Kras inhibitors

Abstract

To provide compounds for treating patients with cancer, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients with cancer.SOLUTION: A compound of the following formula: wherein A is -C(H)- or -N-, B is -C(R4)- or -N-, D1 is -CH2-, -CH2CH2-, or -CH(CH2CN)-, X is -O- or -S-, Y is -C(CN)- or -N-, Z is -C(R3c)- or -N-, G is -C(R3b)- or -N-, R4 is H, methyl, -CH2-OH, etc., R3b and R3c are each independently H, methyl, or halogen, R1 is H, hydroxyl, methoxy, or C1-4 alkyl, and R2 is H, halogen, or methyl.SELECTED DRAWING: None

Description

[Background technology]

[0001] 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. As a GTPase, KRas converts the bound GTP back to GDP, thereby returning itself to its inactive state and once again propagating the signal to inhibit cell division. KRas gain-of-function mutations exhibit an increased degree of GTP binding and a reduced 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 significantly reduce GTPase activity.

[0002] Oncogenic KRas mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, they represent a challenging therapeutic target. (Cox, ADrugging 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., WO2019 / 099524, WO2020 / 081282, WO2020 / 101736, WO2020 / 146613, and WO2021 / 118877 disclose KRas G12C inhibitors), while WO2021 / 041671 discloses KRas G12D small molecule inhibitors, and WO2017 / 011920 discloses KRas G12C, G12D, and G12V small molecule inhibitors.

[0004] There remains a need to provide alternative small molecule KRas inhibitors. Specifically, there is a need to provide more potent, orally deliverable KRas inhibitors useful for the treatment of cancer. More specifically, there is a need to provide small molecule inhibitors that specifically inhibit KRas GTP activity. There is also a need to provide small molecule KRas inhibitors that exhibit greater efficacy with the same or reduced KRas inhibitory 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. There is also a need to provide more potent KRas inhibitors that exhibit selective inhibition preference for the KRas G12D mutant over KRas wild-type. There is also a need to provide more potent KRas inhibitors that exhibit selective inhibition preference for the KRas G12C, G12D, and / or G12V mutant over HRAS or NRAS. The present invention addresses one or more of these needs by providing novel KRas inhibitors. Summary of the Invention

[0005] A compound of formula I,

[0006] [ka] Pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof are provided herein. A is -C(H)- or -N-; B is -C(R4)- or -N-; D1 is -CH2-, -CH2CH2-, or -CH(CH2CN)-; X is —O— or —S—; Y is -C(CN)- or -N-; Z is -C(R 3c )- or -N-, G is -C(R 3b )- or -N-, R1 is H, hydroxyl, methoxy, C1-4 Alkyl, C 2-4 heteroalkyl, azetidine, N-linked piperazine, piperidine, morpholine, or a group of formula selected from:

[0007] [ka] and C 1-4 Alkyl, C 2-4 Heteroalkyl, azetidine, piperidine, or N-linked piperazine is an amino, hydroxyl, methyl, trideuteromethyl, methoxy, oxetane, or C 1-3 alkyl, optionally substituted with one or more of C 1-3 The alkyl may be one or more of halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, difluoromethoxy, -O-trideuteromethyl, cyclopropyl, oxetane, pyrazole, imidazole, amino, -CONR7R7, -O-(CH2) p -OC 1-3 Alkyl, -O-(CH2) p -OH or -O-CO-C 1-3 optionally substituted with alkyl, piperidine or N-linked piperazine is C 1-3 C optionally bridged by alkyl, cyclopropyl, imidazole, or pyrazole each substituted with hydroxyl or one or more hydroxyls 1-3 optionally substituted with alkyl; E1 is -(CR7R7-) n E2 is -CR7R7-, -NR7, - or -O-, and E3 is -(CR7R7-) m wherein m+n is 1, 2, 3, or 4; p is 1, 2, or 3; R2 is H, halogen, or methyl; R 3a , R 3b , and R 3c are each independently H, methyl, or halogen; R4 is azetidine optionally substituted with H, methyl, -CH2-OH, -O-R5-R6, -O-R6, or NR7R7, where R5 is -CH2-, -CH(CH3)-, or -CH2-CH2-, and R6 is H, C 1-3 Alkyl, C 2-3 Heteroalkyl, C 3-6 Cycloalkyl, C 4-6 heterocycloalkyl, 2-oxo-1,3-dihydrobenzimidazole, imidazole, or pyrazole; C 1-3 Alkyl, C 3-6 Cycloalkyl, or C 4-6 Heterocycloalkyl may be one or more of oxo, halogen, hydroxyl, methoxy, difluoromethoxy, NR7R7, C 1-4 Alkyl, C 1-4 optionally substituted with alkenyl, —CN, or —CO—CHOH; 1-4 alkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, or NR7R7; 3-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-4 optionally fused with an alkyl to form a bicyclic ring, or C 3-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-3 optionally bridged with alkyl, and when R4 is H, R1 is not H; Each R7 is independently H or C 1-3 It is alkyl.

[0008] Also provided herein are methods of using the compounds of Formulas I-VIII (including Formulas Ia-VIIa), their pharmaceutically 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. The methods comprise administering to a patient in need thereof a therapeutically effective amount of a compound of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof.

[0009] Further provided herein are compounds of Formulas I-VIII (including Formulas Ia-VIIa), and pharmaceutically acceptable salts thereof, for use in therapy. Additionally provided herein are compounds of Formulas I-VIII (including Formulas Ia-VIIa), and pharmaceutically acceptable salts thereof, for use in the treatment of cancer, specifically, the treatment of 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 a compound of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, specifically, the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer. DETAILED DESCRIPTION OF THE INVENTION

[0010] Novel inhibitors of the KRas gain-of-function mutation G12D are described herein. These novel compounds can address the need for inhibitors of KRas GTP activity in gain-of-function mutants in the treatment of cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. Some of these novel KRas G12D mutant inhibitor compounds are selective for the KRas G12D mutant over wild-type KRas (and possibly other mutant forms such as G12C or G12V). Additionally, some of these novel KRas G12D mutant inhibitor compounds are non-selective, inhibiting both wild-type KRas and the KRas G12D mutant (and possibly other mutant forms such as G12C or G12V). Some of these novel KRas compounds are also non-selective, inhibiting both wild-type KRas and the Kras G12C, G12D, and / or G12V mutants.

[0011] The present invention provides compounds of formula I,

[0012] [ka] In the formula, A, B, D1, X, Y, Z, G, R1, R2, and R 3a is as defined above, or a pharmaceutically acceptable salt thereof.

[0013] In one embodiment, a compound of formula II,

[0014] [ka] In the formula, R1, R2, R 3a , R4, A, D1, X, Y, Z, and G are as defined above, or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment, a compound of formula III,

[0016] [ka] In the formula, R1, R2, R 3a , A, D1, X, Y, Z, and G are as defined above, or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, a compound of formula IV,

[0018] [ka] In the formula, R1, R 3a , B, D1, Z, and G are as defined above, or a pharmaceutically acceptable salt thereof.

[0019] In one embodiment, a compound of formula V,

[0020] [ka] Provided is a compound, or a pharmaceutically acceptable salt thereof, wherein R 1 , B, D 1 , and G are as defined above.

[0021] In one embodiment, a compound of formula VI,

[0022] [ka] Provided is a compound, or a pharmaceutically acceptable salt thereof, wherein R1, B, D1, Z, and G are as defined above.

[0023] In one embodiment, a compound of formula VII,

[0024] [ka] Provided is a compound, or a pharmaceutically acceptable salt thereof, wherein R 1 , B, D 1 , and G are as defined above.

[0025] In one embodiment, a compound of formula VIII,

[0026] [ka] Provided is a compound, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, A, Z, and G are as defined above.

[0027] The present invention provides compounds of formula Ia,

[0028] [ka] In the formula, A, B, D1, X, Y, Z, R1, R2, R 3a , and R 3b is as defined above, or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, a compound of formula IIa,

[0030] [ka] In the formula, R1, R2, R 3a , R 3b , R4, A, D1, X, Y, and Z are as defined above, or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment, a compound of Formula IIIa,

[0032] [ka] In the formula, R1, R2, R 3a , R 3b , A, D1, X, Y, and Z are as defined above, or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, a compound of formula IVa:

[0034] [ka] In the formula, R1, R 3a , R 3b , B, D1, and Z are as defined above, or a pharmaceutically acceptable salt thereof.

[0035] In one embodiment, a compound of formula Va:

[0036] [ka] Provided is a compound, or a pharmaceutically acceptable salt thereof, wherein R 1 , B, and D 1 are as defined above.

[0037] In one embodiment, a compound of formula VIa:

[0038] [ka] Provided is a compound, or a pharmaceutically acceptable salt thereof, wherein R 1 , B, D 1 , and Z are as defined above.

[0039] In one embodiment, a compound of Formula VIIa:

[0040] [ka] Provided is a compound, or a pharmaceutically acceptable salt thereof, wherein R 1 , B, and D 1 are as defined above.

[0041] 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 cycloalkyl refers to a saturated cyclic monovalent hydrocarbon radical containing the specified number of carbon atoms, e.g., "C 4-6 As used herein, the term heteroalkyl refers to a saturated linear or branched monovalent hydrocarbon radical containing the specified number of atoms, including both carbon atoms and one or more heteroatoms, e.g., "C 2-3 Heteroalkyl" and "C 2-4 For example, C heteroalkyl means a saturated linear or branched monovalent hydrocarbon radical containing at least one carbon atom and at least one heteroatom, where the total number of carbon atoms and heteroatoms totals four atoms. As used herein, the term heterocycloalkyl refers to a saturated cyclic heteroalkyl group containing a specified number of atoms, including both carbon atoms and one or more heteroatoms, e.g., "C 4-6 The term "heterocycloalkyl" refers to "heterocycloalkyl." Examples of heteroatoms include, but are not limited to, nitrogen and oxygen.

[0042] For R1, N-linked piperazine (or piperidine) is C 1-3 As used herein, the term "bridged" with respect to an R group means that the R group is 1-3 This means that the alkyl is bicyclic, being linked to two non-adjacent atoms of the N-linked piperazine ring. Examples of bridged N-linked piperazine ring groups include:

[0043] [ka] These include, but are not limited to:

[0044] When it plays a role of cross-linking, C 1-3 Alkyl, as defined, can be optionally substituted with halogen, such as fluorine, for example:

[0045] [ka] In R1, the N-linked piperazine group is not specified as being attached through the carbon or nitrogen, and may be attached through either the carbon or the nitrogen. 2-4 Optional substitutions on a heteroalkyl group or N-linked piperazine group can be on a carbon or heteroatom.

[0046] Regarding R6, C 4-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-4 As used herein, the term "fused" with respect to an R group refers to an R group that is optionally fused to an alkyl group to form a bicyclic ring. 1-4 Alkyl is C 4-6 Cycloalkyl ring or C 4-6 It means that the heterocycloalkyl ring is bicyclic and is connected to two adjacent atoms of the ring. Examples of fused R groups include:

[0047] [ka] Examples include: In R6, C 4-6 Heterocycloalkyl groups are not specified as being attached through carbon or nitrogen and may be attached through either carbon or nitrogen. 4-6 Substitution on a heterocycloalkyl group can be on a carbon or heteroatom.

[0048] In one embodiment of a compound of Formula Ia or a pharmaceutically acceptable salt thereof, A is —C(H)— or —N—; B is —C(R)— or —N—; D is —CH—, —CHCH—, or —CH(CHCN)—; X is -O- or -S-, Y is -C(CN)- or -N-, and Z is -C(R 3c )- or -N-, and R1 is H, C 1-4 Alkyl, C 1-4 Heteroalkyl, or N-linked piperazine, C 1-4 Alkyl, C 1-4 Heteroalkyl, or N-linked piperazine, is an alkyl group consisting of amino, hydroxyl, methyl, oxetane, and C 1-3 alkyl, optionally substituted with one or more of C 1-3 The alkyl is optionally substituted with one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, cyclopropyl, oxetane, or amino, and the N-linked piperazine is C 1-3 optionally bridged by alkyl, R2 is H, halogen, or methyl, and R 3a , R 3b , and R 3c are each independently H or halogen, R4 is H, methyl, -CH2-OH, -O-R5-R6, or -O-R6, R5 is -CH2-, -CH2(CH3)-, or -CH2-CH2-, and R6 is H, C 1-3 Alkyl, C 2-3 Heteroalkyl, C 4-6 Cycloalkyl, or C 4-6 Heterocycloalkyl, C 1-3 Alkyl, C4-6 Cycloalkyl, or C 4-6 Heterocycloalkyl may be one or more of halogen, hydroxyl, methoxy, C 1-4 Alkyl or C 1-4 optionally substituted with alkenyl, C 1-4 The alkyl is optionally substituted with one or more halogens or hydroxyls, and 4-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-4 optionally fused with alkyl to form a bicyclic ring, when R4 is H, then R1 is not H.

[0049] In one embodiment of a compound of Formula I, Ia, II, IIa, III, IIIa, or VIII, or a pharmaceutically acceptable salt thereof, A is -N-.

[0050] In one embodiment of a compound of Formula I, Ia, II, IIa, III, IIIa, or VIII, or a pharmaceutically acceptable salt thereof, A is —C(H)—.

[0051] In one embodiment of a compound of Formula I, Ia, IV, Iva, V, Va, VI, Via, VII, or VIIa, or a pharmaceutically acceptable salt thereof, B is —N—.

[0052] In one embodiment of a compound of Formula I, Ia, IV, Iva, V, Va, VI, Via, VII, or VIIa, or a pharmaceutically acceptable salt thereof, B is —CH—.

[0053] In one embodiment of a compound of Formula I, Ia, IV, Iva, V, Va, VI, Via, VII, or VIIa, or a pharmaceutically acceptable salt thereof, B is —C(R 4 )—.

[0054] In one embodiment of a compound of Formula I, Ia, II, IIa, III, IIIa, IV, Iva, V, Va, VI, Via, VII, or VIIa, or a pharmaceutically acceptable salt thereof, D1 is —CH2—.

[0055] In one embodiment of a compound of Formula I, Ia, II, IIa, III, or IIIa, or a pharmaceutically acceptable salt thereof, X is -S-.

[0056] In one embodiment of a compound of Formula I, Ia, II, IIa, III, or IIIa, or a pharmaceutically acceptable salt thereof, Y is —C(CN)—.

[0057] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, Z is —C(R 3c )-.

[0058] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, Z is —N—.

[0059] In one embodiment of a compound of any of Formula I, II, III, IV, V, or VII, or a pharmaceutically acceptable salt thereof, G is —C(R 3b )-.

[0060] In one embodiment of a compound of any of Formula I, II, III, IV, V, or VII, or a pharmaceutically acceptable salt thereof, G is -N-.

[0061] In one embodiment of a compound of any of Formula I, II, III, IV, or VII, or a pharmaceutically acceptable salt thereof, G is -N- and Z is -C(R 3c )-.

[0062] In one embodiment of a compound of any of Formula I, II, III, IV, V, or VII, or a pharmaceutically acceptable salt thereof, G is —C(R 3b )-.

[0063] In one embodiment of a compound of any of Formula I, II, III, IV, or VII, or a pharmaceutically acceptable salt thereof, G is —C(R 3b )- and Z is -N-.

[0064] In one embodiment of a compound of any of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, R 3b is F, or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R1 is H.

[0066] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R1 is an N-linked piperazine which may be optionally substituted as defined above.

[0067] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R is C 1-3 It is an optionally substituted N-linked piperazine bridged by an alkyl.

[0068] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R is methyl, trideuteromethyl, or C 1-3 N-linked piperazine substituted with one or more of alkyl, C 1-3Alkyl is one or more of halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, difluoromethoxy, -O-trideuteromethyl, cyclopropyl, oxetane, pyrazole, imidazole, -CONR7R7, -O-(CH2) p -OC 1-3 Alkyl, -O-(CH2) p -OH or -O-CO-C 1-3 C optionally substituted with alkyl, and cyclopropyl, imidazole, or pyrazole each substituted with hydroxyl or one or more hydroxyls 1-3 Optionally substituted with alkyl, N-linked piperazine is C 1-3 alkyl-bridged compound, or a pharmaceutically acceptable salt thereof.

[0069] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R is

[0070] [ka]

[0071] [ka] is selected from.

[0072] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R1 is H, methoxy, -CH2-CH2-NH2, or a group of the formula:

[0073] [ka]

[0074] [ka] is.

[0075] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R is

[0076] [ka] is.

[0077] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R is

[0078] [ka] is.

[0079] In one embodiment of a compound of any of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R is H, methoxy, C 1-4 Alkyl, C 2-4 heteroalkyl, N-linked piperazine, piperidine, or a group of the formula:

[0080] [ka] In the formula, C 1-4 Alkyl, C 2-4 Heteroalkyl, piperidine, or N-linked piperazine is an amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, optionally substituted with one or more of C 1-3The alkyl is optionally substituted with one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, -CONR7R7, and the piperidine or N-linked piperazine is C 1-3 C optionally bridged by alkyl, cyclopropyl, imidazole, or pyrazole each substituted with one or more hydroxyl 1-3 Optionally substituted with alkyl.

[0081] In one embodiment of a compound of Formula I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R4 is H, methyl, —CH2—OH, —O—R5—R6, or —O—R6, where R5 is —CH2—, —CH2(CH3)—, or —CH2—CH2— and R6 is H, C 1-3 Alkyl, C 2-3 Heterocycloalkyl, C 4-6 Cycloalkyl, or C 4-6 Heterocycloalkyl, C 1-3 Alkyl, C 4-6 Cycloalkyl, or C 4-6 Heterocycloalkyl is a heterocyclic group containing one or more halogens, hydroxyl, methoxy, C 1-4 Alkyl or C 1-4 optionally substituted with alkenyl, C 1-4 The alkyl is optionally substituted with one or more halogens or hydroxyls, and 4-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-4 optionally fused with alkyl to form a bicyclic ring, when R4 is H, then R1 is not H.

[0082] In one embodiment of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, R 3a , R 3b , and R 3c are each independently H or halogen, and R1 is H, methoxy, C 1-4 Alkyl, C 2-4heteroalkyl, N-linked piperazine, piperidine, or a group of the formula:

[0083] [ka] C 1-4 Alkyl, C 2-4 Heteroalkyl, piperidine, or N-linked piperazine may be an amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, optionally substituted with one or more of C 1-3 Alkyl is one or more of halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, -CONR7R7, -O-(CH2) p -OC 1-3 Alkyl, -O-(CH2) p -OH or -O-CO-C 1-3 Optionally substituted with alkyl, piperidine or N-linked piperazine is C 1-3 C optionally bridged by alkyl, cyclopropyl, imidazole, or pyrazole each substituted with one or more hydroxyl 1-3 R4 is H, methyl, -CH2-OH, -O-R5-R6, -O-R6, or azetidine, optionally substituted with NR7R7, where R5 is -CH2-, -CH(CH3)-, or -CH2-CH2-, and R6 is H, C 1-3 Alkyl, C 2-3 Heteroalkyl, C 3-6 Cycloalkyl, C 4-6 heterocycloalkyl, or 2-oxo-1,3-dihydrobenzimidazole, C 1-3 Alkyl, C 3-6 Cycloalkyl, or C 4-6 Heterocycloalkyl is a heterocyclic group consisting of one or more of halogen, hydroxyl, methoxy, NR7R7, C 1-4 Alkyl or C 1-4 optionally substituted with alkenyl, C 1-4The alkyl is optionally substituted with one or more halogens or hydroxyls, and 3-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-4 optionally fused with an alkyl to form a bicyclic ring, or C 3-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-3 A compound optionally bridged with alkyl, wherein when R4 is H, then R1 is not H, or a pharmaceutically acceptable salt thereof.

[0084] In one embodiment of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, R 3a , R 3b , and R 3c are each independently H or halogen, and R1 is H, methoxy, C 1-4 Alkyl, C 2-4 heteroalkyl, N-linked piperazine, piperidine, or a group of the formula:

[0085] [ka] C 1-4 Alkyl, C 2-4 Heteroalkyl, piperidine, or N-linked piperazine may be an amino, hydroxyl, methyl, trideuteromethyl, oxetane, or C 1-3 alkyl, optionally substituted with one or more of C 1-3 The alkyl is optionally substituted with one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, cyclopropyl, oxetane, pyrazole, imidazole, amino, or -CONR7R7, and the piperidine or N-linked piperazine is C 1-3 C optionally bridged by alkyl, cyclopropyl, imidazole, or pyrazole each substituted with one or more hydroxyl 1-3R4 is H, methyl, -CH2-OH, -O-R5-R6, -O-R6, or azetidine, optionally substituted with NR7R7, where R5 is -CH2-, -CH(CH3)-, or -CH2-CH2-, and R6 is H, C 1-3 Alkyl, C 2-3 Heteroalkyl, C 3-6 Cycloalkyl, C 4-6 heterocycloalkyl, or 2-oxo-1,3-dihydrobenzimidazole, C 1-3 Alkyl, C 3-6 Cycloalkyl, or C 4-6 Heterocycloalkyl is a heterocyclic group consisting of one or more of halogen, hydroxyl, methoxy, NR7R7, C 1-4 Alkyl or C 1-4 optionally substituted with alkenyl, C 1-4 The alkyl is optionally substituted with one or more halogens or hydroxyls, and 3-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-4 optionally fused with an alkyl to form a bicyclic ring, or C 3-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-3 A compound optionally bridged with alkyl, wherein when R4 is H, R1 is not H, or a pharmaceutically acceptable salt thereof.

[0086] In one embodiment of a compound of Formula Ia or a pharmaceutically acceptable salt thereof, R 3a , R 3b , and R 3c are each independently H or halogen, and R1 is H, C 1-4 Alkyl, C 2-4 Heteroalkyl, or N-linked piperazine, C 1-4 Alkyl, C 2-4 Heteroalkyl, or N-linked piperazine, may be an amino, hydroxyl, methyl, oxetane, or C 1-3 alkyl, optionally substituted with one or more of C 1-3The alkyl is optionally substituted with one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, cyclopropyl, oxetane, or amino, and the N-linked piperazine is C 1-3 optionally bridged by alkyl, R4 is H, methyl, -CH2-OH, -O-R5-R6, or -O-R6, R5 is -CH2-, -CH2(CH3)-, or -CH2-CH2-, and R6 is H, C 1-3 Alkyl, C 2-3 Heteroalkyl, C 4-6 Cycloalkyl, or C 4-6 Heterocycloalkyl, C 1-3 Alkyl, C 4-6 Cycloalkyl, or C 4-6 Heterocycloalkyl is a heterocyclic group containing one or more halogens, hydroxyl, methoxy, C 1-4 Alkyl or C 1-4 optionally substituted with alkenyl, C 1-4 The alkyl is optionally substituted with one or more halogens or hydroxyls, and 4-6 Cycloalkyl or C 4-6 Heterocycloalkyl is C 1-4 A compound, or a pharmaceutically acceptable salt thereof, wherein R is optionally fused with an alkyl to form a bicyclic ring, and when R is H, then R is not H.

[0087] In one embodiment of a compound of Formula I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R4 is -O-CH2-R6.

[0088] In one embodiment of a compound of Formula II, IIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, R6 is azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, morpholine, cyclobutane, or 1,4-dioxane.

[0089] In one embodiment of a compound of Formula I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R4 is methyl, methoxy, -CH2-OH, or a group of the formula:

[0090] [ka] is.

[0091] In one embodiment of a compound of Formula I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R4 is

[0092] [ka] is.

[0093] In one embodiment of a compound of Formula I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R4 is

[0094] [ka] is.

[0095] In one embodiment of a compound of Formula I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R4 is

[0096] [ka] is.

[0097] In one embodiment of a compound of Formula I, Ia, II, IIa, IV, IVa, V, Va, VI, VIa, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R4 is

[0098] [ka] is.

[0099] In one embodiment of a compound of Formula I, Ia, II, IIa, IV, Iva, V, Va, VI, Via, VII, VIIa, or VIII, or a pharmaceutically acceptable salt thereof, R4 is

[0100] [ka]

[0101] [ka] is selected from.

[0102] In one embodiment of a compound of Formula I, Ia, II, IIa, III, IIIa, or VIII, or a pharmaceutically acceptable salt thereof, R2 is F or Cl.

[0103] In one embodiment of a compound of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, R 3b and R 3c are each independently H or F.

[0104] In one embodiment of a compound of Formula I, Ia, II, or IIa, or a pharmaceutically acceptable salt thereof, X is S, Y is —C(CN)—, R2 is F or Cl, and R 3a is H and R 3b is H and R 3c is F and D1 is -CH2-.

[0105] In the above embodiments of compounds of Formulas I-VIII (including Formulas Ia-VIIa), the chemical diagrams are shown simply without chiral information. These compounds often have multiple chiral centers and are intended to exist in various forms with various combinations of chiral centers. Additionally, these compounds have various enantiomers, diastereomers, and atropisomers that may exist and are encompassed herein.

[0106] Examples of compounds described herein include the compounds of Table A and their pharmaceutically acceptable salts.

[0107] Table A: Compound Examples [Table 1-1]

[0108] (Continued from Table A) [Table 1-2]

[0109] (Continued from Table A) [Table 1-3]

[0110] (Continued from Table A) [Table 1-4]

[0111] (Continued from Table A) [Table 1-5]

[0112] (Continued from Table A) [Table 1-6]

[0113] (Continued from Table A) [Table 1-7]

[0114] (Continued from Table A) [Table 1-8]

[0115] (Continued from Table A) [Table 1-9]

[0116] (Continued from Table A) [Table 1-10]

[0117] (Continued from Table A) [Table 1-11]

[0118] (Continued from Table A) [Table 1-12]

[0119] (Continued from Table A) [Table 1-13]

[0120] (Continued from Table A) [Table 1-14]

[0121] (Continued from Table A) [Table 1-15]

[0122] (Continued from Table A) [Table 1-16]

[0123] (Continued from Table A) [Table 1-17]

[0124] (Continued from Table A) [Table 1-18]

[0125] (Continued from Table A) [Table 1-19]

[0126] (Continued from Table A) [Table 1-20]

[0127] (Continued from Table A) [Table 1-21]

[0128] (Continued from Table A) [Table 1-22]

[0129] (Continued from Table A) [Table 1-23]

[0130] (Continued from Table A) [Table 1-24]

[0131] (Continued from Table A) [Table 1-25]

[0132] (Continued from Table A) [Table 1-26]

[0133] (Continued from Table A) [Table 1-27]

[0134] (Continued from Table A) [Table 1-28]

[0135] (Continued from Table A) [Table 1-29]

[0136] (Continued from Table A) [Table 1-30]

[0137] (Continued from Table A) [Table 1-31]

[0138] (Continued from Table A) [Table 1-32]

[0139] (Continued from Table A) [Table 1-33]

[0140] (Continued from Table A) [Table 1-34]

[0141] (Continued from Table A) [Table 1-35]

[0142] (Continued from Table A) [Table 1-36]

[0143] (Continued from Table A) [Table 1-37]

[0144] (Continued from Table A) [Table 1-38]

[0145] (Continued from Table A) [Table 1-39]

[0146] (Continued from Table A) [Table 1-40]

[0147] (Continued from Table A) [Table 1-41]

[0148] (Continued from Table A) [Table 1-42]

[0149] (Continued from Table A) [Table 1-43]

[0150] The chemical diagrams of Table A include representations of the chiral aspects of the particular compounds shown. However, the chemical diagrams of Table A do not include all possible chiral features of those compounds, and the chiral representations shown are not intended to exclude variations on the chiral aspects shown. Thus, alternative chiral versions of the compounds, as well as different combinations of chiral attributes, are contemplated and included herein.

[0151] In a compound of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, the compound is

[0152] [ka]

[0153] [ka] or a pharmaceutically acceptable salt thereof.

[0154] In further compounds of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, the compound is

[0155] [ka]

[0156] [ka] is selected from.

[0157] In further compounds of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, the compound is

[0158] [ka]

[0159] [ka]

[0160] [ka]

[0161] [ka]

[0162] [ka] or a pharmaceutically acceptable salt thereof.

[0163] In further compounds of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, the compound is

[0164] [ka]

[0165]

change

[0166]

change

[0167]

change

[0168]

change

[0169]

change

[0170]

change

[0171]

change

[0172]

change

[0173]

change

[0174]

change

[0175]

change

[0176]

change

[0177]

change

[0178]

change

[0179]

change

[0180]

change

[0181]

change

[0182]

change

[0183]

change

[0184]

change

[0185]

change

[0186]

change

[0187] [ka]

[0188] [ka] or a pharmaceutically acceptable salt thereof.

[0189] In further compounds of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa, or a pharmaceutically acceptable salt thereof, the compound is

[0190] [ka] or a pharmaceutically acceptable salt thereof.

[0191] Also provided herein are pharmaceutical compositions comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof (examples include, but are not limited to, the compounds of Table A), and a pharmaceutically acceptable carrier, diluent, or excipient.

[0192] Further provided herein is a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof. In the 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 the method, the cancer can more specifically be 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.

[0193] Also provided herein is a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a 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 the KRas G12D mutant protein. In one embodiment, the cancer is non-small cell lung cancer having one or more cells expressing the KRas G12D mutant protein. In one embodiment, the cancer is mutant pancreatic cancer having one or more cells expressing the KRas G12D mutant protein. In one embodiment, the cancer is colorectal cancer having one or more cells expressing the KRas G12D mutant protein. This method also includes treating cancers of other origins that have the KRas G12D mutant.

[0194] Further provided herein is a method for treating a patient with a cancer harboring a KRas G12D mutation, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VII, or a pharmaceutically acceptable salt thereof. In this method, the cancer harboring 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, or KRas G12D mutant colorectal cancer. In one embodiment, the cancer harboring a KRas G12D mutation can be KRas G12D mutant non-small cell lung cancer. In one embodiment, the cancer harboring a KRas G12D mutation can be KRas G12D mutant pancreatic cancer. In one embodiment, the cancer with a KRas G12D mutation can be a KRas G12D mutant colorectal cancer.

[0195] Additionally provided herein are methods of modulating mutant KRas G12D enzyme in a patient in need thereof by administering a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises inhibiting human mutant KRas G12D enzyme.

[0196] Also provided herein is a method of treating cancer in a patient in need thereof, wherein the patient has a cancer determined to express a KRas G12D mutant protein. The method comprises administering to the patient an effective amount of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof. The G12D 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 mutation status (e.g., G12D mutation 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.

[0197] Further provided herein is a compound according to any one of Formulas I-VII or a pharmaceutically acceptable salt thereof for use in therapy. The compound or a pharmaceutically acceptable salt thereof may be for use in treating cancer. In this case, 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 a mutant KRas G12D protein, such as 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, in which one or more cells express the KRas G12D mutant protein. Furthermore, the cancer may be colorectal cancer, in which one or more cells express the KRas G12D mutant protein. Additionally, the cancer may be pancreatic cancer, in which one or more cells express a KRas G12D mutant protein. The patient may have a cancer determined to have one or more cells expressing a KRas G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. The patient may have been treated with a different course of therapy before being treated as described herein.

[0198] The compounds provided herein according to any one of I-VIII (including Ia-VIIa), or pharmaceutically acceptable salts thereof, can also be used in the manufacture of a medicament for the treatment of cancer. When used in the manufacture of a medicament, the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. The cancer can 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 can have one or more cancer cells expressing a mutant KRas G12D protein. If the cancer cells express the KRas G12D protein, the cancer can be selected from KRas G12D mutant non-small cell lung cancer, KRas G12D mutant colorectal cancer, and KRas G12D mutant pancreatic cancer.

[0199] Also provided herein are methods of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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 pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells that express a mutant KRas G12D protein. Further provided herein is a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof. Additionally provided is a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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 pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer.

[0200] Also provided is a method of treating cancer, comprising administering to a patient in need thereof effective amounts of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of I-VIII (including Ia-VIIa), 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 any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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, a PD-1 or PD-L1 inhibitor may be pembrolizumab, a PD-1 or PD-L1 inhibitor may be nivolumab, a PD-1 or PD-L1 inhibitor may be cemiplimab, a PD-1 or PD-L1 inhibitor may be sintilimab, a PD-1 or PD-L1 inhibitor may be atezolizumab, a PD-1 or PD-L1 inhibitor may be avelumab, a PD-1 or PD-L1 inhibitor may be durvalumab, or a PD-1 or PD-L1 inhibitor may be lodapilimab. As described herein, the cancer can be non-small cell lung cancer, in which the cancer has one or more cells that express a KRas G12D mutant protein, or the cancer can be colorectal cancer, in which the cancer has one or more cells that express a KRas G12D mutant protein, or the cancer can be mutant pancreatic cancer, in which 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, the method comprising administering to a patient in need thereof effective amounts of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein.Further provided is a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, the cancer having one or more cells expressing a mutant KRas G12D protein, in simultaneous, separate, or sequential combination with a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof. Additionally, a combination is provided comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer, wherein the cancer has one or more cells expressing a 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, wherein the cancer has one or more cells expressing a KRas G12D mutant protein; the cancer can be colorectal cancer, wherein the cancer has one or more cells expressing a KRas G12D mutant protein; or the cancer can be mutant pancreatic cancer, wherein the cancer has one or more cells expressing a KRas G12D mutant protein. The methods also include treating cancers of other origins that harbor the KRas G12D mutation.

[0202] Also provided is a method for treating cancer, comprising administering to a patient in need thereof effective amounts of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. Additionally, provided is a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the EGFR inhibitor may be erlotinib, afatinib, gefitinib, or cetuximab. As described herein, the cancer may be non-small cell lung cancer, wherein the cancer has one or more cells expressing a KRas G12D mutant protein; the cancer may be colorectal cancer, wherein the cancer has one or more cells expressing a KRas G12D mutant protein; or the cancer may be mutant pancreatic cancer, wherein the cancer has one or more cells expressing a KRas G12D mutant protein. The method also includes treating cancers of other origins that have a KRas G12D mutant.

[0203] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof effective amounts of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of I-VIII (including Ia-VIIa), 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, the cancer having one or more cells expressing a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), 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 can be non-small cell lung cancer, in which the cancer has one or more cells expressing a KRas G12D mutant protein; the cancer can be colorectal cancer, in which the cancer has one or more cells expressing a KRas G12D mutant protein; or the cancer can be mutant pancreatic cancer, in which the cancer has one or more cells expressing a KRas G12D mutant protein. The method also includes treating cancers of other origins that have a KRas G12D mutant.

[0204] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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 any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, the cancer having one or more cells expressing a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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-pyrazol-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-(5-methyl-1H-pyrazol-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 pharmaceutically 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 may be non-small cell lung cancer, wherein the cancer has one or more cells that express the KRas G12D mutant protein; the cancer may be colorectal cancer, wherein the cancer has one or more cells that express the KRas G12D mutant protein; or the cancer may be mutant pancreatic cancer, wherein the cancer has one or more cells that express the KRas G12D mutant protein. The method also includes treating cancers of other origins that have the KRas G12D mutant.

[0205] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof effective amounts of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, the cancer having one or more cells expressing a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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 pharmaceutically acceptable salt thereof, may be a type I SHP2 inhibitor or a type II SHP2 inhibitor. Examples of type I SHP2 inhibitors include, but are not limited to, PHPS1, GS-493, NSC-87877, NSC-117199, and cefsulodin, and pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salts thereof.As described herein, the cancer may be non-small cell lung cancer, wherein the cancer has one or more cells that express the KRas G12D mutant protein; the cancer may be colorectal cancer, wherein the cancer has one or more cells that express the KRas G12D mutant protein; or the cancer may be mutant pancreatic cancer, wherein the cancer has one or more cells that express the KRas G12D mutant protein. The method also includes treating cancers of other origins that have the KRas G12D mutant.

[0206] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a platinum agent, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of I-VIII (including Ia-VIIa), 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 a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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 a KRas G12D mutant protein, the cancer can be colorectal cancer, where the cancer has one or more cells expressing a KRas G12D mutant protein, or the cancer can be mutant pancreatic cancer, where the cancer has one or more cells expressing a KRas G12D mutant protein. The method also includes treating cancers of other origins that have a KRas G12D mutant.

[0207] Also provided is a method of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically acceptable salt thereof, and pemetrexed, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. Further provided is a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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 a mutant KRas G12D protein. Additionally provided is a combination comprising a compound according to any one of I-VIII (including Ia-VIIa), or a pharmaceutically 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 a mutant KRas G12D protein. As described herein, the cancer has one or more cells that express the KRas G12D mutant protein. Additionally, a platinum agent can be administered to the patient (the platinum agent can be cisplatin, carboplatin, or oxaliplatin). As described herein, the cancer can be colorectal cancer, where the cancer has one or more cells that express the KRas G12D mutant protein, or the cancer can be mutant pancreatic cancer, where the cancer has one or more cells that express the KRas G12D mutant protein. The method also includes treating cancers of other origins that have the KRas G12D mutant.

[0208] Also provided herein are methods for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. In this method, the cancer 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 that express 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.

[0209] Further provided herein is a method of treating a patient having a cancer with a KRas G12C, G12D, and / or G12V mutation, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VII, or a pharmaceutically acceptable salt thereof. In this method, the cancer harboring a KRas G12C, G12D, and / or G12V mutation can be 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 one embodiment, the cancer harboring a KRas G12C, G12D, and / or G12V mutation can be a KRas G12C, G12D, and / or G12V mutant non-small cell lung cancer. In one embodiment, the cancer harboring a KRas G12C, G12D, and / or G12V mutation can be a KRas G12C, G12D, and / or G12V mutant pancreatic cancer. In one embodiment, the cancer harboring a KRas G12C, G12D, and / or G12V mutation can be a KRas G12C, G12D, and / or G12V mutant colorectal cancer.

[0210] Additionally provided herein are methods of modulating mutant KRas G12C, G12D, and / or G12V enzymes in a patient in need thereof by administering a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof. In one embodiment, the method comprises inhibiting human mutant KRas G12C, G12D, and / or G12V enzymes.

[0211] Also provided herein is a method of treating cancer in a patient in need thereof, wherein the patient has a cancer determined to express KRas G12C, G12D, and / or G12V mutant proteins. The method comprises administering to the patient an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof. The G12D 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 mutation status (e.g., G12D mutation 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.

[0212] Further provided herein is a compound according to any one of Formulas I-VII or a pharmaceutically acceptable salt thereof for use in therapy. The compound or a pharmaceutically acceptable salt thereof may be for use in treating cancer. In this case, 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 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 pharmaceutically acceptable salt thereof. The patient may have been treated with a different course of therapy before being treated as described herein.

[0213] The compounds provided herein according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or pharmaceutically acceptable salts thereof, can also be used in the manufacture of a medicament for treating cancer. When used in the manufacture of a medicament, the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, or esophageal cancer. The cancer can 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 can have one or more cancer cells expressing mutant KRas G12C, G12D, and / or G12V proteins. If the cancer cells express KRas G12C, G12D, and / or G12V proteins, the cancer can be selected from KRas G12C, G12D, and / or G12V mutant non-small cell lung cancer, KRas G12C, G12D, and / or G12V mutant colorectal cancer, and KRas G12C, G12D, and / or G12V mutant pancreatic cancer.

[0214] Also provided herein are methods of treating cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically 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 pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells that express mutant KRas G12C, G12D, and / or G12V proteins. Further provided herein is a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, 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 a pharmaceutically acceptable salt thereof. Additionally provided is a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically 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 pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer.

[0215] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), 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 proteins. Further provided is a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, either simultaneously, separately, or sequentially in combination with a PD-1 or PD-L1 inhibitor. Additionally provided is a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically 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, a PD-1 or PD-L1 inhibitor may be pembrolizumab, a PD-1 or PD-L1 inhibitor may be nivolumab, a PD-1 or PD-L1 inhibitor may be cemiplimab, a PD-1 or PD-L1 inhibitor may be sintilimab, a PD-1 or PD-L1 inhibitor may be atezolizumab, a PD-1 or PD-L1 inhibitor may be avelumab, a PD-1 or PD-L1 inhibitor may be durvalumab, or a PD-1 or PD-L1 inhibitor may be lodapilimab. As described herein, the cancer can be non-small cell lung cancer, in which the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, or the cancer can be colorectal cancer, in which the cancer has one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, or the cancer can be mutant pancreatic cancer, in which the cancer has one or more cells that express 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 mutant proteins.

[0216] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins.Further provided is a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, the cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins, in simultaneous, separate, or sequential combination with a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof. Additionally, there is provided a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer, wherein the cancer has one or more cells that express mutant KRas G12C, G12D, and / or G12V proteins. As used herein, the CDK4 / CDK6 inhibitor may be abemaciclib, the CDK4 / CDK6 inhibitor may be palbociclib, or the CDK4 / CDK6 inhibitor may be ribociclib. As described herein, 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; or 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 method also includes treating cancers of other organs that have KRas G12C, G12D, and / or G12V mutant proteins.

[0217] Also provided is a method for treating cancer, comprising administering to a patient in need thereof effective amounts of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Further provided is a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. Additionally, provided is a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the EGFR inhibitor may be erlotinib, afatinib, gefitinib, or cetuximab. As described herein, the cancer may be non-small cell lung cancer, in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; colorectal cancer, in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; or pancreatic cancer, in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers in other organs that have KRas G12C, G12D, and / or G12V mutant proteins.

[0218] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins.Further provided is a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), 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, the cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additionally, there is provided a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), 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 may be LY3214996, the ERK inhibitor may be LTT462, or the ERK inhibitor may be KO-947. 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; or 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 method also includes treating cancers of other organs that have KRas G12C, G12D, and / or G12V mutant proteins.

[0219] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins.Further provided is a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, the cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Additionally, there is provided a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, an Aurora A inhibitor is defined as alisertib, tozasertib, (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, (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 pharmaceutically 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 may be non-small cell lung cancer, wherein the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; the cancer may be colorectal cancer, wherein the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; or the cancer may be mutant pancreatic cancer, wherein the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs that harbor KRas G12C, G12D, and / or G12V mutations.

[0220] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, 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 any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, the cancer having one or more cells that express mutant KRas G12C, G12D, and / or G12V proteins. Additionally, there is provided a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salts thereof.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; or 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 method also includes treating cancers of other organs that have KRas G12C, G12D, and / or G12V mutant proteins.

[0221] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and a platinum agent, 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 any one of Formulas I-VIII (including Formulas Ia-VIIa), 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, the cancer having one or more cells that express mutant KRas G12C, G12D, and / or G12V proteins. Additionally, there is provided a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically 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, carboplatin, or oxaliplatin. As described herein, the cancer can be non-small cell lung cancer, in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; colorectal cancer, in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins; or pancreatic cancer, in which the cancer has one or more cells expressing KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs that harbor KRas G12C, G12D, and / or G12V mutations.

[0222] Also provided is a method of treating cancer, the method comprising administering to a patient in need thereof an effective amount of a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, and pemetrexed, 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 any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with pemetrexed for the treatment of cancer, the cancer having one or more cells that express mutant KRas G12C, G12D, and / or G12V proteins. Additionally, there is provided a combination comprising a compound according to any one of Formulas I-VIII (including Formulas Ia-VIIa), or a pharmaceutically 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. Additionally, a platinum agent may be administered to the patient (the platinum agent may be cisplatin, carboplatin, or oxaliplatin). As described herein, the cancer can be colorectal cancer having one or more cells that express KRas G12C, G12D, and / or G12V mutant proteins, or the cancer can be mutant pancreatic cancer having 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 mutant proteins.

[0223] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is deemed acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and the general methodology for preparing them can be found in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" P.Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M.Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[0224] Pharmaceutical compositions containing the compounds of Formulas I-VII described herein may be prepared using pharmaceutically acceptable excipients. As used herein with respect to pharmaceutical compositions, the term "pharmaceutically acceptable excipients" refers to one or more carriers, diluents, and excipients that are compatible with other excipients in 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., 2002, pp. 221-224. nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically 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.

[0225] 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, for example, 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 patient's size, age, sex, and general health; 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.

[0226] A treating physician, veterinarian, or other medical professional will be able to determine the effective amount of the compound for treating a 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 a patient in need of cancer treatment.

[0227] As used herein, the terms "treating," "treat," or "treatment" include slowing, managing, delaying, 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 cancerous lesions or the progression of abnormal cell growth and / or cell division. Treatment does not necessarily indicate the complete disappearance of all disorder or disease symptoms.

[0228] As used herein, the term "patient" refers to a mammal in need of treatment. Specifically, a patient can be a human in need of treatment for cancer, for example, a cancer with a KRas G12D mutation.

[0229] 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 atmospheric pressure, "Boc-Gly-OH" refers to N-(tert-butoxycarbonyl)glycine, "BrettPhos" refers to 2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl methyl acrylate, and "BrettPhos" refers to 2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl methyl acrylate. "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 "DIBAL- "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 diisobutylaluminum hydride. "DMF" refers to Rubecco'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(β-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 hour, 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, and "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-2-yl]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, and "MTBE" refers to methyl tert-butyl ether. 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, and "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(II); "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-butyldimethylsilyl chloride. "TBDMS" refers to the tert-butyldimethylsilyl group, "tBu" refers to the tert-butyl group, "t-BuOH" refers to tert-butanol or tert-butyl alcohol, "A" refers to triethylamine, "TES" refers to triethylsilane, "TfO" refers to trifluoromethanesulfonic anhydride, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "TMEDA" refers to tetramethylethylenediamine, and "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, and "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.

[0230] 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 E.L. Eliel and S.H. 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 about a single bond. Atropisomers can be isolated as separate chemical species if the energy barrier for rotation about a single bond is sufficiently high and the interconversion rate is slow enough to separate the individual rotamers from each other. The present specification is intended to include all isomers, enantiomers, diastereomers, and atropisomers that are possible for or can be produced using the compounds disclosed herein. In the molecules described herein, only molecules for which the absolute configuration (or atropisomeric configuration) of the chiral center is known use the naming conventions or chemical formulas drawn to indicate chirality or atropisomerism. Those skilled in the art will readily recognize and be able to identify when other chiral centers are present in the molecules described herein.

[0231] Any compound of Formulas I-VII that is capable of chemically forming a salt can be readily converted to and isolated as a pharmaceutically acceptable salt. Salt formation can occur upon addition of a pharmaceutically acceptable acid to form an acid addition salt. Salts can also be formed simultaneously upon deprotection of nitrogen or oxygen, i.e., upon removal of a protecting group. Examples of reactions and conditions for salt formation are described in Gould, PL, "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, RJ, et al., "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19 (1977).

[0232] The compounds of the present invention, or salts thereof, can be prepared by a variety of procedures, some of which are illustrated in the following schemes, preparations, and examples. Specific synthetic steps of each route 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.

[0233] [ka]

[0234] Scheme 1a illustrates the preparation of dihydroisobenzofuran (5). Commercially available 4-chlorophthalic anhydride (1) can be subjected to reductive ring-opening with LiAlH in THF to give diol (2). Subsequent ring closure using a dialkyl carbonate, such as dimethyl carbonate, and a strong base, such as NaOMe, can be used to give heterocycle (3). Subsequent electrophilic aromatic substitution can give nitroaryl compound (4) using KNO or HNO in combination with a strong acid, such as HSO. Heterocycle (4) can be brominated with a variety of suitable reagents, including, but not limited to, NBS, POBr, Br, and 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione, to give 4-bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran (5).

[0235] [ka]

[0236] Scheme 1b illustrates the preparation of dihydroisobenzofuran 9. Palladium-catalyzed carbonylation using commercially available (2-bromo-5-fluorophenyl)methanol 6 can be achieved using a ligand such as XantPhos and a palladium source such as Pd(OAc)2, along with a suitable base, e.g., a polar aprotic solvent such as triethylamine and acetonitrile, to give lactone 7. Those skilled in the art will appreciate that a variety of bidentate phosphine ligands can be used. Subsequent nitration and bromination using the conditions described above can give functionalized isobenzofuranone 8. Reduction of compound 8 can be achieved using a hydride reagent such as DIBAL-H to give the intermediate lactol compound, which can then be further reduced with triethylsilane and TFA to give 4-bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran 9.

[0237] [ka]

[0238] Scheme 2 illustrates the preparation of cyanomethyl-substituted heterocyclic compound 15. Nitroaryl compound 10 can be reduced to the corresponding aniline compound 11 under hydrogenation conditions utilizing a sulfur-doped Pt / C catalyst. Alternatively, those skilled in the art will appreciate that the reduction can be achieved using iron or zinc powder and NH4Cl in a polar solvent such as THF, EtOH, or MeOH. Protection of the amino moiety can be achieved with di-tert-butyl dicarbonate or Boc group using a catalytic amount of DMAP in acetonitrile under reflux conditions. Those skilled in the art will also recognize that other suitable carbamate protecting groups, such as Alloc, Fmoc, and Cbz, can be used in place of the Boc protecting group. For example, the lactone moiety of compound 12, obtained using a dry ice / acetone bath, can be reduced with an appropriate hydrogenation agent, such as DIBAL-H, at low temperature to give hydroxy compound 13. The cyanomethyl compound (14) can be obtained by using diethylcyanomethylphosphonate under Horner-Emmons reaction conditions in a miscible solvent such as THF. Deprotection of the amino group of the cyanomethyl-substituted heterocycle (14) can be achieved using HCl in 1,4-dioxane, which upon basic workup affords the aniline compound (15).

[0239] [ka]

[0240] Scheme 3 illustrates the preparation of isochroman compound 20. Starting with benzoic acid compound 16, ring closure is achieved by a palladium-catalyzed C-H insertion reaction followed by oxidative addition to ethylene oxide dissolved in THF to give isochromanone compound 17. Those skilled in the art will recognize that various N-acylamino acids may be used as palladium ligands. For example, N-acetylvaline may be used. Polar acidic solvents such as trifluoroethanol, TFA, or hexafluoroisopropanol may also be used as solvents. Trifluoroethanol and hexafluoroisopropanol are preferred. Reduction of the carbonyl moiety can be achieved by utilizing a two-step procedure. In the first step, LiBH4 in THF can be used to obtain the isochromanol intermediate, which is then reacted with p-toluenesulfonic acid in toluene under reflux conditions in the second step to give isochroman compound 18. Subsequent bromination using previously described conditions, such as NBS, can give aryl bromide compound 19. The nitro moiety can be reduced using iron powder and NH4Cl in a mixed solvent system such as THF and water to give the aniline compound (20).

[0241] [ka]

[0242] Scheme 4a illustrates the preparation of quinoline compound 25. Nitroaryl compound 21 can be reduced to the corresponding aniline compound 22 using iron or zinc powder under the reaction conditions previously described. Acylation of amine compound 22 using 3-ethoxyprop-2-enoyl chloride in THF and a suitable base, such as pyridine, can give enamide compound 23. Cyclization using HSO as the solvent, followed by trituration in ice water, gives quinolinone compound 24. Subsequent chlorination can be achieved using a suitable reagent, such as (chloromethylene)dimethyliminium chloride or POCl, to give chloroquinoline compound 25.

[0243] [ka]

[0244] Scheme 4b illustrates the preparation of methylsulfanylquinoline compound 29. Commercially available Meldrum's acid can be converted to sulfanyl compound 27 using a polar aprotic solvent such as CS₂ and DMSO, followed by alkylation with methyl iodide. Aniline compound 22 is N-alkylated with methylsulfanyl compound 27 by heating in a nonpolar solvent such as toluene, followed by trituration in a suitable solvent system such as Et₂O / EtOAc to give functionalized compound 28. Cyclization occurs in a suitable high-boiling solvent, such as diphenyl ether, at reflux at approximately 180°C to give quinolinol compound 29.

[0245] [ka]

[0246] Scheme 5 illustrates the preparation of cinnoline compound 34. Dihydroisobenzofuran compound 22 can be iodinated with several reagents known to those skilled in the art, such as NIS, I2, and pyridinium iodide, to give iodoaniline compound 30. Pd(PPh3)4 and other Pd iodides can be used. 0 Stille coupling of iodide (30) using a source and an appropriate tributylstannane, such as tributyl(1-ethoxyvinyl)stannane, can give vinyl compound (31). Acid hydrolysis using aqueous HCl can give acetophenone compound (32). Those skilled in the art will be familiar with the conditions for diazotization of the amine moiety using sodium nitrite and TFA, followed by ring closure to give hydroxycinnoline compound (33). Standard chlorination conditions, such as oxalyl chloride and DMF in DCM, can be used to give chlorocinnoline compound (34).

[0247] [ka]

[0248] Scheme 6 illustrates the preparation of quinazolinyl compounds 39. Thioacylation of aniline compounds 35 can be achieved with an appropriate isothiocyanate, such as ethoxycarbonyl isothiocyanate, to give carbamothioyl compounds 36. S-Alkylation can be achieved using a weak base, such as KCO, in a polar solvent, such as acetone, followed by the slow addition of ethyl iodide to give sulfanyl compounds 37. Ring closure at 175°C in a solvent, such as anhydrous NMP or diphenyl ether, can give hydroxyquinazoline compounds 38, which can then be chlorinated, for example, with oxalyl chloride, thionyl chloride, (chloromethylene)dimethyliminium chloride, or POCl, with adjustment of the solvent as necessary, to give chloroquinazolinyl compounds 39.

[0249] [ka]

[0250] Scheme 7 illustrates the preparation of bicyclic substituted quinolinyl compounds (43). The Suzuki coupling of boronate ester compound (40) with bromoquinoline compound (25) can be carried out using a base such as CsCO in THF in conjunction with a suitable palladium complex known to those skilled in the art, for example, dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II), to give biaryl compounds (41). The Suzuki coupling of boronate ester compound (40) with bromoquinoline compound (25) can be carried out using a strong base such as LiHMDS in THF and a suitable nucleophile such as a primary or secondary alcohol, typically S N Nucleophilic aromatic substitution of the chloro moiety ortho to the quinoline nitrogen, known as AR, can give the substituted quinolinyl compound (42). Removal of the protecting group on the amine moiety using an appropriate acid, such as TFA in DCM, can give the functionalized quinolinyl compound (43).

[0251] [ka]

[0252] Scheme 8 shows two routes for preparing bicyclic substituted quinazoline compounds (48). Chloroquinazolinyl compounds (39) can be converted to S-substituted quinazoline compounds (48) using an appropriate nucleophile such as a substituted piperazine. N The quinazolinyl compound 45 can be subjected to AR. Those skilled in the art will recognize that a variety of non-nucleophilic bases, such as, but not limited to, DIPEA, TEA, or NMM, can be used in this reaction with polar aprotic solvents such as acetonitrile or DMF to afford substituted quinazolinyl compound 44. In one route, compound 44 can first be subjected to desulfurization with triethylsilane and PdCl to afford quinazolinyl compound 45. An alternative desulfurization method involves oxidizing thioether compound 44 with mCPBA to afford an intermediate sulfone moiety, which can then be removed using conditions well known to those skilled in the art, such as NaBH in DCM / MeOH, to afford quinazolinyl compound 45. This can then be reacted with bicyclic boronic acid 40 using Suzuki coupling conditions previously described to afford bicyclic-substituted quinazolinyl compound 47. An alternative route utilizes Suzuki coupling first to give bicyclic substituted quinazolinyl compound 46, which is then subjected to a desulfurization reaction to give quinazolinyl compound 47. The amine moiety of compound 47 can then be suitably deprotected using methods well known to those skilled in the art, for example, using TFA, to remove the Boc protecting group and give substituted quinazolinyl compound 48.

[0253] [ka]

[0254] Scheme 9 also illustrates the preparation of dihydrofuroquinoline compound 56 via two routes. One skilled in the art can select a route based on the desired order of functionalization of the dihydrofuroquinolinyl core. In one route, the hydroxy moiety of quinolinyl compound 29 can be converted to a leaving group (LG) moiety, such as chloride. Chlorination can be achieved using oxalyl chloride and DMF in DCM to afford quinolinyl compound 49. Subsequent nucleophilic substitution with a substituted piperazine in an aprotic solvent, such as DMSO, at elevated temperatures (approximately 130°C) using a suitable hindered base, such as DIPEA, can afford substituted quinolinyl compound 50. Aryl coupling of bromoquinolinyl compound 50 with bicyclic boronic acid 40 can afford biaryl compound 53. Alternatively, to first introduce the bicyclic aryl group, Suzuki coupling of bromide 29 with boronic acid 40 can be performed using conditions well known to those skilled in the art, such as refluxing in dioxane / water using KPO and the palladium complex 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride, to give biaryl compound 51. The hydroxy moiety of quinolinyl compound 51 can then be converted to a leaving group (LG) moiety, such as chloride, bromide, or triflate, by standard methods recognized by those skilled in the art. For example, triflate can be obtained from hydroxyquinoline compound 51 using trifluoromethanesulfonic anhydride and DMAP in DCM at 0 °C, which can then be converted to S using substituted piperazines as previously described. NAR to afford dihydrofuroquinolinyl compound 53. Compound 53 can then be oxidized with mCPBA or other suitable oxidizing agents known to those skilled in the art, optionally with a suitable solvent, to afford sulfone compound 54. The sulfone moiety can then be subjected to nucleophilic displacement with a suitable nucleophile, such as a primary or secondary alcohol, using a strong base, such as LiHMDS in THF, to afford substituted quinolinyl compound 55. Subsequent removal of the protecting group can be achieved by a method appropriate for the protecting group used, for example, Boc removal with TFA in DCM, to afford dihydrofuroquinoline compound 56.

[0255] [ka]

[0256] Scheme 10 illustrates the preparation of dihydrofuroquinazoline 61, along with two different route options for functionalizing the quinazolinyl core. One route to intermediate 60 begins with oxidation of thioether 44 with mCPBA, as previously described, to give sulfone 57. Nucleophilic substitution of the sulfone moiety can then afford bifunctional quinazolinyl 58. Suzuki coupling of boronic acid 40 with bromide 58, such as substituted benzothiophenes, benzothiazoles, and benzofurans, can then afford biaryl 60. The Suzuki coupling can also be achieved in reverse by reacting bromide compound 58 with bis(neopentylglycolato)diboron in the presence of a weak base such as KOAc and a palladium complex such as dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) to form a boronic ester at the quinazolinyl core, followed by coupling to a Boc-protected chlorothienopyridine such as tert-butyl N-(4-chlorothieno[3,2-c]pyridin-2-yl)carbamate to give biaryl compound 60. Another route to intermediate compound 60 involves incorporating the Suzuki coupling upfront, such that bromide compound 44 can be subjected to arylation with boronic acid compound 40 to give biaryl compound 46. Subsequent oxidation of the sulfide moiety of compound 46 using standard conditions previously described can give sulfone compound 59, followed by S-reaction with a nucleophile such as a primary or secondary alcohol. N AR can provide the functionalized compound (60). Subsequent removal of the protecting group can be achieved by a method appropriate for the protecting group used, for example, Boc removal with TFA in DCM, to provide the dihydrofuroquinazoline compound (61).

[0257] Preparation 1 5-Fluoro-3H-isobenzofuran-1-one

[0258] [ka]

[0259] 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) (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 HO (1,000 mL) and then extracted with EtOAc (2 × 2000 mL). The combined organic layers were washed with brine (2 × 1,000 mL), dried over anhydrous NaSO, 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).

[0260] Preparation 2 4-Bromo-5-fluoro-6-nitro-3H-isobenzofuran-1-one

[0261] [ka]

[0262] To a stirred mixture of 5-fluoro-3H-isobenzofuran-1-one (300 g, 1.97 mol) in HSO (1,500 mL) was added HNO (273.38 g, 4.348 mol, 2.2 equiv.) dropwise at 65 °C. The reaction was stirred for 1 hour 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 portionwise over 20 minutes and stirred at room temperature for approximately 18 hours. The mixture was poured into ice / water (pretreated with 3 kg of NaSO) and filtered. The filter cake was dissolved in EtOAc (3,000 mL), washed with saturated aqueous NaCO (2 × 1,000 mL), brine (2 × 1,000 mL), dried over anhydrous NaSO, and concentrated. The residue was triturated with 10:1 hexanes / EtOAc (660 mL), filtered, and dried at 50° C. for approximately 18 hours 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) δ 8.58 (s, 1H), 5.51 (s, 2H).

[0263] Preparation 3 5-chloro-6-nitro-3H-isobenzofuran-1-one

[0264] [ka]

[0265] In a 1 L three-necked round-bottom flask, a solution of 5-chloro-3H-isobenzofuran-1-one (60 g, 355.91 mmol) in HNO (46 mL) and HSO (277 mL) was heated at 100 °C for 4 h under N. The mixture was slowly added to ice water (1 L) and stirred for 30 min. The resulting precipitate was filtered, rinsed with HO (2 × 300 mL), and dried under vacuum at 45 °C to give the title compound (57 g, 70%) as a yellow solid. MS (ES) m / z = 214 (M+1).

[0266] Preparation 4 4-Bromo-5-chloro-6-nitro-3H-isobenzofuran-1-one

[0267] [ka]

[0268] In a 1 L three-neck RBF, a solution of 5-chloro-6-nitro-3H-isobenzofuran-1-one (65 g, 283 mmol) was dissolved in HSO (600 mL) and cooled to 0 °C. NBS (60 g, 337 mmol) was added portionwise under N at a rate that maintained the temperature at 0 °C. The reaction was then stirred at 50 °C for approximately 18 h. The mixture was slowly added to ice water (1 L) and stirred for 30 min. The resulting precipitate was filtered, rinsed with HO (2 × 300 mL), and dried under vacuum at 45 °C to give the title compound (65 g, 72%) as a yellow solid. MS (ES) m / z = 292 (M+1).

[0269] Preparation 5 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran

[0270] [ka]

[0271] To a stirred mixture of 4-bromo-5-fluoro-6-nitro-3H-isobenzofuran-1-one (270 g, 978 mmol) in DCM (2,500 mL) was added DIBAL-H (1 M THF solution, 1,467 mL, 1.467 mol, 1.5 equiv) dropwise under N at −78° C. The reaction was stirred at −78° C. for 5 hours and then quenched with 5 N 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 (2×1,000 mL), dried over anhydrous NaSO, 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 approximately 18 h. The reaction was concentrated to an oil, which was diluted with EtOAc (2,000 mL), washed with saturated aqueous NaCO (2 × 500 mL) and brine (2 × 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) δ 8.16 (d, J = 6.2 Hz, 1H), 5.18-5.15 (m, 2H), 5.11-5.06 (m, 2H).

[0272] Preparation 6 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine

[0273] [ka]

[0274] 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, followed by stirring at 80 °C for approximately 18 h. The mixture was filtered and concentrated. The mixture was diluted with HO (500 mL) and extracted with EtOAc (2 × 1,000 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on silica (25%-50% EtOAc in hexanes) to give the title compound (70 g, 72%) as a yellow solid. MS (ES) m / z = 231 (M+1).

[0275] Preparation 7 [4-chloro-2-(hydroxymethyl)phenyl]methanol

[0276] [ka]

[0277] To a stirred mixture of LiAlH (1.9 L, 2.74 mol, 2 equiv., 2.5 M THF solution) in THF (1 L) was added dropwise a solution of 4-chlorophthalic anhydride (250 g, 1.34 mol, 1.00 equiv.) in THF (500 mL) under N at −20° C. The resulting mixture was stirred at 45° C. under N for 30 min. The reaction was quenched by the addition of H O (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 Na SO . 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)δ 7.45-7.36(m,2H),7.28(dd,J=8.2Hz,1H),5.40-5.13(m,2H),4.54(s,2H),4.49(s,2H).

[0278] Preparation 8 5-chloro-1,3-dihydroisobenzofuran

[0279] [ka]

[0280] To a stirred mixture of [4-chloro-2-(hydroxymethyl)phenyl]methanol (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 approximately 18 h. The mixture was concentrated under reduced pressure, diluted with H O (2 L), and extracted with EtOAc (3 × 2 L). The combined organic layers were washed with brine (2 × 2 L) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica (10:1-8:1 hexane / EtOAc) to give the title compound (165 g, 82%) as a light brown solid. 1 H NMR (300MHz, DMSO-d6) δ 7.42-7.37 (m, 1H), 7.33 (d, J = 1.4Hz, 2H), 4.99 (s, 4H).

[0281] Preparation 9 5-chloro-6-nitro-1,3-dihydroisobenzofuran

[0282] [ka]

[0283] A solution of 5-chloro-1,3-dihydroisobenzofuran (110 g, 712 mmol) in HSO (700 mL) at −10° C. was dropwise charged with a solution of KNO (64.74 g, 640 mmol, 0.9 equiv.) in HSO (200 mL) at −5° C. to 0° C. The resulting mixture was stirred for an additional 30 min at 0° C. and then slowly added to stirred, ice-cold H2O. The precipitated solid was collected by filtration and washed with H2O (3 × 1 L). The filter cake was dried in vacuo to give the title compound (110 g, 77%) as a light brown solid, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6) δ 8.05 (s, 1H), 7.75 (s, 1H), 5.07-5.02 (m, 4H).

[0284] Preparation 10 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran

[0285] [ka]

[0286] To a stirred solution of 5-chloro-6-nitro-1,3-dihydroisobenzofuran (125 g, 626 mmol) in HSO (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 HO. The precipitated solid was collected by filtration and washed with HO (3 × 0.5 L). The filter cake was dried in vacuo and purified on silica (10:1-5:1 hexanes / EtOAc) to give the title compound (83.5 g, 47.9%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.07 (d, J = 1.1 Hz, 1H), 5.19 (dt, J = 2.3, 1.1 Hz, 2H), 5.08 (t, 2H).

[0287] Preparation 11 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine

[0288] [ka]

[0289] 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 approximately 18 h. The resulting mixture was filtered hot, and the filter cake was washed with EtOAc (3 × 500 mL). The filtrate was concentrated under reduced pressure and purified on silica (15:1-10:1 hexanes / EtOAc) to give the title compound (25 g, 76%) as a pale yellow solid. MS (ES) m / z = 248 (M+1).

[0290] Preparation 12 N-(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxy-prop-2-enamide

[0291] [ka]

[0292] 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 hours. The resulting mixture was concentrated in vacuo. 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).

[0293] Preparation 13 N-(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxy-prop-2-enamide

[0294] [ka]

[0295] 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine was used in a manner similar to the method of Preparation 12 to give the title compound (1.4 g, 89%) as a pale yellow solid. MS (ES) m / z=332 (M+1).

[0296] Preparation 14 4-Bromo-5-chloro-3,6-dihydro-1H-furo[3,4-f]quinolin-7-one

[0297] [ka]

[0298] To a stirred solution of H2SO4 (20 mL) was added N-(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxy-prop-2-enamide (6.10 g, 17.6 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature for approximately 18 hours. The mixture was slowly added to stirred ice-cold water (200 mL). The precipitated solid was collected by filtration and washed with HO (3 × 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).

[0299] Preparation 15 4-Bromo-5-fluoro-3,6-dihydro-1H-furo[3,4-f]quinolin-7-one

[0300] [ka]

[0301] N-(7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxy-prop-2-enamide was used in a manner similar to that described for Preparation 14 to give the title compound (1.2 g, quantitative yield) as a brown solid. MS (ES) m / z = 284 (M+1).

[0302] Preparation 16 4-Bromo-5,7-dichloro-1,3-dihydrofuro[3,4-f]quinoline

[0303] [ka]

[0304] To a stirred solution of 4-bromo-5-chloro-3,6-dihydro-1H-furo[3,4-f]quinolin-7-one (5.00 g, 16.6 mmol) in DMF (20 mL) was added POCl (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 HO (3 × 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).

[0305] Preparation 17 4-Bromo-7-chloro-5-fluoro-1,3-dihydrofuro[3,4-f]quinoline

[0306] [ka]

[0307] A suspension of 6-bromo-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (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 hours. The reaction was diluted with DCM and washed with HO and brine. The organic layer was dried over NaSO, 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%-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).

[0308] Preparation 18 6-Amino-4-bromo-5-fluoro-3H-isobenzofuran-1-one

[0309] [ka]

[0310] A suspension of 4-bromo-5-fluoro-6-nitro-3H-isobenzofuran-1-one (1.11 g, 4.02 mmol) in AcOH (4 mL), HO (2 mL), and EtOH (20 mL) was charged with iron (1.0 g, 18 mmol) and heated at 70 °C for 2 h. The reaction was cooled to room temperature, partitioned between DCM and saturated aqueous NaHCO, and filtered through a pad of diatomaceous earth. The pad was rinsed with DCM, the filtrate was partitioned, and the organic layer was dried over MgSO and concentrated to give the title compound (0.90 g, 91%) as a white solid. MS (ES) m / z = 246 (M-1).

[0311] Preparation 19 6-Amino-4-bromo-5-chloro-3H-isobenzofuran-1-one

[0312] [ka]

[0313] To a mixture of 4-bromo-5-chloro-6-nitro-3H-isobenzofuran-1-one (7.98 g, 27.3 mmol) in EtOH (200 mL) and HO (40 mL) was added NH4Cl (5.84 g, 109 mmol), followed by iron powder (6.09 g, 109 mmol). The mixture was stirred in an oil bath at 80 °C for 20 hours. The mixture was filtered through a pad of diatomaceous earth and washed with acetone. The filtrate was concentrated to approximately 50 mL. The resulting precipitate was collected by filtration and dried under vacuum overnight to give the first batch of product (2.57 g) as a beige solid. The diatomaceous earth mixture was stirred in acetone / MeOH (2 / 1) and filtered. This process was repeated twice. The combined filtrate was concentrated and dried in a vacuum oven at 60 °C overnight to give the second batch of product (3.70 g). The batches were combined to give the title compound (6.27 g, 87.5%). MS (ES) m / z = 279 (M + H2O + 1).

[0314] Preparation 20 tert-Butyl N-(7-bromo-6-fluoro-3-oxo-1H-isobenzofuran-5-yl)-N-tert-butoxycarbonyl-carbamate

[0315] [ka]

[0316] A mixture of 6-amino-4-bromo-5-fluoro-3H-isobenzofuran-1-one (36.0 g, 146 mmol), di-tert-butyl dicarbonate (100 g, 444 mmol), and DMAP (4.50 g, 37.0 mmol) in ACN (1,000 mL) was heated to reflux. After refluxing for 30 minutes, the reaction mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in DCM (1,000 mL) and washed with ice-cold 10% citric acid, saturated aqueous NaHCO3, and brine, then dried over MgSO4, filtered, and concentrated. The crude material was purified by silica column chromatography (100% A-100% B, A = 4% MTBE and 20% DCM in hexane, B = 10% MTBE and 20% DCM in hexane) to give the title compound (36.0 g, 55%). 1 H NMR (300MHz, DMSO-d6) δ 8,11(s,1H),5.49(s,2H),1.40(s,18H).

[0317] Preparation 21 tert-Butyl N-(7-bromo-6-chloro-3-oxo-1H-isobenzofuran-5-yl)-N-tert-butoxycarbonyl-carbamate

[0318] [ka]

[0319] 6-Amino-4-bromo-5-chloro-3H-isobenzofuran-1-one was used in a manner similar to the method of Preparation 20 to give the title compound (34.6 g, 61%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.10 (s, 1H), 5.48 (s, 2H), 1.40 (s, 18H).

[0320] Preparation 22 tert-Butyl N-(7-bromo-6-fluoro-3-hydroxy-1,3-dihydroisobenzofuran-5-yl)carbamate

[0321] [ka]

[0322] To a solution of tert-butyl N-(7-bromo-6-fluoro-3-oxo-1H-isobenzofuran-5-yl)-N-tert-butoxycarbonyl-carbamate (36.0 g, 80.7 mmol) in DCM (1,600 mL) was added DIBAL-H (1 M DCM solution, 245 mL, 245 mmol) dropwise over 2 hours at −70° C. After the addition, the reaction mixture was stirred at −70° C. for 1 hour. The reaction was quenched by the dropwise addition of NaOH solution (1 M HO solution, 164 mL, 164 mmol) at −70° C. The mixture was diluted with DCM (1,000 mL) and stirred to room temperature. After the addition of MgSO (200 g), the mixture was stirred for 10 minutes and then allowed to stand over MgSO at room temperature overnight. The mixture was filtered through diatomaceous earth and washed with 10% MeOH in DCM (1,000 mL). The filtrate was concentrated and purified by silica column chromatography (5-40% EtOAc / hexanes) to give the title compound (25.0 g, 89%) as a white solid. MS (ES) m / z = 346 (M-1).

[0323] Preparation 23 tert-Butyl N-(7-bromo-6-chloro-3-hydroxy-1,3-dihydroisobenzofuran-5-yl)carbamate

[0324] [ka]

[0325] N-(7-bromo-6-chloro-3-oxo-1H-isobenzofuran-5-yl)-N-tert-butoxycarbonyl-carbamate tert-butyl was used in a manner similar to the method of Preparation 22 to give the title compound (5.10 g, 65.4%) as a white solid. MS (ES) m / z = 346 (M-HO+1).

[0326] Preparation 24 tert-Butyl N-[7-bromo-3-(cyanomethyl)-6-fluoro-1,3-dihydroisobenzofuran-5-yl]carbamate

[0327] [ka]

[0328] To a flask was added tert-butyl N-(7-bromo-6-fluoro-3-hydroxy-1,3-dihydroisobenzofuran-5-yl)carbamate (9.70 g, 27.9 mmol), THF (200 mL), diethyl cyanomethylphosphonate (7.00 mL, 42.3 mmol), and CsCO (10.0 g, 30.7 mmol). The flask was fitted with a condenser, and the mixture was heated to reflux. After 3 h, the mixture was allowed to cool, filtered through diatomaceous earth, and rinsed with EtOAc. The combined filtrate and washings were concentrated. The crude oil was diluted with EtOAc (500 mL), and HO (500 mL) was added. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was back-extracted with EtOAc (500 mL), and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated. The crude material was purified by flash silica column chromatography eluting with 5-40% EtOAc / hexanes to afford the title compound (9.15 g, 89%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 9.28 (s, 1H), 7.68 (s, 1H), 5.52 (s, H), 5.02 (m, 2H), 3.18 (m, 2H), 1.49 (s, 9H).

[0329] Preparation 25 tert-Butyl N-[7-bromo-6-chloro-3-(cyanomethyl)-1,3-dihydroisobenzofuran-5-yl]carbamate

[0330] [ka]

[0331] tert-Butyl N-(7-bromo-6-chloro-3-hydroxy-1,3-dihydroisobenzofuran-5-yl)carbamate was used in a manner similar to that of Preparation 24 to give the title compound (3.92 g, 72%) as a white solid. MS (ES) m / z = 385 (M-1).

[0332] Preparation 26 2-(6-amino-4-bromo-5-fluoro-1,3-dihydroisobenzofuran-1-yl)acetonitrile

[0333] [ka]

[0334] To a suspension of tert-butyl N-[7-bromo-3-(cyanomethyl)-6-fluoro-1,3-dihydroisobenzofuran-5-yl]carbamate (9.10 g, 24.5 mmol) in MeOH (150 mL) cooled in an ice bath, HCl solution (4 M in 1,4-dioxane, 64.0 mL, 256 mmol) was added. The reaction was stirred at room temperature for 6 hours. The mixture was cooled in an ice bath and first neutralized with 2 N NaOH solution, then washed with saturated aqueous NaHCO3. The mixture was concentrated, and the resulting solid was collected and dried in vacuo at 60 °C overnight to give the title compound (6.10 g, 92%) as a white solid. MS (ES) m / z = 269 (M-1).

[0335] Preparation 27 2-(6-amino-4-bromo-5-chloro-1,3-dihydroisobenzofuran-1-yl)acetonitrile

[0336] [ka]

[0337] tert-Butyl N-[7-bromo-6-chloro-3-(cyanomethyl)-1,3-dihydroisobenzofuran-5-yl]carbamate was used in a manner similar to that of Preparation 26 to give the title compound (2.64 g, 99%) as an off-white solid. MS (ES) m / z = 287 (M+1).

[0338] Preparation 28 7-Methyl-6-nitro-isochroman-1-one

[0339] [ka]

[0340] To a stirred mixture of 3-methyl-4-nitrobenzoic acid (70.0 g, 386 mmol) and N-acetyl-L-leucine (13.4 g, 77.3 mmol) in hexafluoroisopropanol (750 mL) was added KOAc (37.9 g, 386 mmol) and Pd(OAc) (8.68 g, 38.6 mmol), followed by ethylene oxide (155 mL, 386 mmol, 1 equivalent, 2.5 M THF solution) at room temperature. The reaction mixture was stirred at 80 °C under N for 8 h. The mixture was diluted with EtOAc (1,000 mL). The organic layer was washed with brine (500 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (3:1-1:1) to give the product (56.0 g, 52.4%) as a yellow solid. MS(ES) m / z=249(M+1).

[0341] Preparation 29 7-Methyl-6-nitro-isochroman

[0342] [ka]

[0343] To a stirred mixture of 7-methyl-6-nitro-isochroman-1-one (66.0 g, 319 mmol) in THF (800 mL) was added LiBH (2 M THF solution, 400 mL, 800 mmol) dropwise under N at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was diluted with saturated aqueous NH Cl (300 mL) and extracted with EtOAc (2×600 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. To crude 2-[2-(hydroxymethyl)-4-methyl-5-nitrophenyl]ethanol (50.0 g, 237 mmol) was added 4-methylbenzene-1-sulfonic acid (44.8 g, 260 mmol) and toluene (500 mL). The resulting reaction mixture was heated at 115° C. for approximately 18 h. The reaction was allowed to cool to room temperature. The mixture was diluted with EtOAc (1,000 mL), washed with brine (500 mL), then dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (3:1-1:1) to give the product (30.0 g, 36.3%) as a yellow solid. 1 H NMR (300MHz, CDCl3) δ 7.81(s,1H),6.96(s,1H),4.82-4.74(m,2H),4.02-3.96(m,2H),2.96-2.82(m,2H),2.5(s,3H).

[0344] Preparation 30 8-Bromo-7-methyl-6-nitro-isochroman

[0345] [ka]

[0346] To a mixture of 7-methyl-6-nitroisochroman (30 g, 150 mmol) in concentrated HSO (300 mL) was added NBS (32.1 g, 180 mmol) in small portions at room temperature. The reaction was stirred at room temperature for approximately 18 hours. The reaction mixture was poured into ice water (500 mL) and filtered. The filter cake was washed with saturated aqueous NaCO (2 × 50 mL), then dissolved in EtOAc (500 mL), washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (3:1-1:1) to give the product (23.0 g, 56.5%) as a yellow solid. 1 H NMR (300MHz, CDCl3) δ 7.58 (s, 1H), 4.78-4.68 (m, 2H), 4.02-3.92 (m, 2H), 2.98-2.86 (m, 2H), 2.57 (s, 3H).

[0347] Preparation 31 8-Bromo-7-methyl-isochroman-6-amine

[0348] [ka]

[0349] To a mixture of 8-bromo-7-methyl-6-nitroisochroman (23.0 g, 84.5 mmol) and NH4Cl (22.6 g, 423 mmol) in EtOH (250 mL) and HO (50 mL) was added iron powder (23.6 g, 423 mmol) at room temperature. The resulting reaction mixture was heated at 80 °C for 6 h. The mixture was filtered, and the filter cake was washed with EtOAc (2 × 200 mL). The filtrate was diluted with EtOAc (100 mL), washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (2:1-1:2) to give the product (17.0 g, 83%) as a yellow solid. MS (ES) m / z = 242 (M+1).

[0350] Preparation 32 Ethyl N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate

[0351] [ka]

[0352] 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, followed by stirring at room temperature for approximately 4 hours. The solid was filtered. The filtrate was concentrated, 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).

[0353] The following compounds in Table 1 were prepared in a manner similar to that described in Preparation 32. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0354] Table 1: [Table 2]

[0355] Preparation 37 (NZ)-N-[[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino]-ethylsulfanyl-methylene]carbamate

[0356] [ka]

[0357] 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 several portions, followed by the dropwise addition of EtI (7.2 mL, 90 mmol, 1.0 equiv.) over 20 min. The mixture was stirred at room temperature for approximately 18 h. The solid was filtered, and the filtrate was concentrated and partitioned between DCM (500 mL) and HO (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).

[0358] The following compounds in Table 2 were prepared in a manner similar to that described in Preparation 37. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0359] Table 2: [Table 3]

[0360] Preparation 42 6-Bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol

[0361] [ka]

[0362] A 2 L four-neck RBF was equipped with an overhead stirrer, an addition funnel, an N2 inlet, and a thermocouple and purged with N2. NMP (anhydrous, 300 mL) was added. The mixture was heated to 175 °C. In a second flask, ethyl (NZ)-N-[[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino]-ethylsulfanyl-methylene]carbamate (22.63 g, 57.83 mmol) and NMP (anhydrous, 100 mL) were combined and stirred under N2 until a homogeneous solution was obtained. When the first flask reached 175 °C, the contents of the second flask were poured into the addition 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. HO (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 hours to give the title compound (15.2 g, 73%) as an off-white solid. MS (ES) m / z=363 (M+1).

[0363] The following compounds in Table 3 were prepared in a manner similar to that described in Preparation 42. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0364] Table 3: [Table 4]

[0365] Preparation 47 7-Bromo-6-fluoro-4-iodo-1,3-dihydroisobenzofuran-5-amine

[0366] [ka]

[0367] A mixture of 7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (15.0 g, 64.6 mmol) and NIS (16.0 g, 71.1 mmol) in CHCl (400 mL) was stirred under N at 50 °C for approximately 18 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1-5:1) to give the product (16.0 g, 69.2%) as an orange solid. MS (ES) m / z = 358 (M+1).

[0368] Preparation 48 7-Bromo-6-chloro-4-iodo-1,3-dihydroisobenzofuran-5-amine

[0369] [ka]

[0370] 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine was used in a manner similar to that of Preparation 47 to give the title compound (0.19 g, 60%) as a white solid. MS (ES) m / z = 372 (M+1).

[0371] Preparation 49 5-Amino-7-bromo-6-fluoro-1,3-dihydroisobenzofuran-4-carboxylic acid methyl ester

[0372] [ka]

[0373] To a stirred solution of 7-bromo-6-fluoro-4-iodo-1,3-dihydroisobenzofuran-5-amine (1.62 g, 4.53 mmol) in MeOH (20 mL) and DMF (20 mL) was added TEA (1.89 mL, 13.6 mmol) and Pd(dppf)Cl (331 mg, 0.45 mmol) at room temperature under a CO atmosphere. The mixture was stirred at 60 °C under a CO atmosphere using a CO balloon for approximately 18 hours. The resulting mixture was concentrated under reduced pressure and diluted with EtOAc (300 mL). The mixture was washed with HO (3 × 200 mL), brine (200 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (20%-40% gradient over 30 min) to give the product (1.00 g, 76.1%) as a yellow solid. MS(ES) m / z=290(M+1).

[0374] Preparation 50 5-Amino-7-bromo-6-chloro-1,3-dihydroisobenzofuran-4-carboxylic acid methyl ester

[0375] [ka]

[0376] 7-Bromo-6-chloro-4-iodo-1,3-dihydroisobenzofuran-5-amine was used in a manner similar to that of Preparation 49 to give the title compound (6.2 g, 58%) as a pale yellow solid. MS (ES) m / z = 306 (M+1).

[0377] Preparation 51 7-Bromo-4-(1-ethoxyvinyl)-6-fluoro-1,3-dihydroisobenzofuran-5-amine

[0378] [ka]

[0379] To a stirred mixture of 7-bromo-6-fluoro-4-iodo-1,3-dihydroisobenzofuran-5-amine (6.00 g, 16.8 mmol) and tributyl(1-ethoxyvinyl)stannane (22.7 g, 62.9 mmol) in DMF (60 mL) was added Pd(PPh3)4 (3.88 g, 3.34 mmol) in small portions at room temperature. The reaction was then stirred at 80 °C for approximately 18 h. The mixture was allowed to cool to room temperature and extracted with EtOAc (200 mL). The organic layer was washed with HO (3 × 50 mL), brine (50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (5.07 g, quantitative yield), which was used in the next step without further purification. MS (ES) m / z = 301 (M+1).

[0380] Preparation 52 1-(5-amino-7-bromo-6-fluoro-1,3-dihydroisobenzofuran-4-yl)ethanone

[0381] [ka]

[0382] To a stirred mixture of 7-bromo-4-(1-ethoxyvinyl)-6-fluoro-1,3-dihydroisobenzofuran-5-amine (5.00 g, 16.6 mmol) in THF (50 mL) was added 1 M aqueous HCl (50 mL) dropwise at 0 °C, followed by stirring at room temperature for 3 h. The resulting mixture was extracted with EtOAc (100 mL), and the organic layer was washed with 1 M aqueous NaCO (100 mL), brine (50 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EtOAc (3:1-1:1) to give the product (2.00 g, 44.1%) as a yellow solid. MS (ES) m / z = 274 (M+1).

[0383] Preparation 53 6-Bromo-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol

[0384] [ka]

[0385] A mixture of methyl 5-amino-7-bromo-6-fluoro-1,3-dihydroisobenzofuran-4-carboxylate (6.00 g, 20.7 mmol) and formamide (48.0 mL, 1,200 mmol) was stirred at 160 °C under N for 12 h. The mixture was allowed to cool to room temperature and diluted with HO (300 mL) at 0 °C. The precipitated solid was collected by filtration and washed with HO (3 × 50 mL). The solid was dried under vacuum to give the product (5.2 g, 88.1%) as a brown solid. MS (ES) m / z = 285 (M+1).

[0386] Preparation 54 6-Bromo-5-chloro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol

[0387] [ka]

[0388] Methyl 5-amino-7-bromo-6-chloro-1,3-dihydroisobenzofuran-4-carboxylate was used in a manner similar to the method of Preparation 53 to give the title compound (3.5 g, 58%) as a black solid. MS (ES) m / z = 301 (M+1).

[0389] Preparation 55 4-Bromo-5-fluoro-1,3-dihydrofuro[3,4-f]cinnolin-9-ol

[0390] [ka]

[0391] To a stirred mixture of 1-(5-amino-7-bromo-6-fluoro-1,3-dihydroisobenzofuran-4-yl)ethanone (2.00 g, 7.30 mmol) in TFA (40 mL) was added NaNO (0.600 g, 8.76 mmol) at room temperature and stirred at 70 °C for 2 h. The reaction was allowed to cool to room temperature, then concentrated under reduced pressure, HO (100 mL) was added, and the resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with DCM:MeOH (10:1) to give the product (1.20 g, 57.7%) as a yellow solid. MS (ES) m / z = 285 (M+1).

[0392] Preparation 56 6-Bromo-5-fluoro-3-methyl-7,9-dihydrofuro[3,4-f]quinazolin-1-ol

[0393] [ka]

[0394] A stirred mixture of methyl 5-amino-7-bromo-6-fluoro-1,3-dihydro-2-benzofuran-4-carboxylate (350 mg, 1.21 mmol) and ACN (594 mg, 14.5 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was heated at 100 °C under N. The resulting mixture was stirred at 100 °C under N for approximately 18 h. The mixture was diluted with HO (100 mL) and extracted with EtOAc (2 × 50 mL). The organic layer was concentrated under reduced pressure to give the product (290 mg, 80.4%) as a yellow solid. MS (ES) m / z = 299 (M+1).

[0395] Preparation 57 5-[bis(methylsulfanyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0396] [ka]

[0397] To a stirred mixture of Meldrum's acid (20 g, 138.76 mmol) and TEA (42.13 g, 416.30 mmol, 3 equiv.) in DMSO (100 mL) was added CS (15.85 g, 208.15 mmol, 1.5 equiv.). The resulting mixture was stirred at room temperature under N for 3 h. CHCl (59.09 g, 416.30 mmol, 3 equiv.) was added dropwise at 0°C. The temperature was allowed to warm to room temperature, and the reaction was stirred for approximately 18 h. The resulting mixture was diluted with EtOAc (1,000 mL), washed with HO (2 x 200 mL), then brine (200 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica eluting with PE:EtOAc (4:1-2:1) to give the title compound (23 g, 67%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ 2.64 (s, 6H), 1.68 (s, 6H).

[0398] Preparation 58 5-[[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino]-methylsulfanyl-methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[0399] [ka]

[0400] A stirred mixture of 5-[bis(methylsulfanyl)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (16.49 g, 66.40 mmol, 1.1 equiv) and 7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine (15 g, 60 mmol, 1 equiv) in toluene (150 mL) was heated at 80° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by trituration with 10:1 PE:EtOAc (250 mL). The solid was collected by filtration and dried under vacuum to give the title compound (20 g, 73%) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ 11.97 (s, 1H), 7.52 (s, 1H), 5.14 (s, 2H), 5.03 (s, 2H), 2.37 (s, 3H), 1.67 (s, 6H).

[0401] Preparation 59 4-Bromo-5-chloro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-9-ol

[0402] [ka]

[0403] A solution of 5-[[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino]-methylsulfanyl-methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (18 g, 40 mmol, 1 equiv.) in diphenyl ether (200 mL) was stirred at 180° C. for 1 hour. The reaction was allowed to cool to room temperature, then diluted with PE (500 mL) and stirred at room temperature for 20 minutes. After filtration, the filter cake was washed with PE (2×50 mL) and dried under reduced pressure to give the title compound (11.3 g, 81%) as a yellow solid, which was used in the next step without further purification. MS (ES) m / z=346 (M+1).

[0404] Preparation 60 6-Bromo-1-chloro-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline

[0405] [ka]

[0406] A 5 L three-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 approximately 4 °C. Oxalyl chloride (50.0 mL, 576 mmol, 4 equiv.) was added dropwise via the addition funnel over approximately 40 min. After the addition was complete, the reaction was stirred at approximately 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 approximately 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 / hexane (60%-90%) to give the title compound (45.1 g, 89%) as a white solid. MS (ES) m / z = 363 (M+1).

[0407] The following compounds in Table 4 were prepared in a manner similar to that described in Preparation 60. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0408] Table 4: [Table 5] a After removing the ice bath, the reaction was heated at 37° C. for approximately 24 hours.

[0409] Preparation 66 2-(6-bromo-1-chloro-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-9-yl)acetonitrile

[0410] [ka]

[0411] To a solution of DMF (60 mL) and POCl3 (50.00 mL, 538 mmol) was added 2-(6-bromo-3-ethylsulfanyl-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-9-yl)acetonitrile (4.6 g, 12 mmol) in small portions. The mixture was heated in an oil bath at 90 °C for 1 hour. The reaction mixture was cooled to room temperature and then slowly added to an ice-water mixture with stirring. The resulting solid was collected by filtration, washed with cold water, and dried in a vacuum oven at 55 °C overnight to give the title compound (4.5 g, 75%) as a light brown solid. MS (ES) m / z = 402 (M+1).

[0412] Preparation 67 2-(6-bromo-1,5-dichloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-9-yl)acetonitrile

[0413] [ka]

[0414] 2-(6-Bromo-5-chloro-3-ethylsulfanyl-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-9-yl)acetonitrile was used in a manner similar to that of Preparation 66 to give the title compound (0.9 g, 81%) as an off-white solid. MS (ES) m / z = 418 (M+1).

[0415] Preparation 68 6-Bromo-3-ethylsulfanyl-5-methyl-9,10-dihydro-7H-pyrano[4,3-f]quinazoline

[0416] [ka]

[0417] A mixture of 6-bromo-1-chloro-3-ethylsulfanyl-5-methyl-9,10-dihydro-7H-pyrano[4,3-f]quinazoline (1.10 g, 2.94 mmol) and TMEDA (500 mg, 4.30 mmol) in THF (20 mL) was purged with argon. Pd(ddpf)Cl₂·DCM complex (120 mg, 0.144 mmol) and NaBH₃CN (280 mg, 4.46 mmol) were added. The reaction mixture was again purged with argon and heated to 45 °C. After 2 h, the reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NH₄Cl solution, brine, and dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc in hexane (0-40%) to give the product (998 mg, quantitative yield) as a yellow solid. MS(ES) m / z=339(M+1).

[0418] Preparation 300 6-Bromo-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazoline

[0419] [ka]

[0420] 6-Bromo-1,5-dichloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazoline was used in a manner similar to that of Preparation 68 to give the title compound (0.38 g, 51%) as a white solid. MS (ES) m / z = 345,347 (M+1, Br).

[0421] Preparation 301 6-Bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline

[0422] [ka]

[0423] 6-Bromo-1-chloro-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline was used in a manner similar to that of Preparation 68 to give the title compound (1.00 g, 92%). MS (ES) m / z = 329,331 (M+1, Br).

[0424] Preparation 69 4-Bromo-5-fluoro-benzothiophene-2-carboxylic acid methyl ester

[0425] [ka]

[0426] 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)δ 8.23-8.19(dd,J=4.49,8.9Hz,1H),8.05(s,1H),7.62(t,J=9.0Hz,1H),3.93(s,3H).

[0427] Preparation 70 4-Bromo-5-fluoro-benzothiophene-2-carboxylic acid

[0428] [ka]

[0429] A solution of methyl 4-bromo-5-fluoro-benzothiophene-2-carboxylate (19.2 g, 66.4 mmol, 1 equiv.) in MeOH (130 mL) and THF (130 mL) was charged with 5 N NaOH (66 mL, 330 mmol, 5 equiv.) and stirred at room temperature for 40 min. The mixture was concentrated, and HO (500 mL) was added. The pH was adjusted to approximately 2 with 5 N HCl. The mixture was extracted with EtOAc (2 × 500 mL), and the combined organic layers were dried over anhydrous NaSO, 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-CO).

[0430] Preparation 71 tert-Butyl N-(4-bromo-5-fluoro-benzothiophen-2-yl)carbamate

[0431] [ka]

[0432] A solution of 4-bromo-5-fluorobenzothiophene-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 to 95° C. for 1 h. The mixture was cooled and concentrated. The residue was purified on silica eluting with MTBE / hexane (4%-20%) to give the title compound (0.987 g, 52%) as a white solid. MS (ES) m / z=290 (M+1).

[0433] Preparation 72 tert-Butyl N-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-benzothiophen-2-yl]carbamate

[0434] [ka]

[0435] A mixture of tert-butyl N-(4-bromo-5-fluoro-benzothiophen-2-yl)carbamate (3.08 g, 8.90 mmol), 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 N for 20 minutes. To the mixture was added Pd(ddpf)Cl (0.69 g, 0.90 mmol, 0.1 equiv.). The reaction was sonicated for 3 minutes, then subjected to three vacuum / N refill cycles and heated at 100 °C for 3 hours. The mixture was cooled to room temperature, filtered through diatomaceous earth, and rinsed 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)δ 10.81-10.79(bs,1H),7.84-7.74(dd,J=5.07,8.59,1H),7.14(s,1H),6.94-6.88(m,1H),3.89(bs,4H),1.49(s,10H),1.03(s,6H).

[0436] Preparation 73 2-Bromo-3-fluoro-6-methoxy-benzaldehyde

[0437] [ka]

[0438] In a 2 L three-neck RBF equipped with a thermocouple, dropping funnel, and condenser, a solution of 2-bromo-3,6-difluoro-benzaldehyde (95.0 g, 430 mmol) in MeOH (850 mL) was charged dropwise with NaOMe (30% by weight) in MeOH (95 mL, 475 mmol, 1.1 equiv) over approximately 15 minutes and stirred at 60° C. for 5 hours. The reaction was cooled to room temperature.

[0439] The reaction mixture was slowly poured into HO (2 L) with stirring. A thick precipitate formed in the flask. The mixture was stirred at room temperature for 15 minutes and filtered. The filter cake was dried under vacuum at 50°C for about 18 hours to give the title compound (75.4 g, 75%) as a white solid. MS (ES) m / z = 232 (M+1).

[0440] Preparation 74 2-Bromo-3-fluoro-6-hydroxy-benzaldehyde

[0441] [ka]

[0442] A 2 L three-necked RBF equipped with a thermometer, overhead stirrer, and dropping funnel was charged with a solution of 2-bromo-3-fluoro-6-methoxy-benzaldehyde (79.2 g, 340 mmol) in DCM (700 mL). The flask was placed in a dry ice / acetone bath and cooled to -76 °C. BBr3 (1.0 M in DCM, 340 mL, 340 mmol, 1 equiv.) was added dropwise at a rate that kept the internal temperature below -70 °C. The reaction was stirred in the dry ice / acetone bath for 15 minutes, after which the ice bath was removed and the reaction was allowed to stir at room temperature for approximately 18 hours. The reaction flask was placed in an ice / water bath. When the internal temperature reached approximately 2.5 °C, HO (250 mL) was added dropwise via the addition funnel. The ice bath was removed and the reaction was allowed to warm to room temperature and stir for an additional 15 minutes. The reaction mixture was partitioned, and the aqueous phase was treated with DCM (200 mL) and brine (100 mL) and partitioned again. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a brown solid. Hexanes (250 mL) was added, and the slurry was stirred for 30 minutes. The solid was filtered, and upon standing, more solid precipitated in the filtrate, which was filtered and combined with the previously filtered solid (batch 1). The combined batches were dried overnight under vacuum at 50°C. The filtrate was concentrated and purified on silica (5%-30% DCM / hexane) to give more product (batch 2). These two batches were combined to give the title compound (66.7 g, 90%) as a white solid. GCMS (EI) m / z = 219 (M) + .

[0443] Preparation 75 4-Bromo-5-fluoro-benzofuran-2-carboxylic acid

[0444] [ka]

[0445] A solution of 2-bromo-3-fluoro-6-hydroxy-benzaldehyde (64.45 g, 294.3 mmol) in DMF (600 mL, 7,760 mmol) was charged with KCO (89.5 g, 648 mmol, 2.2 equiv.), NaI (8.83 g, 58.9 mmol, 0.2 equiv.), and ethyl bromoacetate (36 mL, 324.2 mmol, 1.1 equiv.) in a 2 L three-neck RBF equipped with an overhead stirrer and thermocouple and heated to 70 °C for approximately 18 h. The temperature was increased to 120 °C for 4 h. The reaction was cooled to approximately 45 °C, after which the solvent was removed and the reaction was allowed to cool. When the internal temperature reached approximately 45 °C, a thick precipitate formed in the flask. HO (1 L) was added slowly via addition funnel to obtain a nearly homogeneous mixture. The pH was adjusted to approximately 3 with concentrated HCl, and the mixture was stirred at room temperature for 30 minutes. The solid was filtered, rinsed with HO (500 mL), and dried under vacuum at 50° C. to give the title compound (52.4 g, 69%) as a white solid. MS (ES), m / z=212 (M-1-CO).

[0446] Preparation 76 tert-Butyl N-(4-bromo-5-fluoro-benzofuran-2-yl)carbamate

[0447] [ka]

[0448] 4-Bromo-5-fluoro-benzofuran-2-carboxylic acid was used in a manner similar to that of Preparation 71, and the product was then purified on silica eluting with MTBE / hexane (5%-30%) to give the title compound (29.1 g, 35%) as a yellow solid. MS (ES), m / z=274 (M+1-tBu).

[0449] Preparation 77 tert-Butyl N-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-benzofuran-2-yl]carbamate

[0450] [ka]

[0451] N-(4-bromo-5-fluoro-benzofuran-2-yl) tert-butylcarbamate was used in a manner similar to that of Preparation 72 to give the title compound (21.3 g, 71%) as a light brown solid. MS (ES), m / z = 240 (M+1, a large amount of boronic acid was observed). 1 H NMR(400MHz,DMSO-d6)δ 10.74(bs,1H),8.43(s,1H),7.82(dd,J=5.1,8.8Hz,1H),6.91(dd,J=8.8,9.5Hz,1H),7.15(s,1H),3.81(s,4H),1.50(s,9H),1.03(s,6H).

[0452] Preparation 78 tert-Butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzothiophen-2-yl]carbamate

[0453] [ka]

[0454] A mixture of tert-butyl N-(4-bromo-3-cyano-benzothiophen-2-yl)carbamate (U.S. Patent Application Publication No. 2021 / 0179633 A1, Preparation 7) (19.0 g, 53.8 mmol), bis(neopentylglycolato)diboron (18.2 g, 80.6 mmol), and KOAc (15.8 g, 161 mmol) in 1,4-dioxane (350 mL) was sparged with N for 40 minutes. Pd-117 (3.93 g, 5.38 mmol) was added, and the resulting mixture was heated at 95 °C for 1.5 hours. The reaction was cooled and filtered through diatomaceous earth, rinsing with DCM. The filtrate was concentrated, and the residue was purified on silica eluting with EtOAc / hexanes (10-50%) to give the title compound (11.7 g, 56%) as an off-white solid. MS (ES), m / z = 317 (M-1, a large amount of boronic acid was observed). 1H NMR(400MHz,DMSO-d6)δ 11.28(s,1H),7.95(dd,J=1.0,8.0Hz,1H),7.54(dd,J=1.0,7.2Hz,1H),7.31(t,J=7.6Hz,1H),3.78(s,4H),1.53(s,9H),1.04(s,6H).

[0455] Preparation 79 tert-Butyl N-(4-chlorothieno[3,2-c]pyridin-2-yl)carbamate

[0456] [ka]

[0457] To a suspension of 4-chlorothieno[3,2-c]pyridine-2-carboxylic acid (78 g, 365.1 mmol) in t-BuOH (1,500 mL) was added TEA (155 mL, 1,110 mmol) and diphenylphosphoryl azide (100 g, 356.1 mmol). The mixture was stirred and heated to approximately 80 °C. After 14 h, the reaction was allowed to cool to room temperature and a solid precipitated. The liquid above the solid was decanted, and the solid was filtered and rinsed with DCM. The filtrate and decanted solution were combined and concentrated. The crude material was purified on silica eluting with MTBE / hexane (10-50%) to give the title compound (65 g, 58.3%) as a white solid. MS (ES) m / z = 285 (M+1).

[0458] Preparation 80 tert-Butyl N-(4-chloro-3-cyano-thieno[3,2-c]pyridin-2-yl)carbamate

[0459] [ka]

[0460] tert-Butyl N-(4-chlorothieno[3,2-c]pyridin-2-yl)carbamate (5.0 g, 18 mmol) in THF (120 mL) was cooled in an ice / water bath. CSI (4.7 mL, 53 mmol) was added dropwise at a steady rate and stirred under N2. After 1.5 h, the cold reaction mixture was transferred to an addition funnel and added dropwise to cold DMF (125 mL) in an ice bath over 14 min. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 1 h. The reaction was diluted with EtOAc and washed with brine and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (twice), and the combined organic layers were dried over Na2SO4. The solvent was evaporated, and the DMF-containing oil was evaporated with a stream of N2 to give a brown solid. EtOH (25 mL) was added to the solid, sonicated, filtered, the solid was rinsed with DCM and air-dried to give the product (2.2 g, 37%) as a white solid. MS (ES) m / z=310 (M+1).

[0461] Preparation 227 tert-Butyl N-(4-bromo-7-fluoro-benzofuran-2-yl)carbamate

[0462] [ka]

[0463] Ethyl 4-bromo-7-fluorobenzofuran-2-carboxylate. 6-Bromo-3-fluoro-2-hydroxy-benzaldehyde (2.9 g, 13 mmol) was combined with a solution of potassium carbonate (2.0 g, 14 mmol) and sodium iodide (0.40 g, 2.7 mmol) in DMF (45 mL). Ethyl bromoacetate (1.6 mL, 14 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Potassium carbonate (2.0 g, 14 mmol) was added. The reaction mixture was stirred at 120 °C for 3 hours and cooled to room temperature. The reaction mixture was diluted with water (60 mL), stirred for 30 minutes, and filtered to give a solid. The solid was washed with water and dried in a vacuum oven (40 °C) to give ethyl 4-bromo-7-fluorobenzofuran-2-carboxylate (1.2 g, 32%) as a light brown solid. MS (ES) m / z = 287, 289 (M+1, Br).

[0464] 4-Bromo-7-fluoro-benzofuran-2-carboxylic acid. Ethyl 4-bromo-7-fluoro-benzofuran-2-carboxylate was used in a manner similar to that of Preparation 70 to give 4-bromo-7-fluoro-benzofuran-2-carboxylic acid (0.97 g, 90%) as a white solid. MS (ES) m / z = 256,258 (M-1, Br).

[0465] N-(4-bromo-7-fluoro-benzofuran-2-yl)carbamate tert-butyl. 4-Bromo-7-fluoro-benzofuran-2-carboxylic acid was used in a manner similar to that of Preparation 79 to give the title compound (0.42 g, 66%). MS (ES) m / z = 328,330 (M-1, Br).

[0466] Preparation 228 tert-Butyl N-(4-bromo-3-cyano-7-fluoro-benzofuran-2-yl)carbamate

[0467] [ka]

[0468] N-(4-bromo-7-fluoro-benzofuran-2-yl)carbamate tert-butyl was used in a manner similar to the method of Preparation 80 to give the title compound (1.75 g, 63%). MS (ES) m / z = 354,356 (M+1, Br).

[0469] Preparation 229 tert-Butyl N-(4-chloro-7-methyl-thieno[3,2-c]pyridin-2-yl)carbamate

[0470] [ka]

[0471] 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).

[0472] 4-Chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylic acid. Methyl 4-chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylate was used in a manner similar to that of Preparation 70 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).

[0473] N-(4-chloro-7-methyl-thieno[3,2-c]pyridin-2-yl)carbamate tert-butyl. 4-Chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylic acid was used in a manner similar to that of Preparation 79 to give the title compound (0.83 g, 63%). MS (ES) m / z = 299 (M+1).

[0474] Preparation 230 tert-Butyl N-(4-chloro-3-cyano-7-methyl-thieno[3,2-c]pyridin-2-yl)carbamate

[0475] [ka]

[0476] N-(4-chloro-7-methyl-thieno[3,2-c]pyridin-2-yl)carbamate tert-butyl was used in a manner similar to the method of Preparation 80 to give the title compound (0.542 g, 31%). MS (ES) m / z = 324 (M+1).

[0477] Preparation 231 tert-Butyl N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate

[0478] [ka]

[0479] Ethyl N-(3-cyano-7-fluoro-thieno[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 minutes, 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).

[0480] 2-Amino-7-fluoro-thieno[3,2-c]pyridine-3-carbonitrile. A suspension of ethyl N-(3-cyano-7-fluoro-thieno[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 solution, 90 mL) was added dropwise over 15 minutes. The reaction mixture was heated to 105 °C for 1 hour and then cooled to room temperature. The reaction mixture was poured into an ice / water mixture (1.8 L), stirred until all the ice had melted, and filtered through diatomaceous earth. The solid was dried in a vacuum oven (50 °C) overnight and separated from the diatomaceous earth to give crude 2-amino-7-fluoro-thieno[3,2-c]pyridine-3-carbonitrile.

[0481] tert-Butyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate. A mixture of crude 2-amino-7-fluoro-thieno[3,2-c]pyridine-3-carbonitrile (8.6 g, 44.4 mmol), DCM (90 mL), DMF (90 mL), and N,N-diisopropylethylamine (15.5 mL, 88.9 mmol) was cooled to 0 °C. 4-Dimethylaminopyridine (0.54 g, 4.42 mmol) and di-tert-butyl dicarbonate (14.6 g, 66.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the remaining material was diluted with DCM (400 mL) and 5% aqueous citric acid solution (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).

[0482] tert-Butyl N-(3-cyano-7-fluoro-5-oxide-thieno[3,2-c]pyridin-5-ium-2-yl)carbamate. 3-Chloroperoxybenzoic acid (9.00 g, 40.2 mmol) was added to a solution of tert-butyl N-(3-cyano-7-fluoro-thieno[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. for approximately 15 minutes. The solid was collected by filtration and dried in a vacuum oven (60° C.). The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified on silica gel eluting with 0-6% MeOH in 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).

[0483] tert-Butyl N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate. A suspension of tert-butyl N-(3-cyano-7-fluoro-5-oxide-thieno[3,2-c]pyridin-5-ium-2-yl)carbamate (5.27 g, 17.0 mmol) in 1,2-dichloroethane (34 mL) was cooled to 0 °C. A solution of phosphoryl chloride (32 mL, 344 mmol) in 1,2-dichloroethane (34 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, at 45 °C for 90 minutes, and cooled to room temperature. The reaction mixture was diluted with 1,2-dichloroethane (100 mL) and added to a mixture of saturated 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. When effervescence ceased, the phases were separated. The aqueous phase was extracted three times with DCM. The combined organic phases were dried over MgSO4 and filtered. The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified on silica eluting with 50-100% DCM in 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).

[0484] Preparation 81 tert-Butyl N-(4-bromobenzofuran-2-yl)carbamate

[0485] [ka]

[0486] 4-Bromobenzofuran-2-carboxylic acid was used in a manner similar to the method of Preparation 71 to give the title compound (6.48 g, 50%). MS (ES) m / z=310 (M-1).

[0487] Preparation 82 N'-(4-bromo-3-cyano-benzofuran-2-yl)-N,N-dimethyl-formamidine

[0488] [ka]

[0489] To a RBF was added tert-butyl N-(4-bromobenzofuran-2-yl)carbamate (6.48 g, 20.8 mmol) and THF (0.3 M, 69.2 mL). The solution was cooled to -78 °C under N2, and CSI (6.0 mL, 68.5 mmol, 3.3 equiv) was added slowly over 5 min. The reaction was stirred for 30 min, then transferred via cannula to stirred DMF (100 mL) at room temperature and rinsed with THF. The reaction mixture was stirred at room temperature for 16 h. The reaction was then cooled in an ice bath, and saturated aqueous NaHCO3 (approximately 160 mL) was added slowly until the effervescence subsided, after which the mixture was diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3 (twice), brine (three times), dried over MgSO4, filtered, and concentrated. The resulting material was mixed with EtOAc to loosen the solids. Hexane was added and the mixture was sonicated to break up any large clumps. The solid was filtered, rinsed with 20% EtOAc / hexane, and dried in vacuo to give the title compound (3.39 g, 55.9%) as a light green solid. MS (ES) m / z = 292 (M+1).

[0490] Preparation 83 N'-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzofuran-2-yl]-N,N-dimethyl-formamidine

[0491] [ka]

[0492] To a RBF was added N'-(4-bromo-3-cyano-benzofuran-2-yl)-N,N-dimethyl-formamidine (3.38 g, 11.6 mmol), bis(neopentylglycolato)diboron (7.84 g, 34.7 mmol, 3.0 equiv), KOAc (3.75 g, 38.2 mmol, 3.3 equiv), and 1,4-dioxane (96 mL). The mixture was sparged with N2, Pd-117 (0.83 g, 1.16 mmol, 0.1 equiv) was added, and the reaction was stirred at 100 °C for 2.5 h. The reaction mixture was cooled and filtered through diatomaceous earth, rinsing with 20% EtOAc / hexanes. The filtrate was concentrated, and the residue was purified on silica eluting with EtOAc / hexanes (0-100%). Fractions containing the desired material were concentrated, and EtOAc was added to give a solid. The solid was filtered, rinsed with EtOAc and hexanes, and dried in vacuo at room temperature to give the title compound (2.64 g, 70%) as a brown solid. MS (ES) m / z = 258 (M+1) for the corresponding boronic acid. 1 H NMR(400MHz,DMSO-d6)δ 8.52(s,1H),7.48-7.44(m,2H),7.17(dd,J=7.4,8.0Hz,1H),3.78(s,4H),3.2(s,3H),3.1(s,3H)1.00(s,6H).

[0493] Preparation 232 tert-Butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzofuran-2-yl]carbamate

[0494] [ka]

[0495] N-(4-bromo-3-cyano-7-fluoro-benzofuran-2-yl)carbamate tert-butyl was used in a manner similar to that of Preparation 83 to give the title compound (0.75 g, 73%). MS (ES) m / z = 321 (M+1, corresponding boronic acid).

[0496] Preparation 84 (2R,4R)-4-Hydroxy-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate methyl ester

[0497] [ka]

[0498] To a stirred mixture of (2R,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (20.0 g, 138 mmol) and 9-bromo-9-phenylfluorene (53.1 g, 165 mmol) in DCM (400 mL) was added chlorotrimethylsilane (37.4 g, 344 mmol), TEA (13.9 g, 138 mmol), and Pb(NO) (41.1 g, 124 mmol) in small portions at room temperature. The resulting mixture was stirred at 70 °C under N for approximately 18 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the product (42 g, 79.2%) as a white solid. MS (ES) m / z = 386 (M+1).

[0499] Preparation 85 (2R)-4-Oxo-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate methyl ester

[0500] [ka]

[0501] To a stirred solution of methyl (2R,4R)-4-hydroxy-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate (30.0 g, 77.8 mmol) and oxalyl chloride (83.0 g, 654 mmol) in DCM (1,000 mL) was added TEA (243 g, 2397 mmol) and DMSO (85.1 g, 1090 mmol) at −40° C. The resulting mixture was stirred at −40° C. under N for 8 h. The mixture was allowed to warm to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give the methyl product (25.7 g, 85.6%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 7.87(dd,J=14.0Hz,2H),7.51-7.23(m,11H),3.76-3.59(m,2H),3.36(s,1H),3.04(s,3H),2.66(dd,J=17.9,8.5Hz,1H),2.28-2.16(m,1H).

[0502] Preparation 86 (2S,3R)-3-Fluoro-4-oxo-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate methyl ester

[0503] [ka]

[0504] To a stirred solution of methyl (2R)-4-oxo-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate (40.0 g, 104 mmol) and TEA (31.7 g, 312 mmol) in DCM (1000 mL) was added trimethylsilyl trifluoromethanesulfonate (119 g, 208 mmol) dropwise at −40° C. The resulting mixture was stirred at −40° C. under N for 2 h. It was concentrated under reduced pressure, diluted with pentane (1,000 mL), washed with saturated aqueous NaHCO (2 × 500 mL) and brine, and the organic layer was dried over anhydrous NaSO. The solution was concentrated in vacuo to give the crude silyl enol ether (47.3 g, quantitative yield). To a solution of the crude silyl enol ether (13.0 g, 28.5 mmol) in DCM (200 mL) was added Selectfluor (131 g, 37.0 mmol) in small portions at room temperature. The resulting mixture was stirred at room temperature for approximately 18 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give the title compound (3.96 g, 34.4%) as a pale yellow solid. 1 H NMR(300MHz, CDCl3)δ 7.83-7.70(m,2H),7.51-7.28(m,11H),5.10(dd,J=50.9,7.9Hz,1H),4.10-3.96(m,2H),3.74-3.61(m,1H),3.25(s,3H).

[0505] Preparation 87 (2S,3R,4S)-3-Fluoro-4-hydroxy-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate methyl ester

[0506] [ka]

[0507] To a stirred solution of methyl (2S,3R)-3-fluoro-4-oxo-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate (8.00 g, 19.93 mmol) in THF (60 mL) and EtOH (60 mL) was added NaBH (0.83 g, 21.9 mmol) in small portions at 0 °C under N. The resulting mixture was stirred at 0 °C under N for 1 h. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with H0 (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with PE:EtOAc (4:1-2:1) to give the title compound (6.66 g, 83%) as a pale yellow solid. MS (ES) m / z = 426 (M + Na).

[0508] Preparation 88 (2S,3R,4R)-3-Fluoro-4-(4-nitrobenzoyloxy)-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate methyl ester

[0509] [ka]

[0510] To a stirred mixture of PPh3 (3.25 g, 12.4 mmol) and DIAD (2.41 g, 11.9 mmol) in THF (100 mL) was added dropwise (2S,3R,4S)-methyl 3-fluoro-4-hydroxy-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate (1.00 g, 2.48 mmol) and 4-nitrobenzoic acid (0.41 g, 2.48 mmol) under N2 at 0 °C. The reaction was stirred at 0 °C for 1 h, then diluted with HO and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with HO (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with PE:EtOAc (4:1-2:1) to give the title compound (450 mg, 38.6%) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 8.30-8.26(m,2H),8.16-8.10(m,2H),7.76-7.72(m,1H),7.70-7.66(m,1H),7.53-7.49(m,2H),7.41-7.35(m,4H),7.28-7.24(m,4 H),7.22-7.18(m,1H),5.74-5.70(m,1H),5.15-5.09(m,1H),4.06-4.02(m,1H),3.68-3.64(m,1H),3.35(s,3H),3.10-3.06(m,1H).

[0511] Preparation 89 (2S,3R,4R)-3-Fluoro-4-hydroxy-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate methyl ester

[0512] [ka]

[0513] To a stirred mixture of methyl (2S,3R,4R)-3-fluoro-4-(4-nitrobenzoyloxy)-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate (3.00 g, 5.43 mmol) in THF (100 mL) and HO (25 mL) was added a solution of LiOH·HO (255 mg, 6.08 mmol) in HO (25 mL) dropwise at 0 °C. After stirring at 0 °C for 2 h, the reaction mixture was adjusted to pH 7 with formic acid and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with PE:EtOAc (1:1) to give the title compound (1.76 g, 80.7%) as a yellow solid. MS (ES) m / z = 426 (M + Na).

[0514] Preparation 90 (3R,4R,5S)-4-Fluoro-5-(hydroxymethyl)-1-(9-phenylfluoren-9-yl)pyrrolidin-3-ol

[0515] [ka]

[0516] To a stirred mixture of methyl (2S,3R,4R)-3-fluoro-4-hydroxy-1-(9-phenylfluoren-9-yl)pyrrolidine-2-carboxylate (3.00 g, 7.44 mmol) in THF (100 mL) was added 1 M LiAlH in THF (15.0 mL, 15.0 mmol) dropwise under N at −60° C. The reaction was stirred at −60° C. for 2 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with aqueous potassium sodium tartrate (100 mL), then with brine, and dried over NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica gel eluting with PE:EtOAc (1:1) to give the title compound (1.85 g, 66.3%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.78(dt,J=7.6,0.9Hz,1H),7.74-7.63(m,2H),7.61-7.43(m,4H),7.37-7.20(m,6H),4.6 1-4.43(m,2H),3.54(d,J=10.0Hz,1H),3.25-3.22(m,1H),2.89-2.63(m,3H),2.25(s,1H).

[0517] Preparation 91 ((2S,3R,4R)-3-Fluoro-4-((methylsulfonyl)oxy)-1-(9-phenyl-9H-fluoren-9-yl)pyrrolidin-2-yl)methyl methanesulfonate

[0518] [ka]

[0519] To a stirred mixture of (3R,4R,5S)-4-fluoro-5-(hydroxymethyl)-1-(9-phenylfluoren-9-yl)pyrrolidin-3-ol (1.00 g, 2.66 mmol) in THF (50 mL) was added TEA (1.62 g, 16.0 mmol) and methanesulfonyl chloride (1.22 g, 10.7 mmol) dropwise under N at 0 °C. When the reaction was complete by LC-MS, the resulting mixture was diluted with HO (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with HO (2 × 30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified on silica gel eluting with PE:EtOAc (4:1-2:1) to give the title compound (1.32 g, 93.4%) as a white solid. MS(ES) m / z=532(M+1).

[0520] Preparation 92 (1S,4S,7S)-7-Fluoro-2-(9-phenyl-9H-fluoren-9-yl)-2,5-diazabicyclo[2.2.1]heptane

[0521] [ka]

[0522] A mixture of [(2S,3R,4R)-3-fluoro-4-(methanesulfonyloxy)-1-(9-phenylfluoren-9-yl)pyrrolidin-2-yl]methyl methanesulfonate (4.00 g, 7.52 mmol) in 2.0 M NH3 in IPA (210 mL, 420 mmol) was heated at 100 °C overnight. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified on silica gel eluting with DCM:MeOH (12:1-10:1) to give the title compound (1.00 g, 37.3%) as a pale yellow solid. MS (ES) m / z = 357 (M+1).

[0523] Preparation 93 Benzyl(1S,4S,7S)-7-fluoro-2-(9-phenyl-9H-fluoren-9-yl)-2,5-diazabicyclo[2.2.1]heptane

[0524] [ka]

[0525] To a stirred mixture of (1S,4S,7S)-7-fluoro-2-(9-phenylfluoren-9-yl)-2,5-diazabicyclo[2.2.1]heptane (1.20 g, 3.37 mmol) and DIEA (1.31 g, 10.1 mmol) in DCM (100 mL) was added Cbz-Cl (0.86 g, 5.05 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (9:1-5:1) to give the product (1.41 g, 85.4%) as a white solid. MS (ES) m / z = 491 (M+1).

[0526] Preparation 94 (1S,4S,7R)-7-fluoro-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate benzyl

[0527] [ka]

[0528] To a stirred solution of benzyl (1S,4S,7R)-7-fluoro-5-(9-phenylfluoren-9-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.41 g, 2.88 mmol) in DCM (16 mL) was added TFA (8.00 mL, 106 mmol) at room temperature. The resulting mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and washed with saturated aqueous NaHCO (3 × 100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the product (1.3 g, crude) as a white solid, which was used in the next step without further purification. MS (ES) m / z = 251 (M+1).

[0529] Preparation 95 ((2S,4R)-4-Fluoro-1-methylpyrrolidin-2-yl)methanol

[0530] [ka]

[0531] To a stirred solution of 1-(tert-butyl)2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (20.0 g, 80.9 mmol, 1.0 equiv.) in THF (200 mL) was added LiAlH (485.3 mL, 485.3 mmol, 6.0 equiv., 1 M THF solution) dropwise at −50° C. under N. The resulting mixture was stirred at −50° C. under N for 1 h. Then, the mixture was stirred at 70° C. under N for 2 h. The mixture was cooled to 0° C. and quenched by the addition of H2O. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (5:1) to give the product (2.94 g, 27.3%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 5.13(dm,J=55.7Hz,1H),3.74(dd,J=3.3,11.4Hz,1H),3.54(ddd,J=26.4,11.9,5.1Hz,1H),3.48(dd,J=2.0,11. 2Hz,1H), 2.89(s,1H),2.82(m,1H),2.67(ddd,J=32.4,11.9,2.5Hz,1H),2.43(s,3H),2.13(m,1H),2.06(m,1H).

[0532] Preparation 96 [2-(hydroxymethyl)-1-methylpyrrolidin-2-yl]methanol

[0533] [ka]

[0534] [2-(hydroxymethyl)pyrrolidin-2-yl]methanol (500 mg, 3.81 mmol, 1.0 equiv) and HCHO (343 mg, 11.4 mmol, 3.0 equiv) in MeOH (10.00 mL) were stirred at room temperature for 0.5 h. Then, NaBHCN (479 mg, 7.62 mmol, 2.00 equiv) was slowly added at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with HO (5 mL) at 0 °C and then diluted with HO. The mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica gel eluting with DCM / MeOH / NH4OH (100:10:1 to 100:20:1) to give the product (400 mg, 72.3%) as a yellow oil. (M+1). 1 H NMR(300MHz,DMSO-d6+D2O)δ 4.31-4.08(m,2H),3.38-3.23(m,4H),2.72(t,J=6.3Hz,2H),2.33 s,3H),1.76-1.50(m,4H).

[0535] Preparation 97 1-[tert-butyl(dimethyl)silyl]oxypropan-2-one

[0536] [ka]

[0537] A solution of 1-hydroxypropan-2-one (25.00 g, 337.48 mmol, 1.0 equiv.), tert-butyldimethylchlorosilane (76.30 g, 506.22 mmol, 1.50 equiv.), and imidazole (50.54 g, 742.45 mmol, 2.20 equiv.) in DCM (100 mL) was stirred at room temperature under N for 4 h. The resulting mixture was diluted with EtOAc (400 mL), washed with HO (3 × 500 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (0-5%) to give the product (56.00 g, 88.10%) as a colorless oil.1 H NMR (400MHz, CDCl3) δ 4.15 (s, 2H), 2.17 (s, 3H), 0.93 (s, 9H), 0.09 (s, 6H).

[0538] Preparation 98 1-Benzyl-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-methoxy-4-methyl-azetidin-2-one

[0539] [ka]

[0540] A mixture of 1-[tert-butyl(dimethyl)silyl]oxypropan-2-one (30.00 g, 159.28 mmol, 1.00 equiv.), benzylamine (17.07 g, 159.30 mmol, 1.00 equiv.), and 4 Å molecular sieves (30 g) in DCM (300 mL) was stirred at 45 °C for 12 h under N. To the mixture was added TEA (37.23 g, 367.92 mmol, 2.31 equiv.), followed by the dropwise addition of methoxyacetyl chloride (22.47 g, 207.06 mmol, 1.30 equiv.) over 30 min at -78 °C. The reaction was allowed to warm to room temperature and stirred for 12 h. The mixture was filtered, and the filter cake was washed with DCM (200 mL). The filtrate was diluted with HO (300 mL) and extracted with DCM (3 × 300 mL). The combined organic layers were washed with saturated aqueous NaCl (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (10%) to give the product (9.00 g, 12.12%) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.37-7.18(m,5H),4.45-4.27(m,2H),4.10(s,1H),3.71-3.56(m,2H),3.50(s,3H),1.22(s,3H),0.86(s,9H),0.05--0.09(m,6H).

[0541] Preparation 99 (1-benzyl-3-methoxy-2-methyl-azetidin-2-yl)methoxy-tert-butyl-dimethyl-silane

[0542] [ka]

[0543] To a stirred mixture of AlCl (1.85 g, 13.85 mmol, 1.21 equiv.) in THF (20 mL) was added dropwise a solution of LiAlH (0.64 g, 16.82 mmol, 1.47 equiv.) in THF (10 mL) at −10° C. under N. The resulting mixture was allowed to warm to room temperature and stirred for 3 h. After cooling to −10° C., a solution of 1-benzyl-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-methoxy-4-methyl-azetidin-2-one (4.00 g, 11.4 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for an additional 1 h. HO (0.64 mL) was then added, followed by 15% NaOH (0.64 mL) and additional HO (1.92 mL). The mixture was filtered, and the filter cake was washed with THF (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (0-10%) to give the product (1.56 g, 40.63%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.27-7.10(m,5H),3.80-3.65(m,3H),3.61(dd,J=6.4,4.7Hz 1H),3.53(d,J=13.2Hz,1H),3.23(d,J=4.9Hz,4H),2.98(dd,J=7.7,4.7Hz,1H),1.22(s,3H),0.83(s,9H),0.00(d,6H).

[0544] Preparation 100 tert-Butyl-[(3-methoxy-1,2-dimethyl-azetidin-2-yl)methoxy]-dimethyl-silane

[0545] [ka]

[0546] To a solution of (1-benzyl-3-methoxy-2-methyl-azetidin-2-yl)methoxy-tert-butyl-dimethyl-silane (1.1 g, 3.28 mmol, 1.00 equiv.) in MeOH (10 mL) was added Pd / C (110 mg, 10 wt%) under N2. The mixture was hydrogenated at room temperature under H2 atmosphere using a hydrogen balloon for 24 hours. To the above mixture was added (HCHO) n (0.20 g, 6.66 mmol, 2.03 equiv) was added at room temperature. The resulting mixture was again placed under a H atmosphere (balloon) and stirred at room temperature for an additional 10 h. The mixture was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give the product (0.8 g, crude) as a colorless oil, which was used in the next step without further purification.

[0547] Preparation 101 (3-Methoxy-1,2-dimethyl-azetidin-2-yl)methanol

[0548] [ka]

[0549] A solution of tert-butyl-[(3-methoxy-1,2-dimethyl-azetidin-2-yl)methoxy]-dimethyl-silane (800 mg, 3.08 mmol, 1 equiv.) in 4 M HCl / MeOH (10.00 mL) was stirred at room temperature under N for 10 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH / NH3H2O (15:3:0.2) to give the product (250 mg, 55.84%) as a pale yellow solid. 1 H NMR(400MHz, CDCl3)δ 3.84(dd,J=6.3,4.8Hz,1H),3.78-3.66(m,2H),3.46(dd,J=8.0,6.3Hz,1H),3.36-3.28(m,4H),2.35(s,3H),1.18(s,3H).

[0550] Preparation 102 tert-Butyl 8-(6-bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0551] [ka]

[0552] 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. HO (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 HO (500 mL), and dried under vacuum at 50 °C to give the title compound (31 g, quantitative yield) as a white solid. MS (ES) m / z = 539 (M+1).

[0553] The following compounds in Table 5 were prepared in a manner similar to that described in Preparation 102. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0554] Table 5: [Table 6-1]

[0555] (Continued from Table 5) [Table 6-2]

[0556] Preparation 108 (1R,4R)-tert-Butyl 5-(6-bromo-5-chloro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0557] [ka]

[0558] To a stirred mixture of 6-bromo-5-chloro-7H,9H-furo[3,4-f]quinazolin-1-ol (3 g, 9.95 mmol) and BrOP (5.79 g, 14.92 mmol) in 1,4-dioxane (30 mL) was added TEA (6.92 mL, 49.75 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C under N for 4 h. After cooling to room temperature, tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.95 g, 19.90 mmol) was added. Heating was resumed at 80 °C under N. After 2 h, the mixture was allowed to cool to room temperature, diluted with HO (200 mL), and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3×200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1-2:1) to give the title compound (780 mg, 14.6%) as a yellow solid. MS (ES) m / z=481 (M+1).

[0559] Preparation 109 (1R,4R)-tert-Butyl 5-[6-bromo-9-(cyanomethyl)-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0560] [ka]

[0561] To a suspension of 2-(6-bromo-1-chloro-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-9-yl)acetonitrile (4.40 g, 8.85 mmol) in DMF (80 mL) cooled in an ice bath was charged tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.00 g, 9.78 mmol) and DIPEA (3.10 mL, 17.8 mmol). The reaction was stirred at room temperature for 2 hours. DMF was removed under reduced pressure. The residue was dissolved in EtOAc (500 mL), washed with saturated aqueous NaHCO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by silica column chromatography eluting with EtOAc / hexane (10-100%) to give the title compound (4.00 g, 80%) as a light brown solid. MS (ES) m / z=564 (M+1).

[0562] Preparation 110 (1R,4R)-tert-Butyl 5-[6-bromo-5-chloro-9-(cyanomethyl)-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0563] [ka]

[0564] 2-(6-Bromo-1,5-dichloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-9-yl)acetonitrile was used in a manner similar to that of Preparation 108 to give the title compound (0.53 g, 76%) as a yellow solid. MS (ES) m / z = 580 (M+1).

[0565] Preparation 111 tert-Butyl 8-(4-bromo-5-chloro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0566] [ka]

[0567] In a dry reaction vessel, DMSO (198 mL) was purged with N for 5 minutes using a gas dispersion tube. DIPEA (3.9 mL, 22 mmol) was added and purged for an additional 3 minutes. Solid 4-bromo-5,9-dichloro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinoline (8.1 g, 22 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (19 g, 89 mmol, 4 equiv.) were added, and the reaction vessel was sealed and heated to 130 °C for 48 hours. After cooling to room temperature, the reaction was poured into a separatory funnel, diluted with DCM (1.5 L), washed with HO (3 × 500 mL), separated, and concentrated. The residue was purified on silica (100% DCM-5% EtOAc / DCM) to give the title compound (5.36 g, 45%) as a white solid. MS (ES) m / z=540 (M+1).

[0568] Preparation 112 (1R,4R)-tert-Butyl 5-(6-bromo-5-fluoro-3-methyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0569] [ka]

[0570] A mixture of 6-bromo-5-fluoro-3-methyl-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (280 mg, 0.936 mmol), phosphonitrile chloride trimer (423 mg, 1.22 mmol), and DIEA (605 mg, 4.68 mmol) in ACN was stirred at 50 °C for 5 h under N. After cooling to room temperature, tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (119 mg, 0.602 mmol) and DIEA (605 mg, 4.68 mmol) were added, and the resulting mixture was stirred for 2 h. The reaction was stirred at room temperature for an additional 2 h. The mixture was diluted with HO (150 mL), extracted with EtOAc (3 × 50 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1-1:1) to give the title compound (280 mg, 62.3%) as a yellow solid. MS (ES) m / z=479 (M+1).

[0571] Preparation 113 6-Bromo-1-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline

[0572] [ka]

[0573] (1R,4R)-tert-Butyl 5-(6-bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 0.951 mmol) was stirred in DCM (5 mL, 78.00 mmol). TFA (2 mL, 26.45 mmol) was added. The reaction mixture was capped and stirred at room temperature for approximately 18 hours. The reaction mixture was loaded onto a 10 g SCX column, washed with 3 column volumes of MeOH, and then eluted with 3 column volumes of 2 N NH3 in MeOH. The basic fractions were concentrated to give the title compound (426 mg, quantitative yield) as a thick oil. MS (ES) m / z = 426 (M+1).

[0574] Preparation 114 tert-Butyl 8-(6-bromo-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0575] [ka]

[0576] A solution of tert-butyl 8-(6-bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.3 g, 8.0 mmol) in DCM (40 mL) was charged with mCPBA (6.21 g, 25.2 mmol, 3.2 equiv.) and stirred at room temperature for 90 minutes. The mixture was diluted with DCM and washed with saturated aqueous NaHCO and brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on silica eluting with EtOAc / hexane (20-80%) to give the title compound (3.0 g, 66%) as a white solid. MS (ES) m / z = 571 (M+1).

[0577] Preparation 235 tert-Butyl 8-(6-bromo-5-chloro-3-ethylsulfonyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0578] [ka]

[0579] tert-Butyl 8-(6-bromo-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was used in a manner similar to the method of Preparation 114 to give the title compound (13.5 g, 86%). MS (ES) m / z = 587,589 (M+1, Br).

[0580] Preparation 302 6-Bromo-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline

[0581] [ka]

[0582] 6-Bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline was used in a manner similar to that of Preparation 114 to give the title compound (1.00 g, 92%). MS (ES) m / z = 361,363 (M+1, Br).

[0583] Preparation 115 tert-Butyl 8-[6-bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0584] [ka]

[0585] To a mixture of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (2.26 g, 13.8 mmol) in THF (110 mL) was added a THF solution (13.7 mL, 13.7 mmol, 1.0 M) dropwise under N2 and stirred for 20 minutes. To this solution was added a THF solution (40 mL) of tert-butyl 8-(6-bromo-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (6.54 g, 11.4 mmol) dropwise via syringe. After 35 minutes, the reaction was diluted with EtOAc (250 mL) and washed with brine. The aqueous layer was extracted with EtOAc (2×200 mL), and the combined organic layers were dried over NaSO and concentrated to give a brown solid. The crude material was purified on silica eluting with 0-10% MeOH / DCM to give the title compound (7.0 g, 96%) as a light brown solid. MS (ES) m / z=636 (M+1).

[0586] Preparation 236 tert-Butyl 8-[6-bromo-5-fluoro-3-[(2-methoxy-1,2,3,5,6,7-hexahydropyrrolidin-8-yl)methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0587] [ka]

[0588] (2-Methoxy-1,2,3,5,6,7-hexahydropyrrolidin-8-yl)methanol was used in a manner similar to the method of Preparation 115 to give the title compound (4.5 g, 85%). MS (ES) m / z = 648,650 (M+1, Br).

[0589] Preparation 237 tert-Butyl 8-[6-bromo-5-chloro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0590] [ka]

[0591] tert-Butyl 8-(6-bromo-5-chloro-3-ethylsulfonyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was used in a manner similar to that of Preparation 115 to give the title compound (12.8 g, 85%). MS (ES) m / z = 652,654 (M+1, Br).

[0592] Preparation 116 6-Bromo-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazoline

[0593] [ka]

[0594] tert-Butyl 8-[6-bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was used in a manner similar to that of Preparation 113 and isolated by partitioning between DCM and saturated aqueous NaHCO to give the title compound (0.83 g, 99%) as a pale yellow foam. MS (ES) m / z = 536 (M+1).

[0595] Preparation 117 3-[8-[6-Bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]propoxy-tert-butyl-dimethyl-silane

[0596] [ka]

[0597] A solution of 6-bromo-1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazoline (0.900 g, 1.68 mmol) in DCM (17 mL) was treated with 3-[(tert-butyldimethylsilyl)oxy]-1-propanol (0.998 g, 5.03 mmol) and NaBH(OAc) (1.12 g, 5.02 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with saturated aqueous NaHCO and stirred for 15 minutes. H2O was added and the layers were separated. The aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The residue was purified on silica eluting with 0%-4% 7N NH3 / MeOH in DCM to give the title compound (0.844 g, 71%) as an off-white solid. MS (ES) m / z=708 (M+1).

[0598] The following compounds in Table 6 were prepared in a manner similar to that described in Preparation 117 using the appropriate aldehyde. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0599] Table 6: [Table 7]

[0600] Preparation 122 tert-Butyl 6-[6-bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0601] [ka]

[0602] tert-Butyl 6-(6-bromo-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate was used in a manner similar to that of Preparation 115 to give the title compound (0.8 g, 84%) as a pale yellow foam. MS (ES) m / z = 622 (M+1).

[0603] Preparation 303 tert-Butyl 8-[6-bromo-3-[[(2R)-1,4-dioxan-2-yl]methoxy]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0604] [ka]

[0605] [(2S)-1,4-Dioxan-2-yl]methanol was used in a manner similar to that of Preparation 115 to give the title compound (1.72 g, 97%) as a white solid. MS (ES) m / z = 595,597 (M+1, Br).

[0606] Preparation 304 6-Bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazoline diazabicyclo[3.2.1]octane-3-carboxylate

[0607] [ka]

[0608] 6-Bromo-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline was used in a manner similar to that of Preparation 115 to give the title compound (0.11 g, 62%) as an off-white solid. MS (ES) m / z = 426,428 (M+1, Br).

[0609] Preparation 123 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-5-fluoro-benzothiophen-4-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0610] [ka]

[0611] A 250 mL three-neck RBF equipped with a thermocouple, condenser, and N sparge line was charged with a suspension of tert-butyl 8-(6-bromo-3-ethylsulfanyl-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 N-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-benzothiophen-2-yl]carbamate (5.53 g, 13.9 mmol, 1.5 equiv.) in 1,4-dioxane (100 mL) and HO (31 mL). The heat was set to 70 °C and started. Simultaneously, N sparge was started. When the internal temperature reached approximately 45 °C, the sparge line was removed, and KPO (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 HO, and partitioned. The aqueous phase was extracted with EtOAc (100 mL), and the combined organic layers were washed with brine, dried over anhydrous NaSO, 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 / hexane (0-30%). The product-containing fractions were concentrated to give a brown foam, which was dissolved in DCM (20 mL) and treated dropwise with hexane (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).

[0612] The following compounds in Table 7 were prepared in a manner similar to that described in Preparation 123. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0613] Table 7: [Table 8-1]

[0614] (Continued from Table 7) [Table 8-2]

[0615] Preparation 126 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0616] [ka]

[0617] To a solution of tert-butyl 8-(6-bromo-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.785 g, 1.36 mmol) in THF (10 mL) was charged tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzothiophen-2-yl]carbamate (0.826 g, 2.04 mmol, 1.5 equiv.) and CsCO (1.39 g, 4.27 mmol, 3.15 equiv.). The mixture was stirred and sparged with N for 10 min. Pd-117 (0.202 g, 0.274 mmol, 0.20 equiv) was added and the mixture was sparged for an additional 5 minutes, after which the reaction flask was fitted with a reflux condenser and heated at 70 °C for 6 hours. The reaction was cooled to room temperature, diluted with HO (1 mL), and stirred for 5 minutes. The mixture was filtered through a 3.0 g ISOLUTE® cartridge (Biotage, LLC; Charlotte, NC) and eluted with EtOAc until the eluate was clear and colorless. The filtrate was concentrated and purified on silica eluting with 20% EtOAc / hexane to give the title compound (0.743 g, 70%) as a white solid. MS (ES) m / z = 767 (M+1).

[0618] The following compounds in Table 8 were prepared in a manner similar to that described in Preparation 126. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0619] Table 8: [Table 9-1]

[0620] (Continued from Table 8) [Table 9-2]

[0621] (Continued from Table 8) [Table 9-3]

[0622] (Continued from Table 8) [Table 9-4]

[0623] (Continued from Table 8) [Table 9-5]

[0624] Preparation 156 tert-Butyl N-[4-[1-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]-1,3-benzothiazol-2-yl]carbamate

[0625] [ka]

[0626] 3-[8-[6-bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]propoxy-tert-butyl-dimethyl-silane (0.110 g, 0.155 mmol), [2-(tert-butyl A mixture of [(hydroxycarbonylamino)-1,3-benzothiazol-4-yl]boronic acid (U.S. Pat. No. 10,968,214 B2, Preparation 17) (0.064 g, 0.217 mmol) and KCO (0.064 g, 0.466 mmol) in 1,4-dioxane (1.5 mL) and HO (0.5 mL) was sparged with N for 5 minutes, followed by the addition of Pd(PPh) (0.036 g, 0.310 mmol). The resulting mixture was heated at 100 °C for 1.5 hours, then cooled to room temperature and partitioned between DCM and HO. The layers were separated, and the aqueous layer was extracted twice with DCM. The organic layers were combined, passed through a hydrophobic frit (ISOLUTE® Phase Separator Cartridge), and concentrated in vacuo. The residue was purified on silica (gradient 0-4% 7N NH3 / MeOH in DCM) to give the title compound (0.098 g, 55%) as a pale yellow solid. MS (ES) m / z=878 (M+1).

[0627] Preparation 157 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, isomer 2

[0628] [ka]

[0629] tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.30 g, 6.94 mmol) was purified by SFC (Chiralpak® IC, 21 × 250 mm, 35% MeOH (containing 0.5% DMEA), 65% CO2, 80 mL / min). The second eluted (t R2 =10.77 min), was collected, concentrated, and lyophilized to give the title compound (1.37 g, 42%) as a white solid in 96% enantiomeric excess. MS (ES) m / z=767 (M+1).

[0630] Preparation 323 8-(6-Bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylic acid O3-tert-butyl O8-methyl

[0631] [ka]

[0632] 6-Bromo-1-chloro-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline (0.10 g, 0.28 mmol), O3-tert-butyl O8-methyl 3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (0.22 g, 0.82 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.022 g, 0.042 mmol) were combined under nitrogen. Toluene (4 mL) was added, and the mixture was sparged with nitrogen for 3 minutes and cooled to 0 °C. LiHMDS (0.8 mL, 0.8 mmol, 1 M THF solution) was added dropwise over 1.5 minutes, and the reaction mixture was allowed to warm to room temperature. After 3 hours, the reaction was poured into brine and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4, filtered, and concentrated.

[0633] 6-Bromo-1-chloro-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline (0.30 g, 0.83 mmol), O3-tert-butyl O8-methyl 3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (0.67 g, 2.5 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.065 g, 0.12 mmol) were combined under nitrogen. Toluene (11 mL) was added, and the mixture was sparged with nitrogen for 3 minutes and cooled to 0 °C. LiHMDS (2.4 mL, 2.4 mmol, 1 M THF solution) was added dropwise over 3 minutes, and the reaction mixture was allowed to warm to room temperature. After 3 hours, the reaction was poured into brine and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4, filtered, and concentrated.

[0634] These two residues were combined and purified by silica gel column chromatography eluting with 0-30% ethyl acetate in hexane to give the product (0.55 g, 83%). MS (ES) m / z=596,598 (M+1, Br).

[0635] Preparation 324 tert-Butyl 8-(6-bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate

[0636] [ka]

[0637] A mixture of 03-tert-butyl 08-methyl 8-(6-bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3-azabicyclo[3.2.1]octane-3,8-dicarboxylate (0.99 g, 1.7 mmol) and LiCl (1.1 g, 25 mmol) in DMSO (9 mL) was stirred at 150 °C for 10 min under microwave irradiation. The reaction was diluted with water and extracted with ethyl acetate (twice). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in hexane to give the product (0.11 g, 12%) as the first-eluting isomer. MS (ES) m / z = 538,540 (M+1, Br).

[0638] Preparation 158 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-thieno[3,2-c]pyridin-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0639] [ka]

[0640] A mixture of tert-butyl 8-[6-bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.500 g, 0.786 mmol), KOAc (0.231 g, 2.35 mmol), and bis(neopentylglycolato)diboron (0.266 g, 1.18 mmol) in 1,4-dioxane (8 mL) was sparged with N for 10 minutes. Pd-117 (0.057 g, 0.078 mmol) was added, and the resulting mixture was heated at 95 °C for 2 hours. The reaction mixture was cooled to room temperature. H2O (2.6 mL) was added, and the mixture was sparged with N2 for 10 minutes. tert-Butyl N-(4-chloro-3-cyano-thieno[3,2-c]pyridin-2-yl)carbamate (0.245 g, 0.791 mmol), XPhos Pd G4 (0.071 g, 0.078 mmol), and K3PO4 (0.250 g, 1.18 mmol) were added, and the resulting mixture was heated at 85 °C for 1 hour. The reaction mixture was cooled to room temperature and partitioned between DCM and H2O. The layers were separated, and the aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The residue was purified on silica (0-6% 7N NH3 / MeOH gradient in DCM) to give the title compound (0.404 g, 62%) as a yellowish-brown solid. MS(ES) m / z=831(M+1).

[0641] Preparation 244 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-thieno[3,2-c]pyridin-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0642] [ka]

[0643] N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl) tert-butylcarbamate was used in a manner similar to that of Preparation 158 to give the title compound (0.667 g, 46%). MS (ES) m / z = 849 (M+1).

[0644] Preparation 245 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-thieno[3,2-c]pyridin-4-yl]-5-fluoro-3-[(2-methoxy-1,2,3,5,6,7-hexahydropyrrolidin-8-yl)methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0645] [ka]

[0646] 8-[6-Bromo-5-fluoro-3-[(2-methoxy-1,2,3,5,6,7-hexahydropyrrolidin-8-yl)methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl and N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate tert-butyl were used in a manner similar to that of Preparation 158 to give the title compound (0.43 g, 42%). MS (ES) m / z=861 (M+1).

[0647] Preparation 246 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-methyl-thieno[3,2-c]pyridin-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0648] [ka]

[0649] N-(4-chloro-3-cyano-7-methyl-thieno[3,2-c]pyridin-2-yl) tert-butylcarbamate was used in a manner similar to the method of Preparation 158 to give the title compound (0.10 g, 24%). MS (ES) m / z = 845 (M+1).

[0650] Preparation 159 tert-Butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-thieno[3,2-c]pyridin-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0651] [ka]

[0652] 6-[6-Bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate tert-butyl was used in a manner similar to the method of Preparation 158 to give the title compound (0.101 g, 42.5%) as a pale yellow solid. MS (ES) m / z = 617 (M+1).

[0653] Preparation 307 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-thieno[3,2-c]pyridin-4-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0654] [ka]

[0655] tert-Butyl 8-(6-bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate and tert-butyl N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate were used in a manner similar to that of Preparation 158 to give the title compound (2.15 g, 61%) as a white solid. MS (ES) m / z = 752 (M+1).

[0656] Preparation 308 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0657] [ka]

[0658] 6-Bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazoline and N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate tert-butyl were used in a manner similar to that of Preparation 158 to give the title compound (0.080 g, 35%). MS (ES) m / z = 639 (M+1).

[0659] Preparation 325 tert-Butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-thieno[3,2-c]pyridin-4-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0660] [ka]

[0661] tert-Butyl 6-(6-bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate and tert-butyl N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate were used in a manner similar to the method of Preparation 158 to give the title compound. MS (ES) m / z=738 (M+1).

[0662] Preparation 326 tert-Butyl N-[3-cyano-4-(3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluoro-thieno[3,2-c]pyridin-2-yl]carbamate

[0663] [ka]

[0664] 6-Bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline and tert-butyl N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate were used in a manner similar to that of Preparation 158 to give the title compound (43.0 g, 72%) as a brown solid. MS (ES) m / z = 542 (M+1).

[0665] Preparation 327 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-thieno[3,2-c]pyridin-4-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3-azabicyclo[3.2.1]octane-3-carboxylate

[0666] [ka]

[0667] 8-(6-Bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate tert-butyl and N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate tert-butyl were used in a manner similar to that of Preparation 158 to give the title compound (0.050 g, 9%). MS (ES) m / z=751 (M+1).

[0668] Preparation 160 tert-Butyl 8-[6-[3-cyano-2-[dimethylaminomethyleneamino]benzofuran-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0669] [ka]

[0670] RBF was charged with tert-butyl 8-[6-bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.1 To the reaction mixture was added N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzofuran-2-yl]-N,N-dimethyl-formamidine (0.67 g, 2.07 mmol, 1.2 equiv), KPO (0.550 g, 2.59 mmol, 1.5 equiv), Pd-118 (0.11 g, 0.173 mmol, 0.10 equiv), 1,4-dioxane (8.6 mL), and HO (1.7 mL). The mixture was sparged with N and then heated at 90 °C for 3 h. The reaction was cooled, diluted with EtOAc, washed with saturated aqueous NaHCO and brine, then dried over MgSO, filtered, and concentrated. The residue was purified on silica (0-10% MeOH / DCM) to give the title compound (0.78 g, 58.7%). MS (ES) m / z=769 (M+1).

[0671] Preparation 161 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-5-fluoro-benzofuran-4-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0672] [ka]

[0673] 8-(6-Bromo-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl and N-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-benzofuran-2-yl]carbamate tert-butyl were used in a manner similar to that of Preparation 160 to give the title compound (0.375 g, 95.0%). MS (ES) m / z = 710 (M+1).

[0674] Preparation 162 [4-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-9-yl]trifluoromethanesulfonate

[0675] [ka]

[0676] To a stirred mixture of tert-butyl N-[4-(5-chloro-9-hydroxy-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (7.5 g, 13.44 mmol, 1 equiv.) and 2,6-lutidine (3.31 g, 30.91 mmol, 2.3 equiv.) in DCM (100 mL) was added DMAP (0.25 g, 2.01 mmol, 0.15 equiv.) and TfO (7.58 g, 26.88 mmol, 2 equiv.) dropwise under N at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified on silica gel eluting with PE:EtOAc (3:1-1:1) to give the title compound (8.0 g, 86%) as a pale yellow solid. MS(ES) m / z=690(M+1).

[0677] Preparation 163 tert-Butyl N-[4-(9-bromo-5-chloro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate

[0678] [ka]

[0679] To a stirred solution of [4-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-9-yl]trifluoromethanesulfonate (8.0 g, 11.5 mmol, 1 equiv.) in ACN (100 mL) was added LiBr (20.13 g, 231.8 mmol, 20 equiv.). The resulting mixture was stirred at 85° C. for 18 hours. The mixture was concentrated under reduced pressure and then poured into HO (200 mL). After filtration, the filter cake was dried under vacuum at 40° C. to give a crude product, which was then suspended in 1,4-dioxane (70 mL) and charged with di-tert-butyl dicarbonate (3.77 g, 17.28 mmol, 1.5 equiv.) and DMAP (0.31 g, 2.53 mmol, 0.22 equiv.). The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified on silica eluting with DCM / EtOAc (15:1-10:1) to give the title compound (6.0 g, 84%) as a yellow solid. MS (ES) m / z=620 (M−1).

[0680] Preparation 164 tert-Butyl 8-[6-(2-amino-3-cyano-benzofuran-4-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0681] [ka]

[0682] To a RBF was added tert-butyl 8-[6-[3-cyano-2-[dimethylaminomethyleneamino]benzofuran-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (780 mg, 1.02 mmol), MeOH (20 mL), and 1 M NaOH (2.5 mL, 2.5 mmol, 2.5 equiv.). The mixture was heated to 60° C. and stirred for 5 hours. The reaction was cooled to 0° C. and adjusted to pH 4 by the addition of 5 N HCl. The reaction mixture was loaded onto a 20 g SCX column, washed with 3 column volumes of MeOH, and then eluted with 3 column volumes of 2 N NH3 in MeOH. The basic fractions were concentrated to give the title compound (588 mg, 81.2%) as an oil. MS (ES) m / z = 715 (M+1).

[0683] Preparation 165 tert-Butyl N-[2-[4-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-9-yl]ethyl]carbamate

[0684] [ka]

[0685] A mixture of tert-butyl N-[4-(9-bromo-5-chloro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluorobenzothiophen-2-yl]carbamate (0.500 g, 0.805 mmol), tert-butyl N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]carbamate (0.466 g, 1.65 mmol), and CsCO (0.787 g, 2.42 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was sparged with N for 15 minutes. Pd(ddpf)Cl (0.059 g, 0.081 mmol) was added, and the resulting mixture was heated at 70 °C for approximately 18 hours. The reaction mixture was cooled to room temperature and partitioned between DCM and H2O. The layers were separated and the aqueous layer was extracted twice with DCM and twice with CHCl3:IPA (4:1). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica eluting with EtOAc / hexanes (10-70%) to give the title compound (0.367 g, 67%) as a white solid. MS (ES) m / z = 685 (M+1).

[0686] Preparation 166 tert-Butyl 8-[4-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-fluoro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-9-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0687] [ka]

[0688] A suspension of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.416 g, 1.90 mmol, 2.5 equiv.), tert-butyl N-[4-(9-bromo-5-fluoro-7-methylsulfanyl-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluoro-benzothiophen-2-yl]carbamate (0.446 g, 0.70 mmol), and CsCO (0.481 g, 1.47 mmol, 2 equiv.) in DMF (25 mL) was purged with N for approximately 5 minutes. Pd2(dba)3 (0.085 g, 0.15 mmol, 0.2 equiv) and BrettPhos (0.165 g, 0.292 mmol, 0.4 equiv) were added, the flask was sealed, and heated to 100 °C for 6 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified on silica eluting with EtOAc / hexanes (0%-60%) to give the title compound (0.221 g, 39%) as a yellow solid. MS (ES) m / z = 737 (M+1).

[0689] Preparation 167 (1R,4R)-tert-Butyl 5-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-methyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0690] [ka]

[0691] To a stirred mixture of (1R,4R)-5-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluorobenzothiophen-4-yl]-5-chloro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (470 mg, 0.68 mmol), KCO (281 mg, 2.03 mmol), and methylboronic acid (406 mg, 6.78 mmol) in 1,4-dioxane (20 mL) was added RuPhos (94.9 mg, 0.20 mmol) and XPhos Palladacycle Gen. 4 (117 mg, 0.14 mmol) in small portions at room temperature. The resulting mixture was stirred at 100 °C under N for 2 h. The mixture was cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1-1:2) to give the title compound (350 mg, 69.0%) as a red solid. MS (ES) m / z = 673 (M+1).

[0692] Preparation 168 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-5-fluoro-benzothiophen-4-yl]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0693] [ka]

[0694] A solution of tert-butyl 8-[6-[2-(tert-butoxycarbonylamino)-5-fluorobenzothiophen-4-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (28.6 g, 37.4 mmol) in THF (375 mL) was charged with TES (24 mL, 150 mmol, 4.00 equiv.) and PdCl (0.688 g, 3.69 mmol, 0.10 equiv.) and stirred at room temperature for 4 hours. HO (100 mL) was added dropwise, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered through diatomaceous earth and rinsed with EtOAc (100 mL). The filtrate was partitioned, and the organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on silica eluting with EtOAc / hexanes (10-60%) to give the title compound (22.35 g, 90%) as a white foam. MS (ES) m / z=666 (M+1).

[0695] The following compounds in Table 9 were prepared in a manner similar to Preparation 168. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0696] Table 9: [Table 10]

[0697] Preparation 172 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluoro-benzothiophen-4-yl]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0698] [ka]

[0699] In a 250 mL three-neck RBF equipped with a thermocouple, N2 inlet, and dropping funnel, tert-butyl 8-[6-[2-(tert-butoxycarbonylamino)-5-fluoro-benzothiophen-4-yl]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.640 g, 0.961 mmol) was dissolved in THF (10 mL). The flask was placed in a -45 °C bath (ACN / dry ice) and flushed with N2. When the internal temperature reached -45 °C, chlorosulfonyl isocyanate (0.42 mL, 4.8 mmol, 5.0 equiv.) was added dropwise at a rate that maintained the internal temperature below -30 °C. After 90 min, the cold reaction mixture was poured into DMF (150 mL) and stirred at room temperature for 1 h. The mixture was diluted with EtOAc and then washed with 0.2 M LiCl (3 × 300 mL) and brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on silica eluting with EtOAc / hexane (10%-100%) to give the title compound (0.553 g, 83%) as a white solid. MS (ES) m / z = 691 (M+1).

[0700] The following compounds in Table 10 were prepared in a manner similar to that described in Preparation 172. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0701] Table 10: [Table 11-1]

[0702] (Continued from Table 10) [Table 11-2]

[0703] (Continued from Table 10) [Table 11-3] 1Chiralpak® AD-H, 50×250mm, 30%EtOH:70%CO2, 180mL / min 2 Chiralpak(R) AD-H, 30×250mm, 35%IPA(0.2%DEA):65%CO2, 50mL / min

[0704] Preparation 255 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluoro-benzothiophen-4-yl]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, isomer 2

[0705] [ka]

[0706] tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluoro-benzothiophen-4-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate was used in a manner similar to that of Preparation 168, followed by chiral purification (Chiralpak® AD-H, 30 × 250 mm, 30% IPA:70% CO2, 100 mL / min) to give the title compound (1.02 g, 35%). MS (ES) m / z = 691 (M+1).

[0707] Preparation 176 tert-Butyl 8-[6-(2-amino-3-cyano-5-fluoro-benzofuran-4-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0708] [ka]

[0709] To a RBF was added tert-butyl 8-[6-[3-cyano-2-[dimethylaminomethyleneamino]-5-fluoro-benzofuran-4-yl]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.225 g, 0.357 mmol), MeOH (2 mL), and 1 M NaOH (0.9 mL, 0.893 mmol, 2.5 equiv.) and heated at 60 °C for 90 min. The reaction was cooled to 0 °C and adjusted to pH 4 by the addition of 5 N HCl. The mixture was washed with brine, extracted with EtOAc (3 x), dried over MgSO4, filtered, and concentrated to give the title compound (0.188 g, 92%). MS (ES) m / z = 576 (M+1).

[0710] Preparation 177 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0711] [ka]

[0712] tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.390 g, 0.498 mmol) in 1,4-dioxane (5 m A solution of CsCO (0.489 g, 1.50 mmol, 3.0 equiv.) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.041 g, 0.051 mmol, 0.10 equiv.) in 1 mL of CsCl and IPA was charged and heated at 100 °C for approximately 18 h. The reaction was cooled to room temperature. 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 by silica gel chromatography eluting with EtOAc / hexanes (10-50%) to give the title compound (0.289 g, 60%) as a 75% pure off-white solid, which was used in the next step without further purification. MS (ES) m / z = 733 (M+1).

[0713] Preparation 256 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-benzothiophen-4-yl]-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0714] [ka]

[0715] 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-benzothiophen-4-yl]-5-chloro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester was used in a manner similar to that of Preparation 177 to give the title compound (0.57 g, 83%). MS (ES) m / z=812 (M+1).

[0716] Preparation 178 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0717] [ka]

[0718] A solution of tert-butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluorobenzothiophen-4-yl]-3-ethylsulfanyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (1.13 g, 1.47 mmol) in DCM (15 mL) was charged with mCPBA (0.842 g, 4.88 mmol, 3.3 equiv.) and stirred at room temperature for 2 hours. The mixture was diluted with DCM and washed with saturated aqueous NaHCO and brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified on silica eluting with 40% EtOAc / hexane to give the title compound (1.15 g, 75%) as a white solid. MS (ES) m / z = 783 (M+1).

[0719] The following compounds in Table 11 were prepared in a manner similar to that described in Preparation 178. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0720] Table 11: [Table 12-1]

[0721] (Continued from Table 11) [Table 12-2]

[0722] (Continued from Table 11) [Table 12-3]

[0723] (Continued from Table 11) [Table 12-4]

[0724] (Continued from Table 11) [Table 12-5]

[0725] (Continued from Table 11) [Table 12-6] 1 Single atropisomer (from precursor of preparation 157) 2 Single atropisomer (from precursor of preparation 248) 3 Single atropisomer (from precursor of preparation 251)

[0726] Preparation 190 tert-Butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluoro-benzothiophen-4-yl]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0727] [ka]

[0728] To a stirred solution of tert-butyl 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluorobenzothiophen-4-yl]-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (1.16 g, 1.50 mmol) in DCM (15 mL) and MeOH (15 mL) was added NaBH (0.58 g, 15 mmol, 10 equiv.) at room temperature. After 15 min, the reaction mixture was diluted with DCM (300 mL), followed by the addition of saturated aqueous NaHCO (100 mL) and HO (500 mL). The reaction mixture was stirred at room temperature until gas evolution ceased. The organic layer was separated, and the aqueous layer was extracted with DCM (300 mL). The organic layers were combined, then dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified on silica eluting with MeOH / DCM (0-2%) to give the title compound (0.80 g, 77%). MS (ES) m / z = 677 (M+1).

[0729] The following compounds in Table 12 were prepared in a manner similar to that described in Preparation 190. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0730] Table 12: [Table 13]

[0731] Preparation 193 (1R,4R)-tert-Butyl 5-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-9-(cyanomethyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0732] [ka]

[0733] A solution of tert-butyl (1R,4R)-5-[6-bromo-9-(cyanomethyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.00 g, 1.98 mmol) in THF (20.0 mL) and tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (1.20 g, 2.97 mmol) was added to a sealed flask. The flask was sparged with N for 15 minutes, after which Pd-117 (430 mg, 0.601 mmol) was added, followed by CsCO (1.30 g, 3.99 mmol). The flask was sealed and heated in an oil bath at 70° C. with stirring for 2 hours. The reaction mixture was cooled to room temperature, diluted with THF, and filtered through a pad of diatomaceous earth. The filter cake was washed with 10% MeOH in DCM. The filtrate was concentrated, and the residue was purified by silica column chromatography using acetone / hexanes (0-40%) to give the crude product, which was purified again on silica using 1%-5% 7N NH3 / MeOH in DCM to give the title compound (0.795 g, 56%) as a yellow solid. MS (ES) m / z=716 (M+1).

[0734] Preparation 194 (1R,4R)-tert-Butyl 5-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-9-(cyanomethyl)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0735] [ka]

[0736] (1R,4R)-tert-butyl 5-[6-bromo-5-chloro-9-(cyanomethyl)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was used in a manner similar to the method of Preparation 193 to give the title compound (0.25 g, 54.7%) as a yellow solid. MS (ES) m / z = 732 (M+1).

[0737] Preparation 333 6-Bromo-3-ethylsulfonyl-5-fluoro-N-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7,9-dihydrofuro[3,4-f]quinazolin-1-amine

[0738] [ka]

[0739] 6-Bromo-1-chloro-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline and [(2S)-1-methylpyrrolidin-2-yl]methanamine were used in a manner similar to the method of Preparation 102 to give the title compound. MS (ES) m / z = 473,475 (M+1, Br).

[0740] Preparation 195 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0741] [ka]

[0742] To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (1.15 g, 7.01 mmol) in THF (30 mL), LiHMDS (6.7 mL, 6.7 mmol, 1 M THF solution) was added dropwise under N2 at room temperature and stirred for 20 minutes. To this solution, a solution of tert-butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluorobenzothiophen-4-yl]-3-ethylsulfonyl-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2.3 g, 2.9 mmol) in THF (20 mL) was added dropwise via syringe. After 40 minutes, the reaction was diluted with EtOAc and washed with brine. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give a brown solid. This material was purified on silica (0%-3.5% 7N NH3 / MeOH in DCM) to give the title compound (2.26 g, 91%) as a yellow solid. MS (ES) m / z = 848 (M+1).

[0743] The following compounds in Table 13 were prepared in a manner similar to that described in Preparation 195. The compounds were purified using a variety of methods that would be apparent to one skilled in the art.

[0744] Table 13: [Table 14-1]

[0745] (Continued from Table 13) [Table 14-2]

[0746] (Continued from Table 13) [Table 14-3]

[0747] (Continued from Table 13) [Table 14-4]

[0748] (Continued from Table 13) [Table 14-5]

[0749] (Continued from Table 13) [Table 14-6]

[0750] (Continued from Table 13) [Table 14-7]

[0751] (Continued from Table 13) [Table 14-8]

[0752] (Continued from Table 13) [Table 14-9]

[0753] (Continued from Table 13) [Table 14-10]

[0754] (Continued from Table 13) [Table 14-11]

[0755] (Continued from Table 13) [Table 14-12]

[0756] (Continued from Table 13) [Table 14-13]

[0757] (Continued from Table 13) [Table 14-14]

[0758] (Continued from Table 13) [Table 14-15]

[0759] (Continued from Table 13) [Table 14-16]

[0760] (Continued from Table 13) [Table 14-17]

[0761] (Continued from Table 13) [Table 14-18]

[0762] (Continued from Table 13) [Table 14-19]

[0763] (Continued from Table 13) [Table 14-20]

[0764] (Continued from Table 13) [Table 14-21]

[0765] (Continued from Table 13) [Table 14-22]

[0766] (Continued from Table 13) [Table 14-23]

[0767] (Continued from Table 13) [Table 14-24]

[0768] (Continued from Table 13) [Table 14-25]

[0769] (Continued from Table 13) [Table 14-26] 1 The reaction was heated at 55° C. for approximately 18 hours. 2 Single atropisomer (from precursor of preparation 157) 3 The reaction was heated at 80° C. for 1 hour. 4 The reaction was heated at 60° C. for approximately 48 hours. 5 Chiralpak(R) AD-H, 21×150mm, 25%IPA(0.5%DMEA):75%CO2, 70mL / min 6 Single atropisomer (from precursor of preparation 248) 7 Single atropisomer (from precursor of preparation 251) 8 Chiralcel(R) OD, 20×250mm, 20%EtOH(0.5%DMEA):80%CO2, 80mL / min

[0770] Preparation 223 4-Bromo-5-fluoro-7-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-1,3-dihydrofuro[3,4-f]quinoline

[0771] [ka]

[0772] A solution of LHMDS (1 M in THF, 7.3 mL, 7.3 mmol) and N-methyl-1-prolinol (0.9 mL, 7 mmol) in DMF (15 mL) was stirred for 5 minutes. A suspension of 4-bromo-7-chloro-5-fluoro-1,3-dihydrofuro[3,4-f]quinoline (1.0 g, 3.3 mmol) in DMF (30 mL) was added and stirred at room temperature for approximately 18 hours. The reaction solution was added to HO (150 mL), and the resulting solid was filtered, washed with HO, and placed under vacuum at 40 °C overnight to give the title compound (1.1 g, 85%) as a white solid. MS (ES) m / z = 381 (M+1).

[0773] Preparation 224 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-3-cyano-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0774] [ka]

[0775] A mixture of tert-butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-3-ethylsulfanyl-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, isomer 2 (Preparation 157, 765 mg, 0.957 mmol) and NaCN (93.8 mg, 1.91 mmol) in DMSO (10 mL) was stirred at room temperature for 1 hour. The resulting mixture was diluted with EtOAc (200 mL), washed with HO (3 × 200 mL), brine (200 mL), then dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (650 mg, 93%) as a yellow solid. MS (ES) m / z = 732 (M+1).

[0776] Preparation 225 6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-1-(3-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-7,9-dihydrofuro[3,4-f]quinazoline-3-carboxylate methyl ester

[0777] [ka]

[0778] To a stirred solution of tert-butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-3-cyano-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (650 mg, 0.888 mmol) in MeOH (10 mL) was added dropwise a solution of NaOH (71.0 mg, 1.78 mmol) in HO (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 °C, acidified to pH 2-3 with 1 N HCl solution, and stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure and extracted with EtOAc (300 mL). The combined organic layers were washed with HO (3 x 200 mL), brine (200 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (580 mg, 85%) as a yellow solid. MS (ES) m / z = 765 (M+1).

[0779] Preparation 226 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-chloro-3-(hydroxymethyl)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0780] [ka]

[0781] To a stirred mixture of methyl 6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-1-(3-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-chloro-7,9-dihydrofuro[3,4-f]quinazoline-3-carboxylate (200 mg, 0.261 mmol) in EtOH (20 mL) was added NaBH (19.8 mg, 0.522 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature under N for 1 h. The reaction was quenched with H O at 0 °C. The resulting mixture was concentrated under reduced pressure and extracted with EtOAc (300 mL). The organic layer was washed with H O (3 × 200 mL), brine (200 mL), and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (150 mg, 78%) as a yellow solid. MS (ES) m / z=737 (M+1).

[0782] Preparation 296 tert-Butyl 8-[6-(2-amino-3-cyano-5-fluoro-benzofuran-4-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, isomer 1

[0783] [ka]

[0784] A mixture of tert-butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluoro-benzofuran-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.548 g, 0.659 mmol) and hexafluoroisopropanol (3 mL) was stirred at 110 °C for 4 minutes under microwave irradiation. The mixture was concentrated and purified by reverse-phase flash purification on a C18 column eluting with 0%-100% ACN in 10 mM aqueous NH4HCO3 (containing 5% MeOH) to give the racemate, which was then subjected to chiral purification (Chiralpak® IC, 21 × 250 mm, 35% EtOH (containing 0.5% DMEA):65% CO2, 80 mL / min) to give the title compound (0.126 g) as a white solid. MS (ES) m / z = 732 (M+1).

[0785] Preparation 297 tert-Butyl 6-[6-(2-amino-3-cyano-5-fluoro-benzofuran-4-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0786] [ka]

[0787] 6-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluoro-benzofuran-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate tert-butyl ester was used in a manner similar to that of Preparation 296 to obtain the title compound (0.28 g). MS (ES) m / z=718 (M+1).

[0788] Preparation 298 tert-Butyl (1R,4R)-5-[6-(2-amino-3-cyano-5-fluoro-benzofuran-4-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, isomer 2

[0789] [ka]

[0790] (1R,4R)-5-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluoro-benzofuran-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate tert-butyl was used in a manner similar to that of Preparation 296, followed by chiral purification (Chiralpak® IC, 21 × 250 mm, 40% MeOH: 60% CO2, 70 mL / min) to give the title compound (0.14 g). MS (ES) m / z = 718 (M + 1).

[0791] Preparation 299 tert-Butyl N-[4-[1-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]-5,7-difluoro-1,3-benzothiazol-2-yl]carbamate

[0792] [ka]

[0793] [2-(tert-butoxycarbonylamino)-5,7-difluoro-1,3-benzothiazol-4-yl]boronic acid was used in a manner similar to that of Preparation 156 to give the title compound (0.50 g). MS (ES) m / z = 914 (M+1).

[0794] Preparation 400 6-Bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazoline

[0795] [ka]

[0796] 6-Bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-ol and trifluoroethanol were used in a manner similar to that of Preparation 112 to give the title compound (2.2 g, 77%) as a pale yellow solid. MS (ES) m / z = 524,526 (M+1, Br).

[0797] Preparation 401 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0798] [ka]

[0799] 6-Bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazoline and N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate tert-butyl were used in a manner similar to the method of Preparation 158 to give the title compound (1.5 g) as a pale yellow solid. MS (ES) m / z = 737 (M+1).

[0800] Preparation 402 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-[[(2S)-1-methylpyrrolidin-2-yl]methylamino]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0801] [ka]

[0802] 6-Bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-N-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7,9-dihydrofuro[3,4-f]quinazolin-1-amine and N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate tert-butyl were used in a manner similar to the method of Preparation 158 to give the title compound. MS (ES) m / z = 751 (M+1).

[0803] Preparation 403 tert-Butyl N-[3-cyano-4-[1-(dimethylamino)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]-7-fluoro-thieno[3,2-c]pyridin-2-yl]carbamate

[0804] [ka]

[0805] N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate tert-butyl and dimethylamine were used in a manner similar to the method of Preparation 111 to give the title compound. MS (ES) m / z = 682 (M+1).

[0806] Preparation 404 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(methylamino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0807] [ka]

[0808] N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate tert-butyl ester and methylamine were used in a manner similar to the method of Preparation 111 to give the title compound. MS (ES) m / z = 668 (M+1).

[0809] Preparation 405 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2-hydroxyethylamino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0810] [ka]

[0811] N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate tert-butyl ester and ethanolamine were used in a manner similar to the method of Preparation 111 to give the title compound. MS (ES) m / z = 698 (M+1).

[0812] Preparation 406 tert-Butyl N-[4-[1-(azetidin-1-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl]carbamate

[0813] [ka]

[0814] N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate tert-butyl ester and azetidine were used in a manner similar to the method of Preparation 111 to give the title compound. MS (ES) m / z = 694 (M+1).

[0815] Preparation 407 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(3-methoxyazetidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0816] [ka]

[0817] N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate tert-butyl and 3-methoxyazetidine were used in a manner similar to the method of Preparation 111 to give the title compound. MS (ES) m / z = 724 (M+1).

[0818] Preparation 408 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-morpholino-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0819] [ka]

[0820] N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate tert-butyl ester and morpholine were used in a manner similar to the method of Preparation 111 to give the title compound. MS (ES) m / z = 724 (M+1).

[0821] Preparation 409 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2-methoxyethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0822] [ka]

[0823] N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate tert-butyl and 2-methoxyethanol were used in a manner similar to the method of Preparation 195 to give the title compound. MS (ES) m / z = 713 (M+1).

[0824] Preparation 410 tert-Butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate

[0825] [ka]

[0826] To a solution of tert-butyl N-[3-cyano-7-fluoro-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-(2,2,2-trifluoroethoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]thieno[3,2-c]pyridin-2-yl]carbamate (0.15 g, 0.20 mmol) in THF (2 mL) was added dropwise a solution of NaOH (0.041 g, 1.02 mmol) in HO (0.2 mL) under nitrogen. After 2 h, the mixture was diluted with HO (50 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was diluted with DMF (2 mL) and purified by reverse-phase flash purification on a C18 column eluting with 24%-37% ACN in 10 mM aqueous NH4HCO3 (containing 0.05% NH4OH) to give the title compound (0.022 g, 16%) as a white solid. MS (ES) m / z = 655 (M+1).

[0827] Preparation 411 tert-Butyl N-(4-hydroxythieno[2,3-b]pyridin-2-yl)carbamate

[0828] [ka]

[0829] A mixture of 4-hydroxythieno[2,3-b]pyridine-2-carboxylic acid; hydrochloride (1.96 g, 8.5 mmol) and triethylamine (4.8 mL, 34 mmol, 4.0 equiv.) in tert-butanol (40 mL) was heated to form a solution and then cooled to room temperature. Diphenylphosphoryl azide (2.5 mL, 11 mmol, 1.3 equiv.) was added. The reaction mixture was stirred at room temperature for 10 minutes and then heated at 85°C overnight. The mixture was concentrated in vacuo. The residue was purified on silica eluting with 10-100% acetone in hexanes to give the title compound (1.70 g, 76%). MS (ES) m / z = 267 (M+1).

[0830] Preparation 412 (2-aminothieno[2,3-b]pyridin-4-yl)trifluoromethanesulfonate

[0831] [ka]

[0832] To a suspension of tert-butyl N-(4-hydroxythieno[2,3-b]pyridin-2-yl)carbamate (1.45 g, 5.4 mmol) in DCM (110 mL) were added 2,6-lutidine (1.2 mL, 10 mmol, 1.9 equiv.) and 4-dimethylaminopyridine (0.067 g, 0.54 mmol, 0.10 equiv.). The reaction mixture was cooled in an ice bath and treated dropwise with trifluoromethanesulfonic anhydride (1.2 mL, 7.0 mmol, 1.3 equiv.) and stirred in the ice bath for 1 hour. Additional 2,6-lutidine (1.2 mL, 10 mmol, 1.9 equiv.) and trifluoromethanesulfonic anhydride (1.2 mL, 7.0 mmol, 1.3 equiv.) were added. The reaction mixture was stirred in the ice bath for 30 minutes and then quenched with saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica eluting with 0-75% MTBE in hexanes to give an impure fraction. The impure fraction was concentrated in vacuo and further purified on silica eluting with 50-100% DCM in hexanes. The aqueous layer was extracted four times with 4:1 CHCl3:isopropanol. Extract with isopropanol. The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica eluting with 10-50% MTBE in hexanes. The clean fractions from the second and third silica purifications were combined and concentrated in vacuo to give the title compound (0.71 g, 44%) as an off-white solid. MS (ES) m / z = 299 (M+1).

[0833] Preparation 413 [2-[bis(tert-butoxycarbonyl)amino]thieno[2,3-b]pyridin-4-yl]trifluoromethanesulfonate

[0834] [ka]

[0835] To a solution of (2-aminothieno[2,3-b]pyridin-4-yl)trifluoromethanesulfonate (0.67 g, 2.26 mmol) in 1,4-dioxane (45 mL) was added di-tert-butyl dicarbonate (1.23 g, 5.64 mmol, 2.5 equiv.) and 4-dimethylaminopyridine (0.028 g, 0.227 mmol, 0.10 equiv.). The reaction mixture was stirred at room temperature for 6 days and concentrated in vacuo. The residue was purified on silica eluting with 0-50% MTBE in hexane to give the title compound (0.93 g, 82%). MS (ES) m / z = 499 (M+1).

[0836] Preparation 414 [2-(tert-butoxycarbonylamino)-3-cyano-thieno[2,3-b]pyridin-4-yl]trifluoromethanesulfonate

[0837] [ka]

[0838] A solution of [2-[bis(tert-butoxycarbonyl)amino]thieno[2,3-b]pyridin-4-yl]trifluoromethanesulfonate (0.550 g, 1.10 mmol) in acetonitrile (11 mL) was cooled in an ice bath. Chlorosulfonyl isocyanate (0.3 mL, 3 mmol, 3 equiv.) was added dropwise, and the reaction mixture was stirred in the ice bath for 5 hours, placed in a -20 °C freezer overnight, allowed to warm to room temperature, and stirred for 3.5 hours. The reaction mixture was cooled in an ice bath, added dropwise to N,N-dimethylformamide (8.5 mL, cooled in an ice bath), stirred for 1 hour, poured slowly into cold saturated aqueous sodium bicarbonate, and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The residue was purified on silica eluting with 0-50% DCM in hexanes to give the title compound (0.118 g, 25%) as an off-white solid. MS (ES) m / z=424 (M+1).

[0839] Preparation 415 tert-Butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-thieno[2,3-b]pyridin-4-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0840] [ka]

[0841] Reaction mixture A: A mixture of tert-butyl 8-[6-bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.370 g, 0.581 mmol), KOAc (0.171 g, 1.74 mmol), and bis(neopentylglycolato)diboron (0.197 g, 0.872 mmol) in 1,4-dioxane (6 mL) was sparged with N for 10 minutes. Dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (0.043 g, 0.059 mmol) was added and the resulting mixture was sealed and heated at 95° C. for 2.5 hours. The reaction mixture was cooled to room temperature and stored overnight.

[0842] Reaction mixture B: A mixture of tert-butyl 8-[6-bromo-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.370 g, 0.581 mmol), KOAc (0.171 g, 1.74 mmol), and bis(neopentylglycolato)diboron (0.197 g, 0.872 mmol) in 1,4-dioxane (6 mL) was sparged with N for 10 minutes. Dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (0.043 g, 0.059 mmol) was added and the resulting mixture was sealed and heated at 95° C. overnight. The reaction mixture was cooled to room temperature.

[0843] Reaction mixture C: A mixture of [2-(tert-butoxycarbonylamino)-3-cyano-thieno[2,3-b]pyridin-4-yl]trifluoromethanesulfonate (0.162 g, 0.383 mmol) in 1,4-dioxane (4 mL) and water (1.2 mL) was sparged with N for 15 minutes. Potassium phosphate (0.162 g, 0.763 mmol) and XPhos Pd G4 (CAS No. 1599466-81-5, 0.035 g, 0.039 mmol) were added, and the resulting mixture was sealed and heated at 85 °C. Reaction mixture A was added via syringe and heated for 1 hour, then cooled to room temperature. The reaction mixture was again heated at 85 °C. One-third of reaction mixture B was added via syringe and heated for 1 hour. The remainder of reaction mixture B was added via syringe and heated for 1 hour. The reaction mixture was partitioned between DCM and water. The layers were separated and the aqueous layer was extracted twice with DCM. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified on silica eluting with 1-5% 7N ammonia-treated methanol / DCM to give the title compound (0.200 g, 45%). MS (ES) m / z = 831 (M+1).

[0844] Example 1 2-Amino-4-[1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]-5-fluoro-benzothiophene-3-carbonitrile, isomer 2

[0845] [ka]

[0846] A solution of tert-butyl 8-[6-[2-(tert-butoxycarbonylamino)-3-cyano-5-fluoro-benzothiophen-4-yl]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (0.605 g, 0.876 mmol) in DCM (5 mL) was charged with TFA (4 mL) and stirred at room temperature for 25 minutes. The mixture was concentrated, DCM was added, and the mixture was concentrated again, and this procedure was repeated three times. The mixture was filtered through an SCX column eluting with MeOH (4 CV) followed by 7N NH3 / MeOH (4 CV) to give the crude product, which was purified on silica gel eluting with a gradient of 1%-10% 7N NH3 / MeOH in DCM to give the racemate, followed by chiral purification (Chiralpak® AS-H, 21 × 250 mm, 35% MeOH (with 0.5% DMEA): 65% CO2, 80 mL / min) to give the title compound (0.129 g, 30%) as a white solid. MS (ES) m / z = 491 (M+1).

[0847] The example compounds in Table 14 were prepared in a manner similar to that described in Preparation 296 or Example 1. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Chiral purification methods (where applicable) for the examples in Table 14 are provided in Table 18.

[0848] Table 14: [Table 15-1]

[0849] (Continued from Table 14) [Table 15-2]

[0850] (Continued from Table 14) [Table 15-3]

[0851] (Continued from Table 14) [Table 15-4]

[0852] (Continued from Table 14) [Table 15-5]

[0853] (Continued from Table 14) [Table 15-6]

[0854] (Continued from Table 14) [Table 15-7]

[0855] (Continued from Table 14) [Table 15-8]

[0856] (Continued from Table 14) [Table 15-9]

[0857] (Continued from Table 14) [Table 15-10]

[0858] (Continued from Table 14) [Table 15-11]

[0859] (Continued from Table 14) [Table 15-12]

[0860] (Continued from Table 14) [Table 15-13]

[0861] (Continued from Table 14) [Table 15-14]

[0862] (Continued from Table 14) [Table 15-15]

[0863] (Continued from Table 14) [Table 15-16]

[0864] (Continued from Table 14) [Table 15-17]

[0865] (Continued from Table 14) [Table 15-17]

[0866] (Continued from Table 14) [Table 15-18]

[0867] (Continued from Table 14) [Table 15-19]

[0868] (Continued from Table 14) [Table 15-20]

[0869] (Continued from Table 14) [Table 15-21]

[0870] (Continued from Table 14) [Table 15-22]

[0871] (Continued from Table 14) [Table 15-23]

[0872] (Continued from Table 14) [Table 15-24]

[0873] (Continued from Table 14) [Table 15-25]

[0874] (Continued from Table 14) [Table 15-26]

[0875] (Continued from Table 14) [Table 15-27]

[0876] (Continued from Table 14) [Table 15-28]

[0877] (Continued from Table 14) [Table 15-29]

[0878] (Continued from Table 14) [Table 15-30]

[0879] (Continued from Table 14) [Table 15-31]

[0880] (Continued from Table 14) [Table 15-32]

[0881] (Continued from Table 14) [Table 15-33] 1 Single diastereomer 2 Single atropisomer (from precursor of preparation 157) 3 Single atropisomer (from precursor of preparation 266) 4 Single atropisomer (from precursor of preparation 248) 5 Single atropisomer (from precursor of preparation 296) 6 Single atropisomer (from precursor of preparation 251) 7 Single atropisomer (from precursor of preparation 255) 8 Single atropisomer (from precursor of preparation 298) a MS(ES) - Measured at

[0882] Example 46 2-Amino-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-[3-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile

[0883] [ka]

[0884] A solution of tert-butyl N-[4-[1-[3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]-3-cyano-benzothiophen-2-yl]carbamate (0.250 g, 0.281 mmol) in THF (2 mL) was treated with 1 M TBAF in THF (0.7 mL, 0.7 mmol) and stirred at room temperature for 1.5 hours. A second portion of 1 M TBAF in THF (0.7 mL, 0.7 mmol) was added, and the mixture was stirred for approximately 18 hours. The mixture was concentrated and dried in vacuo. The residue was dissolved in DCM (5 mL), treated with TFA (2 mL), and stirred at room temperature for approximately 18 hours. The mixture was concentrated. DCM was added, and the mixture was concentrated again. The residue was dissolved in DCM / MeOH and loaded onto an SCX column, eluting with MeOH and DCM, followed by 1:1 2N NH3 / MeOH:DCM. The ammoniated eluent was concentrated in vacuo, and the residue was further purified by reverse-phase flash chromatography on a C18 column, eluting with 5-50% ACN in 10 mM aqueous NH4HCO3 (containing 5% MeOH), to give the title compound (0.111 g, 59%) as an off-white solid. MS (ES) m / z = 674 (M+1).

[0885] Example 47 2-Amino-7-fluoro-4-[5-fluoro-1-[(1S,4S,7S)-7-fluoro-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile

[0886] [ka]

[0887] Benzyl (1S,4S,7R)-5-[6-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-7-fluoro-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (280 mg, 0.384 mmol) was stirred in TFA (10.0 mL) at room temperature. The resulting mixture was then stirred at 70° C. for 5 hours. The mixture was concentrated under reduced pressure and diluted with DMF (3 mL). The mixture was then basified to pH 9 with NH3H2O. The mixture was purified on a C18 column eluting with a gradient of 46%-65% ACN in 10 mM aqueous NH4HCO3 to give the title compound (39.5 mg, 20.2%) as a white solid. MS(ES) m / z=495(M+1).

[0888] Example 48 2-Amino-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-[3-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile

[0889] [ka]

[0890] A solution of 2-amino-4-[1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile (0.800 g, 1.27 mmol) in DCM (13 mL) and MeOH (2.5 mL) was treated with 3-[(tert-butyldimethylsilyl)oxy]-1-propanol (0.756 g, 3.81 mmol) and NaBH(OAc) (0.850 g, 3.81 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured directly onto an SCX column and eluted first with MeOH and DCM, then with 1:1 2N NH3 / MeOH:DCM. The ammoniated fraction was concentrated. The residue was dissolved in DCM / MeOH and passed through an SCX column a second time. The residue from the concentration of the ammoniated fraction was purified by silica (eluting with 0%-5% 7N NH3 / MeOH in DCM) followed by reverse-phase flash chromatography on a C18 column (eluting with 5%-51% ACN in 10 mM aqueous NH4HCO3 (containing 5% MeOH)) to give the title compound (0.541 g, 62%) as a light beige solid. MS (ES) m / z = 688 (M+1).

[0891] The example compounds in Table 15 were prepared in a manner similar to that described in Example 48. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Chiral purification methods (where applicable) for the examples in Table 15 are provided in Table 18.

[0892] Table 15: [Table 16-1]

[0893] (Continued from Table 15) [Table 16-2]

[0894] (Continued from Table 15) [Table 16-3]

[0895] (Continued from Table 15) [Table 16-4]

[0896] (Continued from Table 15) [Table 16-5]

[0897] (Continued from Table 15) [Table 16-6]

[0898] (Continued from Table 15) [Table 16-7]

[0899] (Continued from Table 15) [Table 16-8]

[0900] (Continued from Table 15) [Table 16-9]

[0901] (Continued from Table 15) [Table 16-10]

[0902] (Continued from Table 15) [Table 16-11]

[0903] (Continued from Table 15) [Table 16-12]

[0904] (Continued from Table 15) [Table 16-13]

[0905] (Continued from Table 15) [Table 16-14]

[0906] (Continued from Table 15) [Table 16-15]

[0907] (Continued from Table 15) [Table 16-16]

[0908] (Continued from Table 15) [Table 16-17]

[0909] (Continued from Table 15) [Table 16-18]

[0910] (Continued from Table 15) [Table 16-19]

[0911] (Continued from Table 15) [Table 16-20]

[0912] (Continued from Table 15) [Table 16-21]

[0913] (Continued from Table 15) [Table 16-22]

[0914] (Continued from Table 15) [Table 16-23]

[0915] (Continued from Table 15) [Table 16-24]

[0916] (Continued from Table 15) [Table 16-25]

[0917] (Continued from Table 15) [Table 16-26]

[0918] (Continued from Table 15) [Table 16-27]

[0919] (Continued from Table 15) [Table 16-28]

[0920] (Continued from Table 15) [Table 16-29]

[0921] (Continued from Table 15) [Table 16-30]

[0922] (Continued from Table 15) [Table 16-31] 1 Single atropisomer (from precursor of Example 1) 2 Prepared using 37 wt% formaldehyde in water without MeOH co-solvent. 3 Single atropisomer (from precursor of preparation 266) 4 Single atropisomer (from precursor of preparation 248) 5 Single atropisomer (from precursor of preparation 296) 6 Single atropisomer (from precursor of preparation 251) 7 Single atropisomer (from precursor of preparation 255)

[0923] Example 55 2-Amino-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-[3-[(2R)-2-hydroxypropyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile

[0924] [ka]

[0925] A solution of 2-amino-4-[1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile (0.120 g, 0.191 mmol) in MeOH (4 mL) was treated with (R)-(+)-propylene oxide (0.056 g, 0.945 mmol). The mixture was heated in a sealed tube at 70 °C for 2 h and then concentrated. The residue was purified by reverse-phase flash chromatography on C18 (eluting with 5%-64% ACN in 10 mM aqueous NH4HCO3 (containing 5% MeOH)) to give the title compound (0.089 g, 62%) as a light beige solid. MS (ES) m / z = 688 (M+1).

[0926] The example compounds in Table 16 were prepared in a manner similar to that described in Example 48 or Example 55. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Chiral purification methods (where applicable) for the examples in Table 16 are provided in Table 18.

[0927] Table 16: [Table 17-1]

[0928] (Continued from Table 16) [Table 17-2]

[0929] (Continued from Table 16) [Table 17-3]

[0930] (Continued from Table 16) [Table 17-4]

[0931] (Continued from Table 16) [Table 17-5]

[0932] (Continued from Table 16) [Table 17-6]

[0933] (Continued from Table 16) [Table 17-7]

[0934] (Continued from Table 16) [Table 17-8]

[0935] (Continued from Table 16) [Table 17-9]

[0936] (Continued from Table 16) [Table 17-10]

[0937] (Continued from Table 16) [Table 17-11]

[0938] (Continued from Table 16) [Table 17-12]

[0939] (Continued from Table 16) [Table 17-13]

[0940] (Continued from Table 16) [Table 17-14]

[0941] (Continued from Table 16) [Table 17-15] 1 Single atropisomer (from precursor of preparation 296) 2 Single atropisomer (from precursor of preparation 248) 3 Single atropisomer (from precursor of preparation 298)

[0942] Examples 56 and 57 2-Amino-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-[3-[(2S)-2-hydroxypropyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile and 2-Amino-4-[5-fluoro-1-[3-[(2S)-2-hydroxypropyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-methoxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile

[0943] [ka]

[0944] 2-Amino-4-[1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile was used in a manner similar to that described in Example 55, using (S)-(-)-propylene oxide and heating the reaction at 70° C. for approximately 18 hours. Upon purification by reverse-phase flash purification on C18 eluting with 5%-50% ACN in aqueous NH4HCO3 (containing 5% MeOH), two products were isolated as pink solids, 2-amino-4-[5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-1-[3-[(2S)-2-hydroxypropyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-7,9-dihydrofuro[3, [4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile (0.033 g, 37%) (MS(ES) m / z = 688 (M+1)) and 2-amino-4-[5-fluoro-1-[3-[(2S)-2-hydroxypropyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-methoxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]benzothiophene-3-carbonitrile (0.020 g, 26%) were obtained as an off-white solid. MS(ES) m / z = 561 (M+1).

[0945] Example 189 3-[8-[6-(2-amino-3-cyano-5-fluoro-benzothiophen-4-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-N-methyl-propanamide

[0946] [ka]

[0947] A mixture of 2-amino-4-[1-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]-5-fluoro-benzothiophene-3-carbonitrile (single atropisomer, from the precursor of Preparation 248, 0.060 g, 0.093 mmol), 3-chloro-N-methylpropanamide (0.056 g, 0.465 mmol), potassium iodide (0.0077 g, 0.046 mmol), and triethylamine (0.019 g, 0.186 mmol) in acetonitrile (3 mL) was heated at 80 °C for approximately 12 hours. The mixture was concentrated, diluted with DMF (2 mL), and purified by reverse-phase flash purification on a C18 column eluting with 35%-51% ACN in 10 mM aqueous NH4HCO3 (containing 0.1% NH4OH) to give the title compound (0.021 g, 30%) as a white solid. MS (ES) m / z = 733 (M+1).

[0948] The example compounds in Table 17 were prepared in a manner similar to that described in Example 189. The compounds were purified using a variety of methods that would be apparent to one skilled in the art. Chiral purification methods (where applicable) for the examples in Table 17 are provided in Table 18.

[0949] Table 17: [Table 18-1]

[0950] (Continued from Table 17) [Table 18-2]

[0951] (Continued from Table 17) [Table 18-3] 1 Single atropisomer (from precursor of preparation 248) 2 Single atropisomer (from precursor of preparation 266)

[0952] Example 194 3-[8-[6-(2-amino-5,7-difluoro-1,3-benzothiazol-4-yl)-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-1-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]propan-1-ol

[0953] [ka]

[0954] N-[4-[1-[3-[3-[tert-butyl(dimethyl)silyl]oxypropyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-5-fluoro-3-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7,9-dihydrofuro[3,4-f]quinazolin-6-yl]-5,7-difluoro-1,3-benzothiazol-2-yl]carbamate tert-butyl was used in a similar manner to the method of Example 1 to obtain the title compound (0.028 g, 16%). MS (ES) m / z=700 (M+1).

[0955] Chiral purification methods for the example compounds in Tables 14 to 17 are shown in Table 18.

[0956] Table 18: Purification methods [Table 19-1]

[0957] (Continued from Table 18) [Table 19-2] a Chiralpak® columns available from Daicel Chiral Technologies (West Chester, PA) b XBridge columns available from Waters Corp. (Milford, MA) c Chiral ART columns available from YMC America, Inc. (Devens, MA) d Lux® columns available from Phenomenex, Inc. (Torrance, CA)

[0958] Biological assays The following assays demonstrate that the exemplified compounds are potent inhibitors of Kras G12D and inhibit the growth of certain tumors in vitro and / or in vivo.

[0959] Example 376 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 No. CRL-1469). The RAS GTPase ELISA kit (Active Motif catalog 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 with the kit. Activated pan-RAS (GTP-bound) in cell extracts specifically binds to the 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.

[0960] PANC-1 cells were plated at a concentration of 75,000 cells / well in 80 μL of 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 test compounds (in complete medium) (highest concentrations 1-50 μM) and 20 μL of serially diluted controls (in complete medium) (maximum signal wells: 0.5% DMSO and minimum signal wells: 10 μM reference positive control compound) were added to the cell plate and incubated for 2 h at 37°C / 5% CO2. Complete lysis / binding buffer containing protease inhibitor cocktail (PIC) was prepared and stored on ice. One hour before the cell plate incubation is complete, GST-Raf-RBD is diluted in lysis / binding buffer, and 50 μL of the mixed buffer per well is added to the supplied milky-white ELISA assay plate. The plate is incubated at 4°C for at least 1 hour with gentle rocking. After 2 hours, the cells are washed with 100 μL of ice-cold Ca2+ / Mg2+-free PBS and lysed with 100 μL of the kit-supplied lysis / binding buffer (AM11). After 30-50 minutes of vigorous shaking at ambient temperature, the cell plate is centrifuged at 410 × g (approximately 1500 rpm) for 10 minutes. During the centrifugation step, a wash buffer (3 × 100 μL) diluted 1x with ultrapure HO and filtered through a 0.2 μm filter is prepared at ambient temperature and then used to wash the GST-Raf-RBD-coated assay plate. 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 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), followed by the addition of 50 μL of primary RAS antibody (supplied in the kit, number 101678) diluted 1:500 in 1x antibody binding buffer. After 1 hour 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 1x antibody binding buffer) is added to each well of the assay plate and incubated for an additional hour at ambient temperature with gentle shaking. Finally, the assay plate is washed with 1x wash buffer (4 x 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.

[0961] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test Compound Signal - Median Minimum Signal) / (Median Maximum Signal - Median Minimum Signal) x 100]. The maximum signal is the control wells with no inhibitor (DMSO). The 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+((B-A) / (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).

[0962] In the above assay, the compounds of Examples 1-5, 7-12, 14-18, 20-26, 28-59, 62, 64, 67, 68, 93-192, 194, 206-209, 211-239, 241-250, 279, 323, 327, 328, 331, 332, 334, 336, 340-345, 348, 351, 354-356, 358, 363, 364, 367-372, and 374 all exhibited the ability to inhibit constitutive RAS GTPase activity with relative IC values of less than 100 nM. 50This data shows that compounds of Formulas I-VIII (including Formulas Ia-VIIa) 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.

[0963] Example 377 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 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 specifically binds to the 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.

[0964] MKN-45 cells were plated at a concentration of 75,000 cells / well in 80 μL of complete medium (DMEM, high glucose, L-glutamine, GIBCO; 10% heat-inactivated fetal bovine serum, GIBCO) and incubated overnight at 37°C / 5% CO2. After approximately 24 h, 20 μL (1:3) of serially diluted test compounds (in complete medium) (highest concentration 1-10 μM) and 20 μL of serially diluted controls (in complete medium) (maximum signal well: 0.1% DMSO and minimum signal well: 10 μM reference positive control compound) were added to the cell plate and incubated for 2 h at 37°C / 5% CO2. Complete lysis / binding buffer containing protease inhibitor cocktail (PIC) was prepared and stored on ice. One hour before the cell plate incubation is complete, GST-Raf-RBD is diluted in lysis / binding buffer, and 50 μL of the mixed buffer per well is added to the supplied milky-white ELISA assay plate. Incubate at 4°C for a minimum of 1 hour with gentle rocking. After 2 hours, the cells are washed with 100 μL of ice-cold Ca2+ / Mg2+-free PBS and lysed with 100 μL of the kit-supplied lysis / binding buffer (AM11). After vigorously shaking the plate at ambient temperature for 30-50 minutes, the cell plate is centrifuged at 410 x g (approximately 1500 rpm) for 10 minutes. During the centrifugation step, the wash buffer is diluted 1x with ultrapure HO and then used to wash the GST-Raf-RBD-coated assay plate (3 x 100 μL). Next, 50 μL of the cell lysate is added to the GST-Raf-RBD-coated assay plate and incubated at ambient temperature for 1 hour with gentle rocking. During this incubation period, prepare 1x antibody binding buffer from thawed concentrate. Wash the assay plate with 1x wash buffer (3 x 100 µL) and then add 50 µL of primary RAS antibody (supplied in the kit, number 101678) diluted 1:500 in 1x antibody binding buffer. After 1 hour of incubation at ambient temperature with gentle shaking, wash the assay plate 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 1x antibody binding buffer) is added to each well of the assay plate and incubated for an additional hour at ambient temperature with gentle shaking. Finally, the assay plate is washed with 1x wash buffer (4 x 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.

[0965] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test Compound Signal - Median Minimum Signal) / (Median Maximum Signal - Median Minimum Signal) x 100]. The maximum signal is the control wells with no inhibitor (DMSO). The 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+((B-A) / (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).

[0966] Examples 1, 3, 5, 7, 9-11, 13-18, 20, 22-28, 45, 46, 48, 49, 51-58, 62, 64, 68, 95, 96, 98-100, 103, 106-108, 110, 113, 114, 116-127, 130-146, 148-151, 153, 156-158, 161, 162, 170-187, 189-192, 194, 212-214, 213-215, 216-217, 218-219, 220-221, 222-223, 224-225, 226-227, 228-229, 230-231, 232-233, 234-235, 236-237, 238-239, 240-241, 242-243, 244-245, 246-247, 248-249, 250-251, 252-253, 254-255, 256-257, 258-259, 260-261, 262-263, 264-265, 266-267, 268-269, 270-272, 273-274, 275-276, 276-277, 277-278, 278-279, 280- Compounds 16-218, 220, 224-229, 231, 232, 234-239, 241-243, 247-249, 327, 328, 330-332, 334-338, 340, 341, 343, 344, 348, 349, 351, 354-356, 358, 363, 364, 366, 367, and 372-374 were tested in both assays (PANC-1 cell active RAS GTPase ELISA and MKN-45 cell active RAS GTPase ELISA) and all showed significant (i.e., >10-fold) selective inhibition preference for KRas G12D mutant over KRas wild-type.

[0967] Example 378 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 an activating KRAS G12 mutation (Table 19). 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) engineered to express only KRAS wild-type, HRAS, and NRAS, respectively (Table 19). MEF cells were used to confirm the KRAS selectivity of the test compounds.

[0968] Table 19: Cell line information [Table 20]

[0969] The activity of compounds is determined by measuring changes in the 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 (product number ALSU-PERK-A50K, PerkinElmer®, Waltham, MA). The AlphaLISA® assay is a quantitative sandwich immunoassay that can be used to detect the phosphorylation of target proteins from cell lysates using bead-based alpha technology. This 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, while 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. 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).

[0970] 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 densities to the assay plates in 8 μL / well of assay medium (HBSS, Sigma #55021C, 10% FBS, GIBCO #10082-147) (Error! Reference source not found). Final compound concentrations in each well range from 0.5 to 10,000 nM, and the final DMSO concentration is 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 a protease / phosphatase inhibitor cocktail (Thermo Scientific No. 78442). The assay plate is covered with an opaque lid and shaken at 750 rpm at room temperature for 30 minutes on a multiplate shaker (Heidolph, Schwabach, Germany) to induce cell lysis. During lysis, AlphaLISA® Acceptor Beads are diluted 1:50 in a prepared buffer mixture (1:1 AlphaLISA® Reaction Buffers 1 and 2 and a 1:25 dilution of AlphaLISA® Activation Buffer). After cell lysis, the plate is briefly centrifuged, and 5 μL / well of prepared Acceptor Beads is added. The plate is then covered and incubated in the dark at room temperature for 2 hours. During the incubation of the acceptor beads, the donor beads are prepared by diluting Alpha Streptavidin donor beads 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.

[0971] The raw signals from the AlphaLISA® assays are analyzed using Genedata Screener® 17.0.3, within which data are normalized to 32 wells treated with the 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.

[0972]

number

[0973]

number

[0974] In the above assays, the compounds of the Examples described herein exhibit the ability to reduce phosphorylated ERK-1 / 2 levels in cells expressing KRAS and KRAS variants, and G12C (Examples 2, 24, 29, 32, 35, 37, 40, 42 to 45, 48, 55, 56, 59, 68, 93, 95 to 97, 101, 103, 106 to 109, 113, 114, 116, 129, 152, 159, 161, 162, 164 to 166, 168, 169, 172, 190 to 192, 206, 208, 211 to 213, 218, 219, 243, 244, 280 to 289, 292 to 318, 320, 321, 343, 346, 347, 370, and 375), KRAS G12D (Examples 2, 14, 24, 29, 35, 37, 42 to 45, 48, 55, 56, 59, 68, 93, 95 to 97, 101, 103, 106 to 109, 113, 114, 116, 129, 152, 159, 161, 162, 164 to 166, 168, 169, 175, 188, 190 to 193, 212, 213, 218 to 220, 229, 231, 233, 243, 244, 280 to 289, 292 to 313, 316, 318, 343, 346, 347, 370, and 375), KRAS G12V (Examples 29, 30, 32, 35, 37 to 40, 42 to 45, 59, 93, 97, 108, 109, 165, 166, 168, 209, 211, 219, 280 to 289, 292 to 318, 320, 321, 346, 347, 370, and 375), or KRAS It was shown to inhibit constitutive RAS activity in cells expressing WT (Examples 2, 29, 30, 32, 35, 37-40, 42-45, 48, 56, 59, 62, 93, 95-97, 101, 103, 107-109, 113, 114, 116, 129, 159, 161, 162, 164-166, 168, 169, 190-192, 209, 211, 218, 219, 244, 280-289, 292-314, 316-318, 320, 321, 346, 347, 370, and 375) with a relative IC50 of less than 500 nM.Examples 2, 14, 24, 45, 48, 49, 55, 56, 59, 68, 95-97, 101, 103, 106-109, 113, 114, 116, 121-124, 126, 129, 130, 142, 152, 159, 161, 162, 164-166, 168, 169, 172, 175, 188, 190-193, 211-213, Compounds 218-220, 229, 231, 233, 243, 244, 280-289, 293, 295-302, 305-311, 314-322, 343, 346, 347, 370, and 375 were tested in the mouse embryo fibroblast cell line assays (MEF-NRAS, MEF-HRAS) described above and all exhibited relative IC50s greater than 2 μM.

[0975] This data indicates that the compounds of Formulas I-VIII (including Formulas Ia-VIIa) described herein are potent inhibitors of KRAS-expressing human cancer cells, demonstrating their ability to inhibit KRAS G12C, G12D, or G12V mutants with significant selective inhibition preference for KRAS mutants over HRAS or NRAS.

[0976] Table 10: Abbreviations [Table 21]

Claims

1. The following compounds: 【Chemistry 1】 【change】 A compound selected from or a pharmaceutically acceptable salt thereof.

2. The compound is the following compound: 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound is the following compound: 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound is the following compound: 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. The compound is the following compound: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. The compound is the following compound: 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. The compound is the following compound: 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. The compound is the following compound: 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. The compound is the following compound: 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. The compound is the following compound: 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. The compound is the following compound: 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. The compound is the following compound: 【Chemistry 12】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. The compound is the following compound: 【Chemistry 13】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. The compound is the following compound: 【Chemistry 14】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. The compound is the following compound: 【Chemistry 15】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

16. The compound is the following compound: 【Chemistry 16】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. The compound is the following compound: 【Chemistry 17】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

18. The compound is the following compound: [Chemistry 18] The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. The compound is the following compound: 【Chemistry 19】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. The compound is the following compound: 【Chemistry 20】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

21. The compound is the following compound: 【Chemistry 21】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

22. The compound is the following compound: 【Chemistry 22】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. The compound is the following compound: 【Chemistry 23】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

24. The compound is the following compound: 【Chemistry 24】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

25. The compound is the following compound: 【Chemistry 25】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

26. The compound is the following compound: 【Chemistry 26】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

27. The compound is the following compound: 【Chemistry 27】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

28. The compound is the following compound: 【Chemistry 28】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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