeOH (2×150 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase purification eluting with 45%-55% ACN in 10 mM aqueous NH4HCO3 (containing 0.05% NH4OH) to give the title compound (0.079 g, 48%) as a white solid. MS (ES) m / z=719 (M+1).

[0359] The following compounds in Table 27 were prepared in a similar manner as described in Example 1. In some cases, (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanal was used instead of (R)-2-hydroxypropanal. The compounds were purified using a variety of methods, including but not limited to strong cation exchange chromatography using ammoniated methanol, which would be apparent to one skilled in the art. Table 27: [Table 27-1] (Continued from Table 27) [Table 27-2] (Continued from Table 27) [Table 27-3] (Continued from Table 27) [Table 27-4] (Continued from Table 27) [Table 27-5] (Continued from Table 27) [Table 27-6] (Continued from Table 27) [Table 27-7] (Continued from Table 27) [Table 27-8] (Continued from Table 27) [Table 27-9] (Continued from Table 27) [Table 27-10] (Continued from Table 27) [Table 27-11] (Continued from Table 27) [Table 27-12] (Continued from Table 27) [Table 27-13] (Continued from Table 27) [Table 27-14] (Continued from Table 27) [Table 27-15] (Continued from Table 27) [Table 27-16] (Continued from Table 27) [Table 27-17] (Continued from Table 27) [Table 27-18] 1 Preparative chiral HPLC; CHIRAL ART Cellulose-SZ, 20 x 250 mm, 50% hexane (containing 10 mM ammoniated methanol): 50% EtOH, 20 mL / min 2 Single atropisomer (from precursor of preparation 9B) 3 Preparative chiral HPLC; CHIRAL ART Cellulose-SZ, 30 x 250 mm, 50% hexane (containing 10 mM ammoniated methanol): 50% EtOH, 40 mL / min 4 Preparative chiral HPLC; Chiralpak-IG, 30 x 250 mm, 10% MeOH (1:1 hexane:MTBE (containing 0.5% 2M ammoniated methanol)), 40 mL / min

[0360] Example 29A 2-Amino-7-fluoro-4-(5-fluoro-3-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile [ka] 2-Amino-7-fluoro-4-(5-fluoro-3-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile and formaldehyde (with acetic acid as solvent) were used in a manner similar to that of Example 1 to give the title compound (0.014 g, 48%). MS (ES) m / z=506 (M+1).

[0361] Example 30A 2-Amino-7-fluoro-4-(5-fluoro-3-((S)-1-methyl-1,6-diazaspiro[3.4]octan-6-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile [ka] 2-Amino-7-fluoro-4-(5-fluoro-3-((S)-1,6-diazaspiro[3.4]octan-6-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile and formaldehyde (with acetic acid as the solvent) were used in a manner similar to that of Example 1 to give the title compound (0.028 g, 51%). MS (ES) m / z=506 (M+1).

[0362] Example 19 2-Amino-7-fluoro-4-(5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile [ka] tert-Butyl (3-cyano-7-fluoro-4-(5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridin-2-yl)carbamate (0.33 g, 0.51 mmol) and 1,1,1,3,3,3-hexafluoropropan-2-ol (4 mL) were combined. The mixture was stirred at 100° C. for 1 h and then concentrated under reduced pressure. The residue was purified by reverse phase purification eluting with 31%-48% ACN in 10 mM aqueous NH4HCO3 to give the title compound (0.070 g, 29%) as a white solid. MS (ES) m / z=551 (M+1).

[0363] The following compounds in Table 28 were prepared in a similar manner as described in Preparation 94 or Example 19. Various deprotection reagents were used, such as HCl, TFA, or TBAF. Compounds were purified using a variety of methods that would be apparent to one skilled in the art. Table 28: [Table 28-1] (Continued from Table 28) [Table 28-2] (Continued from Table 28) [Table 28-3] (Continued from Table 28) [Table 28-4] (Continued from Table 28) [Table 28-5] (Continued from Table 28) [Table 28-6] (Continued from Table 28) [Table 28-7] (Continued from Table 28) [Table 28-8] (Continued from Table 28) [Table 28-9] (Continued from Table 28) [Table 28-10] (Continued from Table 28) [Table 28-11] (Continued from Table 28) [Table 28-12] (Continued from Table 28) [Table 28-13] (Continued from Table 28) [Table 28-14] (Continued from Table 28) [Table 28-15] (Continued from Table 28) [Table 28-16] (Continued from Table 28) [Table 28-17] (Continued from Table 28) [Table 28-18] (Continued from Table 28) [Table 28-19] (Continued from Table 28) [Table 28-20] (Continued from Table 28) [Table 28-21] (Continued from Table 28) [Table 28-22] (Continued from Table 28) [Table 28-23] (Continued from Table 28) [Table 28-24] (Continued from Table 28) [Table 28-25] (Continued from Table 28) [Table 28-26] (Continued from Table 28) [Table 28-27] (Continued from Table 28) [Table 28-28] (Continued from Table 28) [Table 28-29] (Continued from Table 28) [Table 28-30] (Continued from Table 28) [Table 28-31] (Continued from Table 28) [Table 28-32] (Continued from Table 28) [Table 28-33] (Continued from Table 28) [Table 28-34] (Continued from Table 28) [Table 28-35] (Continued from Table 28) [Table 28-36] (Continued from Table 28) [Table 28-37] (Continued from Table 28) [Table 28-38] (Continued from Table 28) [Table 28-39] (Continued from Table 28) [Table 28-40] (Continued from Table 28) [Table 28-41] (Continued from Table 28) [Table 28-42] (Continued from Table 28) [Table 28-43] (Continued from Table 28) [Table 28-44] (Continued from Table 28) [Table 28-45] (Continued from Table 28) [Table 28-46] (Continued from Table 28) [Table 28-47] (Continued from Table 28) [Table 28-48] (Continued from Table 28) [Table 28-49] (Continued from Table 28) [Table 28-50] (Continued from Table 28) [Table 28-51] (Continued from Table 28) [Table 28-52] (Continued from Table 28) [Table 28-53] (Continued from Table 28) [Table 28-54] (Continued from Table 28) [Table 28-55] (Continued from Table 28) [Table 28-56] (Continued from Table 28) [Table 28-57] (Continued from Table 28) [Table 28-58] (Continued from Table 28) [Table 28-59] (Continued from Table 28) [Table 28-60] (Continued from Table 28) [Table 28-61] (Continued from Table 28) [Table 28-62] (Continued from Table 28) [Table 28-63] (Continued from Table 28) [Table 28-64] (Continued from Table 28) [Table 28-65] (Continued from Table 28) [Table 28-66] (Continued from Table 28) [Table 28-67] (Continued from Table 28) [Table 28-68] (Continued from Table 28) [Table 28-69] (Continued from Table 28) [Table 28-70] (Continued from Table 28) [Table 28-71] (Continued from Table 28) [Table 28-72] (Continued from Table 28) [Table 28-73] (Continued from Table 28) [Table 28-74] (Continued from Table 28) [Table 28-75] (Continued from Table 28) [Table 28-76] (Continued from Table 28) [Table 28-77] (Continued from Table 28) [Table 28-78] (Continued from Table 28) [Table 28-79] (Continued from Table 28) [Table 28-80] (Continued from Table 28) [Table 28-81] (Continued from Table 28) [Table 28-82] 1 Pure trans isomer; separation of the trans isomer pair occurred in preparations 47A and 48A. 2 Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-53% in heptane (EtOH with 0.1% isopropylamine), 42.5 mL / min 3 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-90% in heptane (1:1 MeOH:EtOH), 50 mL / min 4 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-70% EtOH in heptane, 42.5 mL / min 5 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-55% (1:1 MeOH:EtOH) in heptane, 50 mL / min 6 Preparative chiral HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 13-100% in heptane (EtOH with 0.1% isopropylamine), 42.5 mL / min 7 Preparative chiral HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 5-100% in heptane (1:1 MeOH:EtOH with 0.1% isopropylamine), 42.5 mL / min; diastereomers 78A-81A each consist of a single atropisomer and a single trans isomer. 8 Preparative chiral HPLC; Phenomenex Lux Cellulose-1, 30 x 150 mm, 50-100% in heptane (isopropanol with 0.1% isopropylamine), 40.0 mL / min 9 Preparative chiral HPLC; Chiralpak-IK, 3×25 cm, 50% EtOH in (10 mM ammoniated methanol in hexanes), the pure fractions gave diastereomer 4. The mixed fractions were further separated by preparative chiral HPLC; Chiralpak-IF, 3×25 cm, 30% EtOH in (10 mM ammoniated methanol in hexanes), the pure fractions gave diastereomer 3. The mixed fractions were further separated by preparative chiral HPLC; Chiralpak-IH, 3×25 mm, 30% EtOH in (10 mM ammoniated methanol in hexanes), the first pure fractions gave diastereomer 1 and the second pure fractions gave diastereomer 2. 10 Preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 10-100% in heptane (isopropanol with 0.1% isopropylamine), 36 mL / min 11 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 5-45% in heptane (1:1 MeOH:EtOH with 0.1% isopropylamine), 42.5 mL / min 12 Preparative chiral HPLC; Chiralpak-ID, 30 x 250 mm, 50% EtOH in (10 mM ammoniated methanol in hexane), 40 mL / min 13 Preparative chiral SFC; S,S Whelk-O, 20 x 250 mm, 30% in CO2 (EtOH with 0.5% dimethylethylamine), 80 mL / min 14 Pure trans isomer; preparative chiral SFC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 15% in CO2 (MeOH with 0.1% isopropylamine) 15 Example 61B is a mixture of cis isomers and Example 62B is a mixture of trans isomers; Preparative chiral HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 5-70% EtOH in heptane, 42.5 mL / min 16 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-65% EtOH in heptane, 42.5 mL / min 17 Preparative HPLC; C18, 5-98% acetonitrile (in 10 mM ammonium acetate in 95:5 water:MeOH), the first eluting peak contained Examples 82B and 83B, and the second eluting peak contained Examples 84B and 85B. Examples 82B and 83B were further separated by preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30×150 mm, 6-80% in heptane (isopropanol with 0.2% isopropylamine), 40 mL / min, Example 82B was the first eluting peak. Examples 84B and 85B were further separated by preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30×150 mm, 4-45% in heptane (1:1 MeOH:EtOH), 42.5 mL / min, Example 84B was the first eluting peak. 18 Preparative chiral HPLC; Chiralpak-IK, 3 x 25 cm, 50% EtOH in (10 mM ammoniated methanol in hexane), 40 mL / min 19 Pure cis isomer; Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-70% in heptane (EtOH with 0.1% isopropylamine), 42.5 mL / min 20 Preparative chiral HPLC; Chiralpak-ID, 3 x 25 cm, 50% EtOH in (10 mM ammoniated methanol in hexane), 40 mL / min 21 Preparative chiral SFC; Chiralpak-AD, 20 x 250 mm, 45% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 22 Preparative chiral SFC; Chiralpak-IC, 20 x 250 mm, 45% in CO2 (EtOH with 0.5% dimethylethylamine), 80 mL / min 23Single atropisomer (from precursor of preparation 17B) 24 Single atropisomer (from precursor of preparation 18B) 25 Ring-opened by-product from Example 125B 26 Single atropisomer (from precursor of preparation 14B) 27 Mixture of cis isomers 28 Pure cis isomer; preparative chiral SFC; S,S Whelk-O, 20 x 250 mm, 40% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 29 Preparative chiral HPLC; Chiralpak-IG, 19 x 150 mm, 70-100% acetonitrile in 20 mM ammonium bicarbonate, 40 mL / min 30 Preparative chiral SFC; Chiralpak-IC, 20 x 250 mm, 30% (EtOH with 0.5% dimethylethylamine) in CO2, 80 mL / min. Example 8C is the second isomer to elute and was assigned (S,S) stereochemistry after analysis of Example 7C (known (R,R) stereochemistry) which is consistent with the first isomer to elute. 31 Preparative chiral HPLC; Chiralpak-IC, 20 x 150 mm, 70-100% acetonitrile in 20 mM ammonium bicarbonate, 40 mL / min 32 Pure cis isomer; preparative chiral SFC; Chiralpak-IG, 20 x 250 mm, 45% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 33 Mixture of cis isomers 34 Preparative chiral HPLC; Chiralpak-AD, 20 x 150 mm, 100% (EtOH) containing 0.2% dimethylethylamine, 10 mL / min 35 Mixture of cis isomers 36Pure cis isomer; preparative chiral SFC; Chiralpak-IH, 20 x 250 mm, 30% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 37 Preparative chiral SFC; Chiralpak-IH, 20 x 250 mm, 30% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 38 Preparative chiral SFC; Chiralpak-IC, 20 x 250 mm, 40% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 39 Preparative chiral SFC; Chiralpak-IH, 20 x 250 mm, 30% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 40 Preparative chiral HPLC; CHIRAL ART Cellulose-SB, 20 x 250 mm, 50% hexane (containing 10 mM ammoniated methanol): 50% EtOH, 20 mL / min 41 Preparative chiral HPLC; CHIRAL ART Cellulose-SB, 30 x 250 mm, 50% hexane (containing 10 mM ammoniated methanol): 50% EtOH, 40 mL / min 42 Preparative chiral SFC; Chiralpak-IG, 30 x 250 mm, 50% hexane (with 10 mM ammoniated methanol): 50% EtOH, 40 mL / min 43 Preparative chiral HPLC; Chiralpak-IK, 30 x 250 mm, 50% hexane (with 10 mM ammoniated methanol): 50% EtOH, 40 mL / min 44 Preparative chiral HPLC; Chiralpak-ID, 30 x 250 mm, 50% 1:1 hexane:MTBE (with 0.5% 2M ammoniated methanol):50% MeOH, 40 mL / min 45Diastereomers refer to each compound being a single atropisomer and a single quaternary center. Preparative chiral HPLC; Chiralpak-IE, 30×250 mm, 80% 1:1 hexane:MTBE (with 0.5% 2M ammoniated methanol):20% EtOH, 40 mL / min, the first eluting peak contained Examples 60C and 61C, the second eluting peak contained Example 62C, and the third eluting peak contained Example 63C. Examples 60C and 61C were further separated by preparative chiral SFC; Chiralpak-IH, 30×250 mm, 50% (MeOH with 20 mM ammoniated methanol) in CO2, 90 mL / min, Example 60C was the first eluting peak. 46 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 5-85% EtOH in heptane, 42.5 mL / min 47 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-100% EtOH in heptane, 42.5 mL / min 48 Preparative chiral HPLC; Phenomenex Lux Cellulose-1, 30 x 150 mm, 10-75% EtOH in heptane, 42.5 mL / min 49 Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-55% in heptane (EtOH with 0.1% isopropylamine), 42.5 mL / min 50 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-75% in heptane (EtOH with 0.1% isopropylamine), 42.5 mL / min 51 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-63% EtOH in heptane, 42.5 mL / min 52Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-40% EtOH in heptane, 42.5 mL / min 53 Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-40% in heptane (EtOH with 0.1% isopropylamine), 37.5 mL / min 54 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 15-60% EtOH in heptane, 40 mL / min 55 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 15-45% 1:1 MeOH:EtOH in heptane, 42.5 mL / min 56 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-60% EtOH in heptane, 37.5 mL / min 57 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-55% EtOH in heptane, 37.5 mL / min 58 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 15-45% 1:1 MeOH:EtOH in heptane, 37.5 mL / min 59 Preparative chiral HPLC; Chiralpak-IG, 30 x 250 mm, 70% hexane (with 10 mM ammoniated methanol): 30% isopropanol, 40 mL / min 60 Preparative chiral HPLC; Chiral NQ(2) 5u, 30 x 250 mm, 50% hexane (with 10 mM ammoniated methanol): 50% isopropanol, 40 mL / min 61 Preparative chiral HPLC; Chiral NQ(2) 5u, 30 x 250 mm, 50% hexane (with 10 mM ammoniated methanol): 50% isopropanol, 40 mL / min 62 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 5-60% in heptane (EtOH with 0.1% isopropylamine), 42.5 mL / min 63 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-90% isopropanol in heptane, 37.5 mL / min 64 Pure cis isomer; Preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30 x 150 mm, 5-45% in heptane (1:1 MeOH:EtOH with 0.1% isopropylamine), 42.5 mL / min 65 Preparative HPLC; C18, acetonitrile in water 66 Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-100% in heptane (EtOH with 0.1% isopropylamine), 40 mL / min 67 Preparative chiral SFC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 25% MeOH in CO2, 37.5 mL / min 68 Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 18-60% 1:1 MeOH:EtOH in heptane, 50 mL / min 69 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 15-100% 1:1 MeOH:EtOH in heptane, 40 mL / min 70 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 15-60% in heptane (1:1 MeOH:EtOH with 0.1% isopropylamine), 42.5 mL / min 71Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 5-60% EtOH in heptane, 42.5 mL / min 72 Preparative chiral HPLC; Phenomenex Lux Cellulose-1, 30 x 150 mm, 10-100% isopropanol in heptane, 30 mL / min 73 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 20-50% 1:1 MeOH:EtOH in heptane, 42.5 mL / min 74 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-100% 1:1 MeOH:EtOH in heptane, 37.5 mL / min 75 Preparative chiral HPLC; Phenomenex Lux Cellulose-2, 30 x 150 mm, 10-70% 1:1 MeOH:EtOH in heptane, 37.5 mL / min 76 Preparative chiral SFC; Chiralpak-AD, 20 x 250 mm, 45% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 77 Mixture of trans isomers 78 Mixture of trans isomers 79 Pure trans isomer isolated in preparations 5D and 6D 80 Pure trans isomer isolated in preparation 7D 81 Pure trans isomer; Preparative chiral HPLC; Chiralpak-IG, 20 x 150 mm, 50-100% acetonitrile (in 20 mM ammonium bicarbonate in pH 9 buffer), 40 mL / min 82 Pure trans isomer isolated in preparation 7D 83Pure trans isomer; Preparative chiral HPLC; Chiralpak-IG, 20 x 150 mm, 50-100% acetonitrile (in 20 mM ammonium bicarbonate in pH 9 buffer), 40 mL / min 84 Mixture of trans isomers 85 Pure trans isomer; preparative chiral SFC; Chiralpak-AD, 20 x 250 mm, 45% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 86 Pure trans isomer isolated in preparations 9D and 10D 87 Pure trans isomer; Preparative chiral HPLC; Chiralpak-IC, 20 x 150 mm, 70-100% acetonitrile (in 20 mM ammonium bicarbonate in pH 9 buffer), 40 mL / min 88 Pure trans isomer; Preparative chiral HPLC; Chiralpak-IC, 20 x 150 mm, 70-100% acetonitrile (in 20 mM ammonium bicarbonate in pH 9 buffer), 40 mL / min 89 Preparative chiral SFC; S,S Whelk-O, 20 x 150 mm, 30% in CO2 (isopropanol with 0.5% dimethylethylamine), 80 mL / min 90 Preparative chiral SFC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 20% in CO2 (EtOH with 0.1% isopropylamine) 91 Preparative chiral SFC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 18% in CO2 (EtOH with 0.1% isopropylamine) 92 Pure trans isomer; preparative chiral SFC; Chiralpak-IC, 20 x 250 mm, 40% in CO2 (MeOH with 0.5% dimethylethylamine), 65 g / min 93 Mixture of trans isomers 94 Mixture of cis isomers 95 Mixture of trans isomers 96 Pure trans isomer; preparative chiral SFC; Chiralpak-AD, 20 x 250 mm, 45% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 97 Mixture of trans isomers (nitrogen and oxygen substituents) 98 Pure trans isomer (nitrogen and oxygen substituents) 99 Pure trans isomer (nitrogen and oxygen substituents) 100 Pure cis isomer (nitrogen and oxygen substituents) 101 Pure cis isomer; Preparative HPLC; C18, 35-70% acetonitrile in (20 mM ammonium bicarbonate in pH 9 buffer), 40 mL / min 102 Pure trans isomers separated in preparations 12D and 13D 103 Preparative chiral SFC; Chiralpak-AD, 20 x 250 mm, 40% in CO2 (EtOH with 0.5% dimethylethylamine), 65 g / min 104 Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 20-100% in heptane (EtOH with 0.1% isopropylamine), 45 mL / min 105 Preparative chiral HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 20-100% in heptane (1:1 MeOH:EtOH with 0.1% isopropylamine), 50 mL / min 106 Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 10-60% in heptane (1:1 MeOH:EtOH with 0.1% isopropylamine), 34.5 mL / min 107Preparative chiral HPLC; Chiralpak-IG, 20 x 150 mm, 70-100% acetonitrile (in 20 mM ammonium bicarbonate in pH 9 buffer), 40 mL / min 108************ Pure isomers derived from 109 Preparative chiral SFC; Chiralpak-IC, 20 x 250 mm, 45% in CO2 (MeOH with 0.5% dimethylethylamine), 80 mL / min 110 By-products separated from impurities in Example 231D 111 Preparative chiral HPLC; Chiralpak-IG, 30 x 250 mm, 50% hexane (with 10 mM ammoniated methanol): 50% EtOH, 40 mL / min 112 Preparative chiral HPLC; Chiral Art Cellulose-SC, 30 x 250 mm, 50% hexane (with 10 mM ammoniated methanol): 50% isopropanol, 40 mL / min 113 Preparative chiral HPLC; Chiralpak-IE, 30 x 250 mm, 70% 1:1 hexane:MTBE (with 0.5% 2M ammoniated methanol):30% EtOH, 35 mL / min 114 Preparative chiral HPLC; Chiralpak-IG, 30 x 250 mm, 50% hexane (with 10 mM ammoniated methanol): 50% EtOH, 40 mL / min 115 Preparative chiral HPLC; Chiralpak-IK, 30 x 250 mm, 80% hexane (with 10 mM ammoniated methanol): 20% EtOH, 40 mL / min 116 Preparative chiral HPLC; Chiralpak-ID, 30 x 250 mm, 50% hexane (with 10 mM ammoniated methanol): 50% EtOH, 40 mL / min 117 Preparative chiral HPLC; Chiralpak-IG, 30 x 250 mm, 60% hexane (with 10 mM ammoniated methanol): 40% EtOH, 40 mL / min 118 Preparative chiral HPLC; Chiral Art Cellulose-SZ, 30 x 250 mm, 70% Hexane (with 10 mM ammoniated methanol): 30% EtOH, 40 mL / min 119 Preparative chiral HPLC; Chiralpak-IE, 30 x 250 mm, 75% 1:1 hexane:MTBE (with 0.5% 2M ammoniated methanol):25% MeOH, 40 mL / min

[0364] The following compounds in Table 29 were prepared in a manner similar to that described in Preparation 33B or Example 1. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 29: [Table 29-1] (Continued from Table 29) [Table 29-2] (Continued from Table 29) [Table 29-3] 1 Preparative HPLC; C18, 35-70% acetonitrile in (20 mM ammonium bicarbonate in pH 9 buffer), 40 mL / min 2 Preparative chiral SFC; Phenomenex Lux Cellulose-4, 30×100 mm, 40% MeOH in CO; chiral purification was performed on Example 141B. Example 142B is the second isomer to elute and was assigned the (R) stereochemistry after analysis of Example 140B (known (S) stereochemistry) which is consistent with the first isomer to elute. 3 Single atropisomer (from precursor of preparation 14B) 4 Preparative chiral HPLC; Chiralpak-ID, 30 x 250 mm, 70% hexane (with 10 mM ammoniated methanol): 30% EtOH, 40 mL / min 5 Diastereomers refer to each compound being a single atropisomer and a single spiro center. Preparative chiral HPLC; Phenomenex Lux Cellulose-4, 30 x 150 mm, 10-60% 1:1 MeOH:EtOH in heptane, 37.5 mL / min, the first eluting peak contained Examples 260D and 261D, the second eluting peak contained Example 262D and the fourth diastereomer. Examples 260D and 261D were further separated by preparative chiral SFC; Phenomenex Lux Cellulose-3, 30 x 100 mm, 15% in CO2 (MeOH with 0.1% isopropylamine), Example 260D was the first eluting peak. Example 262D and the fourth diastereomer were further separated by preparative chiral HPLC; Phenomenex Lux i-Cellulose-5, 30×150 mm, 10-100% (isopropanol with 0.1% isopropylamine) in heptane, 34.5 mL / min, with Example 262D being the first eluting peak.

[0365] Example 263D 2-Amino-7-fluoro-4-(5-fluoro-3-((2R,3R)-3-(isopropylamino)-2-methylpyrrolidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile [ka]

[0366] tert-Butyl (4-(3-((2R,3R)-3-amino-2-methylpyrrolidin-1-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (0.150 g, 0.259 mmol), acetone (0.038 mL, 0.518 mmol), and sodium triacetoxyborohydride (0.110 g, 0.518 mmol) were dissolved in MeOH (8 mL) and acetic acid (2 mL). The reaction mixture was heated at 50° C. for 18 h. Additional acetone (0.038 mL, 0.518 mmol) and sodium triacetoxyborohydride (0.110 g, 0.518 mmol) were added. The reaction mixture was heated at 50° C. for 18 h, then concentrated under reduced pressure and diluted with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with EtOAc (3×40 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica eluting with 0-20% MeOH in DCM to give the BOC-protected intermediate, tert-butyl (3-cyano-7-fluoro-4-(5-fluoro-3-((2R,3R)-3-(isopropylamino)-2-methylpyrrolidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridin-2-yl)carbamate.

[0367] The intermediate was dissolved in DCM (5 mL) and treated with TFA (3 mL). The reaction mixture was heated at 38° C. for 1 h and then concentrated under reduced pressure. The residue was purified by reverse phase purification eluting with 0-100% acetonitrile in 10 mM aqueous ammonium chloride (containing 5% MeOH) to give the title compound (0.022 g, 15%) as a yellow solid. MS (ES) m / z=522 (M+1).

[0368] The following compounds in Table 30 were prepared in a similar manner as described in Example 263D. The compounds were purified using a variety of methods that would be apparent to one of skill in the art. Table 30: [Table 30-1] (Continued from Table 30) [Table 30-2] 1 Preparative chiral HPLC; Phenomenex Lux i-Amylose-3, 30 x 150 mm, 20-100% 1:1 MeOH:EtOH in heptane, 40 mL / min 2 Preparative chiral HPLC; Phenomenex Lux i-Amylose-1, 30 x 150 mm, 18-90% in heptane (1:1 MeOH:EtOH with 0.1% isopropylamine), 60 mL / min

[0369] Example 273D 2-Amino-7-fluoro-4-(5-fluoro-3-(4-(propan-2-yl-d7)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile [ka] A solution of 2-amino-7-fluoro-4-(5-fluoro-3-(octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile (50 wt%, 0.045 g, 0.045 mmol) in acetonitrile was treated with diisopropylethylamine (0.039 mL, 0.22 mmol) and 2-iodopropane-1,1,1,2,3,3,3-d7 (0.0045 mL, 0.045 mmol). The reaction mixture was heated at 60° C. for 1 h and 70° C. for 3 days, then concentrated under reduced pressure. The residue was purified by reverse phase purification eluting with acetonitrile in aqueous ammonium bicarbonate buffer to give the title compound (0.018 g, 66%) as a yellow solid. MS(ES) m / z=555(M+1).

[0370] Example 274D 2-Amino-4-(3-(4-(ethyl-d5)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile [ka] 1-Iodoethane-1,1,2,2,2-d5 was used in a manner similar to that of Example 273D to give the title compound (0.034 g, 77%) as a yellow solid. MS (ES) m / z=539 (M+1).

[0371] Example 122C 2-Amino-7-fluoro-4-(5-fluoro-3-((2S,3S)-2-methyl-3-(((R)-3,3,3-trifluoro-2-hydroxypropyl)amino)pyrrolidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile [ka] A solution of tert-butyl (4-(3-((2S,3S)-3-amino-2-methylpyrrolidin-1-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (0.150 g, 0.259 mmol) and (R)-2-(trifluoromethyl)oxirane (0.029 g, 0.259 mmol) in isopropanol (4 mL) was heated to 75° C. for 8 hours and then cooled to room temperature. The material was purified by reverse phase purification eluting with 10% to 100% ACN in water (both containing 0.1% formic acid) to give the title compound (0.0054 g, 3.4%) as a yellow solid. MS (ES) m / z=592 (M+1).

[0372] Example 275D 2-Amino-7-fluoro-4-(5-fluoro-3-((2S,3S)-2-methyl-3-(((S)-3,3,3-trifluoro-2-hydroxypropyl)amino)pyrrolidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile formic acid [ka] (S)-2-(trifluoromethyl)oxirane was used in a manner similar to that of Example 122C to give the title compound (0.0086 g, 5%). MS (ES) m / z=592 (M+1).

[0373] Biological assays The following assays demonstrate that the exemplified compounds are potent inhibitors of Kras G12C, G12D, and / or G12V, and inhibit the growth of certain tumors in vitro and / or in vivo.

[0374] PANC-1 Cell Active RAS GTPase ELISA (KRas G12D Mutation) The purpose of this assay is to measure the ability of test compounds to inhibit the activity of constitutive RAS GTPase in human PANC-1 (RRID: CVCL_0480) pancreatic ductal adenocarcinoma cells (supplier: ATCC number CRL-1469). The RAS GTPase ELISA kit (Active Motif catalog number 52097) contains a 96-well glutathione-coated capture plate and Glutathione-S-Transferase (GST) fused to the Raf-Ras Binding Domain (RBD) protein provided in the kit. Activated pan-RAS (GTP-bound) in cell extracts binds specifically to Raf-RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K-Ras (and H-Ras). An HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and a developing substrate solution facilitates the chemiluminescent readout.

[0375] PANC-1 cells are plated at a concentration of 75,000 cells / well in 80 μL complete medium (DMEM, high glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37°C / 5% CO2. Approximately 24 hours later, 20 μL (1:3) of serially diluted (in complete medium) test compounds (highest concentration 1-50 μM) and 20 μL of serially diluted (in complete medium) controls (maximum signal wells: 0.5% DMSO and minimum signal wells: 10 μM reference positive control compound) are added to the cell plate and incubated for 2 hours at 37°C / 5% CO2. Complete lysis / binding buffer containing Protease Inhibitor cocktail (PIC) is prepared and stored on ice. One hour before the incubation of the cell plate is completed, GST-Raf-RBD is diluted in lysis / binding buffer and 50 μL of mixed buffer per well is added to the supplied milky white ELISA assay plate and incubated at 4 °C for a minimum of 1 hour with gentle rocking. After 2 hours, cells are washed with 100 μL of ice-cold Ca2+ / Mg2+-free PBS and lysed with 100 μL of lysis / binding buffer (AM11) supplied in the kit. After shaking the plate vigorously for 30-50 minutes at ambient temperature, the cell plate is centrifuged at 410 × g (approximately 1500 rpm) for 10 minutes. A wash buffer, diluted 1x with ultrapure HO and filtered through 0.2 μm, is prepared at ambient temperature during the centrifugation step and then used to wash the GST-Raf-RBD-coated assay plate (3 × 100 μL). Next, 50 μL of cell lysate is added to the GST-Raf-RBD-coated assay plate and incubated for 1 h at ambient temperature with gentle shaking. During this incubation period, 1x antibody binding buffer is prepared from thawed concentrate. The assay plate is washed with 1x wash buffer (3 x 100 μL) and then 50 μL of primary RAS antibody (supplied in the kit, no. 101678) diluted 1:500 in 1x antibody binding buffer is added. After 1 h of incubation at ambient temperature with gentle shaking, the assay plate is washed with 1x wash buffer (3 x 100 μL).Then, 50 μL of anti-rat HRP-conjugated IgG secondary antibody (0.25 μg / μL) (diluted 1:5000 in 1× antibody binding buffer) is added to each well of the assay plate and incubated for another hour at ambient temperature with gentle shaking. Finally, the assay plate is washed with 1× wash buffer (4×100 μL), followed by the addition of 50 μL of mixed chemiluminescence working solution (a combination of reaction buffer and chemiluminescent substrate) at ambient temperature. Data from the luminescence emission of each well is recorded on a 2104 EnVision™ plate reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.

[0376] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test compound signal - Median minimum signal) / (Median maximum signal - Median minimum signal) x 100]. Maximum signal is the control wells with no inhibitor (DMSO). Minimum signal is the control wells containing enough reference inhibitor to completely inhibit activity. IC 50 is determined by fitting the percent inhibition at each inhibitor concentration to a four-parameter nonlinear logistic equation using Genedata Screener® version 17: y=(A+((BA) / (1+((x / C)^D)))), where y is the % inhibition, A is the minimum asymptote, B is the maximum asymptote, and C is the relative IC 50 or the inhibitor concentration that produces 50% inhibition within the fit range of both asymptote, where D is the Hill slope).

[0377] The compounds of Examples 1-3, 5-9, 11-18, 37, 1A-5A, 7A-11A, 13A-22A, 25A, 30A, 42A, 52A, 55A, 58A, 65A, 76A, 1B, 20B, 21B, and 105B were tested in the above assay and all demonstrated the ability to inhibit constitutive RAS GTPase activity with a relative IC of <100 nM. 50The data show that compounds of formula I described herein are potent inhibitors of KRAS-GTP activity in this human pancreatic cancer cell culture, demonstrating their ability to inhibit the KRas G12D mutant.

[0378] MKN-45 cell activity RAS GTPase ELISA (KRas wild type) The purpose of this assay is to measure the ability of test compounds to inhibit constitutive RAS GTPase activity in human MKN-45 gastric adenocarcinoma cells (Supplier: JCRB, Supplier ID: JCRB 0254, Lot: 05222009). The RAS GTPase ELISA kit (Active Motif Cat. No. 52097) contains a 96-well glutathione-coated capture plate and glutathione-S-transferase (GST) fused to the Raf-Ras binding domain (RBD) protein provided in the kit. Activated pan-RAS (GTP bound) in cell extracts binds specifically to Raf-RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K-Ras (and H-Ras). An HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and a developing substrate solution facilitates chemiluminescent readout.

[0379] MKN-45 cells are plated at a concentration of 75,000 cells / well in 80 μL complete medium (DMEM, high glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37 °C / 5% CO2. Approximately 24 h later, 20 μL (1:3) of serially diluted (in complete medium) test compounds (highest concentration 1-10 μM) and 20 μL of serially diluted (in complete medium) controls (maximum signal wells: 0.1% DMSO and minimum signal wells: 10 μM reference positive control compound) are added to the cell plate and incubated for 2 h at 37 °C / 5% CO2. Complete lysis / binding buffer containing protease inhibitor cocktail (PIC) is prepared and stored on ice. One hour before the incubation of the cell plate is completed, GST-Raf-RBD is diluted in lysis / binding buffer and 50 μL of mixed buffer per well is added to the supplied milky white ELISA assay plate and incubated for a minimum of 1 hour at 4 °C with gentle rocking. After 2 hours, cells are washed with 100 μL of ice-cold Ca2+ / Mg2+-free PBS and lysed with 100 μL of lysis / binding buffer (AM11) supplied in the kit. After shaking the plate vigorously for 30-50 minutes at ambient temperature, the cell plate is centrifuged for 10 minutes at 410 × g (approximately 1500 rpm). During the centrifugation step, the wash buffer is diluted 1x with ultrapure H2O and then used to wash the GST-Raf-RBD-coated assay plate (3 × 100 μL). Next, 50 μL of cell lysate is added to the GST-Raf-RBD-coated assay plate and incubated for 1 hour at ambient temperature with gentle rocking. During this incubation period, 1x antibody binding buffer is prepared from thawed concentrate. The assay plate is washed with 1x wash buffer (3x100 μL) and then 50 μL of primary RAS antibody (supplied in the kit, no. 101678) diluted 1:500 in 1x antibody binding buffer is added. After 1 h of incubation at ambient temperature with gentle shaking, the assay plate is washed with 1x wash buffer (3x100 μL).Then, 50 μL of anti-rat HRP-conjugated IgG secondary antibody (0.25 μg / μL) (diluted 1:5000 in 1× antibody binding buffer) is added to each well of the assay plate and incubated for another hour at ambient temperature with gentle shaking. Finally, the assay plate is washed with 1× wash buffer (4×100 μL), followed by the addition of 50 μL of mixed chemiluminescence working solution (a combination of reaction buffer and chemiluminescent substrate) at ambient temperature. Data from the luminescence emission of each well is recorded on a 2104 EnVision™ plate reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.

[0380] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test compound signal - Median minimum signal) / (Median maximum signal - Median minimum signal) x 100]. Maximum signal is the control wells with no inhibitor (DMSO). Minimum signal is the control wells containing enough reference inhibitor to completely inhibit activity. IC 50 is determined by fitting the percent inhibition at each inhibitor concentration to a four-parameter nonlinear logistic equation using Genedata Screener® version 17: y=(A+((BA) / (1+((x / C)^D)))), where y is the % inhibition, A is the minimum asymptote, B is the maximum asymptote, and C is the relative IC 50 or the inhibitor concentration that produces 50% inhibition within the fit range of both asymptote, where D is the Hill slope).

[0381] The compounds of Examples 1-3, 5-9, 11-18, 37, 1A, 3A, 4A, 6A, 7A, 9A, 10A, 13A-17A, 19A, 20A, 22A-25A, 1B-5B, 7B-11B, 13B, 14B, 17B, and 20B-23B were tested in both assays described above (PANC-1 cell active RAS GTPase ELISA and MKN-45 cell active RAS GTPase ELISA) and all showed significant (i.e., greater than 10-fold) selective inhibitory preference for KRas G12D mutant over KRas wild type.

[0382] Cellular Phospho-ERK AlphaLISA® Assay for KRAS Inhibition The purpose of these assays is to quantify the ability of test compounds to selectively inhibit KRAS signaling in cells that have KRAS amplification and express activating KRAS G12 mutations (Table 31). The cancer cell lines used in this study were selected based on the presence of homozygous activating KRAS G12 mutations or KRAS gene amplification. In addition, these assays were performed on a set of RAS-null mouse embryonic fibroblasts (MEFs) that were engineered to express only KRAS wild type, HRAS, and NRAS, respectively (Table 31). MEF cells were used to confirm the KRAS selectivity of the test compounds. Table 31: Cell line information [Table 31]

[0383] The activity of the compounds is determined by measuring the change in phosphorylation level of the downstream effector extracellular signal-regulated kinase 1 and 2 (ERK1 / 2) in compound-treated cells. The phosphorylation level of ERK-1 / 2 is measured using the AlphaLISA® SureFire® Ultra™ p-ERK1 / 2 (Thr202 / Tyr204) Assay Kit (No. 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. The assay kit contains two antibodies, one of which binds to the phospho-Thr202 / Tyr204 epitope on ERK-1 / 2 and the other of which recognizes a separate site on the protein. One of these antibodies is biotinylated and bound to streptavidin-coated alpha donor beads, and the other antibody is conjugated to AlphaLISA® acceptor beads. When ERK-1 / 2 is phosphorylated in a cell lysate, the donor and acceptor beads are brought into close proximity to each other. When the donor beads are excited with 600 nm wavelength light, a photosensitizer within the beads converts ambient oxygen to an excited singlet state. When the acceptor beads are within 200 nm of this reaction, the singlet oxygen reacts with the acceptor, resulting in chemiluminescent emission. The amount of light measured is proportional to the amount of phosphorylated ERK-1 / 2 in the lysate. The AlphaLISA® SureFire® Ultra™ p-ERK 1 / 2 (Thr202 / Tyr204) Assay Kit contains AlphaLISA® antibody-conjugated donor and acceptor beads, lysis buffer concentrate, and a set of proprietary buffers (Activation Buffer, Reaction Buffer 1, Reaction Buffer 2, and Dilution Buffer).

[0384] To perform these assays, test compounds and controls are acoustically dispensed into white 384-well assay plates (Proxiplate-384, PerkinElmer #6008280) in a 10-point 3-fold dilution series in 30 nL of DMSO (Labcyte ECHO®, San Jose, CA). Cells are then added at cell line specific density to the assay plate in 8 μL / well of assay medium (HBSS, Sigma #55021C, 10% FBS, GIBCO #10082-147) (Table 31). Final compound concentrations in each well range from 0.5 to 10,000 nM, with a final DMSO concentration of 0.375%. Maximum signal control wells contain 0.375% DMSO only (negative control), and minimum signal control wells contain 10,000 nM of control compound (positive control). Cells in suspension are incubated with test and reference compounds for 2 hours at 37°C / 5% CO2. After 2 hours of incubation, cells are lysed by adding 2 μL of AlphaLISA® Lysis Buffer Concentrate (5x) supplemented with protease / phosphatase inhibitor cocktail (Thermo Scientific #78442). The assay plate is covered with an opaque lid and shaken at 750 rpm for 30 minutes at room temperature on a multiplate 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 Buffer 1 and 2 and 1:25 dilution of AlphaLISA® Activation Buffer). After cell lysis, the plate is briefly centrifuged and 5 μL / well of prepared Acceptor Beads are 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 1:50 in AlphaLISA® Dilution Buffer. After the 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.

[0385] The raw signals from the AlphaLISA® assays are analyzed using Genedata Screener® 17.0.3, within which the data are normalized to 32 wells treated with inhibition control (maximum inhibition / positive control) and 32 wells treated with 0.375% DMSO only (minimal inhibition / negative control) to calculate the % activity of the compounds.

number

number

[0386] Compounds of the Examples presented herein were tested in the above assays and demonstrated the ability to reduce levels of phosphorylated ERK-1 / 2 in cells expressing KRAS and KRAS mutants, including KRAS G12C (Examples 1, 3, 8, 9, 19-30, 32-36, 29A-44A, 47A-70A, 72A-79A, 82A-84A, 28B-30B, 33B-94B, 96B-120B, 122B-148B, 1C-49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C-71C, 73C-79C, 81C, 83C-88C, 90C, 92C, 94C~122C, 2D, 3D, 5D, 6D, 8D~10D, 12D, 14D, 16D~99D, 101D~126D, 128D~195D, 197D~201D, 203D~20 7D, 209D~236D, 239D, 240D, 242D, 244D, 246D~248D, 250D~252D, 254D, 256D~259D, and 262D~275D), KRAS G12D (Examples 1-3, 5-9, 11-15, 19-30, 32-37, 25A, 29A-44A, 47A-67A, 70A, 73A, 74A, 76A, 78A, 79A, 82A-84A, 19B, 28B-30B, 33B-45B, 47B-51B, 53B-65B, 67B-94B, 96B-108B, 110B-148B, 1C-27C, 29C-49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C, 70C, 73C, 75C-79C, 81C, 83C-88C, 90C, 92C, 94C-122 C, 2D, 3D, 5D, 6D, 8D, 10D, 12D, 14D, 16D, 18D~20D, 22D~46D, 48D~73D, 75D~8 1D, 83D~95D, 98D, 99D, 101D, 103D~139D, 141D~159D, 161D, 163D, 165D~178 D, 180D, 181D, 183D~195D, 197D~201D, 203D~207D, 209D~236D, 239D, 240D, 242D, 244D, 246D~248D, 250D, 252D, 254D, 256D~259D, and 262D~275D), KRAS G12V (Examples 9, 19-30, 32-36, 29A-44A, 47A-62A, 64A-70A, 72A-74A, 76A, 78A, 79A, 82A-84A,28B~30B, 33B~53B, 55B~88B, 90B~94B, 96B~107B, 110B~120B, 122B~136B, 138B~146B, 148B, 1C~27C, 29C~49C, 51C, 53C, 54C, 57C, 58C , 60C, 61C, 65C, 67C, 69C, 70C, 73C, 75C~78C, 81C, 83C~88C, 92C, 94C~120C, 122C, 2D, 3D, 6D, 8D, 10D, 12D, 14D, 16D, 18D~46D, 48D~73D , 75D-81D, 83D-96D, 99D, 101D, 104D-133D, 135D-139D, 141D-143D, 145D-159D, 161D, 163D, 165D-173D, 175D, 177D, 178D, 180D, 183D-195D, 197D-203D, 206D, 207D, 209D, 211D-236D, 240D, 242D, 244D, 246D-248D, 250D, 252D, 254D, 256D-259D, and 262D-275D), or KRAS WT (Examples 2, 3, 9, 19~30, 32~36, 29A~44A, 47A~70A, 73A, 74A, 76A, 78A, 79A, 82A~84A, 28B~30B, 33B~88B, 90B~94B, 96B~108B, 11 0B~120B, 122B~148B, 1C~49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C, 70C, 73C~79C, 81C, 83C~88C, 90C, 92C, 94C~122 The present invention also shows inhibition of constitutive RAS activity in cells expressing the 5'-aminobutyric acid agonist, 5'-aminobutyric acid agonist, 6'-aminobutyric acid agonist, 8'-aminobutyric acid agonist, 9'-aminobutyric acid agonist, and 10'-aminobutyric acid agonist (C, 2D, 3D, 5D, 6D, 8D-10D, 12D, 14D, 16D-46D, 48D-73D, 75D-81D, 83D-99D, 101D-143D, 145D-195D, 197D-207D, 209D-236D, 239D, 240D, 242D, 244D, 246D-248D, 250D, 252D, 254D, 256D-259D, and 262D-275D) with a relative IC50 of <500 nM. Examples 1, 2, 4~15, 21, 22, 24~26, 29~34, 37, 29A, 34A~38A, 41A, 43A~47A, 53A, 59A, 60A, 62A ~64A, 69A, 71A, 72A, 75A, 77A, 80A, 81A, 18B, 19B, 31B, 32B, 34B, 35B, 39B~43B, 46B, 48B,51B~54B, 57B, 60B, 63B, 65B, 66B, 68B, 70B, 73B~77B, 83B, 86B, 87B, 89B, 93B, 95B, 98B, 99B, 101B~103B, 108B, 109B , 112B, 115B~121B, 123B, 124B, 136B, 140B~142B, 144B, 147B, 2C, 8C, 14C, 16C, 17C, 20C, 21C, 26C, 28C, 30C, 33C~36C , 38C, 40C, 46C~50C, 52C, 53C, 55C, 56C, 59C, 62C~64C, 66C, 68C, 71C, 72C, 74C, 80C, 82C, 89C, 91C, 93C, 101C, 112C, 1 13C, 118C, 121C, 1D, 4D, 5D, 7D, 9D, 11D, 13D, 15D, 17D, 18D, 20D~28D, 31D, 33D~35D, 37D, 38D, 40D, 43D, 44D, 46D, 47D , 51D~54D, 56D, 58D~62D, 64D~78D, 80D, 91D, 93D, 96D~106D, 109D~111D, 113D, 114D, 117D, 121D~123D, 126D~128D, 132D~136D, 139D, 140D, 144D, 147D, 148D, 150D, 152D~155D, 157D~162D, 164D, 172D~186D, 188D, 194D, 195D, 199D~2 Compounds 10D, 212D, 216D, 218D, 222D, 223D, 225D, 226D, 228D, 229D, 232D, 233D, 237D, 238D, 241D, 243D, 245D, 249D, 251D, 253D, 255D, 259D-261D, 263D, and 268D were tested in the mouse embryonic fibroblast cell line assays (MEF-NRAS, MEF-HRAS) described above and all showed relative IC50s >2 μM. Examples 8, 9, 19~30, 32~36, 29A~44A, 47A, 49A, 50A, 52A, 54A~69A, 72A, 74A~76A, 78A, 79A, 84A, 28B, 29B, 33B~36B, 39B~53B, 55B~60B, 62B~79B, 82B~87B, 90B, 91B, 96B~103B, 105B~107B, 109B~115B, 117B~120B, 122B~128B, 130B, 131B, 136B, 138B~144B, 147B, 1C~6C, 8C, 9C, 11C~22C,24C~28C, 30C~38C, 40C~43C, 45C~49C, 51C, 53C, 54C, 57C, 60C, 65C, 67C, 69C, 70C, 73C, 74C, 76C, 77C, 84C, 87C, 88C, 98C, 99C, 101C, 104C ~120C, 122C, 2D, 3D, 8D, 10D, 14D, 18D~40D, 42D~46D, 48D~73D, 75D~80D, 83D~87D, 89D~93D, 95D~119D, 121D~145D, 147D~164D, 167D, 168D Compounds 170D-173D, 175D-181D, 183D, 184D, 186D-188D, 190D, 192D-195D, 197D-204D, 206D, 207D, 209D, 212D, 213D, 215D-236D, 240D, 244D, 246D-251D, 254D, 256D, 257D, 259D, 262D-265D, 267D, 268D, 270D-272D, 274D, and 275D were tested in the three assays described above (SW620, MEF-NRAS, or MEF-HRAS). Cellular Phospho-ERK AlphaLISA® Assay), all showed a striking (i.e., >10-fold) selective inhibition preference for the KRas G12V mutant over HRAS and NRAS.

[0387] This data indicates that compounds of formula I described herein are potent inhibitors of KRAS human cancer cells expressing KRAS, demonstrating the ability to inhibit KRAS G12C, G12D, or G12V mutants with significant selective inhibitory preference for KRAS mutants over HRAS or NRAS. Table 32: Abbreviations [Table 32]

Claims

1. The following formula: 【Chemistry 1】 A compound represented by the formula: 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 is H, R ２ is H, halogen, or methyl; R ３ｂ , and R ３ｃ are each independently H, halogen, or methyl; R ４ is an N-linked cyclic amine or a compound of the formula: 【Chemistry 2】 Based on The N-linked cyclic amine is an 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 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, -NR ６ａ R ６ａ , (1-methylpiperidin-4-yl)oxy, optionally -NR ６ａ R ６ａ C substituted with １～３ Alkoxy, optionally one or more halogens, -NR ６ａ R ６ａ or hydroxyl-substituted C １～３ and optionally substituted with alkyl, a monocyclic ring selected from imidazole, azetidine, piperidine, piperazine, morpholine, oxazepane, or diazepane, optionally substituted with methyl, a bicyclic ring selected from hexahydro-1H-furo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, or octahydropyrrolo[1,2-a]pyrazine, or a spiro 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, said monocyclic ring being １～３ Optionally bridged by alkylene, one or more of halogen, 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 optionally substituted with １～３ which may be optionally substituted with alkyl, or 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]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, tetrahydrofuro[3,4-d]oxazol-2(3H)-one, hexahydro-1H-furo[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-dia azaspiro[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 of which is selected from the group consisting of one or more halogens, —NR ６ａ R ６ａ , or -NR ６ａ R ６ａ or C optionally substituted with hydroxyl １～３ is optionally substituted with alkyl; R ４ａ But, N.R. ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine or morpholine is selected from the group consisting of halogen, hydroxyl, C １～３ Alkoxy or -NR ６ａ R ６ａ and optionally substituted with R ４ｂ is H, hydroxyl, or C １～３ is alkyl, R ４ｃ is independently cyclopropyl or oxetane; R ４ｄ But independently, C １～３ is alkyl, Each R ６ is independently H or deuterium; Each R ６ａ are independently H, trideuteromethyl, 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 of deuterium, hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH ２ C optionally substituted with １～３ alkyl, ３～５ cycloalkyl is optionally substituted with one or more hydroxyl or methyl; E １ But -O-C １～３ Alkylene or C optionally substituted with one or more halogens １～３ is alkylene, E ２ , and E ４ each independently represents one or more hydroxyl, C １～３ C optionally substituted with alkoxy or halogen １～３ alkylene, and E ２ and E ４ is a bond or C １～３ can be optionally bridged by alkylene, E ３ However, -O-, -CR ７ R ７ --, --NR ９ -, or -CO-NR ６ａ -or- The ring 【Chemistry 3】 is hexahydro-1H-furo[3,4-c]pyrrole, Each E ２ａ is independently selected from the group consisting of C, optionally substituted with one or more hydroxyls; １～３ is alkylene, E ５ However, -O-, -CR ７ R ７ - or -NR ９ - and Each R ７ are independently H, halogen, CN, hydroxyl, C １～３ Alkoxy or C optionally substituted with one or more halogens or hydroxyls １～３ is alkyl, Each R ８ But independently, C １～３ is alkyl, R ９ each independently represents H, optionally substituted C １～３ Alkyl or -CO-C １～３ alkyl, １～３ the alkyl is optionally substituted with one or more halogens; R １０ is H or C optionally substituted with one or more deuterium atoms; １～３ alkyl, or a pharma- ceutically acceptable salt thereof.

2. R ４ is an N-linked cyclic amine or a compound of the formula: 【Chemistry 4】 Based on The N-linked cyclic amine is an 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 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, C １～３ Alkoxy, -NR ６ａ R ６ａ , azetidine, piperazine, morpholine, C １～３ and optionally substituted imidazole optionally substituted with alkyl or methyl, and the azetidine is hydroxyl or C １～３ Optionally substituted with alkoxy, said piperazine is optionally substituted with methyl, said C １～３ The alkyl may be one or more halogens, —NR ６ａ R ６ａ or optionally substituted with hydroxyl, or 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]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-b]pyrrole, octahydropyrrolo[3,4-b]pyrazine ... tetrahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol-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, 5-azaspiro[2.4]heptane, or 2-oxa-6-azaspiro[3.4]octane, each of which is selected from the group consisting of one or more halogens, —NR ６ａ R ６ａ Or -NR ６ａ R ６ａ C optionally substituted with １～３ is optionally substituted with alkyl; R ４ａ But, N.R. ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine or morpholine is selected from the group consisting of halogen, hydroxyl, C １～３ Alkoxy or -NR ６ａ R ６ａ and optionally substituted with Each R ６ａ are independently H, trideuteromethyl, C ３～５ Cycloalkyl, tetrahydrofuran, tetrahydropyran, bicyclo[1.1.1]pentan-1-yl, or one or more of hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH ２ C optionally substituted with １～３ alkyl, ３～５ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein cycloalkyl is optionally substituted with one or more hydroxyl or methyl.

3. R ４ is an N-linked cyclic amine or a compound of the formula: 【Chemistry 5】 Based on The N-linked cyclic amine is an 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 Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, C １～３ Alkoxy, -NR ６ａ R ６ａ , Azetidine, C １～３ and optionally substituted imidazole optionally substituted with alkyl or methyl, and the azetidine is hydroxyl or C １～３ Optionally substituted with alkoxy, １～３ The alkyl is a halogen -NR ６ａ R ６ａ or optionally substituted with hydroxyl, or 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, tetrahydrofuro[3,4-d] oxazol-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 of which is selected from the group consisting of one or more halogens, —NR ６ａ R ６ａ Or -NR ６ａ R ６ａ C optionally substituted with １～３ is optionally substituted with alkyl; R ４ａ But, N.R. ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine, or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, or morpholine is selected from the group consisting of halogen, hydroxyl, C １～３ Alkoxy or -NR ６ａ R ６ａ and each R ６ａ are independently H, trideuteromethyl, C ３～５ C optionally substituted with cycloalkyl or hydroxyl １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

4. R ３ｂ , and R ３ｃ are each independently H or halogen; R ４ is an N-linked cyclic amine or a compound of the formula: 【Chemistry 6】 Based on The N-linked cyclic amine is an N-linked i.R ４ａ and R ４ｂ azetidine substituted with ii. pyrrolidine, piperidine, piperazine, or morpholine, each of which is C １～３ Optionally bridged by alkylenes, each of which may be one or more of halogen, hydroxyl, -NR ６ａ R ６ａ , imidazole or C １～３ the imidazole is optionally substituted with methyl; １～３ The alkyl is -NR ６ａ R ６ａ or optionally substituted with hydroxyl, or 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 of which is selected from the group consisting of one or more halogens, or C １～３ optionally substituted with alkyl; R ４ａ But, N.R. ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, or morpholine, wherein the cyclopropyl, azetidine, pyrrolidine, or morpholine is halogen, or —NR ６ａ R ６ａ and optionally substituted with R ４ｂ is H or C １～３ is alkyl, Each R ６ａ are independently H or C １～３ is alkyl, E ２ , and E ４ each independently represents one or more of C optionally substituted with hydroxyl or halogen; １～３ alkylene, and E ２ and E ４ is a bond or C １～３ can be optionally bridged by alkylene, E ３ is -O-, -CR ７ R ７ --, --NR ９ -, or -CO-NR ６ａ The compound of claim 1, wherein R is -, or a pharma- ceutically acceptable salt thereof.

5. R ３ｂ , and R ３ｃ are each independently H or halogen; R ４ is expressed by the following formula: 【Chemistry 7】 Based on E １ C optionally substituted with one or more halogens １～３ is alkylene, E ２ , and E ４ each independently represents a C optionally substituted with one or more hydroxyl １～３ alkylene, and E ２ and E ４ is a bond or C １～３ may be optionally bridged by alkylene, E ３ However, -O-, -CR ７ R ７ --, --NR ９ -, or -CO-NR ６ａ - and Each R ６ａ are independently H or C １～３ is alkyl, Each R ７ are independently H, halogen, hydroxyl, C １～３ Alkoxy or C optionally substituted with one or more halogens or hydroxyls １～３ is alkyl, R ９ Each independently represents H, C １～３ Alkyl or -CO-C １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

6. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein G is -N-.

7. G is -C(R ３ｂ 2. The compound of claim 1, wherein R 1 is -R 2 , or a pharma- ceutically acceptable salt thereof.

8. R ３ｂ is F, or a pharma- ceutically acceptable salt thereof.

9. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Z is -N-.

10. Z is -C(R ３ｃ 2. The compound of claim 1, wherein R 1 is -R 2 , or a pharma- ceutically acceptable salt thereof.

11. R ３ｃ is H or F, or a pharma- ceutically acceptable salt thereof.

12. R ３ｂ , and R ３ｃ 2. The compound of claim 1, wherein each is independently H or halogen, or a pharma- ceutically acceptable salt thereof.

13. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is -N-.

14. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein A is -C(H)-.

15. R ２ The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is F or Cl.

16. R ２ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

17. R ２ The compound of claim 1 , or a pharma- ceutically acceptable salt thereof, wherein:

18. R ４ but, 【Chemistry 8】 2. The compound of claim 1, wherein:

19. R ４ but, 【Chemistry 9】 2. The compound of claim 1, wherein:

20. R ４ but, 【Chemistry 10】 2. The compound of claim 1, wherein:

21. Each R ６ is H, or a pharma- ceutically acceptable salt thereof.

22. R ４ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: is an N-linked cyclic amine.

23. R ４ but, 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 2. The compound of claim 1, selected from:

24. R ４ but, 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 2. The compound of claim 1, selected from:

25. R ４ but, 【Chemistry 24】 2. The compound of claim 1, selected from:

26. R ４ but, 【Chemistry 25】 2. The compound of claim 1, selected from:

27. The compound of claim 1, 【Chemistry 26】 【Chemical 27】 【Chemistry 28】 【Chemical 29】 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 【Chemical 33】 or a pharma- ceutically acceptable salt thereof.

28. The compound of claim 1, 【Chemical 34】 【Chemistry 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical 39】 【Chemistry 40】 【Chemistry 41】 or a pharma- ceutically acceptable salt thereof.

29. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, diluent, or excipient.

30. 30. A medicament for treating a patient with cancer comprising the pharmaceutical composition of claim 29, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

31. 29. A medicament for treating a patient with cancer, comprising a compound according to any one of claims 1 to 28, or a pharma- ceutically 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.

32. The medicament of claim 31 , wherein the patient has a 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 pharmaceutical acceptable salt thereof.

33. The method of claim 31 , wherein one or more cells express KRas G12C, G12D, and / or G12V mutant proteins.

34. A medicament for treating a patient with a cancer having a KRas G12C, G12D, and / or G12V mutation, comprising a compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof.

35. 35. The method of claim 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. 32. The medicament of claim 31, wherein the patient is also administered one or more of 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 pharma- ceutical acceptable salt thereof.

37. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, for use in therapy.

38. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, for use in the treatment of cancer.

39. 39. The pharmaceutical composition of claim 38, wherein the cancer has a KRas G12C, G12D, and / or G12V mutation.

40. 39. The pharmaceutical composition of claim 38, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

41. 39. The pharmaceutical composition of claim 38 for use in the treatment of cancer in simultaneous, separate or sequential combination with one or more of 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 pharma- ceutical acceptable salts thereof.

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