Kras inhibitors

Abstract

To provide more potent, orally deliverable KRas inhibitors that are useful for treating cancer.SOLUTION: The present invention provides compounds of the following formula, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients for cancer. Specific examples of the compound include the following compounds.SELECTED DRAWING: None

Description

Technical Field

[0001] Background Art The MAPK / ERK signaling pathway transmits extracellular stimuli to the nucleus, thereby regulating various cellular responses including cell proliferation, differentiation, and apoptosis. The KRas protein initiates the MAPK / ERK signaling pathway and functions as a switch involved in the induction of cell division. In its inactive state, KRas binds to guanosine diphosphate (GDP), effectively sending a negative signal and suppressing cell division. In response to extracellular signals, KRas is allosterically activated, enabling nucleotide exchange between GDP and guanosine triphosphate (GTP). In its active state bound to GTP, KRas recruits and activates proteins necessary for the propagation of growth factor-induced signaling, as well as other cellular signal transduction receptors. Examples of proteins mobilized by KRas-GTP are c-Raf and PI3 kinase. As a GTPase, KRas converts the bound GTP back to GDP, thereby returning itself to the inactive state and suppressing signal propagation and cell division again. Gain-of-function mutations in KRas exhibit an increased degree of GTP binding and a decreased ability to convert GTP to GDP. As a result, the MAPK / ERK signal that promotes the proliferation of cancerous cells increases. The missense mutation of KRas at codon 12 is the most common mutation and significantly reduces GTPase activity.

Background Art

[0002] Oncogenic KRas mutations are found in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, they have proven to be difficult therapeutic targets. (Cox, A. D. Drugging 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, studies have focused on inhibitors of the KRas G12C variant (for example, WO 2019 / 099524, WO 2020 / 081282, WO 2020 / 101736, WO 2020 / 146613, and WO 2021 / 118877 disclose KRas G12C inhibitors), while WO 2021 / 041671 discloses a KRas G12D small molecule inhibitor and WO 2017 / 011920 discloses KRas G12C, G12D, and G12V small molecule inhibitors.

[0004] There remains a need to provide alternative small molecule KRas inhibitors. Specifically, there is a need to provide more potent and 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. Further, there is a requirement 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. Further, there is a need to provide more potent KRas inhibitors that exhibit selective inhibition preferentially inhibiting the KRas G12D variant over the KRas wild type. Further, there is also a need to provide more potent KRas inhibitors that exhibit selective inhibition preferentially inhibiting the KRas G12C, G12D, and / or G12V variants over HRAS or NRAS. Still further, there is also a need to provide more potent KRas inhibitors that exhibit selective inhibition preferentially inhibiting the KRas G12C, G12D, and G12V variants over HRAS or NRAS. These panKRas inhibitors may be KRas wild type inhibitors or may be more selective than the KRas wild type. The present invention addresses one or more of these needs by providing novel KRas inhibitors.

Summary of the Invention

[0005] Formula I:

Chem.

Chem.

Chemical formula

Chemical formula

[0006] Also provided herein is a method of using a compound of formula I, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof for the treatment of cancer, specifically for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. The method includes administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0007] Further provided herein are a compound of formula I, and a pharmaceutically acceptable salt thereof, for use in therapy. Also provided herein are a compound of formula I, and a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, specifically for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. Also provided herein is the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, specifically for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

Mode for Carrying Out the Invention

[0008] Novel inhibitors of KRas gain-of-function mutations G12C, G12D, and / or G12V are described herein. These novel compounds can address the need for inhibitors of KRas GTP activity in gain-of-function mutants in the treatment of cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, or esophageal cancer. Some of these novel KRas inhibitor compounds are selective for the KRas G12D variant over wild-type KRas (and possibly other variants such as G12C or G12V). Additionally, some of these novel KRas inhibitor compounds are non-selective and inhibit both wild-type KRas and the KRas G12D variant (and / or possibly other variants such as G12C or G12V). Also, some of these novel KRas inhibitor compounds are non-selective and inhibit both wild-type KRas and both the Kras G12C, G12D, and / or G12V variants.

[0009] The present invention provides a compound of formula I:

Chemical formula

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

[0011] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is an N - linked cyclic amine or the following formula:

Chemical formula

[0012] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is an N-linked cyclic amine or the following formula:

Chemical formula

[0013] ​In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 3b , and R 3c are each independently H or halogen, R4 is an N-linked cyclic amine or a group of the following formula:

Chemical formula

[0014] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R 3b , and R 3c are each independently H or halogen, and R4 is of the following formula:

Chemical formula

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0039] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R2 is F or Cl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0113] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of the following formula:

Chemical formula

[0114] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of the following formula:

Chemical formula

[0115] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 is C 1~4 alkyl optionally substituted with one or more hydroxyls, methoxys or oxetanes.

[0116] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R5 is C 1~4 alkyl optionally substituted with one or more hydroxyls or methoxys.

[0117] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of the following formula:

Chemical formula

[0118] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of the following formula:

Chemical formula

[0119] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is of the following formula:

Chemical formula

[0120] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

Chemical formula

Chem.

[0121] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

Chem.

[0122] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R1 is

Chem.

[0123] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, ring

Chem.

Chem.

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

[0125] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is an N-linked pyrrolidine, piperidine, piperazine, or morpholine, each of which is optionally crosslinked by C 1~3 alkylene, each of which is optionally substituted with one or more halogens, hydroxyl, -NR 6a R 6a , imidazole or C 1~3 alkyl, imidazole is optionally substituted with methyl, C1~3 alkyl is optionally substituted with -NR 6a R 6a or hydroxyl.

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

[0127] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is N-linked pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole, each of which is optionally bridged by C 1~3 alkylene, and each of which is optionally substituted with one or more halogens, hydroxyl, C 1~3 alkoxy, -NR 6a R 6a , azetidine, C 1~3 alkyl, or imidazole optionally substituted with methyl, and azetidine is optionally substituted with hydroxyl or C 1~3 alkoxy, and C 1~3 alkyl is optionally substituted with -NR 6a R 6a or hydroxyl.

[0128] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is N-linked 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-6-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane, each of which is optionally substituted with one or more halogens, -NR 6a R 6a or -NR 6a R 6a and is optionally substituted with C 1~3 alkyl which is optionally substituted.

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

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0130] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] an N-bonded cyclic amine selected from

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

[0132] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is [Chemical formula] an N-bonded cyclic amine selected from

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

Chem.

Chem.

Chem.

Chem.

[0134] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is,

Chem.

Chem.

[0135] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is,

Chem.

[0136] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is,

Chem.

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

Chem.

Chem.

Chem.

Chem.

[0138] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chem.

Chem.

[0139] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chem.

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

Chem.

[0141] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chem.

[0142] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chem.

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

Chemical formula

[0144] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0145] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0146] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0147] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0148] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0149] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is of the following formula:

Chemical formula

[0150] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0151] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0152] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is [ka] is selected from.

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

[0154] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is [ka] is selected from.

[0155] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is [ka] is selected from.

[0156] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is [ka] is selected from.

[0157] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is [ka] is selected from.

[0158] In one embodiment of the compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is [ka] is as follows.

[0159] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

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

Chemical formula

[0161] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0162] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0163] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0164] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0165] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0166] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0167] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0168] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0169] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0170] In one embodiment of the compound of formula I or a pharmaceutically acceptable salt thereof, R4 is

Chemical formula

[0171] In the above-mentioned one embodiment of the compound of formula I, or a pharmaceutically acceptable salt thereof, R4 is the following formula:

Chemical formula

Chemical formula

[0172] In one embodiment of the compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is of the following formula:

Chemical formula

[0173] Examples of these compounds of Formula I are shown below.

Chemical formula

[0174] In the above embodiment of the compound of Formula I, the chemical diagrams are shown monotonously 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 can have various enantiomers, diastereomers, and atropisomers that may exist and are included herein.

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

[0176] It is understood that isotope derivatives can be prepared using any of the various techniques recognized in the art. For example, isotope derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein using isotope-labeled reagents or pharmaceutically acceptable salts thereof instead of non-isotope-labeled reagents.

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

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

[0179] The compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0180] The compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

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

[0182] A compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is [ka] [ka] [ka] [ka] [ka]

Chem.

Chem.

Chem.

[0183] The compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is

Chem.

Chem.

Chem.

Chem.

[0184] The compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is

Chem.

Chem.

Chem.

Chem.

[0185] The compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is

Chem.

[0186] A compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is [Chemistry] It is selected from or a pharmaceutically acceptable salt thereof.

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

[0188] Also provided herein is a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof (examples include, but are not limited to, the compounds disclosed herein), and a pharmaceutically acceptable carrier, diluent, or excipient.

[0189] Further provided herein is a method of treating cancer, the method comprising administering to a patient in need of treatment an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In this method, the cancer can be lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, gastric cancer, or esophageal cancer. In this method, the cancer can 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.

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

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

[0192] A method of treating a patient having cancer with a KRas G12C, G12D, and / or G12V mutation, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, is further provided herein. In this method, the cancer having a KRas G12C, G12D, and / or G12V mutation can be a KRas G12C, G12D, and / or G12V mutant lung cancer, a KRas G12C, G12D, and / or G12V mutant pancreatic cancer, a KRas G12C, G12D, and / or G12V mutant cervical cancer, a KRas G12C, G12D, and / or G12V mutant esophageal cancer, a KRas G12C, G12D, and / or G12V mutant endometrial cancer, a KRas G12C, G12D, and / or G12V mutant ovarian cancer, a KRas G12C, G12D, and / or G12V mutant cholangiocarcinoma, and a KRas G12C, G12D, and / or G12V mutant colorectal cancer. In one embodiment, the cancer having 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 having 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 having a KRas G12C, G12D, and / or G12V mutation can be a KRas G12C, G12D, and / or G12V mutant colorectal cancer.

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

[0194] Also provided herein is a method of treating cancer in a patient in need thereof, wherein the patient has cancer determined to express a KRas G12D variant protein. The method comprises administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Also provided herein is a method of treating cancer in a patient in need thereof, wherein the patient has cancer determined to express a KRas G12C, G12D, and / or G12V variant protein. The method comprises administering to the patient an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The G12C, G12D, and / or G12V mutation status of one or more cancer cells can be determined by several assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained and subjected to sequencing and / or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, for example, in advanced cancers. Non-limiting examples of sequencing techniques and PCR techniques used to determine the mutation status (e.g., G12C, G12D, and / or G12V 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, and pyrosequencing and multi-analyte profiling.

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

[0196] The compounds provided herein according to Formula I, or pharmaceutically acceptable salts thereof, may 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. More specifically, the cancer can 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 that express a mutant KRas G12D protein. When 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. The cancer may have one or more cancer cells that express mutant KRas G12C, G12D, and / or G12V proteins. When the cancer cells express the 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.

[0197] A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, 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 expressing a mutant KRas G12D protein, is also provided herein. A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, 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 expressing a mutant KRas G12C, G12D, and / or G12V protein, is also provided herein. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in 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, simultaneously, separately, or sequentially, is further provided herein. A combination comprising a compound of formula I, 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 use simultaneously, separately, or sequentially in the treatment of cancer, is additionally provided.

[0198] A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12D protein, is also provided. A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, is also provided. Further provided is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination with, separately from, or sequentially with a PD-1 or PD-L1 inhibitor for use in the treatment of cancer. Additionally provided is a combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor for use simultaneously, separately, or sequentially in the treatment of cancer. As used herein, the PD-1 or PD-L1 inhibitor can be pembrolizumab, or the PD-1 or PD-L1 inhibitor can be nivolumab, or the PD-1 or PD-L1 inhibitor can be semiprimab, or the PD-1 or PD-L1 inhibitor can be sintilimab, or the PD-1 or PD-L1 inhibitor can be atezolizumab, or the PD-1 or PD-L1 inhibitor can be avelumab, or the PD-1 or PD-L1 inhibitor can be durvalumab, or the PD-1 or PD-L1 inhibitor can be lodapilimab. As described herein, the cancer can be non-small cell lung cancer having one or more cells expressing a KRas G12D mutant protein, or the cancer can be colorectal cancer having one or more cells expressing a KRas G12D mutant protein, or the cancer can be mutant pancreatic cancer having one or more cells expressing a KRas G12D mutant protein. The method also includes treating cancers of other origins having a KRas G12D mutant.As described herein, the cancer can be non-small cell lung cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins, or the cancer can be colorectal cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins, or the cancer can be mutant pancreatic cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having the KRas G12C, G12D, and / or G12V mutants.

[0199] A method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer having one or more cells expressing a mutant KRas G12D protein, in combination with, separately from, or sequentially with, a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, is further provided. A combination comprising a compound of formula I, 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 having one or more cells expressing a mutant KRas G12D protein is additionally provided. As used herein, the CDK4 / CDK6 inhibitor can be abemaciclib, or 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 having one or more cells expressing a KRas G12D mutant protein, the cancer can be colorectal cancer having one or more cells expressing a KRas G12D mutant protein, the cancer can be mutant pancreatic cancer having one or more cells expressing a KRas G12D mutant protein. The method also includes treating cancers of other origins having a KRas G12D mutant. A method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, is also provided.A compound of formula I, or a pharmaceutically acceptable salt thereof, is further provided for use in the treatment of cancer in combination with, separately in combination with, or sequentially in combination with a CDK4 / CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, in the presence of one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. Also provided is a combination comprising a compound of formula I, 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 in the presence of one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. As used herein, the CDK4 / CDK6 inhibitor can be abemaciclib, the CDK4 / CDK6 inhibitor can be palbociclib, or the CDK4 / CDK6 inhibitor can be ribociclib. As described herein, the cancer can be non-small cell lung cancer having one or more cells expressing the KRas G12C, G12D, and / or G12V mutant proteins, the cancer can be colorectal cancer having one or more cells expressing the KRas G12C, G12D, and / or G12V mutant proteins, or the cancer can be mutant pancreatic cancer having one or more cells expressing the KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having the KRas G12C, G12D, and / or G12V mutants.

[0200] A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, is further provided for use in combination with, separately from, or sequentially with an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. Additionally, a combination is further provided comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for use simultaneously, separately, or sequentially in the treatment of cancer. As used herein, the EGFR inhibitor can be erlotinib, the EGFR inhibitor can be afatinib, the EGFR inhibitor can be gefitinib, the EGFR inhibitor can be cetuximab. As described herein, the cancer can be non-small cell lung cancer having one or more cells expressing a KRas G12D mutant protein, the cancer can be colorectal cancer having one or more cells expressing a KRas G12D mutant protein, or the cancer can be mutant pancreatic cancer having one or more cells expressing a KRas G12D mutant protein. The method also includes treating cancers of other origins having a KRas G12D mutant.

[0201] A method of treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins, is also provided. Also provided is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination with, separately from, or sequentially with, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. Further provided is a combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for use simultaneously, separately, or sequentially in the treatment of cancer. As used herein, the EGFR inhibitor can be erlotinib, the EGFR inhibitor can be afatinib, the EGFR inhibitor can be gefitinib, the EGFR inhibitor can be cetuximab. As described herein, the cancer can be non-small cell lung cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins, the cancer can be colorectal cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins, or the cancer can be mutant pancreatic cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins. The method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V mutants.

[0202] A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12D protein, is also provided. A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, is also provided. A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, 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, is also provided. A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, is further provided for use in the treatment of cancer having one or more cells expressing a mutant KRas G12D protein, in combination simultaneously, separately, or sequentially with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof. A compound of formula I, or a pharmaceutically acceptable salt thereof, is further provided for use in the treatment of cancer having one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, in combination simultaneously, separately, or sequentially with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof. A compound of formula I, or a pharmaceutically acceptable salt thereof, is further provided for use in the treatment of cancer having one or more cells expressing a mutant KRas G12D protein, in combination simultaneously, separately, or sequentially with an ERK inhibitor, or a pharmaceutically acceptable salt thereof.For the treatment of cancer having one or more cells expressing mutant KRas G12C, G12D, and / or G12V proteins, a compound of formula I, or a pharmaceutically acceptable salt thereof, is further provided for use in combination with, separately in combination with, or sequentially in combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof. Also provided is a combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the ERK inhibitor can be LY3214996, or 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 having one or more cells expressing the KRas G12D mutant protein, the cancer can be colorectal cancer having one or more cells expressing the KRas G12D mutant protein, the cancer can be mutant pancreatic cancer having one or more cells expressing the KRas G12D mutant protein. The method also includes treating cancers of other origins having the KRas G12D mutant. As described herein, the cancer can be non-small cell lung cancer having one or more cells expressing the KRas G12C, G12D, and / or G12V mutant proteins, the cancer can be colorectal cancer having one or more cells expressing the KRas G12C, G12D, and / or G12V mutant proteins, the cancer can be mutant pancreatic cancer having one or more cells expressing the KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having the KRas G12C, G12D, and / or G12V mutants.

[0203] A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, 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, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in combination simultaneously, separately, or sequentially with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, is further provided, wherein the cancer has one or more cells expressing a mutant KRas G12D protein. A combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer, is additionally provided. A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in combination simultaneously, separately, or sequentially with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, is further provided, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein. A combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer, is additionally provided.As used herein, an Aurora A inhibitor can be 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-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 can be non-small cell lung cancer having one or more cells that express the KRas G12D mutant protein, the cancer can be colorectal cancer having one or more cells that express the KRas G12D mutant protein, and the cancer can be mutant pancreatic cancer having one or more cells that express the KRas G12D mutant protein. The method also includes treating cancers of other origins having the KRas G12D mutant. As described herein, the cancer can be non-small cell lung cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins, the cancer can be colorectal cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins, and the cancer can be mutant pancreatic cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins.This method also includes treating cancers of other organs having KRas G12C, G12D, and / or G12V variants.

[0204] A method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12D protein, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, which has one or more cells expressing a mutant KRas G12D protein, in combination with, separately from, or sequentially with, an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, is further provided. Also provided is a method for treating cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, which has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, in combination with, separately from, or sequentially with, an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, is further provided. Additionally provided is a combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and an SHP2 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the 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 cephusrogin, 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.Examples of additional 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 having one or more cells that express the KRas G12D mutant protein, the cancer can be colorectal cancer having one or more cells that express the KRas G12D mutant protein, and the cancer can be mutant pancreatic cancer having one or more cells that express the KRas G12D mutant protein. The method also includes treating cancers of other origins having the KRas G12D mutant. As described herein, the cancer can be non-small cell lung cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins, the cancer can be colorectal cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins, and the cancer can be mutant pancreatic cancer having one or more cells that express the KRas G12C, G12D, and / or G12V mutant proteins. The method also includes treating cancers of other organs having the KRas G12C, G12D, and / or G12V mutants.

[0205] A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, wherein the cancer has one or more cells expressing a mutant KRas G12D protein, is also provided. A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, is further provided for use in combination with, separately from, or sequentially with a platinum agent, or a pharmaceutically acceptable salt thereof, for the treatment of cancer having one or more cells expressing a mutant KRas G12D protein. A combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, for simultaneous, separate, or sequential use in the treatment of cancer is additionally provided. 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 having one or more cells expressing a KRas G12D mutant protein, the cancer can be colorectal cancer having one or more cells expressing a KRas G12D mutant protein, the cancer can be mutant pancreatic cancer having one or more cells expressing a KRas G12D mutant protein. The method also includes treating cancers of other origins having a KRas G12D mutant. As used herein, the platinum agent can be cisplatin, the platinum agent can be carboplatin, or the platinum agent can be oxaliplatin.As described herein, the cancer can be non-small cell lung cancer having one or more cells in which the cancer expresses a KRas G12C, G12D, and / or G12V mutant protein, the cancer can be colorectal cancer having one or more cells in which the cancer expresses a KRas G12C, G12D, and / or G12V mutant protein, and the cancer can be mutant pancreatic cancer having one or more cells in which the cancer expresses a KRas G12C, G12D, and / or G12V mutant protein. The method also includes treating cancers of other organs having a KRas G12C, G12D, and / or G12V mutant.

[0206] A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, wherein the cancer has one or more cells expressing a mutant KRas G12D protein, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer having one or more cells expressing a mutant KRas G12D protein, in combination with, separately from, or sequentially with pemetrexed is further provided. A combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed for simultaneous, separate, or sequential use in the treatment of cancer having one or more cells expressing a mutant KRas G12D protein is additionally provided. As described herein, the cancer has one or more cells expressing a KRas G12D mutant protein. Further, 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 having one or more cells expressing a KRas G12D mutant protein, or the cancer can be mutant pancreatic cancer having one or more cells expressing a KRas G12D mutant protein. The method also includes treating cancers of other origins having a KRas G12D mutant. A method for treating cancer, comprising administering to a patient in need of treatment an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, wherein the cancer has one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, is also provided. A compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer having one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein, in combination with, separately from, or sequentially with pemetrexed is further provided.A combination is additionally provided for the simultaneous, separate, or sequential use in the treatment of cancer of a compound of formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, having one or more cells expressing a mutant KRas G12C, G12D, and / or G12V protein. As described herein, the cancer has one or more cells expressing a KRas G12C, G12D, and / or G12V 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 having one or more cells expressing a KRas G12C, G12D, and / or G12V mutant protein, or the cancer can be mutant pancreatic cancer having one or more cells expressing a KRas G12C, G12D, and / or G12V mutant protein. The method also includes treating cancers of other organs having a KRas G12C, G12D, and / or G12V mutant.

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

[0208] The pharmaceutical composition containing the compound of Formula I described herein may be prepared using pharmaceutically acceptable additives. As used herein, the term "pharmaceutically acceptable additives" with respect to pharmaceutical compositions refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the composition or formulation and are not harmful to the patient. Examples of pharmaceutical compositions and processes for their preparation can be found in "Remington: The Science and Practice of Pharmacy", Loyd, V., et al. Eds., 22 ndIt can be found in Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include physiological saline, water, starch, sugar, mannitol, and silica derivatives; binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethylene glycol.

[0209] As used herein, the term "effective amount" refers to an amount of a dosage that is effective to achieve a desired therapeutic result, such as the treatment of a disorder or disease, e.g., the treatment of cancerous lesions or the progression of abnormal cell growth and / or cell division. Factors considered in determining the effective amount or dosage of a compound include the following: whether the compound or its salt is administered, if used, the co-administration of other agents, the type of patient being treated, the size, age, gender, and general health status of the patient, the degree 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 medications.

[0210] A treating physician, veterinarian, or other medical practitioner will be able to determine the effective amount of the compound for the treatment of a patient in need thereof. The pharmaceutical composition can be formulated as tablets or capsules for oral administration, as a solvent for oral administration, or as a solvent for injection. The tablets, capsules, or solvents can contain an effective amount of the compound of the present invention for treating a patient in need of cancer treatment.

[0211] As used herein, the terms "treating," "treat," or "treatment" include delaying, managing, retarding, alleviating, preventing, reversing, preventing, or improving the progression or severity of an existing symptom, disorder, condition, which may include specifically delaying 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 symptoms of a disorder or disease.

[0212] As used herein, the term "patient" refers to a mammal in need of treatment. Specifically, the patient can be a human in need of treatment for cancer, such as cancer having KRas G12C, G12D, and / or G12V variants.

[0213] Certain abbreviations are defined as follows: "ACN" refers to acetonitrile, "AcOH" or "HOAc" refers to acetic acid, "AIBN" refers to azobisisobutyronitrile, "Alloc" refers to an 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-1,1'-biphenyl, "BroP" refers to bromotris(dimethylamino)phosphonium hexafluorophosphate, "Cbz" refers to a 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, "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, "DMEM" refers to Dulbecco's modified Eagle's medium, "DMF" refers to N,N-dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "DNA" refers to deoxyribonucleic acid, "DPEPhosPdCl2" refers to dichlorobis(diphenylphosphinophenyl)ether palladium(II), "DTT" refers to dithiothreitol, "EDTA" refers to ethylenediaminetetraacetic acid, "EGTA" refers to ethylene glycol-bis(b-aminoethyl ether)-N,N,N',refers to N'-tetracetic 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, "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] refers to pyridinium 3-oxide hexafluorophosphate, "Hex" or "hex" refers to hexane or hexanes, "HPLC" refers to high performance liquid chromatography, "HRP" refers to horseradish peroxidase, "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 methyl group, "MeOH" refers to methanol, "min" refers to minute, "MTBE" refers to methyl tert-butyl ether, "NaBH(OAc)3 refers to sodium triacetoxyborohydride, "NaOMe" refers to sodium methoxide, "NBS" refers to N-bromosuccinimide, "NCS" refers to N-chlorosuccinimide, "N-methyl-L-prolinol" refers to [(2S)-1-methylpyrrolidin-2-yl]methanol, "NMM" refers to N-methylmorpholine, "NMP" refers to 1-methylpyrrolidin-2-one, "NIS" refers to N-iodosuccinimide, "PCR" refers to polymerase chain reaction, "Pd-117" refers to dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II), CAS 205319-06-8, "Pd-118" refers to 1,1’-bis(di-tert-butylphosphino)ferrocene palladium dichloride, CAS 95408-45-0, "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium(0), "Pd(dppf)Cl2" refers to [1,1’-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) refers to, "Pd(OAc)2 refers to palladium(II) acetate, Pd(PPh3)4 refers to tetrakis(triphenylphosphine)palladium(0), "PE" refers to petroleum ether or diethyl ether, "Ph" refers to phenyl, "RBF" refers to a round bottom flask, "RPMI" refers to the 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 (trademark)" 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, "TBDMSCl" refers to tert-butyldimethylsilyl chloride, "TBDMS" refers to the tert-butyldimethylsilyl group, "tBu" refers to the tert-butyl group, "t-BuOH" refers to tert-butanol or tert-butyl alcohol, "A" refers to triethylamine, "TES" refers to triethylsilane, "Tf2O" refers to trifluoromethanesulfonic anhydride, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "TMEDA" refers to tetramethylethylenediamine, "t, R" refers to the retention time, "XantPhos" refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, "XPhos" refers to 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl, "XPhos Palladacycle G2" refers to chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), CAS 1310584-14-5, "XPhos Palladacycle Gen.4" or "XPhos Pd G4" refers to methanesulfonato(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II), CAS 1599466-81-5.

[0214] Individual isomers, enantiomers, diastereomers, and atropisomers can be separated or resolved at any convenient point in the synthesis of the compounds listed below by methods such as selective crystallization techniques or chiral chromatography (see, e.g., 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 that can exist in different conformations or as different rotational isomers. Atropisomers are compounds that exist in different conformations resulting from restricted rotation around a single bond. Atropisomers can be isolated as distinct chemical species when the energy barrier to rotation around the single bond is sufficiently high and the rate of interconversion is sufficiently slow to separate the individual rotational isomers from one another. This specification is intended to include all isomers, enantiomers, diastereomers, and atropisomers that are possible for the compounds disclosed herein or that can be made using the compounds disclosed herein. In the molecules described herein, only those molecules for which the absolute configuration (or atropisomer conformation) of the chiral center is known are depicted using the nomenclature rules or chemical formulas drawn to show chirality or atropisomerism. One of ordinary skill in the art will readily understand and be able to identify when other chiral centers are present in the molecules described herein.

[0215] Any one of the compounds of Formula I that can form a salt chemically can be readily converted to a pharmaceutically acceptable salt and isolated as a pharmaceutically acceptable salt. Salt formation can occur upon addition of a pharmaceutically acceptable acid to form an acid addition salt. The salt can also be formed simultaneously upon deprotection of nitrogen or oxygen, i.e., upon removal of a protecting group. Examples of reactions and conditions for salt formation can be found in Gould, P.L., "Salt selection for basic drugs," International Journal of Pharmaceutics, 33:201-217 (1986); Bastin, R.J., et al. "Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities," Organic Process Research and Development, 4:427-435 (2000); and Berge, S.M., et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 66:1-19, (1977).

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

[0217] Preparation 1 5-Fluoroisobenzofuran-1(3H)-one

Chemical formula

[0218] Preparation 2 4-Bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one [Chemical formula] To a stirred mixture of 5-fluoroisobenzofuran-1(3H)-one (300 g, 1.97 mol) in H2SO4 (1,500 mL), HNO3 (273.38 g, 4.348 mol, 2.2 equiv) was added dropwise at 65 °C. The reaction was stirred for 1 h and then cooled to room temperature. 1,3-Dibromo-5,5-dimethylimidazolidine-2,4-dione (2,255.43 g, 7.88 mol, 4 equiv) was added portionwise over 20 min and stirred at room temperature for about 18 h. The mixture was poured into ice / water (pretreated with 3 kg of Na2SO3) and filtered. The filter cake was dissolved in EtOAc (3,000 mL), washed with saturated aqueous Na2CO3 (2 × 1,000 mL), brine (2 × 1,000 mL), dried over anhydrous Na2SO4, and concentrated. The residue was triturated with 10:1 hexane / EtOAc (660 mL), filtered, and dried at 50 °C for about 18 h to give the title compound (270 g, 49%) as a yellow solid, which was used in the next step without further purification.1 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 5.51 (s, 2H).

[0219] Preparation 3 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran

Chem.

[0220] Preparation 4 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine [Chemistry] 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (110 g, 420 mmol) and NH4Cl (112.3 g, 2.10 mol, 5 eq) in a stirred mixture of EtOH (1,000 mL) and H2O (200 mL) were added Fe (117.22 g, 2.09 mol, 5 eq) portionwise at room temperature, and then stirred at 80 °C for about 18 h. The mixture was filtered and concentrated. The mixture was diluted with H2O (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 by silica (25% - 50% EtOAc / hexane) to give the title compound (70 g, 72%) as a yellow solid. MS(ES) m / z = 231 (M+1).

[0221] Preparation 5 (4-Chloro-1,2-phenylene)dimethanol [Chemistry] A solution of 4-chlorophthalic anhydride (250 g, 1.34 mol, 1.00 eq) in THF (500 mL) was added dropwise to a stirred mixture of LiAlH4 (1.9 L, 2.74 mol, 2 eq, 2.5 M THF solution) in THF (1 L) at -20 °C under N2. The resulting mixture was stirred at 45 °C for 30 min under N2. H2O (1.5 L) and 15% NaOH (500 mL) were added at room temperature to quench the reaction. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (219.5 g, 93%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d6) δ 7.45 - 7.36 (m, 2H), 7.28 (dd, J = 8.2 Hz, 1H), 5.40 - 5.13 (m, two H), 4.54 (s, 2H), 4.49 (s, 2H).

[0222] Preparation 6 5-Chloro-1,3-dihydroisobenzofuran [Chemical formula] (4-Chloro-1,2-phenylene)dimethanol (219.5 g, 1.271 mol) and dimethyl carbonate (458.2 g, 5.082 mol, 4 equivalents) in ACN (3 L) were stirred, and NaOMe (137.4 g, 2.544 mol, 2 equivalents) was added portionwise at room temperature. The resulting mixture was stirred at 80 °C for about 18 h under N2. The mixture was concentrated under reduced pressure, diluted with H2O (2 L), and extracted with EtOAc (3 × 2 L). The combined organic layers were washed with brine (2 × 2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica (10:1 - 8:1 hexane / EtOAc) to give the title compound (165 g, 82%) as a light brown solid. 1 1H NMR (300 MHz, DMSO-d6) δ 7.42 - 7.37 (m, 1H), 7.33 (d, J = 1.4 Hz, 2H), 4.99 (s, 4H).

[0223] Preparation 7 5-Chloro-6-nitro-1,3-dihydroisobenzofuran [Chemical formula] To a solution of 5-chloro-1,3-dihydroisobenzofuran (110 g, 712 mmol) in H2SO4 (700 mL) at -10 °C, a solution of KNO3 (64.74 g, 640 mmol, 0.9 equivalent) in H2SO4 (200 mL) was added dropwise at -5 °C to 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 min and then slowly added to stirred ice-cold H2O. The precipitated solid was collected by filtration and washed with H2O (3 × 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. 11H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.75 (s, 1H), 5.07 - 5.02 (m, 4H).

[0224] Preparation 8 4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran

Chem.

[0225] Preparation 9 7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine

Chem.

[0226] Preparation 10 N-(7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide

Chemical Structure

[0227] Preparation 11 N-(7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)-3-ethoxyacrylamide

Chemical Structure

[0228] Preparation 12 4-Bromo-5-chloro-3,6-dihydrofuro[3,4-f]quinolin-7(1H)-one

Chem.

[0229] Preparation 13 4-Bromo-5-fluoro-3,6-dihydrofuro[3,4-f]quinolin-7(1H)-one

Chem.

[0230] Preparation 14 4-Bromo-5,7-dichloro-1,3-dihydrofuro[3,4-f]quinoline

Chem.

[0231] Preparation 15 4-Bromo-7-chloro-5-fluoro-1,3-dihydrofuro[3,4-f]quinoline [Chemical formula] To a stirred suspension of 4-bromo-5-fluoro-3,6-dihydrofuro[3,4-f]quinolin-7(1H)-one (1.2 g, 4.2 mmol) in DCM (40 mL) was charged (chloromethylene)dimethyliminium chloride (2.2 g, 17 mmol, 4 equiv) and stirred at room temperature for about 18 h. The reaction was diluted with DCM and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered, concentrated to give a solid, which was triturated with a little DCM. The solid was filtered, washed with a little DCM and air dried to give Batch 1. The filtrate was concentrated and purified by silica gel eluting with EtOAc / hexane (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).

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

[0233] Preparation 17 (1-(((4-Bromo-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)oxy)methyl)cyclopropyl)methyl methanesulfonate

Chemical formula

[0234] Preparation 18 4-Bromo-5-fluoro-7-((1-(morpholinomethyl)cyclopropyl)methoxy)-1,3-dihydrofuro[3,4-f]quinoline

Chemical formula

[0235] Preparation 19 N - [(7 - bromo - 6 - fluoro - 1,3 - dihydroisobenzofuran - 5 - yl) carbamothioyl]ethyl carbamate

Chemical formula

[0236] Preparation 1A N - [(7 - bromo - 6 - chloro - 1,3 - dihydroisobenzofuran - 5 - yl)carbamothioyl]ethyl carbamate

Chemical formula

[0237] Preparation 20 (((7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamic acid ethyl

Chem.

[0238] Preparation 2A (((7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamic acid ethyl

Chem.

[0239] Preparation 21 6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol

Chem.

[0240] Preparation 3A 6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol

Chem.

[0241] Preparation 22 6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline

Chem.

[0242] Preparation 1B 6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline

Chem.

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

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

[0245] Preparation 24 tert-Butyl 8-(6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [Chemistry] 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 minutes. H2O (1 L) was slowly added via an addition funnel, and the mixture was stirred at room temperature for 1 hour. The solid was filtered, washed with H2O (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).

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

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

[0248] Preparation 26 Methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate

Chem.

[0249] Preparation 27 4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid

Chem.

[0250] Preparation 28 (4-Bromo-5-fluorobenzo[b]thiophen-2-yl)carbamic acid tert-butyl [Chemical formula] A solution of 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid (1.5 g, 5.5 mmol) in t-butanol (30 mL) was charged with TEA (1.5 mL, 11 mmol, 2.0 equiv) and diphenylphosphoryl azide (1.5 mL, 6.9 mmol, 1.3 equiv) and heated at 95 °C for 1 hour. The mixture was cooled and concentrated. The residue was purified by 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).

[0251] Preparation 29 (4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamic acid tert-butyl [Chemical formula] (4-Bromo-5-fluorobenzo[b]thiophen-2-yl)carbamic acid tert-butyl (3.08 g, 8.90 mmol), bis(neopentyl glycolato)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) were sparged with N2 for 20 min. Pd(ddpf)Cl2 (0.69 g, 0.90 mmol, 0.1 equiv) was added to the mixture. The reaction was sonicated for 3 min and then subjected to a vacuum / N2 refill cycle (3×) and heated at 100 °C for 3 h. The mixture was cooled to room temperature, filtered through Celite, and rinsed with 1:4 EtOAc / hexane. The filtrate was concentrated, and the residue was purified by silica (0–40% MTBE / hexane) to give the title compound (2.95 g, 87%) as a white solid. 1 H NMR (400 MHz, 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).

[0252] Preparation 30 (4-Chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl

Chem.

[0253] 2-Amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile. A suspension of (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)ethyl carbamate (11.9 g, 44.4 mmol) in DMSO (90 mL) was cooled to 0 °C. NaOH (5 M aqueous solution, 90 mL) was added dropwise over 15 minutes. The reaction mixture was heated to 105 °C over 1 hour and then cooled to room temperature. The reaction mixture was poured into an ice / water mixture (1.8 L), stirred until all the ice had melted, and filtered through diatomaceous earth. The solid was dried in a vacuum oven (50 °C) overnight, separated from the diatomaceous earth, and obtained as crude 2-amino-7-fluoro-thieno[3,2-c]pyridine-3-carbonitrile.

[0254] (3-Cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl. A mixture of crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (8.6 g, 44.4 mmol), DCM (90 mL), DMF (90 mL), and N,N-diisopropylethylamine (15.5 mL, 88.9 mmol) was cooled to 0 °C. 4-Dimethylaminopyridine (0.54 g, 4.42 mmol) and di-tert-butyl dicarbonate (14.6 g, 66.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the remaining material was diluted with DCM (400 mL) and 5% aqueous citric acid (250 mL). The aqueous phase was washed twice with DCM. The combined organic phases were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give (3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl (7.5 g, 58%) as a brown solid. MS (ES) m / z = 294 (M+1).

[0255] 2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide. 3-Chloroperoxybenzoic acid (9.00 g, 40.2 mmol) was added to a solution of (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl (7.85 g, 26.8 mmol) in DCM (180 mL). The reaction mixture was stirred at room temperature overnight and then cooled to 0 °C over about 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 by silica gel eluting with 0 - 6% MeOH / DCM. The fractions containing the desired material were combined with the solid obtained by filtration and concentrated to give N-(3-cyano-7-fluoro-5-oxide-thieno[3,2-c]pyridin-5-ium-2-yl)carbamic acid tert-butyl (7.26 g, 88%) as an off-white solid. MS (ES) m / z = 310 (M+1).

[0256] (4-Chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl. A suspension of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-5-oxide (5.27 g, 17.0 mmol) in 1,2-dichloroethane (34 mL) was cooled to 0 °C. A solution of phosphoryl chloride (32 mL, 344 mmol) in 1,2-dichloroethane (34 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, stirred at 45 °C for 90 minutes, and cooled to room temperature. The reaction mixture was diluted with 1,2-dichloroethane (100 mL) and added to a mixture of saturated aqueous NaHCO3 (500 mL), NaOH (5 M aqueous solution, 40 mL), and ice. Solid NaHCO3 was added to the stirred mixture to maintain the pH at about 6 - 7. When the foaming ended, 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 by silica gel eluting with 50 - 100% DCM / hexane. The fractions containing the desired substance were concentrated to give the title compound (3.87 g, 69%) as a white solid. MS(ES) m / z = 328 (M+1).

[0257] Preparation 1C (4-Bromo-7-chloro-3-cyanothieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl

Chemical Structure

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

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

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

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

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

[0263] Preparation 4B (4-Chloro-7-methylthieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl [Chemical Structure] Methyl 4-chloro-7-methylthieno[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, heated at 70 °C overnight, and cooled to room temperature. The reaction mixture was added to water (500 mL) and filtered. The solid was washed with water and dried to give methyl 4-chloro-7-methyl-thieno[3,2-c]pyridine-2-carboxylate (8.30 g, 90%) as a white solid. MS(ES) m / z = 242 (M+1).

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

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

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

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

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

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

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

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

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

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

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

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

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

Table 1

[0277] Preparation 32 tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Chemical Structure

[0278] Preparations 8B and 9B tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate, Atropisomer 1 and Atropisomer 2

Chemical Structure

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

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

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

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

[0283] The compounds in Table 2 below were prepared in a similar manner as described in Preparation 22. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 2:

Table 2

[0284] The compounds in Table 3 below were prepared in a similar manner as described in Preparation 23. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 3:

Table 3

[0285] Preparations 13B and 14B (3-Cyano-4-(3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamic acid tert-butyl, atropisomer 1 and atropisomer 2

Chem.

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

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

[0288] The compounds in Table 4 below were prepared in a manner similar to that described for Preparation 33. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 4:

Table 4-1

Table 4-2

[0289] Preparation 37 tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-3-(ethylsulfonyl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Chem.

[0290] The compounds in Table 5 below were prepared in a similar manner as described for Preparation 37. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 5:

Table 5-1

Table 5-2

Table 5-3

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

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

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

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

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

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

[0297] The compounds in Table 6 below were prepared in a similar manner to that described in Preparation 42. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 6:

Table 6-1

Table 6-2

Table 6-3

[0298] Preparation 29B (3S,4R)-tert-Butyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate

Chem.

[0299] Preparation 30B (3R,4S)-tert-Butyl 3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate

Chem.

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

[0301] [[ID=D10]] Preparation 4D tert-Butyl 3-(azetidin-1-yl)-4-hydroxypyrrolidine-1-carboxylate [Chemical formula] A mixture of tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (3 g, 20 mmol) and azetidine (1 mL, 20 mmol) in water (20 mL) was heated at 80 °C for 4.5 h and then cooled to room temperature. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase purification eluting with 20% ACN in aqueous NH4HCO3 containing a pH 9 buffer to give the title compound (2.4 g, 60%) as a white solid. MS (ES) m / z = 243 (M+1). The title compound is a mixture of trans isomers.

[0302] The compounds in Table 7 below were prepared in a similar manner to that described for Preparation 4D. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 7: [Table 7] 1 Pure trans isomers, analysis of Preparations 5D and 6D by preparative chiral SFC; Chiralpak-IC, 25 - 50% isopropanol in CO2 (containing 0.2% isopropylamine) indicates that Preparation 6D elutes first and Preparation 5D elutes second. 2 Pure trans isomers, preparative chiral-SFC; Chiralpak-AD, 20×250 mm, 20% MeOH in CO2 (containing 0.5% dimethylethylamine), 65 g / min indicates that Preparation 7D elutes second. 3 Mixture of trans isomers 4 Pure trans isomers, preparative chiral-SFC; Chiralpak-AD, 20×250 mm, 25% MeOH in CO2 (containing 0.5% dimethylethylamine), 80 mL / min 5 Trans isomer 6 Pure trans isomers, preparative chiral-SFC; Chiralpak-AD, 20×250 mm, 10% MeOH in CO2 (containing 0.5% dimethylethylamine), 80 mL / min

[0303] Preparation 32B (2S,3S)-3-((tert-butoxycarbonyl)(methyl)amino)-2-methylpyrrolidine-1-carboxylic acid tert-butyl

Chem.

[0304] The compounds in Table 8 below were prepared in a similar manner to that described in Preparation 32B. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 8:

Table 8-1

Table 8-2

[0305] Preparation 24D (2R,3S)-tert-Butyl 2-methyl-3-(4-methylpiperazin-1-yl)pyrrolidine-1-carboxylate

Chem.

[0306] Preparation 25D (2S,3R)-2-Methyl-3-(4-methylpiperazin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl

Chem.

[0307] Preparation 15C (2S,3S)-3-(Dimethylcarbamoyl)-2-methylpyrrolidine-1-carboxylic acid tert-butyl

Chem.

[0308] The compounds in Table 9 below were prepared in a similar manner as described in Preparation 15C. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 9:

Table 9

[0309] Preparation 16C (S)-3-(3-Methoxyazetidin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl

Chem.

[0310] Preparation 17C (S)-3-((Cyclopropylmethyl)(methyl)amino)pyrrolidine-1-carboxylic acid tert-butyl

Chemical formula

[0311] The compounds in Table 10 below were prepared in a manner similar to that described for Preparation 16C. In some cases, tosylate was used instead of mesylate. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 10:

Table 10-1

Table 10-2

Table 10-3

Table 10-4

Table 10-5

Table 10-6

[0312] The compounds in Table 11 below were prepared in a manner similar to that described for Preparation 32B. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 11 [Table 11]

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

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

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

[0316] The compounds in Table 13 below were prepared in the same manner as described in Preparation 122D. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 13: [Table 13]

[0317] Preparation 163D (2S,3S)-tert-Butyl 2-methyl-3-(4-methylpiperazin-1-yl)pyrrolidine-1-carboxylate [Chemical formula] Sodium triacetoxyborohydride (3.74 g, 17.7 mmol) was added portionwise to a solution of tert-butyl (S)-2-methyl-3-oxopyrrolidine-1-carboxylate (2.20 g, 11.0 mmol), 1-methylpiperazine (1.66 g, 16.6 mmol), and acetic acid (0.63 mL, 11.0 mmol) in DCM (15 mL). The mixture was stirred at room temperature. After 28 hours, the mixture was cooled to 0 °C and diluted with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (3.18 g) as a yellow oil. MS (ES) m / z = 284 (M+1).

[0318] The compounds in Table 14 below were prepared in the same manner as described in Preparation 163D. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 14: [Table 14-1] (Continued from Table 14) [Table 14-2]

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

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

[0321] The compounds in Table 15 below were prepared in the same manner as described in Preparation 186D. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 15: [Table 15]

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

[0323] The compounds in Table 16 below were prepared in a similar manner as described for Preparation 54B. In some cases, TFA was used instead of HCl. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 16: [Table 16-1] (Continued from Table 16) [Table 16-2] (Continued from Table 16) [Table 16-3] (Continued from Table 16) [Table 16-4] (Continued from Table 16) [Table 16-5] (Continued from Table 16) [Table 16-6] (Continued from Table 16)

Table 16-7

Table 16-8

Table 16-9

Table 16-10

Table 16-11

Table 16-12

Table 16-13

Table 16-14

Table 16-15

Table 16-16

Table 16-17

Table 16-18

Table 16-19

Table 16 - 20

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

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

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

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

[0328] The compounds in Table 17 below were prepared in a similar manner as described for Preparation 81B. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 17:

Table 17

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

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

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

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

[0333] Preparation 72C N,N-Dimethyl-1-((2S,3R)-2-methylpyrrolidin-3-yl)methanamine [Chemical formula] Lithium aluminum hydride (1 M in ether, 13.7 mL, 13.7 mmol) was added to a solution of (2S,3S)-N,N,2-trimethylpyrrolidine-3-carboxamide hydrochloride (0.660 g, 3.43 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 18 hours. A Fisher workup of the aluminum hydride reaction was performed. The filtrate was concentrated under reduced pressure to give the crude title compound (0.405 g, 83%). MS (ES) m / z = 143 (M+1).

[0334] The compounds in Table 18 below were prepared in the same manner as described for Preparation 72C. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 18: [Table 18]

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

[0336] The following compounds in Table 19 were prepared in a similar manner as described in Preparation 73C. Lithium aluminum deuteride may be used instead of lithium aluminum hydride. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 19:

Table 19

[0337] Preparation 369D (R)-tert-Butyl 4-(pyrrolidin-3-yl)piperazine-1-carboxylate

Chem.

[0338] The compounds in Table 20 below were prepared in the same manner as described for Preparation NEW. In some cases, the benzyl protecting group was removed. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 20:

Table 20

[0339] Preparation 57 8-(6-(2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl

Chemical formula

[0340] The compounds in Table 21 below were prepared in a similar manner as described in Preparation 57. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 21:

Table 21-1

Table 21-2

Table 21-3

Table 21-4

Table 21-5

Table 21-6

Table 21-7

Table 21-8

Table 21-9

[0341] Preparation 38A (tert-Butyl (3-cyano-7-fluoro-4-(5-fluoro-3-(3-morpholinoazetidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridin-2-yl)carbamate)

Chemical Structure

[0342] The compounds in Table 22 below were prepared in a manner similar to that described for Preparation 38A. Various bases such as sodium hydride or lithium bis(trimethylsilyl)amide were used instead of diisopropylethylamine. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 22:

Table 22-1

Table 22-2

Table 22-3

Table 22-4

Table 22-5

Table 22-6

Table 22-7

Table 22-8

Table 22-9

Table 22-10

Table 22-11

Table 22-12

Table 22-13

Table 22-14

Table 22-15

Table 22-16

Table 22-17

Table 22-18

Table 22-19

Table 22-20

Table 22-21

Table 22-22

Table 22-23

Table 22-24

Table 22-25

Table 22-26

Table 22-27

Table 22-28

Table 22-29

Table 22-30

Table 22-31

Table 22-32

Table 22-33

Table 22-34

Table 22-35

Table 22-36

Table 22-37

Table 22-38

Table 22-39

Table 22-40

Table 22-41

Table 22-42

Table 22-43

Table 22-44

Table 22-45

Table 22-46

Table 22-47

Table 22-48

Table 22-49

Table 22-50

Table 22-51

Table 22-52

Table 22-53

Table 22-54

Table 22-55

Table 22-56

Table 22-57

Table 22-58

Table 22-59

Table 22-60

Table 22-61

Table 22-62

Table 22-63

[0343] Preparation 88 8-(3-((1-((4-Acetylpiperazin-1-yl)methyl)cyclopropyl)methoxy)-6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl

Chem.

[0344] Preparation 89 6-Bromo-3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline

Chem.

[0345] Preparations 90 and 91 6-Bromo-3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline, Isomer 1 and Isomer 2

Chem.

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

[0347] Preparation 194B tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(((S)-2-(fluoromethyl)azetidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Chem.

[0348] Preparation 195B tert-Butyl 8-(6-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridin-4-yl)-5-fluoro-3-((1-(((S)-2-(methoxymethyl)azetidin-1-yl)methyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

Chem.

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

Table 23-1

Table 23-2

[0350] Preparation 92 tert-Butyl (3-cyano-4-(3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate, isomer 1

Chem.

[0351] Preparation 93 tert-Butyl (3-cyano-4-(3-((2,2-difluoro-1-(morpholinomethyl)cyclopropyl)methoxy)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate, isomer 2

Chem.

[0352] Preparation 95A (3-Cyano-4-(7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate tert-butyl

Chem.

[0353] Preparation 196B (3-Cyano-4-(7-((S)-3-(dimethylamino)pyrrolidin-1-yl)-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-7-fluorothieno[3,2-c]pyridin-2-yl)carbamic acid tert-butyl [Chemical Structure Diagram] (S)-1-(4-Bromo-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-7-yl)-N,N-dimethylpyrrolidin-3-amine was used in a manner similar to that of Preparation 33 to obtain the title compound (0.060 g, 8%). MS (ES) m / z = 609 (M+1).

[0354] The compounds in Table 24 below were prepared in a manner similar to that described for Preparation 33. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 24: [Table 24]

[0355] The compounds in Table 25 below were prepared in a manner similar to that described for Preparation 33B. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 25: [Table 25-1] (Continued from Table 25) [Table 25-2]

[0356] Modulation 94 4-(1-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile

Chemical Structure

[0357] The compounds in Table 26 below were prepared in a similar manner as described for Modulation 94. The compounds were purified using various methods that would be apparent to those skilled in the art. Table 26:

Table 26-1

Table 26-2

Table 26-3

Table 26-4

Table 26-5

Table 26-6

Table 26-7

Table 26-8

Table 26-9

Table 26-10

Table 26-11

Table 26-12

Table 26-13

[0358] Example 1 2-Amino-7-fluoro-4-(5-fluoro-1-(3-((R)-2-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile

Chemical Structure

[0359] The compounds in Table 27 below were prepared in a similar manner as described in Example 1. (2R)-2-((Tetrahydro-2H-pyran-2-yl)oxy)propanal was sometimes used in place of (R)-2-hydroxypropanal. The compounds were purified using various methods (including, but not limited to, strong cation exchange chromatography using ammonia-treated methanol), which would be apparent to those skilled in the art. Table 27:

Table 27-1

Table 27-2

Table 27-3

Table 27-4

Table 27-5

Table 27-6

Table 27-7

Table 27-8

Table 27-9

Table 27-10

Table 27-11

Table 27-12

Table 27-13

Table 27-14

Table 27-15

Table 27-16

Table 27-17

Table 27-18

[0360] Example 29A 2-Amino-7-fluoro-4-(5-fluoro-3-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile

Chemical Structure

[0361] Example 30A 2-Amino-7-fluoro-4-(5-fluoro-3-((S)-1-methyl-1,6-diazaspiro[3.4]octan-6-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile

Chemical formula

[0362] Example 19 2-Amino-7-fluoro-4-(5-fluoro-3-((1-(morpholinomethyl)cyclopropyl)methoxy)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile

Chemical formula

[0363] The compounds in Table 28 below were prepared in a similar manner to that described in Preparation 94 or Example 19. Various deprotection reagents such as HCl, TFA, or TBAF were used. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 28:

Table 28-1

Table 28-2

Table 28-3

Table 28-4

Table 28-5

Table 28-6

Table 28-7

Table 28-8

Table 28-9

Table 28-10

Table 28-11

Table 28-12

Table 28-13

Table 28-14

Table 28-15

Table 28-16

Table 28-17

Table 28-18

Table 28-19

Table 28-20

Table 28-21

Table 28-22

Table 28-23

Table 28-24

Table 28-25

Table 28-26

Table 28-27

Table 28-28

Table 28-29

Table 28-30

Table 28-31

Table 28-32

Table 28 - 33

Table 28 - 34

Table 28 - 35

Table 28 - 36

Table 28 - 37

Table 28 - 38

Table 28 - 39

Table 28 - 40

Table 28 - 41

Table 28 - 42

Table 28 - 43

Table 28 - 44

Table 28-45

Table 28-46

Table 28-47

Table 28-48

Table 28-49

Table 28-50

Table 28-51

Table 28-52

Table 28-53

Table 28-54

Table 28-55

Table 28-56

Table 28-57

Table 28-58

Table 28-59

Table 28-60

Table 28-61

Table 28-62

Table 28-63

Table 28-64

Table 28-65

Table 28-66

Table 28-67

Table 28-68

Table 28-69

Table 28-70

Table 28-71

Table 28-72

Table 28-73

Table 28-74

Table 28-75

Table 28-76

Table 28-77

Table 28-78

Table 28-79

Table 28-80

Table 28-81

Table 28-82

[0364] The compounds in Table 29 below were prepared in a manner similar to that described for Preparation 33B or Example 1. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 29:

Table 29-1

Table 29-2

Table 29-3

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

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

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

[0368] The compounds in Table 30 below were prepared in a similar manner as described in Example 263D. The compounds were purified using various methods that will be apparent to those skilled in the art. Table 30:

Table 30-1

Table 30-2

[0369] Example 273D 2-Amino-7-fluoro-4-(5-fluoro-3-(4-(propan-2-yl-d7)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile

Chem.

[0370] Example 274D 2-Amino-4-(3-(4-(ethyl-d5)octahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothieno[3,2-c]pyridine-3-carbonitrile

Chem.

[0371] Example 122C 2-Amino-7-fluoro-4-(5-fluoro-3-((2S,3S)-2-methyl-3-(((R)-3,3,3-trifluoro-2-hydroxypropyl)amino)pyrrolidin-1-yl)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)thieno[3,2-c]pyridine-3-carbonitrile

Chem.

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

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

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

[0375] PANC-1 cells were seeded at a density 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 hours later, 20 μL (1:3) serially diluted (in complete medium) test compounds (highest concentration 1 - 50 μM) and 20 μL serially diluted (in complete medium) controls (max signal well: 0.5% DMSO and min signal well: 10 μM reference positive control compound) were added to the cell plates and incubated at 37 °C / 5% CO2 for 2 hours. Complete lysis / binding buffer containing protease inhibitor cocktail (PIC) was prepared and stored on ice. One hour before the incubation of the cell plates was completed, GST-Raf-RBD was diluted in the lysis / binding buffer and 50 μL of the mixed buffer per well was added to the supplied opalescent ELISA assay plates and incubated at 4 °C for at least 1 hour with gentle rocking. After 2 hours, the cells were washed with 100 μL of ice-cold Ca2+ / Mg2+-free PBS and lysed with 100 μL of the lysis / binding buffer (AM11) supplied in the kit. After vigorously shaking the plates at ambient temperature for 30 - 50 minutes, the cell plates were centrifuged at 410 × g (approximately 1500 rpm) for 10 minutes. Wash buffer diluted 1-fold with ultra-high purity H2O and filtered through 0.2 μm was prepared at ambient temperature during the centrifugation step and then used to wash the assay plates coated with GST-Raf-RBD (3 × 100 μL). Next, 50 μL of the cell lysate was added to the assay plates coated with GST-Raf-RBD and incubated at ambient temperature for 1 hour with gentle shaking. During this incubation period, 1-fold antibody binding buffer was prepared from the thawed concentrate. The assay plates were washed with 1-fold wash buffer (3 × 100 μL) and then 50 μL of primary RAS antibody (supplied in the kit, number 101678) diluted 1:500 in 1-fold antibody binding buffer was added. After incubation at ambient temperature for 1 hour with gentle shaking, the assay plates were washed with 1-fold wash buffer (3 × 100 μL).Subsequently, 50 μL of anti-rat HRP-conjugated IgG secondary antibody (0.25 μg / μL), diluted 1:5000 in 1× antibody binding buffer, is added to each well of the assay plate and incubated for an additional 1 hour at ambient temperature with gentle shaking. Finally, the assay plate is washed with 1× wash buffer (4 × 100 μL), and subsequently 50 μL of a mixed chemiluminescent dilution standard solution (combination of reaction buffer and chemiluminescent substrate) is added at ambient temperature. Data from the luminescence emission of each well is recorded on a 2104 EnVision™ plate reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.

[0376] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test compound signal - Median minimum signal) / (Median maximum signal - Median minimum signal) × 100]. The maximum signal is the control well (DMSO) without inhibitor. The minimum signal is the control well containing a reference inhibitor sufficient to completely inhibit activity. IC 50 50 is determined by fitting the percent inhibition at each inhibitor concentration to a four-parameter non-linear logistic equation using Genedata Screener® version 17: y = (A + ((B - A) / (1 + ((x / C)^D)))) where y is the percent inhibition, A is the minimum asymptote, B is the maximum asymptote, C is the relative IC 50 50 or the inhibitor concentration that results in 50% inhibition within the fitting range of either or both asymptotes, and D is the Hill slope).

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

[0378] MKN-45 Cell Active 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 No. 52097) contains a 96-well glutathione-coated capture plate and glutathione-S-transferase (GST) conjugated to the Raf-Ras binding domain (RBD) protein supplied in the kit. Activated pan-RAS (GTP-bound) in cell extracts binds specifically to the Raf-RBD. Bound RAS is detected with a primary Ras antibody that recognizes human K-Ras (and H-Ras). The HRP-conjugated anti-rat IgG secondary antibody recognizes the primary antibody, and the developing substrate solution facilitates chemiluminescent reading.

[0379] MKN-45 cells were seeded at a density 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 hours later, 20 μL (1:3) of serially diluted (in complete medium) test compounds (highest concentration 1 - 10 μM) and 20 μL of serially diluted (in complete medium) controls (maximum signal well: 0.1% DMSO and minimum signal well: 10 μM reference positive control compound) were added to the cell plates and incubated at 37 °C / 5% CO2 for 2 hours. A complete lysis / binding buffer containing protease inhibitor cocktail (PIC) was prepared and stored on ice. One hour before the incubation of the cell plates was completed, GST-Raf-RBD was diluted in the lysis / binding buffer and 50 μL of the mixed buffer per well was added to the supplied opaque ELISA assay plates and incubated at 4 °C for at least 1 hour with gentle rocking. After 2 hours, the cells were washed with 100 μL of ice-cold Ca2+ / Mg2+-free PBS and lysed with 100 μL of the lysis / binding buffer (AM11) supplied in the kit. After the plates were vigorously shaken at ambient temperature for 30 - 50 minutes, the cell plates were centrifuged at 410 × g (approximately 1500 rpm) for 10 minutes. During the centrifugation step, the wash buffer was diluted 1:1 with ultrapure H2O and then used to wash the assay plates coated with GST-Raf-RBD (3 × 100 μL). Next, 50 μL of the cell lysate was added to the assay plates coated with GST-Raf-RBD and incubated at ambient temperature for 1 hour with gentle shaking. During this incubation period, 1× antibody binding buffer was prepared from the thawed concentrate. The assay plates were washed with 1× wash buffer (3 × 100 μL) and then 50 μL of the primary RAS antibody (supplied in the kit, number 101678) diluted 1:500 in 1× antibody binding buffer was added. After incubation at ambient temperature for 1 hour with gentle shaking, the assay plates were washed with 1× wash buffer (3 × 100 μL).Subsequently, 50 μL of anti-rat HRP-conjugated IgG secondary antibody (0.25 μg / μL), diluted 1:5000 in 1× antibody binding buffer, is added to each well of the assay plate and incubated for an additional 1 hour at ambient temperature with gentle shaking. Finally, the assay plate is washed with 1× wash buffer (4 × 100 μL), followed by the addition of 50 μL of a mixed chemiluminescent dilution standard solution (a combination of reaction buffer and chemiluminescent substrate) at ambient temperature. Data from the luminescence emission of each well is recorded on a 2104 EnVision™ plate reader (Perkin Elmer) using a luminescence program optimized for the assay plate dimensions.

[0380] The signal is converted to percent inhibition using the following equation: % Inhibition = 100 - [(Test compound signal - Median minimum signal) / (Median maximum signal - Median minimum signal) × 100]. The maximum signal is the control well (DMSO) without inhibitor. The minimum signal is the control well containing a reference inhibitor sufficient to completely inhibit activity. IC 50 is determined by fitting the percent inhibition at each inhibitor concentration to a four-parameter non-linear 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, C is the relative IC 50 or the inhibitor concentration that results in 50% inhibition within the fitting range of either or both asymptotes, and D is the Hill slope).

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

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

Table 31

[0383] The activity of the compound is determined by measuring the change in the phosphorylation level of extracellular signal-regulated kinases 1 and 2 (ERK1 / 2), which are downstream effectors in cells treated with the compound. The phosphorylation level of ERK-1 / 2 is measured using the AlphaLISA® SureFire® Ultra™ p-ERK1 / 2 (Thr202 / Tyr204) assay kit (number ALSU-PERK-A50K, PerkinElmer® Waltham, MA). The AlphaLISA® assay is a quantitative sandwich immunoassay that can be used to detect the phosphorylation of target proteins from cell lysates using bead-based alpha technology. This assay kit contains two antibodies, one that binds to the phospho-Thr202 / Tyr204 epitope on ERK-1 / 2 and the other that recognizes a distinct site on the protein. One of these antibodies is biotinylated and bound to streptavidin-coated alpha donor beads, and the other antibody is conjugated to AlphaLISA® acceptor beads. When ERK-1 / 2 is phosphorylated in the cell lysate, the donor beads and acceptor beads are brought into proximity with each other. When the donor beads are excited with light at a wavelength of 600 nm, the photosensitizer within the beads converts ambient oxygen to the singlet excited state. If the acceptor beads are within 200 nm of this reaction, the singlet oxygen reacts with the acceptor to produce 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 beads and acceptor beads, lysis buffer concentrate, and a set of proprietary buffers (activation buffer, reaction buffer 1, reaction buffer 2, and dilution buffer).

[0384] To perform these assays, test compounds and controls are acoustically dispensed (Labcyte ECHO®, San Jose, CA) into a white 384-well assay plate (Proxiplate-384, PerkinElmer part number 6008280) in a 10-point 3-fold dilution series in 30 nL of DMSO. Cells are then added to the assay plate (HBSS, Sigma part number 55021C, 10% FBS, GIBCO part number 10082-147) in assay medium at 8 μL / well at cell line-specific densities (Table 31). In each well, the final compound concentration ranges from 0.5 to 10,000 nM and the final DMSO concentration is 0.375%. The maximum signal control wells contain only 0.375% DMSO (negative control), and the minimum signal control wells contain 10,000 nM of a control compound (positive control). Cells in suspension are incubated with the test compounds and reference compounds for 2 hours at 37 °C / 5% CO2. After 2 hours of incubation, the cells are lysed by adding 2 μL of AlphaLISA® lysis buffer concentrate (5X) supplemented with a protease / phosphatase inhibitor cocktail (Thermo Scientific part number 78442). The assay plate is covered with an opaque lid and shaken at 750 rpm for 30 minutes at room temperature on a multiplate shaker (Heidolph, Schwabach, Germany) to induce cell lysis. During lysis, AlphaLISA® acceptor beads are diluted 1:50 in a prepared buffer mixture (1:1 AlphaLISA® reaction buffers 1 and 2 and 1:25 diluted AlphaLISA® activation buffer). After cell lysis, the plate is centrifuged briefly and 5 μL / well of the prepared acceptor beads are added. The plate is then covered and incubated for 2 hours at room temperature in the dark. During the incubation of the acceptor beads, donor beads are prepared by diluting Alpha streptavidin donor beads 1:50 in AlphaLISA® dilution buffer. After incubation of the acceptor beads, 5 μL / well of the donor bead mixture is added to the plate. The plate is then covered and incubated for 2 hours at room temperature in the dark.After this incubation period, the AlphaLISA signal is read using a PHERAstar® FSX multimode plate reader (BMG Labtech, Ortenberg, Germany) equipped with an AlphaLISA®-compatible optical cube.

[0385] The raw signal obtained from the AlphaLISA® assay is analyzed using Genedata Screener® 17.0.3. Within this program, the data are normalized to 32 wells treated with the inhibition control (maximum inhibition / positive control) and 32 wells treated with 0.375% DMSO only (minimum inhibition / negative control) to calculate the % activity of the compound.

Number

Number

[0386] In the above assay, the compounds of the examples shown herein were tested and demonstrated the ability to reduce the levels of phosphorylated ERK-1 / 2 in cells expressing KRAS and KRAS variants, including KRAS G12C (Examples 1, 3, 8, 9, 19 - 30, 32 - 36, 29A - 44A, 47A - 70A, 72A - 79A, 82A - 84A, 28B - 30B, 33B - 94B, 96B - 120B, 122B - 148B, 1C - 49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C - 71C, 73C - 79C, 81C, 83C - 88C, 90C, 92C, 94C - 122C, 2D, 3D, 5D, 6D, 8D - 10D, 12D, 14D, 16D - 99D, 101D - 126D, 128D - 195D, 197D - 201D, 203D - 207D, 209D - 236D, 239D, 240D, 242D, 244D, 246D - 248D, 250D - 252D, 254D, 256D - 259D, and 262D - 275D), KRAS G12D (Examples 1 - 3, 5 - 9, 11 - 15, 19 - 30, 32 - 37, 25A, 29A - 44A, 47A - 67A, 70A, 73A, 74A, 76A, 78A, 79A, 82A - 84A, 19B, 28B - 30B, 33B - 45B, 47B - 51B, 53B - 65B, 67B - 94B, 96B - 108B, 110B - 148B, 1C - 27C, 29C - 49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C, 70C, 73C, 75C - 79C, 81C, 83C - 88C, 90C, 92C, 94C - 122C, 2D, 3D, 5D, 6D, 8D, 10D, 12D, 14D, 16D, 18D - 20D, 22D - 46D, 48D - 73D, 75D - 81D, 83D - 95D, 98D, 99D, 101D, 103D - 139D, 141D - 159D, 161D, 163D, 165D - 178D, 180D, 181D, 183D - 195D, 197D - 201D, 203D - 207D, 209D - 236D, 239D, 240D, 242D, 244D, 246D - 248D, 250D, 252D, 254D, 256D - 259D, and 262D - 275D), KRAS G12V (Examples 9, 19 - 30, 32 - 36, 29A - 44A, 47A - 62A, 64A - 70A, 72A - 74A, 76A, 78A, 79A, 82A - 84A,Inhibition of constitutive RAS activity in cells expressing 28B - 30B, 33B - 53B, 55B - 88B, 90B - 94B, 96B - 107B, 110B - 120B, 122B - 136B, 138B - 146B, 148B, 1C - 27C, 29C - 49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C, 70C, 73C, 75C - 78C, 81C, 83C - 88C, 92C, 94C - 120C, 122C, 2D, 3D, 6D, 8D, 10D, 12D, 14D, 16D, 18D - 46D, 48D - 73D, 75D - 81D, 83D - 96D, 99D, 101D, 104D - 133D, 135D - 139D, 141D - 143D, 145D - 159D, 161D, 163D, 165D - 173D, 175D, 177D, 178D, 180D, 183D - 195D, 197D - 203D, 206D, 207D, 209D, 211D - 236D, 240D, 242D, 244D, 246D - 248D, 250D, 252D, 254D, 256D - 259D, and 262D - 275D), or KRAS WT (Examples 2, 3, 9, 19 - 30, 32 - 36, 29A - 44A, 47A - 70A, 73A, 74A, 76A, 78A, 79A, 82A - 84A, 28B - 30B, 33B - 88B, 90B - 94B, 96B - 108B, 110B - 120B, 122B - 148B, 1C - 49C, 51C, 53C, 54C, 57C, 58C, 60C, 61C, 65C, 67C, 69C, 70C, 73C - 79C, 81C, 83C - 88C, 90C, 92C, 94C - 122C, 2D, 3D, 5D, 6D, 8D - 10D, 12D, 14D, 16D - 46D, 48D - 73D, 75D - 81D, 8The compounds of 51B~54B, 57B, 60B, 63B, 65B, 66B, 68B, 70B, 73B~77B, 83B, 86B, 87B, 89B, 93B, 95B, 98B, 99B, 101B~103B, 108B, 109B, 112B, 115B~121B, 123B, 124B, 136B, 140B~142B, 144B, 147B, 2C, 8C, 14C, 16C, 17C, 20C, 21C, 26C, 28C, 30C, 33C~36C, 38C, 40C, 46C~50C, 52C, 53C, 55C, 56C, 59C, 62C~64C, 66C, 68C, 71C, 72C, 74C, 80C, 82C, 89C, 91C, 93C, 101C, 112C, 113C, 118C, 121C, 1D, 4D, 5D, 7D, 9D, 11D, 13D, 15D, 17D, 18D, 20D~28D, 31D, 33D~35D, 37D, 38D, 40D, 43D, 44D, 46D, 47D, 51D~54D, 56D, 58D~62D, 64D~78D, 80D, 91D, 93D, 96D~106D, 109D~111D, 113D, 114D, 117D, 121D~123D, 126D~128D, 132D~136D, 139D, 140D, 144D, 147D, 148D, 150D, 152D~155D, 157D~162D, 164D, 172D~186D, 188D, 194D, 195D, 199D~210D, 212D, 216D, 218D, 222D, 223D, 225D, 226D, 228D, 229D, 232D, 233D, 237D, 238D, 241D, 243D, 245D, 249D, 251D, 253D, 255D, 259D~261D, 263D, and 268D were tested in the above mouse embryonic fibroblast cell line assays (MEF-NRAS, MEF-HRAS), and all showed relative IC50 > 2 μM. Examples 8, 9, 19~30, 32~36, 29A~44A, 47A, 49A, 50A, 52A, 54A~69A, 72A, 74A~76A, 78A, 79A, 84A, 28B, 29B, 33B~36B, 39B~53B, 55B~60B, 62B~79B, 82B~87B, 90B, 91B, 96B~103B, 105B~107B, 109B~115B, 117B~120B, 122B~128B, 130B, 131B, 136B, 138B~144B, 147B, 1C~6C, 8C, 9C, 11C~22C,Compounds of 24C - 28C, 30C - 38C, 40C - 43C, 45C - 49C, 51C, 53C, 54C, 57C, 60C, 65C, 67C, 69C, 70C, 73C, 74C, 76C, 77C, 84C, 87C, 88C, 98C, 99C, 101C, 104C - 120C, 122C, 2D, 3D, 8D, 10D, 14D, 18D - 40D, 42D - 46D, 48D - 73D, 75D - 80D, 83D - 87D, 89D - 93D, 95D - 119D, 121D - 145D, 147D - 164D, 167D, 168D, 170D - 173D, 175D - 181D, 183D, 184D, 186D - 188D, 190D, 192D - 195D, 197D - 204D, 206D, 207D, 209D, 212D, 213D, 215D - 236D, 240D, 244D, 246D - 251D, 254D, 256D, 257D, 259D, 262D - 265D, 267D, 268D, 270D - 272D, 274D, and 275D were tested in the above three assays (SW620, MEF - NRAS, or MEF - HRAS Cellular Phospho - ERK AlphaLISA® assay), and all showed significant (i.e., greater than 10 - fold) selective inhibition preference for the KRas G12V variant over HRAS and NRAS.,

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

Table 32

Claims

1. A compound represented by the following formula: 【Chemical 1】 wherein A is -C(H)- or -N-; is a group of; Z is -C(R ３ｃ )- or -N-, and G is, -C(R ３ｂ )- or -N-, and R １ is H, or the following formula: 【Chemical Formula 2】 is a group of; R ２ is H, halogen, or methyl, R ３ｂ 、and R ３ｃ are each independently H, halogen, or methyl, R ４ is an N-bonded cyclic amine or the following formula: 【Chemical Formula 3】 the N-bonded cyclic amine is N-bonded; the ring i. R ４ａ and R ４ｂ azetidine substituted with ii. Pyrrolidine, piperidine, piperazine, morpholine, diazepane, imidazole, or pyrazole, each of which is optionally cross-linked by C １～３ alkylene, each of which is one or more halogens, hydroxyl, -NR ６ａ R ６ａ , (1-methylpiperidin-4-yl)oxy, optionally -NR ６ａ R ６ａ substituted C １～３ alkoxy, optionally one or more halogens, -NR ６ａ R ６ａ substituted C １～３ alkyl, optionally imidazole substituted with methyl, azetidine, piperidine, piperazine, morpholine, oxazepane, or diazepane, a monocyclic ring selected from hexahydro-1H-furo[3,4-c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, or octahydropyrrolo[1,2-a]pyrazine, a bicyclic ring, or 4,7-diazaspiro[2.5]octane, 2-oxa-7-azaspiro[3.5]nonane, 2,6-diazaspiro[3.4]octane, or 2-azaspiro[3.3]heptane, optionally substituted with a spiro ring selected from, the monocyclic ring being optionally cross-linked by C １～３ alkylene, one or more halogens, hydroxyl, -CN, C １～３ alkoxy, -NR １０ R １０ , cyclopropyl, oxetane, -CO-C １～３ alkyl, or hydroxyl, C １～３ alkoxy, -NR １０ R １０ , halogen, or -CF ３ optionally substituted with C １～３ alkyl that can be optionally substituted, or iii. 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.1]octane, 2,6-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, 2-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-1H-pyrrolo[3,2-b]pyridine, octahydro-6H-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol-2(3H)-one, hexahydro-1H-furo[3,4-b]pyrrole, octahydro-1H-pyrrolo[3,2-b]pyridine, (3as,6as)-tetrahydro-1H,4H-3a,6a-(methanoxymethano)pyrrolo[3,4-c]pyrrole, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, 5-azaspiro[2.4]heptane e, 2-oxa-6-azaspiro[3.4]octane, 2,7-diazaspiro[4.4]nonane, 2-oxa-6-azaspiro[3.4]octane, or 1-oxa-7-azaspiro[4.4]nonane, each of which is optionally substituted with one or more halogens, -NR ６ａ R ６ａ , or -NR ６ａ R ６ａ or C optionally substituted with hydroxyl １～３ alkyl which is optionally substituted, R ４ａ is NR ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine or imidazole, wherein said cyclopropyl, azetidine, pyrrolidine, piperidine, piperazine, or morpholine is halogen, hydroxyl, C １～３ alkoxy, or -NR ６ａ R ６ａ optionally substituted with, R ４ｂ is H, hydroxyl, or C １～３ alkyl, and R ４ｃ is independently cyclopropyl or oxetane, and R ４ｄ is independently C １～３ alkyl, and R ５ is trideuteromethyl, oxetane, or one or more of halogen, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, trideuteromethoxy, oxetane, cyclopropyl, imidazole, pyrazole, -CO-NR ６ａ R ６ａ 、-O-(CH ２ ) ２ -OR ６ａ 、or -O-CO-C １～３ C optionally substituted with alkyl １～４ alkyl, wherein said cyclopropyl is optionally substituted with hydroxyl or hydroxymethyl, and said imidazole or pyrazole is optionally substituted with hydroxyl or one or more hydroxyls on each C １～３ alkyl, R ５ａ is C １～３ alkylene, and Each R ６ is independently H or deuterium, Each R ６ａ is independently H, trideuteriomethyl, C ３～５ cycloalkyl, N-methylpyrrolidine, tetrahydrofuran, tetrahydropyran, bicyclo[1.1.1]pentan-1-yl, bicyclo[1.1.1]pentan-1-ol, or one or more deuterium, hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, -CO-NHMe, or -CO-NH ２ optionally substituted C １～３ alkyl, wherein said C ３～５ cycloalkyl is optionally substituted with one or more hydroxyl or methyl, E １ is -O-C １～３ alkylene, or C optionally substituted with one or more halogens １～３ alkylene, and E ２ and E ４ are each independently C optionally substituted with one or more hydroxyls, C １～３ alkoxy or halogen, and C １～３ alkylene, E ２ and E ４ can be optionally crosslinked by a bond or C １～３ alkylene, and E ３ is -O-, -CR ７ R ７ -, -NR ９ -, or -CO-NR ６ａ -, or is hexahydro-1H-furo[3,4-c]pyrrole; 【Chemical Formula 4】

2. Each E ２ａ is independently C １～３ alkylene optionally substituted with one or more hydroxyls, E ５ is -O-, -CR ７ R ７ -, or -NR ９ -, and Each R ７ is independently H, halogen, CN, hydroxyl, C １～３ alkoxy, or C optionally substituted with one or more halogens or hydroxyls １～３ alkyl, Each R ８ is independently C １～３ alkyl, R ９ is, independently of each other, H, optionally substituted C １～３ alkyl or -CO-C １～３ alkyl, wherein the optionally substituted C １～３ alkyl is optionally substituted with one or more halogens, R １０ is H, or C optionally substituted with one or more deuteriums １～３ alkyl, a compound, or a pharmaceutically acceptable salt thereof. is a group of; R ４ is an N-bonded cyclic amine or the following formula: 【Chemical Formula 5】 the N-bonded cyclic amine is N-bonded;

3. i. R ４ａ and R ４ｂ substituted azetidine, ii. Pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole, each of which is optionally crosslinked by C １～３ alkylene and each of which is optionally substituted with one or more halogens, hydroxyl, C １～３ alkoxy, -NR ６ａ R ６ａ , azetidine, piperazine, morpholine, C １～３ alkyl, or imidazole optionally substituted with methyl and the azetidine is optionally substituted with hydroxyl or C １～３ alkoxy, the piperazine is optionally substituted with methyl, and the C １～３ alkyl is optionally substituted with one or more halogens, -NR ６ａ R ６ａ or hydroxyl, or iii. 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.1]octane, 2,6-diazabicyclo[3.2.1]octane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, 2-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-1H-pyrrolo[3,2-b]pyridine, octahydro-6H-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, 5-azaspiro[2.4]heptane, or 2-oxa-6-azaspiro[3.4]octane, each of which is optionally substituted with one or more halogens, -NR ６ａ R ６ａ or -NR ６ａ R ６ａ and is optionally substituted with C １～３ alkyl optionally substituted with R ４ａ is NR ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine or imidazole, wherein said cyclopropyl, azetidine, pyrrolidine, piperidine, or morpholine is halogen, hydroxyl, C １～３ alkoxy or -NR ６ａ R ６ａ optionally substituted with, Each R ６ａ are independently H, trideuteromethyl, C ３～５ cycloalkyl, tetrahydrofuran, tetrahydropyran, bicyclo[1.1.1]pentan-1-yl, or one or more of hydroxyl, methyl, methoxy, halogen, cyclopropyl, oxetane, tetrahydrofuran, tetrahydropyran, —CO—NHMe, or —CO—NH ２ C optionally substituted with １～３ alkyl, ３～５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein cycloalkyl is optionally substituted with one or more hydroxyl or methyl. is a group of; R ４ is an N-bonded cyclic amine or the following formula: 【Chemical Formula 6】 the N-bonded cyclic amine is N-bonded;

4. i. R ４ａ and R ４ｂ azetidine substituted with ii pyrrolidine, piperidine, piperazine, morpholine, imidazole or pyrazole, each of which is optionally crosslinked by C １～３ alkylene, each of which is optionally substituted with one or more halogen, hydroxyl, C １～３ alkoxy, -NR ６ａ R ６ａ azetidine, C １～３ alkyl, or imidazole optionally substituted with methyl, said azetidine being optionally substituted with hydroxyl or C １～３ alkoxy, said C １～３ alkyl being optionally substituted with halogen -NR ６ａ R ６ａ or hydroxyl, or iii. 2,6-diazabicyclo[3.2.0]heptane, 3,6-diazabicyclo[3.2.0]heptane, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, octahydro-1H-pyrrolo[3,4-b]pyridine, octahydro-6-pyrrolo[3,4-b]pyrazine, octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,2-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-c]pyrrole, tetrahydrofuro[3,4-d]oxazol-2(3H)-one, (R)-1,7-diazaspiro[4.4]nonane, (S)-1,7-diazaspiro[4.4]nonane, 1,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.4]octane, 2,5-diazaspiro[3.4]octane, 2,5-diazaspiro[3.5]nonane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 4-azaspiro[2.4]heptane, or 5-azaspiro[2.4]heptane, each of which is optionally substituted with one or more halogen, -NR ６ａ R ６ａ or -NR ６ａ R ６ａ and is optionally substituted with C １～３ alkyl which is optionally substituted, R ４ａ is NR ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, piperidine, morpholine, or imidazole, wherein the cyclopropyl, azetidine, pyrrolidine, piperidine, or morpholine is optionally substituted with halogen, hydroxyl, C １～３ alkoxy, or -NR ６ａ R ６ａ , and each R ６ａ is independently H, trideuteriomethyl, C ３～５ cycloalkyl, or C １～３ alkyl optionally substituted with hydroxyl, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. is a group of; R ３ｂ 、and R ３ｃ are each independently H or halogen, and R ４ is an N-linked cyclic amine or the following formula: 【Chemical Formula 7】 the N-bonded cyclic amine is N-bonded;

5. i. R ４ａ and R ４ｂ azetidine substituted with ii. pyrrolidine, piperidine, piperazine, or morpholine, each of which is optionally crosslinked by C １～３ alkylene, each of which is optionally substituted with one or more halogen, hydroxyl, -NR ６ａ R ６ａ , imidazole or C １～３ alkyl, said imidazole being optionally substituted with methyl, said C １～３ alkyl being optionally substituted with -NR ６ａ R ６ａ or hydroxyl, or iii. Octahydropyrrolo[1,2-a]pyrazine, octahydropyrrolo[3,4-c]pyrrole, 1,6-diazaspiro[3.3]heptane, or 1,6-diazaspiro[3.4]octane, each optionally substituted with one or more halogens or C １～３ alkyl, R ４ａ is NR ４ｃ R ４ｄ , cyclopropyl, azetidine, pyrrolidine, morpholine, wherein said cyclopropyl, azetidine, pyrrolidine or morpholine is optionally substituted with halogen, or -NR ６ａ R ６ａ and is optionally substituted with R ４ｂ is H or C １～３ and is alkyl, Each R ６ａ is independently H or C １～３ alkyl, E ２ and E ４ are each independently C １～３ alkylene optionally substituted with one or more hydroxyls or halogens, E ２ and E ４ can be optionally crosslinked by a bond or C １～３ alkylene, E ３ is -O-, -CR ７ R ７ -, -NR ９ -, or -CO-NR ６ａ -, a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. is a group of; R ３ｂ 、and R ３ｃ are each independently H or halogen, and R ４ is the following formula: [Chemical 8]

6. E １ is C optionally substituted with one or more halogens １～３ alkylene, and E ２ and E ４ are each independently C １～３ alkylene optionally substituted with one or more hydroxyls, and E ２ and E ４ can be joined or optionally crosslinked by C １～３ alkylene E ３ is -O-, -CR ７ R ７ -, -NR ９ -, or -CO-NR ６ａ - and Each R ６ａ is independently H or C １～３ alkyl, Each R ７ is independently H, halogen, hydroxyl, C １～３ alkoxy, or C optionally substituted with one or more halogens or hydroxyls １～３ alkyl, R ９ is, independently of each other, H, C １～３ alkyl or -CO-C １～３ alkyl, a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. The compound according to any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein G is -N-.

7.

8. G is -C(R ３ｂ ) - and is a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

9. R ３ｂ The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R is F. The compound according to any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Z is -N-.

10.

11. Z is -C(R ３ｃ )-, the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

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

13. R ３ｂ and R ３ｃ each independently is H or halogen, a compound according to any one of claims 1 to 5, 7 or 10, or a pharmaceutically acceptable salt thereof.

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

15. The compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein A is -C(H)-.

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

17. R ２ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R is F.

18. R ２ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R is Cl.

19. R １ The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R is H.

20. R １ is the formula: 【Chemical Formula 9】 The compound according to any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, which is a group of;

21. R １ is the formula: 【Chemical 10】 The compound according to any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, which is a group of;

22. R ５ is C １～４ alkyl optionally substituted with one or more hydroxyl, methoxy, or oxetane, the compound according to claim 19 or 20, or a pharmaceutically acceptable salt thereof.

23. R ５ａ The compound according to any one of claims 19 to 21, or a pharmaceutically acceptable salt thereof, wherein R is ethylene.

24. R １ is 【Chemical 11】 The compound according to any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, selected from;

25. R １ is 【Chemical 12】 The compound according to any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, selected from;

26. R ４ is 【Chemical 13】 The compound according to any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, which is;

27. R ４ is 【Chemical Formula 14】 The compound according to any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, which is;

28. R ４ is 【Chemical Formula 15】 The compound according to any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, which is;

29. Each R ６ is H, the compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

30. R ４ wherein R is an N-linked cyclic amine, the compound according to any one of claims 1 to 4, 6 to 24, or a pharmaceutically acceptable salt thereof.

31. R ４ is 【Chemical Formula 16】 【Chemical 17】 【Chemical Formula 18】 【Chemical Formula 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 The compound according to any one of Claims 1, 6 to 24, or a pharmaceutically acceptable salt thereof, selected from;

32. R ４ is 【Chemical 24】 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical Formula 28】 The compound according to any one of Claims 1, 6 to 24, or a pharmaceutically acceptable salt thereof, selected from;

33. R ４ is 【Chemical 29】 A compound according to any one of claims 1, 6 to 24, or a pharmaceutically acceptable salt thereof, selected from

33. R ４ is 【Chemical 30】 A compound according to any one of claims 1, 6 to 24, or a pharmaceutically acceptable salt thereof, selected from

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

35. A method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of the pharmaceutical composition according to claim 34, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

36. A method of treating a cancer patient, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, bile duct cancer, and colorectal cancer.

37. The method according to claim 35 or 36, wherein the patient has a cancer determined to have one or more cells expressing the Kras G12D mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.

38. The method according to claim 35 or 36, wherein the patient has a cancer determined to have one or more cells expressing the Kras G12C, G12D, and / or G12V mutant proteins prior to administration of the compound or a pharmaceutically acceptable salt thereof.

39. The method according to any one of claims 35 to 38, wherein the cancer is non-small cell lung cancer.

40. The method according to any one of claims 35 to 35, wherein the cancer is colorectal cancer.

41. The method according to any one of claims 35 to 35, wherein the cancer is pancreatic cancer.

42. The method according to any one of claims 35, 36, or 39 to 41, wherein one or more cells express the Kras G12D mutant protein.

43. The method according to any one of claims 35, 36, or 39 to 41, wherein one or more cells express the Kras G12C, G12D, and / or G12V mutant proteins.

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

45. A method for treating a patient having cancer with a KRas G12C, G12D, and / or G12V mutation, comprising administering to a patient in need of treatment an effective amount of the compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

46. The method according to claim 44 or 45, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, mutant ovarian cancer, cholangiocarcinoma, and colorectal cancer.

47. The method according to claim 46, wherein the cancer is non-small cell lung cancer.

48. The method according to claim 46, wherein the cancer is colorectal cancer.

49. The method according to claim 46, wherein the cancer is pancreatic cancer.

50. The method according to any one of claims 35 to 49, wherein the patient is also administered an effective amount of 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.

51. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, for use in therapy.

52. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

53. The compound or a pharmaceutically acceptable salt thereof for use according to claim 52, wherein the cancer has a KRas G12D mutation.

54. The compound or a pharmaceutically acceptable salt thereof for use according to claim 52, wherein the cancer has a KRas G12C, G12D, and / or G12V mutation.

55. The compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 52 to 54, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

56. 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 use in the treatment of cancer, either simultaneously, separately, or sequentially in combination with the compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof.

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